This systematic review and meta-analysis examined the relationship between menstrual cycle phases and the incidence of muscle injuries in female team sport athletes, following PRISMA 2020 and PERSiST guidelines. A comprehensive search was conducted in PubMed, Scopus, and SPORTDiscus from inception to mid-January 2024. Studies were included if they examined female team sport athletes of reproductive age with regular menstrual cycles and compared the occurrence of muscle injuries across at least two menstrual phases. Studies involving hormonal contraceptive use, medications affecting the menstrual cycle or musculoskeletal system, or menstrual dysfunction were excluded. Three studies met the inclusion criteria, involving 318 participants. Meta-analysis yielded a pooled Risk Ratio of 1.18 (95% CI: 0.75 to 1.86, p = 0.46) for injury risk between the luteal and follicular phases, suggesting no statistically significant association. However, the certainty of the cumulative evidence was rated as very low due to methodological limitations, including inconsistent phase classifications and reliance on imprecise methods for identifying menstrual phases. Consequently, no practical or clinical recommendations can be made at this time. Future research employing standardised, physiologically accurate methods for classifying and detecting menstrual cycle phases is necessary to better understand the potential links between hormonal fluctuations and injury risk. The online version contains supplementary material available at 10.1038/s41598-026-36763-0.
EndometriosisMenstrual Distress and PainPsychological FactorsDysmenorrhea and Endometriosis
Self-reported dietary intake varies across menstrual cycle phases, but objective assessments of dietary intake together with appetite and resting metabolic rate (RMR) are limited. This study aimed to assess differences in dietary intake, appetite, and RMR during two hormonally-distinct menstrual cycle phases in laboratory and free-living settings. Healthy premenopausal females with predictable normal-length menstrual cycles one in the late-follicular and one in the mid-luteal phase. Menstrual cycle phases were assessed using urinary luteinizing hormone surge and prospective cycle days. Participants consumed a 2-day energyand macronutrient-balanced run-in diet prior to each visit. RMR was measured with indirect calorimetry, followed by appetite ratings before and after a standardized breakfast, and a food cravings questionnaire. Appetite was also tracked for 2.5 days post-visit in a free-living environment. Ad libitum energy and macronutrient intakes were measured using pre-weighed plus weighing of uneaten food at an in-laboratory lunch meal, as well as during the 2.5-day free-living period. Eighteen participants were included (age: 21 ± 4 years; 21.2 ± 1.5 kg/m2). There were no differences between in-laboratory ad libitum energy or macronutrient intakes, appetite, or food cravings between phases. RMR did not differ between phases, although the mid-luteal phase RMR tended to be higher (104 ± 218 kcal/day higher; P = 0.074). No main or interaction effects for phase or time were observed for free-living dietary intake nor appetite ratings. Although RMR tended to be increased during the luteal phase, comprehensive appetite and energy intake assessments showed no significant cycle-phase differences in these 18 participants.
Menstrual CycleOvulatory DisturbancesBreast ChangesPhysical Markers
Open Access
Background Reproductive hormones of the fertile window are often referenced to women in regular cycles, but this may not be representative of the hormonal profiles of women in different circumstances like polycystic ovarian syndrome, the postpartum period, and the perimenopause transition. This observational cohort study sought to identify the variability in the hormones of the fertile window in various reproductive categories and to establish potential thresholds for each category based on hormone measurements with the Mira urinary hormone monitor. Results A total of 57 women (ages 22–51) in various circumstances (regular cycles, polycystic ovarian syndrome, postpartum and perimenopause) tracked Mira urine hormone measurements (estrone-3-glucuronide, luteinizing hormone, pregnanediol glucuronide), contributing 444 cycles of data. Using additive mixed models, hormone values were stratified by the four different reproductive categories. The perimenopause and polycystic ovararian syndrome groups demonstrated relative hypoestrogenic states, while the perimenopause group showed low luteal pregnanediol glucuronide and the polycystic ovarian syndrome group showed high luteal pregnanediol glucuronide. The perimenopause group had higher luteinizing hormone values throughout the whole cycle. Conclusion The fertile window hormone thresholds vary depending on a woman’s specific reproductive category. Women in different circumstances should not necessarily use the same hormonal thresholds for the fertile window and ovulation. A larger dataset with ultrasound correlation to ovulation is required to delineate the fertile window with more precision. Hormone differences across the menstrual cycle could be used for targeted treatments in polycystic ovarian syndrome and perimenopause women.
Menstrual CycleCardiac Electrophysiology EffectsCardiovascularMenstrual Cycle Variations
Open Access
Are dietary patterns associated with age at menarche after accounting for BMI-for-age (BMIz) and height? We observed associations between both the Alternative Healthy Eating Index (AHEI) and the Empirical Dietary Inflammatory Pattern (EDIP) and age at menarche. Dietary patterns have been sparsely examined in relation to age at menarche and no studies have examined the association between the AHEI, a healthier diet, and EDIP, a pro-inflammatory diet, and menarche. STUDY DESIGN, SIZE, The Growing Up Today Study (GUTS) is a prospective cohort of children ages 9-14 years at study enrollment. GUTS enrolled in two waves with enrollment beginning in 1996 (GUTS1) and 2004 (GUTS2). For this analysis, GUTS1 and GUTS2 participants were followed through 2001 and 2008, respectively. PARTICIPANTS/MATERIALS, SETTING, We included 7530 participants who completed food frequency questionnaire(s) (FFQ) prior to menarche who then self-reported age at menarche during study follow-up. Cox proportional hazard models were used to calculate multivariable hazard ratios (HRs) and 95% CIs for the associations between two dietary patterns, the AHEI and EDIP, and age at menarche, with and without adjustment for time-varying BMIz and height. MAIN Six thousand nine hundred ninety-two participants (93%) reported menarche during the study period. On average, participants completed the baseline FFQ 1.75 years prior to menarche. Participants in the highest quintile of AHEI diet score (indicating a healthier diet) were 8% less likely to attain menarche within the next month compared to those in the lowest quintile (95% CI = 0.85-0.99; Ptrend = 0.03). This association remained after adjustment for BMIz and height (corresponding HR = 0.93; 95% CI = 0.86-1.00; Ptrend = 0.04). Participants in the highest quintile of the EDIP score (i.e. most inflammatory diet), were 15% more likely to attain menarche in the next month relative to those in the lowest quintile (95% CI = 1.06-1.25; Ptrend = 0.0004), and the association remained following adjustment for BMIz and height (corresponding HR = 1.15; 95% CI = 1.06-1.25; Ptrend = 0.0004). LIMITATIONS, Self-reported questionnaires are subject to some error; however, given our prospective study design it is likely this error is non-differential with respect to the outcome. Our findings of an association between both the AHEI and EDIP and age at menarche indicate that diet quality may play a role in age at menarche independent of BMI or height. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Breast Cancer Research Foundation. The GUTS is supported by the National Institutes of Health U01 HL145386. C.P.D. was supported by National Institutes of Health T32 CA094880. The authors have no conflicts of interest to disclose. N/A.
Menstrual CycleCycle VariabilityUrinary Hormone MonitoringHeat Map Analysis
Open Access
There is considerable individual day-to-day variation within the menstrual cycle and between cycles in women. Average hormone curves inadequately describe the individual hormone patterns experienced by women. The present study applies a novel application of a statistical array (heat map) to demonstrate both individual and group menstrual cycle hormone variability.
Using pre-existing datasets, two cohorts of women were analysed using a statistical method to visualise quantitative hormonal variation. In one cohort, 107 women contributed a total of 283 menstrual cycles and in the second cohort, 21 women contributed a total of 62 menstrual cycles. Women collected first morning urine samples for analysis of estrone-3-glucuronide (E1G) and luteinizing hormone (LH) in both datasets. In the larger dataset, pregnanediol-3-alpha-glucuronide (PDG) and follicle-stimulating hormone (FSH) were also collected. Serial ultrasounds identified the precise day of ovulation in the larger dataset. In the smaller dataset, peak LH was used to identify the estimated day of ovulation.
The main outcome measure was identifying hormonal variability using hormone array heat maps. Heat maps were able to quickly show clustering of hormone patterns in the fertile window and on the day of ovulation. Individual differences were identified in rows on the heat map relative to the day of ovulation. This new tool to visually represent hormonal changes with heat maps identifies both individual and group variability of menstrual cycle hormones.
To investigate the efficacy and safety of open-label placebos (OLP) in premenstrual syndrome (PMS).
Randomised controlled trial.
Switzerland, 2018-2020. 150 women (18-45 years of age) with PMS or premenstrual dysphoric disorder. Random assignment (1:1:1) to treatment as usual (TAU), OLP without treatment rationale (OLP-), or OLP with treatment rationale (OLP+). OLP consisted of two placebo pills per day for 6 weeks. Primary outcomes were PMS symptom intensity and interference between groups across three menstrual cycles (MC1-MC3); adverse events (ie, safety) were measured at weeks 3 and 6 after the start of the intervention. Secondary outcomes were psychological and somatic subscales of PMS symptom intensity, and adherence. From 2 August 2018 to 3 December 2020,
Menstrual CycleHormonal RegulationHormonal
Open Access
Self-reported dietary intake varies across menstrual cycle phases, but objective assessments of dietary intake together with appetite and resting metabolic rate (RMR) are limited. This study aimed to assess differences in appetite, dietary intake, and RMR during two hormonally-distinct menstrual cycle phases in laboratory and free-living settings. Healthy premenopausal females with predictable normal-length menstrual cycles one in the late-follicular and one in the mid-luteal phase. Menstrual cycle phases were identified using urinary luteinizing hormone surge and cycle days. Participants consumed a 2-day energy- and macronutrient-balanced run-in diet prior to each visit. RMR was measured with indirect calorimetry, followed by appetite ratings before and after a standardized breakfast, and completed a food cravings questionnaire. Appetite was also tracked for 2.5 days post-visit in a free-living environment. Ad libitum energy and macronutrient intake were measured using pre-weighed plus weighing of uneaten food at an in-laboratory lunch meal, as well as during the 2.5-day free-living period. Eighteen participants were included (age: 21±4 years; 21.2±1.5 kg/m 2 ). There were no differences between in-laboratory ad libitum energy or macronutrient intakes, appetite, or food cravings between phases. RMR did not differ between phases, although the mid-luteal phase RMR trended toward higher (104±218 kcal/day higher ; P =0.074). No main nor interaction effects for phase and time were observed for free-living dietary intake nor appetite ratings. Accurate measurements show no differences in appetite or energy intake between menstrual cycle phases, though RMR may be slightly elevated in the luteal phase.
Menstrual CyclePhase Length VariabilityCycle Phase MeasurementProspective Ovulation Cohort
Open Access
What is the relative length variance of the luteal phase compared to the follicular phase within healthy, non-smoking, normal-weight, proven normally ovulatory, premenopausal women with normal-length menstrual cycles? Prospective 1-year data from 53 premenopausal women with two proven normal-length (21-36 days) and normally ovulatory (≥10 days luteal) menstrual cycles upon enrollment showed that, despite 29% of all cycles having incident ovulatory disturbances, within-woman follicular phase length variances were significantly greater than luteal phase length variances. Many studies report menstrual cycle variability, yet few describe variability in follicular and luteal phase lengths. Luteal lengths are assumed 'fixed' at 13-14 days. Most studies have described follicular and luteal phase variability between-women. STUDY DESIGN, SIZE, This study was a prospective, 1-year, observational cohort study of relative follicular and luteal phase variability both between and within community-dwelling women with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Eighty-one women enrolled in the study and 66 women completed the 1-year study. This study analyzed data from 53 women with complete data for ≥8 cycles (mean 13). PARTICIPANTS/MATERIALS, SETTING, Participants were healthy, non-smoking, of normal BMI, ages 21-41 with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Participants recorded first morning temperature, exercise durations, and menstrual cycle/life experiences daily in the Menstrual Cycle Diary. We analyzed 694 cycles utilizing a twice-validated least-squares Quantitative Basal Temperature method to determine follicular and luteal phase lengths. Statistical analysis compared relative follicular and luteal phase variance in ovulatory cycles both between-women and within-woman. Normal-length cycles with short luteal phases or anovulation were considered to have subclinical ovulatory disturbances (SOD). Main The 1-year overall 53-woman, 676 ovulatory cycle variances for menstrual cycle, follicular, and luteal phase lengths were 10.3, 11.2, and 4.3 days, respectively. Median variances within-woman for cycle, follicular, and luteal lengths were 3.1, 5.2, and 3.0 days, respectively. Menstrual cycles were largely of normal lengths (98%) with 55% of women experienced >1 short luteal phase (<10 days) and 17% experienced at least one anovulatory cycle. Within-woman follicular phase length variances were greater than luteal phase length variances (P < 0.001). However, follicular (P = 0.008) and luteal phase length (P = 0.001) variances, without differences in cycle lengths, were greater in women experiencing any anovulatory cycles (n = 8) than in women with entirely normally ovulatory cycles (n = 6). LIMITATIONS, Limitations of this study include the relatively small cohort, that most women were White, initially had a normal BMI, and the original cohort required two normal-length and normally ovulatory menstrual cycles before enrollment. Thus, this cohort's data underestimated population menstrual cycle phase variances and the prevalence of SOD. Our results reinforce previous findings that the follicular phase is more variable than the luteal phase in premenopausal women with normal-length and ovulatory menstrual cycles. However, our study adds to the growing body of evidence that the luteal phase is not predictably 13-14 days long. STUDY FUNDING/COMPETING INTEREST(S): This medical education project of the University of British Columbia was funded by donations to the Centre for Menstrual Cycle and Ovulation Research. The authors do not have any conflicts of interest to disclose. N/A.
Menstrual CycleAdolescent DevelopmentProgesteroneOvulatory Function
Open Access
Hormones produced by the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis are crucial for modulating central nervous system (CNS) function and development throughout a person's life. Disruptions in HPAG function can impact psychological development, particularly during adolescence-a period marked by psychological growth and the maturation of the HPAG axis. An early indicator of HPAG alterations is ovulatory dysfunction (OD), a common condition among adolescents. This study explored the associations between neuroactive hormones and personal growth in adolescents with OD. Female participants aged 12-25 years with OD were recruited, and assessments were conducted to profile their basic hormonal levels and various dimensions of individual development, including self-concept clarity, sense of coherence, self-esteem, perfectionism, self-control, and mood states. Adolescents with OD (n = 117) had lower self-concept clarity and self-esteem compared to reference data. A significant portion of the sample displayed elevated levels of tension (71.25%), confusion (62.5%), fatigue (58.22%), and depression (52.6%). Self-esteem scores were negatively correlated with DHEAS (r = -0.224; p = 0.026) and glucose (r = -0.249; p = 0.010). Higher levels of free testosterone were associated with increased depression scores (coef = 0.2398; p = 0.002), whereas higher estradiol levels were linked to lower aggressiveness scores (coef = -0.0648; p = 0.001). These findings indicate that hormonal imbalances in adolescents with OD could affect personal growth. Further research is needed to establish causal relationships between the variables considered.
Menstrual CycleAmenorrhea in HIVHIV and Reproductive HealthProspective HIV
Open Access
The menstrual cycle is a critical indicator of women's health. Early prolonged secondary amenorrhea increases risks for morbidity and mortality. Menstrual cycle research in women with HIV is inconsistent and often lacks an adequate comparison sample. We aimed to determine whether women with HIV have a higher lifetime prevalence of amenorrhea and whether this is independently associated with HIV and/or other biopsychosocial variables. With data from 2 established HIV cohorts, participants assigned female at birth were eligible if aged ≥16 years, not pregnant/lactating, and without anorexia/bulimia nervosa history. Amenorrhea was defined by self-reported history of (1) no menstrual flow for ≥12 months postmenarche not due to pregnancy/lactation, medications, or surgery or (2) early menopause or premature ovarian insufficiency. Multivariable logistic regression models explored biopsychosocial covariates of amenorrhea. Overall, 317 women with HIV (median age, 47.5 years [IQR, 39.2-56.4]) and 420 women without HIV (46.2 [32.6-57.2]) were included. Lifetime amenorrhea was significantly more prevalent among women with HIV than women without HIV (24.0% vs 13.3%). In the multivariable analysis, independent covariates of amenorrhea included HIV (adjusted odds ratio, 1.70 [95% CI, 1.10-2.64]), older age (1.01 [1.00-1.04]), White ethnicity (1.92 [1.24-3.03]), substance use history (6.41 [3.75-11.1]), and current food insecurity (2.03 [1.13-3.61]). Nearly one-quarter of women with HIV have experienced amenorrhea, and this is associated with modifiable risk factors, including substance use and food insecurity. Care providers should regularly assess women's menstrual health and advocate for actionable sociostructural change to mitigate risks.
Menstrual CycleDysmenorrheaOvulation and Pain RelationshipMenstrual Pain
Open Access
To study whether the menstrual cycle has a circaseptan (7 days) rhythm and whether it is associated with the lunar cycle (also defined as the synodic month, it is the cycle of the phases of the Moon as seen from Earth, averaging 29.5 days in length).
Cross-sectional study. A total of 35,940 European and North American women aged 18-40 years. Data were collected in real-life conditions. No intervention was performed. The onset of menstruation was assessed in prospectively measured menstrual cycles (311,064 cycles) over 3 full years (2019-2021). Associations were calculated between the onset of menstruation and the day of the week, and between the onset of menstruation and the lunar phase. In this large data set, a circaseptan (7-day) rhythmicity of menstruation was observed, with a peak (acrophase) of menstrual onset on Thursdays and Fridays. This circaseptan rhythm was observed in every age group, in every phase of the lunar cycle, and in all seasons. This feature was most pronounced for cycle durations between 27 and 29 days. In winter, the circaseptan rhythm was found in cycles of 27-29 days, but not in other cycle lengths. A circalunar rhythm was also statistically significant, but not as clearly defined as the circaseptan rhythm. The peak (acrophase) of the circalunar rhythm of menstrual onset varied according to the season. In addition, there was a small but statistically significant interaction between the circaseptan rhythm and the lunar cycle. Although relatively small in amplitude, the weekly rhythm of menstruation was statistically significant. Menstruation occurs more often on Thursdays and Fridays than on other days of the week. This is particularly true for women whose cycles last between 27 and 29 days. Circalunar rhythmicity was also statistically significant. However, it is less pronounced than the weekly rhythm.
PCOSDaily Symptom TrackingDaily Diary MethodCycle-Based Monitoring
Open Access
Women are considered to have an irregular menstrual cycle if their cycle length is less than 21 days or more than 35 days, accompanied by less or very severe blood flow. The prevalence of menstrual cycle irregularities varies across countries. Irregular periods can occur due to changes in the body's levels of estrogen and progesterone hormones, which disrupt the normal pattern of the period. Menstrual irregularity has been found to be associated with various diseases and medical conditions, such as metabolic syndrome, coronary heart disease, type 2 diabetes mellitus, and rheumatoid arthritis. Anemia, osteoporosis, psychological problems, impaired quality of life, and infertility have also been recorded. Moreover, a significant correlation between irregular periods and the risk of developing pregnancy-related hypertensive disorders, as well as an increased risk of adverse obstetric and neonatal outcomes, has been proven. Therefore, irregular menstruation is considered an important health indicator among women. Physical, mental, social, psychological, and reproductive problems are often associated with menstrual irregularities. Thus, evaluating the factors associated with irregular menstruation is necessary to determine appropriate preventive and treatment strategies and to decrease the associated health problems. The aim of this review was to define normal and irregular menstruation, their types, and prevalence, to recognize the risk factors and causes of irregular menstruation, and to understand their impact on women's health.
Reproductive EndocrinologyBreast Cancer RiskCancer Risk AssessmentProgesterone Safety Evidence
A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.
Five to ten percent of women experience period pains that disrupt their lives yet 4 in 5 women believe that their claims for their dysmenorrhea are not taken seriously. Within the process of seeking support and understanding about their pain, they face various barriers that prevent them from finding the answers they deserve. Semi-structured interviews were conducted with 8 women aged 20-28 to discuss their experiences with dysmenorrhea throughout their time since menarche. Using Scheper-Hughes and Lock understanding of the mindful body, this research explores women's experiences of dysmenorrhea through their physical body (relationship with the body and needing control), the social body (cultural concepts and comparisons to others) and the body politic (medicalisation, the medical team and the transvaginal ultrasound). The impact of these aspects of their mindful bodies developed arguments showing how different actors had an impact on preventing them obtaining the patient-centred care they required without resistance. More must be done to honour the experience of pain women have regarding their periods, especially by healthcare professionals. There must be consistency in the way women are approached for their dysmenorrhea to prevent discrepancies of support. This must be done with clearer guidance on what is offered to women with dysmenorrhea, especially in the primary care setting.
Menstrual CycleVitamin D IntakeVitamin D DeficiencyHIV Populations
Patterns of vitamin D intake are relatively unexplored among women living with HIV, despite its importance for women's health. We compared vitamin D dietary and supplement intakes in women with HIV and population-based national controls and investigated barriers to intake. In this case-control study, women with AntiRetrovirals and Markers of Aging (CARMA) cohort were matched with Canadian Multicentre Osteoporosis Study (CaMos) controls. Participants were queried for vitamin D in dairy consumption, supplementation/dosage, and sociodemographic variables. We assessed barriers to supplementation and factors associated with dietary intake by regression modelling. Ninety-five women living with HIV were age-matched to 284 controls. Women with HIV had lower income and bone mineral density and were more likely to smoke, take multiple medications and be non-white. Vitamin D dietary intake was lower in women living with HIV versus controls [0.76 vs. 1.79 μg/day; adjusted odds ratio (aOR) for greater than or equal to median intake 0.29 (0.12-0.61), p = 0.002], but any supplementation was higher [62.2% vs. 44.7%; aOR = 3.44 (95% CI: 1.16-11.00), p = 0.03]. Total vitamin D intake was similar between groups. Smoking was associated with no supplementation; non-white ethnicity and low income were related to lower dietary intake. Women living with HIV showed lower dietary vitamin D intake but higher supplementation rates, suggesting that care providers are promoting supplementation. Women living with HIV who smoke, have low incomes and are non-white may particularly benefit from targeted efforts to improve vitamin D intake.
Miscarriage is defined as spontaneous loss of pregnancy prior to 20 weeks gestation. With an estimated risk of 15% of clinically confirmed pregnancies ending in miscarriage, it is the most common adverse event in pregnancy. Woman's age is the primary risk factor for miscarriage, while medical conditions, including hormonal abnormalities, are also associated. Progesterone is essential for maintaining pregnancy. A short luteal phase may reflect inadequate levels of progesterone production, but it is unclear whether a short luteal phase correlates with an increase in the risk of miscarriage. Using a cohort study design, we conducted a secondary data analysis from four cohorts of couples who used a standardized protocol to track biomarkers of the female cycles. A short luteal phase was defined as less than 10 days, with < 11, < 9, and < 8 days as alternate definitions in sensitivity analyses. We included women who experienced a pregnancy with a known outcome, identified the length of the luteal phase in up to 3 cycles prior to conception and assessed the relationship with miscarriage using a modified Poisson regression analysis, adjusting for demographic characteristics, smoking, alcohol use and previous pregnancy history. In our sample of 252 women; the overall miscarriage rate was 18.7%. The adjusted incident risk ratio of miscarriage in women who had at least one short luteal phase < 10 days, compared to those who had none, was 1.01 (95% CI: 0.57, 1.80) Similar null risk was found when assessing alternative lengths of short luteal phase. Women who had short luteal phases < 10 days in all 3 cycles prior to the conception cycle had an incident risk ratio of 2.14 (95% CI: 0.7, 6.55). Our study found that a short luteal phase in the three cycles prior to conception was not associated with higher rates of miscarriage in an international cohort of women tracking their cycles, but our sample size was limited. Further research to determine if short luteal phases or luteal phase deficiency is associated with early pregnancy losses among preconception cohorts with daily tracking of cycle parameters, in addition to progesterone and human chorionic gonadotropin levels, is warranted. Additionally, future studies should include women with recurrent short luteal phases as a more likely risk factor than isolated short luteal phases.
Reproductive EndocrinologyMenstrual Cycle
Open Access
Does sexual intercourse enhance the cycle fecundability in women without known subfertility? Sexual intercourse (regardless of timing during the cycle) was associated with cycle characteristics suggesting higher fecundability, including longer luteal phase, less premenstrual spotting and more than 2 days of cervical fluid with estrogen-stimulated qualities. Human females are spontaneous ovulators, experiencing an LH surge and ovulation cyclically, independent of copulation. Natural conception requires intercourse to occur during the fertile window of a woman's menstrual cycle, i.e. the 6-day interval ending on the day of ovulation. However, most women with normal fecundity do not ovulate on Day 14, thus the timing of the hypothetical fertile window varies within and between women. This variability is influenced by age and parity and other known or unknown elements. While the impact of sexual intercourse around the time of implantation on the probability of achieving a pregnancy has been discussed by some researchers, there are limited data regarding how sexual intercourse may influence ovulation occurrence and menstrual cycle characteristics in humans. This study is a pooled analysis of three cohorts of women, enrolled at Creighton Model FertilityCare 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006) and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cycle phase lengths, bleeding and cervical mucus patterns and estimated the fertile window in 2564 cycles of 530 women, followed for up to 1 year. Participants were US or Canadian women aged 18-40 and not pregnant, who were heterosexually active, without known subfertility and not taking exogenous hormones. Most of the women were intending to avoid pregnancy at the start of follow-up. Women recorded daily vaginal bleeding, mucus discharge and sexual intercourse using a standardized protocol and recording system for up to 1 year, yielding 2564 cycles available for analysis. The peak day of mucus discharge (generally the last day of cervical fluid with estrogen-stimulated qualities of being clear, stretchy or slippery) was used to identify the estimated day of ovulation, which we considered the last day of the follicular phase in ovulatory cycles. We used linear mixed models to assess continuous cycle parameters including cycle, menses and cycle phase lengths, and generalized linear models using Poisson regression with robust variance to assess dichotomous outcomes such as ovulatory function, short luteal phases and presence or absence of follicular or luteal bleeding. Cycles were stratified by the presence or absence of any sexual intercourse, while adjusting for women's parity, age, recent oral contraceptive use and breast feeding. MAIN Most women were <30 years of age (75.5%; median 27, interquartile range 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators and nulliparous (70.9%). Cycles with no sexual intercourse compared to cycles with at least 1 day of sexual intercourse were shorter (29.1 days (95% CI 27.6, 30.7) versus 30.1 days (95% CI 28.7, 31.4)), had shorter luteal phases (10.8 days (95% CI 10.2, 11.5) versus 11.4 days (95% CI 10.9, 12.0)), had a higher probability of luteal phase deficiency (<10 days; adjusted probability ratio (PR) 1.31 (95% CI 1.00, 1.71)), had a higher probability of 2 days of premenstrual spotting (adjusted PR 2.15 (95% CI 1.09, 4.24)) and a higher probability of having two or fewer days of peak-type (estrogenic) cervical fluid (adjusted PR 1.49 (95% CI 1.03, 2.15)). LIMITATIONS Our study participants were geographically dispersed but relatively homogeneous in regard to race, ethnicity, income and educational levels, and all had male partners, which may limit the generalizability of the findings. We cannot exclude the possibility of undetected subfertility or related gynecologic disorders among some of the women, such as undetected endometriosis or polycystic ovary syndrome, which would impact the generalizability of our findings. Acute illness or stressful events might have reduced the likelihood of any intercourse during a cycle, while also altering cycle characteristics. Some cycles in the no intercourse group may have actually had undocumented intercourse or other sexual activity, but this would bias our results toward the null. The Creighton Model FertilityCare System (CrM) discourages use of barrier methods, so we believe that most instances of intercourse involved exposure to semen; however, condoms may have been used in some cycles. Our dataset lacks any information about the occurrence of female orgasm, precluding our ability to evaluate the independent or combined impact of female orgasm on cycle characteristics. Sexual activity may change reproductive hormonal patterns, and/or levels of reproductive hormones may influence the likelihood of sexual activity. Future work may help with understanding the extent to which exposure to seminal fluid, and/or female orgasm and/or timing of intercourse could impact menstrual cycle function. In theory, large data sets from women using menstrual and fertility tracking apps could be informative if women can be appropriately incentivized to record intercourse completely. It is also of interest to understand how cycle characteristics may differ in women with gynecological problems or subfertility. Funding for the research on the three cohorts analyzed in this study was provided by the Robert Wood Johnson Foundation #029258 (Creighton Model MultiCenter Fecundability Study), the Eunice Kennedy Shriver National Institute of Child Health and Human Development 1K23 HD0147901-01A1 (Time to Pregnancy in Normal Fertility) and the Office of Family Planning, Office of Population Affairs, Health and Human Services 1FPRPA006035 (Creighton Model Effectiveness, Intentions, and Behaviors Assessment). The authors declare that they have no conflict of interest. N/A.
Menstrual CycleEstradiol-Progesterone BalanceHealth ImplicationsDeficiency and Well-being
Prior JC, 2022·The Cambridge Handbook of Evolutionary Perspectives on Sexual Psychology
Periodic vaginal bleeding occurs in humans (who are henceforth called “women,” a word describing culture as well as biology), old-world apes, and few other mammals. By current concepts, women’s menstrual cycles provide estrogen for thirty to fifty years; following one year of no flow they become menopausal and “estrogen deficient.” By contrast we now know that the purpose of menstrual cycles is to supply all cells and tissues with the balanced essential actions of estradiol (E2) and progesterone (P4) produced in feedback-controlled patterns to facilitate fecundability and preserve younger women’s well-being. We also now know that menopausal women’s health is negatively affected (by increased osteoporosis, heart disease, breast and endometrial cancers) if those past menstrual cycles produced inadequate net P4 to counterbalance and complement E2’s actions. Menstrual periodicity, flow, and ovulatory characteristics in women reflect the integrated actions/interactions of the central nervous system through the hypothalamus and pituitary, ideally leading to each cycle’s stimulation of a dominant egg-containing follicle. That follicle, by central complex feedback loops, produces the cyclic, graded amounts of estradiol (E2) and progesterone (P4) for that threeto five-week period and releases a viable egg. Central reproductive connections allow adult premenopausal women’s menstrual cycle periodicity, ovulation or not, and luteal phase lengths, that can be adapted to the challenges and demands of each woman’s current physiological and sociocultural/emotional environments. These new ideas are based on the differing and complementary cellular and tissue actions of E2 and P4. E2 is essential for cell growth and stimulates cell proliferation. P4 uniquely counterbalances and controls proliferation while stimulating cell differentiation and tissue maturation. Thus, E2–P4 actual and relative productions integrate cycles within each woman’s reproductive lifecycle (adolescent, premenopausal, perimenopausal), and are related to her nutrition, illness, energy expenditure, and social/emotional/spiritual environments. The subtlest indication of a stressed reproductive system is truncated P4 production in the short luteal phase within a normal-length, ovulatory menstrual cycle. This adaptation protects a woman from pregnancy when she has inadequate net energy balance or is under emotional/social/spiritual or physical duress. Thus, a normal luteal phase length within a threeto five-week regular menstrual cycle is a bellwether of women’s well-being. By contrast, regular cycles with ovulatory disturbances (anovulation or short luteal phases; E2>P4) predict current decreased well-being and poor later life health. The purpose of this review is to provide a practical approach to understanding this new women’s menstrual cycle balanced E2–P4 paradigm applied to common clinical situations including subfertility with regular cycles, premenstrual symptoms, and heavy menstrual flow.
Bouchard TP et al., 2022·J Womens Health (Larchmt)
Some studies have suggested minor changes in the menstrual cycle after COVID-19 vaccination, but more detailed analyses of the menstrual cycle are needed to evaluate more specific changes in the menstrual cycle that are not affected by survey-based recall bias. Using a pretest-post-test quasi-experimental evaluation of menstrual cycle parameters before and after COVID-19 vaccination, we conducted an anonymous online survey of two groups of North American women who prospectively monitor their menstrual cycle parameters daily including bleeding patterns, urinary hormone levels using the ClearBlue Fertility Monitor, or cervical mucus observations. The primary outcome measures were cycle length, length of menses, menstrual volume, estimated day of ovulation (EDO), luteal phase length, and signs of ovulation. Perceived (subjective) menstrual cycle changes and stressors were also evaluated in this study as secondary outcome measures. Of the 279 women who initiated the survey, 76 met the inclusion criteria and provided 588 cycles for analysis (227 pre-vaccine cycles, 145 vaccine cycles, 216 post-vaccine cycles). Although 22% of women subjectively identified changes in their menstrual cycle, there were no significant differences in menstrual cycle parameters (cycle length, length of menses, EOD, and luteal phase length) between the pre-vaccine, vaccine, and post-vaccine cycles. COVID-19 vaccines were not associated with significant changes in menstrual cycle parameters. Perceived changes by an individual woman must be compared with statistical changes to avoid confirmation bias.
Menstrual CycleReproductive Endocrinology
Open Access
Stress is known to be associated with adverse health outcomes. The COVID-19 pandemic and its associated lockdowns are examples of chronic stressors. Lockdown measures inadvertently caused significant psychological distress and became a powerful source of anxiety/stress, sleep disturbances, nutritional changes and weight gain. Stress is known to impact women's health specifically, through hypothalamic-pituitary-gonadal (HPG) axis dysfunction and resultant ovulatory dysfunction. Such dysfunction may manifest in menstrual irregularities and/or infertility due to hypothalamic hypogonadism. Here, we review the key physiological mediators of stress and associated ovulatory dysfunction. The kisspeptinergic system is comprised of sets of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and the arcuate nucleus (ARC). This system links nutrition, reproductive signals and stress. It plays a key role in the function of the HPG axis. During chronic stress, the kisspeptinergic system affects the HPG axis, GnRH pulsatility, and, therefore, ovulation. Leptin, insulin and corticotrophin-releasing hormone (CRH) are thought to be additional key modulators in the behavioral responses to chronic stress and may contribute to stress-related ovulatory dysfunction. This mini-review also summarizes and appraises the available evidence on the negative impact of chronic stress as a result of the COVID-19 pandemic lockdowns. It proposes physiological mechanisms to explain the observed effects on women's reproductive health and well-being. The review suggests areas for future research.
To evaluate variations in micronutrient biomarker concentrations and deficiencies across the menstrual cycle in a cohort of healthy women. This prospective cohort study was conducted among healthy women of reproductive age living in the State College area, Pennsylvania, (n = 45). Data collection occurred at the early follicular phase, the late follicular phase, and the midluteal phase. Fasting blood samples were collected to measure micronutrient biomarkers. At the early follicular phase, the mean ± SD concentrations for zinc, copper, magnesium, and retinol were 81.8 ± 16.2 µg/dL, 80.1 ± 12.8 µg/dL, 17.9 ± 1.4 mg/L, and 39.4 ± 9.3 µg/dL, respectively. The geometric mean (95% CI) for manganese, iron and ferritin concentrations were 1.51 [1.21, 1.87] µg/L, 106.7 [90.8, 125.4] µg/dL, and 26.4 [20.5, 34.0] µg/L, respectively. Mean concentrations of zinc and magnesium declined by 6.6% (p = 0.009) and 4.6% (p < 0.001) from the early follicular phase to the midluteal phase, respectively. Other biomarkers remained relatively constant across the cycle. At the early follicular phase, the prevalence of low serum concentrations for zinc, copper, magnesium, manganese, iron, and ferritin was 22%, 7%, 29%, 13%, 14%, and 28%, respectively. Also, in early follicular phase, 36% had anemia, and 13% specifically had iron deficiency anemia. The prevalence of magnesium deficiency was significantly higher at the midluteal phase vs. the early follicular phase (p = 0.025). Our study suggests that while many micronutrient concentrations are relatively constant across the menstrual cycle in healthy women, zinc and magnesium decline, and the prevalence of magnesium deficiency increases. Supplemental data for this article is available online at.
After participating in this activity, learners • Discuss and outline the general and overlapping effects of the menstrual cycle on women's mental health. A growing body of research demonstrates menstrual cycle-dependent fluctuations in psychiatric symptoms; these fluctuations can therefore be considered as prevalent phenomena. Possible mechanisms underlying these fluctuations posit behavioral, psychological, and neuroendocrine influences. Recent reviews document cyclic exacerbation of symptoms and explore these mechanisms in the context of specific and often single disorders. The question remains, however, as to whether there are general and overlapping effects of the menstrual cycle on women's mental health. To address this gap, we synthesized the literature examining the exacerbation of a variety of psychiatric symptoms across the menstrual cycle in adult women. Results show that the premenstrual and menstrual phases are most consistently implicated in transdiagnostic symptom exacerbation. Specifically, strong evidence indicates increases in psychosis, mania, depression, suicide/suicide attempts, and alcohol use during these phases. Anxiety, stress, and binge eating appear to be elevated more generally throughout the luteal phase. The subjective effects of smoking and cocaine use are reduced during the luteal phase, but fewer data are available for other substances. Less consistent patterns are demonstrated for panic disorder, symptoms of posttraumatic stress disorder, and borderline personality disorder, and it is difficult to draw conclusions for symptoms of generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and trichotillomania because of the limited data. Future research should focus on developing standardized approaches to identifying menstrual cycle phases and adapting pharmacological and behavioral interventions for managing fluctuations in psychiatric symptoms across the menstrual cycle.
A new fertility monitor is now available that provides quantitative measurement of urinary hormones, but clinical use requires validation against an established fertility monitor that provides only qualitative results. Two fertility monitors were compared using daily first morning urine samples over 3 cycles of use in 21 women users with experience using a fertility monitor with the Marquette Method of Natural Family Planning. Women were aged 33.4 ± 5.5 years and had menstrual cycles ranging between 23 and 41 days. The quantitative Mira Monitor estimates of ovulation were highly correlated with the qualitative ClearBlue Fertility Monitor (CBFM) estimates of ovulation. Both monitors provided an accurate estimate of the fertile window. In this preliminary trial, the Mira monitor was shown to be effective at delineating the fertile window and ovulation. We demonstrated the feasibility of applying the Marquette Method algorithm with the use of the Mira monitor. Satisfaction differences between the two monitors did not reach statistical significance. We anticipate that quantitative fertility monitoring will give couples and health-care providers new and unprecedented insights into the menstrual cycle and fertility.
What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. STUDY DESIGN, SIZE, This study is a secondary data analysis, combining data 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. PARTICIPANTS/MATERIALS, SETTING, Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. MAIN The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. LIMITATIONS, We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. STUDY FUNDING/COMPETING INTEREST(S): Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. N/A.
Menstrual CycleHormonal Effects on BehaviorMid-Cycle Hormonal EffectsBasal Body Temperature Analysis
Allison B Macbeth et al., 2021·Women's Reproductive Health
Women's interest in sex is asserted to increase at the mid-cycle pre-ovulatory estradiol peak. We explored this belief in healthy, spontaneously normally menstruating/ovulating women. Women recorded "interest in sex" in a daily diary; validated Quantitative Basal Temperature analysis documented ovulation. Interest in sex showed no mid-cycle peak in 61 normal-weight, nonsmoking women, ages 33.7 ± 5.6 years, over a mean of 311 consecutive days. The cycle-plotted diary "self-worth" factor (including feelings of energy, interest in sex) also showed no mid-cycle peak. Thus, interest in sex is related more strongly to women's feelings/experiences than to hormones, challenging deterministic or sex-hormone-dependent cultural and sociobiological understandings.
Reproductive EndocrinologyMenstrual CycleDiagnostics
Open Access
Saei Ghare Naz M et al., 2021·Int J Endocrinol Metab
Menstrual cycle is considered the fifth vital sign among women. This study aimed to summarize the menstrual disturbances in different endocrine disorders.
In this narrative review, relevant studies (up to December 2019) were searched based on the MeSH keywords diabetes, polycystic ovary syndrome, Cushing's syndrome, thyroid dysfunction, hyperprolactinemia, menstrual cycle, uterine bleeding, and menstruation. Databases used for searching articles included Google Scholar, Scopus, PubMed, and Web of science for observational, experimental, and review studies. Endocrine disorders trigger the onset of menstrual disturbance across the reproductive lifespan of women. Endocrine glands (pituitary, thyroid, pancreas, adrenal, and ovaries) have a functional role in endocrine regulation of the menstrual cycle. According to available evidence, oligomenorrhea (cycles longer than 35 days) is the most common menstrual disturbance among endocrine disorders (thyrotoxicosis, hypothyroidism, polycystic ovary syndrome, Cushing's syndrome, and diabetes). Complex endocrine pathways play an essential role in a women's menstrual calendar. The menstrual cycle length and amount of bleeding can be indicative of endocrine disorders. Further studies are needed to identify the unknowns about the association between endocrine disorders and the menstrual cycle.
Catamenial epilepsy (CE) is exacerbated by hormonal fluctuations during the menstrual cycle. Approximately 1.7 million women have epilepsy in the United States. CE affects more than 40% of women with epilepsy. There is a paucity of literature addressing this condition from a clinical standpoint, and the literature that does exist is limited to the neurological community. This article reviews the diagnosis and management of CE for the non-neurologist. Women with CE have early touch points in their care with numerous health care providers before ever consulting with a specialist, including OB/GYNs, pediatricians, emergency department physicians, and family medicine providers. In addition, women affected by CE have seizures that are more recalcitrant to traditional epilepsy treatment regimens. To optimize management in patients affected by CE, menstrual physiology must be understood, individualized hormonal contraception treatment considered, and adjustments and interactions with antiepileptic drugs addressed.
CE is a unique subset of seizure disorders affected by menstrual fluctuations of progesterone and estrogen. The diagnosis of CE has been refined and clarified. There is an ever-increasing understanding of the importance and variety of options of hormonal contraception available to help manage CE. Furthermore, antiepileptic drugs and contraception can interact, so attention must be directed to optimizing both regimens to prevent uncontrolled seizures and pregnancy. CE can be diagnosed with charting of menstrual cycles and seizure activity. Hormonal treatments that induce amenorrhea have been shown to reduce CE. Optimizing antiepileptic drug dosing and contraceptive methods also can minimize unplanned pregnancies in women affected by CE.
DeVilbiss EA et al., 2020·Paediatr Perinat Epidemiol
Attaining pregnancy is conditional upon a series of complex processes, including adequately timed intercourse, ovulation, fertilisation, and implantation. Anovulation is a first-line treatment target for couples with difficulty conceiving and is frequently examined in studies of fecundability. To identify whether sporadic anovulation is an important determinant of cumulative pregnancy rates and time to pregnancy among fertile women with regular menstrual cycles. We simulated cumulative pregnancy rates and time to pregnancy for 12 consecutive menstrual cycles among 100 000 women based on data-driven probabilities of implantation, fertilisation, ovulation, and intercourse occurring in the fertile window. We assumed anovulation probabilities of 1%, 8%, or 14.5% and intercourse averaging once per week, every other day, or daily. The model incorporated reductions in implantation and fertilisation rates for successive cycles of non-pregnancy. After 12 cycles, a reduction in the per cycle incidence of anovulation from 14.5% to 1% resulted in a 4.0% higher cumulative pregnancy rate (86.7% vs 90.7%) and similar time to pregnancy (1-cycle median difference). In contrast, increasing mean unscheduled sexual intercourse frequency from weekly to every other day was associated with a 5-cycle median reduction in time to pregnancy (weekly: 7 cycles; 2 cycles) and a 28.9% increase in the cumulative pregnancy rate (weekly: 59.9%, 88.8%; 91.6%). In presumed fertile women with regular menstrual cycles, routine investigation of anovulation may not be an informative outcome in studies of fecundability, and routine testing to ensure ovulation and treatment of anovulation are unlikely to be medically necessary. While biomarkers or cervical fluid may help time intercourse to the fertile window, time to pregnancy can also be improved through increasing the frequency of unscheduled intercourse. These findings need corroboration in large preconception time to pregnancy studies.
Reproductive EndocrinologyNeuroendocrine EffectsProgesterone and MoodAllopregnanolone Treatment
Open Access
Sundström-Poromaa I et al., 2020·Front Neuroendocrinol
Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
Bone HealthAntiretroviral Therapy EffectsBone Mineral DensityHR-pQCT Assessment
With the advent of combined antiretroviral therapy (cART), life expectancy has increased among persons living with HIV, but so too has risk for comorbidities including osteoporosis and fragility fracture. To explore whether HIV status and cART influence three-dimensional measures of BMD, bone microarchitecture and strength we aimed to compare these outcomes between women living with HIV (WLWH; n = 50; 50.4 ± 1.2 years, 44% postmenopausal) and without HIV (controls; n = 50; 51.8 ± 1.2 years, 52% postmenopausal). Outcomes were lumbar spine, total hip and femoral neck areal BMD by DXA; distal radius and tibia trabecular BMD, thickness and number, and cortical BMD and area by HR-pQCT; and finite element analysis-derived bone strength (failure load). Multivariable regression analysis compared bone outcomes between groups adjusting for known osteoporosis risk factors. Within WLWH, we examined associations between bone outcomes and HIV-related factors including disease severity and cART duration. WLWH were diagnosed 20 ± 4 years ago, were on cART for 123 ± 37 months and 80% had HIV plasma viral load <40 copies/mL. For women ≥50 years (n = 61), total hip aBMD T-Score was lower among WLWH than controls. Adjusted distal radius trabecular BMD and thickness and distal tibia trabecular BMD and failure load were 8-19% lower in WLWH than controls (p < 0.05). Cortical BMD and area did not differ between groups at either site. Lifetime cART duration and current plasma viral load were not associated with bone outcomes in WLWH; however, previous treatment with tenofovir was negatively associated with distal radius trabecular BMD and trabecular number and LS aBMD T-score. WLWH have compromised BMD, bone microarchitecture and strength vs. controls of similar age and reproductive status. Treatment with tenofovir may contribute to bone deficits in WLWH.
Menstrual CycleHIV-AssociatedAmenorrhea EffectsReproductive Health
Women living with HIV (WLWH) have higher rates of prolonged secondary amenorrhea (no flow for ≥1 year) than HIV-negative women. Both having amenorrhea and being HIV positive are associated with lower areal bone mineral density (BMD). However, their combined BMD effects remain unclear. Therefore, we investigated prolonged amenorrhea and BMD in WLWH and controls. This cross-sectional study enrolled WLWH and HIV-negative control women aged 19-68 years of similar backgrounds. We assessed BMD (Hologic; as ageand ethnicity-matched Z-scores) AntiRetrovirals and Markers of Aging cohort. Participants were stratified by amenorrhea history defined as past/present lack of menses for ≥1 year at age 45 and younger and not because of surgery, breastfeeding, pregnancy, or hormonal contraception. Hip and spine Z-scores by amenorrhea/no amenorrhea used linear models with multivariable analysis for relationships within WLWH. WLWH (N = 129) were similar to controls (N = 129) in age, body mass index, ethnicity, and substance use. Among WLWH, 21% experienced prolonged amenorrhea vs. 9% in controls. WLWH had significantly lower total hip (mean ± SD: -0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (-0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores than controls. Amenorrhea was independently associated with hip (P = 0.01) but not spine (P = 0.94) BMD by multivariable linear regression. WLWH with amenorrhea had lower hip Z-scores (-0.8 ± 0.9) than those without (-0.3 ± 0.8; P = 0.01). They also had higher rates of substance use, smoking, opioid therapy, hepatitis C coinfection, and lower CD4 nadir. WLWH had higher rates of prolonged amenorrhea and lower BMD than controls. WLWH with amenorrhea experienced lower hip BMD Z-scores than those without. Prolonged amenorrhea is an added osteoporosis risk in WLWH.
Premenstrual syndrome (PMS) affects millions of women. While over-the-counter products have helped with the physical symptoms of PMS, emotional symptoms have been less well supported. The objective of this trial was to measure the effect of an oxaloacetate/vitamin C combination on the major emotional symptoms of PMS, including depression, anxiety, perceived stress, aggression, and suicidal ideation. Forty-eight women experiencing PMS completed a baseline survey comprising the Beck's Depression Inventory, Cohen Perceived Stress Scale, Generalized Anxiety Disorder Test, and Buss-Perry Aggression Questionnaire. After baseline measurements, participants were randomly assigned to take either 2 capsules of 100 mg oxaloacetate/150 mg ascorbic acid, or 2 capsules of rice flour (placebo) for their entire menstrual cycle. At menstruation, the women completed the 4 surveys again. The women then switched capsules in a cross-over design and continued the study for an additional menstrual cycle. The final assessment was repeated at menstruation. Statistical analysis of the 4 surveys was performed to examine efficacy. Oxaloacetate/vitamin C supplementation during PMS significantly improved depression, perceived stress, anxiety, aggression, and suicidal ideation. The mean improvement in depression was 54.1%, 35.8% for perceived stress, 51.43% for generalized anxiety, and 17.8% for aggression. Suicidal ideation was reduced by 47.9%. All results were highly significant. A combination of oxaloacetate and vitamin C supplementation helped to alleviate depression, anxiety, perceived stress, aggression, and suicidal ideation symptoms associated with PMS. ClinicalTrials.gov NCT03509714.
Najmabadi S et al., 2020·Paediatr Perinat Epidemiol
There is variability between women for days of menstrual bleeding, cycle lengths, follicular phase lengths, and luteal phase lengths, related to age and parity. To describe total cycle length; anovulatory cycles; follicular and luteal phase lengths; and days and intensity of menstrual and non-menstrual bleeding in women without known subfertility over the course of 1 year. 581 women (3,324 cycles) with no known subfertility (18-40 years of age) were followed for up to 1 year. Women recorded vaginal bleeding and mucus discharge daily. We used the peak day of cervical mucus as the estimated day of ovulation and the last day of the follicular phase. We used generalised linear mixed models stratified by age and parity to describe menstrual cycle parameters. The majority of women were <30 years of age (74.5%), non-Hispanic White (88.6%), and nulliparous (70.4%). The mean menses length was 6.2 (1.5) days, median 6; cycle length 30.3 (6.7) days, median 29; follicular phase length 18.5 (6.5) days, median 17; and luteal phase length 11.7 (2.8) days, median 12. Nulliparous women aged ≥30 years vs nulliparous women aged <30 had shorter cycles (29.2 days, 95% confidence interval (CI) 27.8, 30.7 vs 31.5 days, 95% CI 30.8, 32.2) and shorter follicular phases (17.6 days, 95% CI 16.2, 18.9 vs 19.6 days, 95% CI 18.9, 20.2). Among all women, within-woman differences between the longest and shortest menses length >3 days, total cycle length >7 days, follicular phase >7 days, and luteal phase >3 days were found in 11.6%, 43.0%, 41.7%, and 58.8% of women, respectively. Our findings confirm variability between women of menstrual cycle parameters related to age and parity, and also highlight within-woman variability in the follicular and luteal phases.
Despite research indicating that sleep disorders influence reproductive health, the effects of sleep on reproductive hormone concentrations are poorly characterized. We prospectively followed 259 regularly menstruating women across one to two menstrual cycles (the BioCycle Study, 2005-2007), measuring fasting serum hormone concentrations up to eight times per cycle. Women provided information about daily sleep in diaries and chronotype and night/shift work on a baseline questionnaire. We evaluated percent differences in mean hormone concentrations, the magnitude of shifts in the timing and amplitude of hormone peaks, and the risk for sporadic anovulation associated with self-reported sleep patterns and night/shift work. We estimated chronotype scores - categorizing women below and above the interquartile range (IQR) as "morning" and "evening" chronotypes, respectively. For every hour increase in daily sleep duration, mean estradiol concentrations increased by 3.9% (95% confidence interval [CI] 2.0, 5.9%) and luteal phase progesterone by 9.4% (CI 4.0, 15.2%). Receiving less than 7 hours of sleep per day was associated with slightly earlier rises in peak levels for several hormones. Women reporting night/shift work (n = 77) had lower testosterone relative to women employed without night/shift work (percent -9.9%, CI -18.4, -0.4%). Women with morning chronotypes (n = 47) had earlier rises in estradiol during their cycles and potentially an earlier rise in luteinizing hormone. Compared to those who had intermediate chronotypes, women with evening chronotypes (n = 42) had a later luteinizing hormone peak of borderline statistical significance. A reduced risk for sporadic anovulation was suggested, but imprecise, for increasing hours of daily sleep leading up to ovulation (risk ratio 0.79, CI 0.59, 1.06), while an imprecise increased risk was observed for women with morning chronotypes (risk ratio 2.50, CI 0.93, 6.77). Sleep-related hormonal changes may not greatly alter ovarian function in healthy women, but have the potential to influence gynecologic health.
Reproductive EndocrinologyPFAS EffectsEnvironmental Chemical ExposureEndometrial Function Disruption
Female fecundity is finely regulated by hormonal signaling, representing a potential target for endocrine-disrupting chemicals. Among the chemicals of most concern are the perfluoroalkyl substances (PFAS), widely used in consumer goods, that are associated with adverse effects on reproductive health. In this context, the endometrium clearly represents an important fertility determining factor. The aim of this study was to investigate PFAS interference on hormonal endometrial regulation. This study was performed within a screening protocol to evaluate reproductive health in high schools. We studied a cohort of 146 exposed females aged 18-21 from the Veneto region in Italy, one of the four areas worldwide heavily polluted with PFAS, and 1080 non-exposed controls. In experiments on Ishikawa cells included UV-Vis spectroscopy, microarray analysis and qPCR. We report a significant dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity. The most differentially-expressed genes upon PFOA coincubation were ITGB8, KLF5, WNT11, SULT1E1, ALPPL2 and G0S2 (all p < 0.01). By qPCR, we confirmed an antagonistic effect of PFOA on all these genes, which was reversed at higher progesterone levels. Molecular interference of PFOA on progesterone was confirmed by an increase in the intensity of absorption spectra at 250 nm in a dose-dependent manner, but not in the presence of β-estradiol. Age at menarche (+164 days, p = 0.006) and the frequency of girls with irregular periods (29.5% vs 21.5%, p = 0.022) were significantly higher in the exposed group. Our results are indicative of endocrine-disrupting activity of PFAS on progesterone-mediated endometrial function.
In 2006-2008, 610 premenopausal, spontaneously menstruating women in the Metro Vancouver region participated in a Canadian Institutes of Health Research (CIHR)-funded singlecycle in which they collected first morning urine specimens for estrogen and progesterone metabolites1. Following that study, after analyses, we retrieved the remaining urine specimens from the analyzing laboratory (University of Washington). We sorted data so that samples from all those women who were anovulatory by the two combined urinary steroid evaluation methods2,3, plus from those who were ovulatory with the highest and the lowest urinary hormone values were shipped to Health Canada (HC) via Dr. Warren Foster’s laboratory at McMaster University. Those data on flame retardant contaminants in women’s urine have been published4, but the cycle-phase specific data are still in analysis (personal communication, S Kalyan, 2019). In 2017, HC basic scientists launched applications to HC to fund a similar study to assess flame retardant excretory changes in the same population/locale 10 years later. This application was funded in 2018 at Health Canada with Dr. JC Prior as a collaborator. Extensive negotiations by CeMCOR and HC scientists ensued about funding the process of obtaining these follow-up specimens. CeMCOR managed to obtain a HC agreement to fund the minimal cost of recruiting, training and obtaining two menstrual phase-specific urine specimens from 250 Metro Vancouver women. Because of the lack of a progesterone threshold for ovulation, we will collect one follicular and one luteal/premenstrual urine sample per woman. However, this time we will better characterize the ovulatory cycle using a validated quantitative basal temperature method5,6 that can assess luteal phase length as well as the presence/absence of evidence for ovulation. In addition we will collect serial salivary progesterone and estradiol values measured by the state-of-the-art sensitive and specific tandem mass spectrometry (LC-MS/MS) methods7 to use as the gold standard for an ovulatory cycle. There is increasing evidence that many variables differ across women’s two follicular and luteal7-10. These real and potential differences in metabolism may alter the susceptibility of women to environment exposures, and also could change their urinary elimination. Those are the root reasons for doing this study.
This review is to challenge current concepts of women’s reproduction with its cultural over-emphasis on estrogen and positive actions, while progesterone tends to be ignored or associated with negative effects. To explore the physiology, and the clinical implications of understanding that progesterone and estradiol interact in counterbalancing and complementary ways within a complex system that is Women’s Reproductive Health. Fundamental, descriptive, quantitative and experimental data all show that estradiol’s important cellular action is to promote growth and proliferation; by contrast, despite short-term proliferative effects, progesterone’s dominant actions are to inhibit proliferation, to enhance differentiation and promote maturation. Estradiol and progesterone variably interact in every cell and tissue in women’s bodies and across the life cycle. Since ovulation and thus progesterone’s presence is subclinical in normal-length cycles, we urgently need a convenient, home, once/cycle, inexpensive test of normal ovulation. Major funding is needed for ovulation-testing cycle-by-cycle over months or years in large population-based cohorts of adolescent, premenopausal and perimenopausal women. These women need to be followed for fertility and their later-life experiences of osteoporotic fracture, myocardial infarction, breast and endometrial cancers. In addition, all research with menstruating women participants and female mammals needs cycle-phase specific testing. It is difficult to perceive, much less to change, a current paradigm. With this journal issue, however, we have begun the important tasks of transforming concepts about women’s health, and setting the research agenda to advance the innovative understanding that women's reproductive and overall health becomes optimal when premenopausal menstrual cycle estradiol and progesterone actions are balanced within this complex system.
Bone HealthHIV PopulationBone Mineral Density ImpactMenstrual Disturbances
Open Access
King EM et al., 2019·Open forum infectious diseases
Background Women living with HIV (WLWH) have higher rates of long-term amenorrhea (no flow for ≥12 months) than HIV-negative women. However, little is known about the consequences of amenorrhea for WLWH. Both amenorrhea and HIV are associated with lower areal bone mineral density (BMD); though the combined effect of both on BMD remains unclear. In this cross-sectional study we investigated whether prolonged amenorrhea adversely affects BMD among WLWH. Methods We investigated BMD (using a Hologic bone densitometer) and prolonged amenorrhea among WLWH and HIV-negative control women of similar socioeconomic backgrounds aged 19–68 in the CARMA cohort. Participants were stratified by HIV status and history of prolonged secondary amenorrhea defined as a self-reported absence of menses for at least one year in the past or present, occurring at age <45 years and not due to surgery, breastfeeding, pregnancy or hormonal contraception. Hip and spine Z-scores (ageand racestandardized BMD values) were compared between groups using linear models, followed by multivariable analysis of BMD-related factors. Results WLWH (N = 129) had significantly lower hip (mean±SD −0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (−0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores vs. controls (N = 129). Multivariable linear regression found prolonged amenorrhea was independently related to lower hip (P = 0.01), but not spine (P = 0.94) BMD. Within WLWH, the effect of amenorrhea was also additive to that of HIV, with hip Z-scores of -0.8±0.9for those with amenorrhea vs. -0.3±0.8for those normally cycling (P = 0.01). Amongst WLWH, those with prolonged amenorrhea had higher rates of illicit substance use, smoking, chronic opioid therapy, hepatitis C viral infection, and poorer HIV viral control than those with normal menstruation. Conclusion These data suggest that WLWH having prolonged amenorrhea of ≥1 year’s duration are at increased risk for hip bone loss, a finding influenced by comorbid, HIV-associated conditions. Screening WLWH for menstrual history will allow early discovery of osteoporosis risk, and stimulate preventative measures to mitigate bone loss. No reported disclosures.
Menstrual CycleDigital Health DataApp-Based TrackingBig Data
For most women of reproductive age, assessing menstrual health and fertility typically involves regular visits to a gynecologist or another clinician. While these evaluations provide critical information on an individual's reproductive health status, they typically rely on memory-based self-reports, and the results are rarely, if ever, assessed at the population level. In recent years, mobile apps for menstrual tracking have become very popular, allowing us to evaluate the reliability and tracking frequency of millions of self-observations, thereby providing an unparalleled view, both in detail and scale, on menstrual health and its evolution for large populations. In particular, the primary aim of this study was to describe the tracking behavior of the app users and their overall observation patterns in an effort to understand if they were consistent with previous small-scale medical studies. The secondary aim was to investigate whether their precision allowed the detection and estimation of ovulation timing, which is critical for reproductive and menstrual health. Retrospective self-observation data were acquired from two mobile apps dedicated to the application of the sympto-thermal fertility awareness method, resulting in a dataset of more than 30 million days of observations from over 2.7 million cycles for two hundred thousand users. The analysis of the data showed that up to 40% of the cycles in which users were seeking pregnancy had recordings every single day. With a modeling approach using Hidden Markov Models to describe the collected data and estimate ovulation timing, it was found that follicular phases average duration and range were larger than previously reported, with only 24% of ovulations occurring at cycle days 14 to 15, while the luteal phase duration and range were in line with previous reports, although short luteal phases (10 days or less) were more frequently observed (in up to 20% of cycles). The digital epidemiology approach presented here can help to lead to a better understanding of menstrual health and its connection to women's health overall, which has historically been severely understudied.
Menstrual CycleClassification SystemsFIGO StandardsAbnormal Uterine Bleeding
Open Access
The International Federation of Gynecology and Obstetrics (FIGO) systems for nomenclature of symptoms of normal and abnormal uterine bleeding (AUB) in the reproductive years (FIGO AUB System 1) and for classification of causes of AUB (FIGO AUB System 2; PALM-COEIN) were first published together in 2011. The purpose was to harmonize the definitions of normal and abnormal bleeding symptoms and to classify and subclassify underlying potential causes of AUB in the reproductive years to facilitate research, education, and clinical care. The systems were designed to be flexible and to be periodically reviewed and modified as appropriate. To review, clarify, and, where appropriate, revise the previously published systems. To a large extent, the process has been an iterative one involving the FIGO Menstrual Disorders Committee, as well as a number of invited contributions from epidemiologists, gynecologists, and other experts in the field from around the world between 2012 and 2017. Face-to-face meetings have been held in Rome, Vancouver, and Singapore, and have been augmented by a number of teleconferences and other communications designed to evaluate various aspects of the systems. Where substantial change was considered, anonymous voting, in some instances using a modified RAND Delphi technique, was utilized.
Bone HealthProgesterone and Ovulation RoleBone Health ConsequencesBeyond Estrogen Paradigm
Open Access
To assess prospectively luteinized unruptured follicle (LUF) syndrome in juvenile idiopathic arthritis (JIA) patients with and without non-steroidal anti-inflammatory drugs (NSAIDs) and healthy controls. Twenty-three adolescent and young adult female JIA patients (ILAR criteria) and 11 female healthy subjects were studied by pelvic ultrasound monitoring for follicular development and ovulation in one menstrual cycle. LUF syndrome was prospectively investigated by pelvic ultrasound with a dominant ovarian follicle without signs of follicular rupture, with elevation of serum progesterone in the luteal phase of the menstrual cycle and luteinizing hormone (LH) detected in the urine. Comparison between JIA patients with (n = 8) vs. without NSAIDs (n = 15) and healthy controls (n = 11) revealed that LUF syndrome was significantly higher in the former group (2 (25%) vs. 0% vs. 0%, p = 0.049). These two patients with LUF syndrome had normal menstrual cycles without reduced ovarian reserve, and they were under naproxen 500 mg bid during the menstrual cycle. Disease duration was comparable in JIA with and without NSAIDs [19.8 (4.4-25) vs. 13 (3.1-33) years, p = 0.232]. Further comparison between JIA patients with and without NSAIDs and healthy controls showed similar mean anti-Müllerian hormone levels (p = 0.909), estradiol (p = 0.436), FSH (p = 0.662), LH (p = 0.686), and mean antral follicle count (p = 0.240) and ovarian volume (p = 0.363). No differences were evidenced in three groups regarding Caucasian race, body mass index, duration, and length of menstrual cycles (p > 0.05). This is the first study to identify that JIA patients have a high frequency of LUF without impaired ovarian reserve. Future prospective studies are necessary to determine if chronic/continuous use of NSAIDs in JIA will have an impact in these patients' fertility.
Bone HealthProgesterone TherapyBone FormationBone Mineral Density Impact
Open Access
Estradiol (E2) is women's dominant 'bone hormone' since it is essential for development of adolescent peak bone mineral density (BMD) and physiological levels prevent the rapid (3-week) bone resorption that causes most adult BMD loss. However, deceasing E2 levels trigger bone resorption/loss. Progesterone (P4) is E2's physiological partner, collaborating with E2 in every cell/tissue; its bone 'job' is to increase P4-receptor-mediated, slow (3-4 months) osteoblastic new bone formation. When menstrual cycles are normal length and normally ovulatory, E2 and P4 are balanced and BMD is stable. However, clinically normal cycles commonly have ovulatory disturbances (anovulation, short luteal phases) and low P4 levels; these are more frequent in teen and perimenopausal women and increased energy insufficiency, emotional/social/economic threats and illness. Meta-analysis shows that almost 1%/year spinal BMD loss occurs in those with greater than median (∼31%) of ovulatory disturbed cycles. Prevention of osteoporosis and fragility fractures requires the reversal of stressors, detection and treatment of teen-to-perimenopausal recurrent cycle/ovulatory disturbances with cyclic oral micronized progesterone. Low 'Peak Perimenopausal BMD' is likely the primary risk for fragility fractures in later life. Progesterone plus estradiol or other antiresorptive therapies adds 0.68%/year and may be a highly effective osteoporosis treatment. Randomized controlled trials are still needed to confirm progesterone's important role in women's bone formation.
Menstrual CycleDietary Minerals and Ovulatory FunctionMicronutrient InfluenceDietary Mineral Deficiency
Although minerals are linked to several reproductive outcomes, it is unknown whether dietary minerals are associated with ovulatory function. We hypothesised that low intakes of minerals would be associated with an increased risk of anovulation. We investigated associations between dietary mineral intake and both reproductive hormones and anovulation in healthy women in the BioCycle Study, which prospectively followed up 259 regularly menstruating women aged 18-44 years who were not taking mineral supplements for two menstrual cycles. Intakes of ten selected minerals were assessed through 24-h dietary recalls at up to four times per cycle in each participant. Oestradiol, progesterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex-hormone-binding globulin and testosterone were measured in serum up to eight times per cycle. We used weighted linear mixed models to evaluate associations between minerals and hormones and generalised linear models for risk of anovulation. Compared with Na intake ≥1500 mg, Na intake <1500 mg was associated with higher levels of FSH (21·3 %; 95 % CI 7·5, 36·9) and LH (36·8 %; 95 % CI 16·5, 60·5) and lower levels of progesterone (-36·9 %; 95 % CI -56·5, -8·5). Na intake <1500 mg (risk ratio (RR) 2·70; 95 % CI 1·00, 7·31) and Mn intake <1·8 mg (RR 2·00; 95 % CI 1·02, 3·94) were associated with an increased risk of anovulation, compared with higher intakes, respectively. Other measured dietary minerals were not associated with ovulatory function. As essential minerals are mostly obtained via diet, our results comparing insufficient levels with sufficient levels highlight the need for future research on dietary nutrients and their associations with ovulatory cycles.
Reproductive EndocrinologyHormonal Predictors of DeficiencyPreovulatory-Luteal Phase RelationshipsCycle Hormone Pattern Analysis
Open Access
Explore potential relationships between preovulatory, periovulatory, and luteal-phase characteristics in normally cycling women.
Observational study.
Eight European natural family planning clinics. Patient(s): Ninety-nine women contributing 266 menstrual cycles. Intervention(s): The participants collected first morning urine samples that were analyzed for estrone-3 glucuronide (E1G), pregnanediol-3alpha-glucuronide (PDG), follicle stimulating hormone (FSH), and luteinizing hormone (LH). The participants underwent serial ovarian ultrasound examinations. Main Outcome Measure(s): Four short luteal phase, low mid-luteal phase PDG level (mPDG), normal then low luteal PDG level, low then normal luteal PDG level. A long preovulatory phase was a predictor of short luteal phase, with or without adjustment for other variables. A high periovulatory PDG level was a predictor for short luteal phase as well as normal then low luteal PDG level. A low periovulatory PDG level predicted low mPDG and low then normal luteal PDG level, with or without adjustment for other variables. A small maximum follicle predicted normal then low luteal PDG level, with or without adjustment for other variables. The relationship between small maximum follicle size and short luteal phase or small maximum follicle size and low mPDG was no longer present when the regression was adjusted for certain characteristics. A younger age at menarche and a high body mass index were both predictors of low mPDG. Luteal phase abnormalities exist over a spectrum where some ovulation disorders may exist as deviations from the normal ovulatory process.This study confirms the negative impact of a small follicle size on the quality of the luteal phase. The occurrence of normal then low luteal PDG level is confirmed as a potential sign of luteal phase abnormality.
Reproductive EndocrinologySteroid Hormones and BrainMood and Cognitive FunctionHormonal Transition
Open Access
Sex hormones significantly impact women's lives. Throughout the different stages of life, from menarche to menopause and all stages in between, women experience dramatic fluctuations in the levels of progesterone and estradiol, among other hormones. These fluctuations affect the body as a whole, including the central nervous system (CNS). In the CNS, sex hormones act via steroid receptors. They also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Additionally, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities. This review emphasizes the benefits a proper hormonal balance during the different stages of life has in the CNS. To achieve this goal, it is essential that hormone levels are evaluated considering a woman's age and ovulatory status, so that a correct diagnosis and treatment can be made. Knowledge of steroid hormone activity in the brain will give women and health providers an important tool for improving their health and well-being.
Bone HealthPremenopausal BMD DeterminantsBone Density ConsequencesCaMos Reproductive Data
Open Access
Goshtasebi A et al., 2018·Int J Environ Res Public Health
Amenorrhea is important for women's bone health. However, few have reported reproductive, anthropometric (body mass index [BMI], height) and bone health (areal bone mineral density [BMD], prevalent fractures) in a population-based study. The purposes of this cross-sectional study of women in the randomly-selected Canadian Multicentre Osteoporosis Study (CaMos) (1) to describe reproductive, demographic, anthropometric and lifestyle variables; and (2) in menstruating women, to relate reproductive and other variables to BMD at the lumbar spine (L1-4, LS), femoral neck (FN) and total hip (TH) sites and to prevalent fragility fractures. This study describes the reproductive characteristics of 1532 women aged 30⁻60 years. BMD relationships with reproductive and other variables were described in the 499 menstruating women. Mean menarche age was 12.8 years, 96% of women were parous and 95% had used combined hormonal contraceptives (CHC). Infertility was reported by 9%, androgen excess by 13%, amenorrhea by 8% and nulliparity by 4%. LS BMD was negatively associated with amenorrhea and androgen excess and positively related to current BMI and height. A later age at menarche negatively related to FN BMD. BMI and height were strongly related to BMD at all sites. Prevalent fragility fractures were significantly associated with quartiles of both LS and TH BMD.
Menstrual CycleMolimina Diagnostic UtilityPremenstrual Symptoms and OvulationDetection
Open Access
Jerilynn C Prior et al., 2018·Int J Environ Res Public Health
Approximately 33% of normal-length (21⁻35 days) cycles have subclinical ovulatory disturbances and lack sufficient progesterone, although their normal length ensures enough estrogen. Subclinical ovulatory disturbances are related to significant premenopausal spine bone loss (-0.86%/year). Molimina, non-distressing premenstrual experiences, may detect ovulation within normal-length cycles. This prospective study assessed the relationship between molimina and ovulation. After 1-cycle of daily diary and first morning urine collections, women answered the Molimina Question (MQ): "Can you tell by the way you feel that your period is coming?" and were invited to share (a) predictive premenstrual experience(s). A 3-fold increase in follicular-luteal pregnanediol levels confirmed ovulation. In 610 spontaneously menstruating women (not on hormonal contraception, mean age 31.5 ± 5.3, menarche age 12.7 ± 1.5, cycle length [CL] 29 days, MQ positive in 89%), reported premenstrual experiences which included negative moods (62%), cramps (48%), bloating (39%), and front (26%) or axillary (25%) breast tenderness. Of 432 women with pregnanediol-documented cycles, 398 (92%) were ovulatory (CL: 29 ± 5) and 34 (8%) had ovulatory disturbances (CL: 32 ± 14). Women with/without ovulatory cycles were similar in parity, body mass index, smoking, dietary restraint and the MQ; ovulatory-disturbed cycles were longer. Molimina did not confirm ovulation. A non-invasive, inexpensive ovulation indicator is needed to prevent osteoporosis.
PregnancyHair Dye and Birth WeightChemical Exposure InteractionEnvironmental Reproductive Risk
Open Access
Limited evidences were reported about the risk of pre-pregnancy hair dye use or irregular menstruation with abnormal birth weight during pregnancy, and their joint effects were also unknown. The aim of our study was to explore whether the pre-pregnancy exposure of hair dye and irregular menstruation were associated with the risk of abnormal birth weight. We conducted a nested case-control study from a prospective cohort of 6203 pregnant women. Low birth weight study included 315 mother-infant pairs (105 LBW cases and 210 matched controls), and macrosomia study included 381 mother-infant pairs (127 macrosomia cases and 254 matched controls). Meanwhile, lifestyle information including hair dying custom and menstrual history were collected by face-to-face questionnaires and birth outcomes were extracted from the medical records. The logistic regressions models were used to analyze the join effect of irregular menstruation and hair dye use. Pre-pregnancy hair dye use was associated with increased risk of LBW (adjusted OR = 1.71, 95% CI: 1.01-2.92, P = 0.048). Irregular menstruation had high risk of LBW (adjusted OR = 2.79, 95% CI: 1.53-5.09, P = 0.001) and macrosomia (adjusted OR = 1.93, 95% CI: 1.09-3.44, P = 0.023). Additionally, in the LBW study, women who used hair dye with pre-pregnancy BMI < 18.5 kg/m(2) had higher OR than those with only one risk factor (3.07 vs 2.53, P (trend) = 0.015), and women with both hair dye use and irregular menstruation also had higher risk than those with only one factor (4.53 vs 2.07, P (trend) = 0.05). Moreover, in macrosomia study, women with irregular menstruation and pre-pregnancy BMI ≥ 24 kg/m(2) had higher risk than those with one factor (13.31 vs 2.09, P (trend) = 0.001). Our study showed that either pre-pregnancy hair dye use or irregular menstruation was associated with abnormal birth weight, especially, their joint effects could furthermore increase the risk of low birth weight infants when these two factors existed simultaneously.
Contraception/ComparisonArterial StiffnessCycle Phase and Arterial ComplianceSex Differences in Vascular Health
Priest SE et al., 2018·Am J Physiol Heart Circ Physiol
Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, β-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. β-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). β-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (β-stiffness: r = 0.003, P = 0.99; r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence β-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.
Many women experience emotional and physical symptoms around the time of ovulation and more so before menstruation interfering with their daily normal life also known as premenstrual syndrome (PMS). Recent observational data suggest that supplementation with Lipogen's phosphatidylserine (PS) and phosphatidic acid (PA) complex (PAS) alleviates these PMS symptoms. The aim of this study was to confirm these observations on the effects of PAS on PMS symptom severity within a controlled clinical trial setting. Forty women aged 18-45 years with a diagnosis of PMS were assigned to either take PAS (containing 400 mg PS & 400 mg PA per day) or a matching placebo. The study comprised 5 on-site visits including 1 baseline menstrual cycle followed by 3 treatment cycles. Treatment intake was controlled for by using an electronic device, the Medication Event Monitoring System (MEMS(®)). Primary outcome of the study was the PMS symptoms severity as assessed by using the Daily Record of Severity of Problems (DRSP). Further, SIPS questionnaire (a German version of the Premenstrual Symptoms Screening Tool (PSST)), salivary hormone levels (cortisol awakening response (CAR) and evening cortisol levels) as well as serum levels (cortisol, estradiol, progesterone and corticosteroid binding globulin (CBG)) were assessed. PMS symptoms as assessed by the DRSP Total score showed a significantly better improvement (p = 0.001) over a 3 cycles PAS intake as compared to placebo. In addition, PAS treated women reported a greater improvement in physical (p = 0.002) and depressive symptoms (p = 0.068). They also reported a lower reduction of productivity (p = 0.052) and a stronger decrease in interference with relationships with others (p = 0.099) compared to the placebo group. No other DRSP scale or item showed significant results. Likewise, the reduction in the number of subjects fulfilling PMS or premenstrual dysphoric disorder (PMDD) criteria as classified by the SIPS did not differ between the PAS and the placebo group. For the biomarkers, the salivary cortisol percentage increase of the CAR was significantly less pronounced in the follicular phase of cycle 4 than in the follicular phase of cycle 1 for subjects taking PAS when compared to subjects taking placebo (p = 0.018). Furthermore, the change of serum cortisol levels between visit 1 and visit 5 differed significantly between groups (p = 0.043). While serum cortisol levels of PAS treated females slightly decreased between visit 1 and visit 5, cortisol levels of females treated with placebo increased. For all other biomarkers, no treatment effects were observed over the 4 cycles study period. Overall, this study confirms that a daily intake of PAS, containing 400 mg PS and 400 mg PA, can be considered as safe. Results substantiate the efficacy of PAS in reducing symptoms of PMS. In view of the recent inclusion of severe PMS symptoms (PMDD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the positive results of this clinical study merits consideration of developing the PAS complex as a botanical drug for treatment of PMDD. The study is registered at Deutsches Register Klinischer Studien with the registration number DRKS00009005.
InfertilityCRP and FecundabilityInflammation-Mediated AnovulationEAGeR Trial Inflammation Analysis
To assess systemic inflammation in relation to fecundability and anovulation.
Prospective cohort study among participants in the Effects of Aspirin in Gestation and Reproduction trial who were assigned to the placebo.
Academic medical centers. PATIENT(S): Healthy eumenorrheic women (n = 572), 18-40 years of age, with one or two pregnancy losses, attempting spontaneous pregnancy. INTERVENTION(S): Baseline serum high-sensitivity C-reactive protein (hsCRP) values <10 mg/L were categorized into tertiles. MAIN OUTCOME MEASURE(S): Discrete Cox proportional hazards models estimated the fecundability odds ratio (FOR) and 95% confidence interval (CI) and adjusted for potential confounders. Log-binomial regression estimated the risk ratio (RR) and 95% CI of anovulation. The algorithm to define anovulation used data on urinary concentrations of hCG, pregnanediol-3-glucuronide, and LH as well as fertility monitor readings. RESULT(S): Higher hsCRP was associated with reduced fecundability but not with an increased risk of anovulation. CONCLUSION(S): Among healthy women attempting pregnancy after one or two pregnancy losses, we found preliminary evidence that systemic inflammation is associated with reduced fecundability, but not independently from adiposity. Sporadic anovulation did not appear to drive this association. Trial ClinicalTrials.gov: NCT00467363.
Body LiteracyWomen's Lifespan HealthHealth Indicator Beyond FertilityLifespan Hormonal Health
The concept of the ovarian continuum can be understood as a process that occurs during a woman's lifetime and begins during intrauterine life with fertilization. Women start their reproductive years with approximately five hundred thousand follicles containing oocytes, of which only around five hundred will be released during ovulation. Ovulation has been recognized as an event linked with reproduction; however, recent evidence supports the role of ovulation as a sign of health. The use of biomarkers that help women recognize ovulation enables them to identify their health status. This knowledge helps medical healthcare providers in the prevention, diagnosis, and treatment of different pathologies related with endocrine disorders, gynecological abnormalities, autoimmune, genetic, and neoplastic diseases, as well as pregnancy-related issues. The knowledge of the ovarian continuum and the use of biomarkers to recognize ovulation should be considered a powerful tool for women and medical professionals.
The ovarian continuum is a process that occurs during a woman's lifetime. It begins during intrauterine life with fertilization and ends with menopause. This process can be greatly affected by different conditions such as changes in hormonal levels and illnesses. Therefore, understanding and promoting the knowledge and use of biomarkers of ovulation in women is a key aspect to consider when evaluating their health status. The knowledge and education about the ovarian continuum should be taken into account as a powerful tool for women and medical professionals.
Fertility AwarenessSelf-Tracking App Ovulation AnalysisApp-Based Population DataMobile App Menstrual Cycle Protocols
Open Access
There are many mobile phone apps aimed at helping women map their ovulation and menstrual cycles and facilitating successful conception (or avoiding pregnancy). These apps usually ask users to input various biological features and have accumulated the menstrual cycle data of a vast number of women. The purpose of our study was to clarify how the data obtained from a self-tracking health app for female mobile phone users can be used to improve the accuracy of prediction of the date of next ovulation. Using the data of 7043 women who had reliable menstrual and ovulation records out of 8,000,000 users of a mobile phone app of a health care service, we analyzed the relationship between the menstrual cycle length, follicular phase length, and luteal phase length. Then we fitted a linear function to the relationship between the length of the menstrual cycle and timing of ovulation and compared it with the existing calendar-based methods. The correlation between the length of the menstrual cycle and the length of the follicular phase was stronger than the correlation between the length of the menstrual cycle and the length of the luteal phase, and there was a positive correlation between the lengths of past and future menstrual cycles. A strong positive correlation was also found between the mean length of past cycles and the length of the follicular phase. The correlation between the mean cycle length and the luteal phase length was also statistically significant. In most of the subjects, our method (ie, the calendar-based method based on the optimized function) outperformed the Ogino method of predicting the next ovulation date. Our method also outperformed the ovulation date prediction method that assumes the middle day of a mean menstrual cycle as the date of the next ovulation. The large number of subjects allowed us to capture the relationships between the lengths of the menstrual cycle, follicular phase, and luteal phase in more detail than previous studies. We then demonstrated how the present calendar methods could be improved by the better grouping of women. This study suggested that even without integrating various biological metrics, the dataset collected by a self-tracking app can be used to develop formulas that predict the ovulation day when the data are aggregated. Because the method that we developed requires data only on the first day of menstruation, it would be the best option for couples during the early stages of their attempt to have a baby or for those who want to avoid the cost associated with other methods. Moreover, the result will be the baseline for more advanced methods that integrate other biological metrics.
Fertility AwarenessWrist Wearable Temperature MonitoringContinuous Temperature TrackingOvulation Detection Validation
Open Access
Core and peripheral body temperatures are affected by changes in reproductive hormones during the menstrual cycle. Women worldwide use the basal body temperature (BBT) method to aid and prevent conception. However, prior research suggests that taking one's daily temperature can prove inconvenient and subject to environmental factors. We investigate whether a more automatic, non-invasive temperature measurement system can detect changes in temperature across the menstrual cycle. We examined how wrist skin temperature (WST), measured with wearable sensors, correlates with urinary tests of ovulation and may serve as a new method of fertility tracking. One hundred and thirty-six eumenorrheic, non-pregnant women participated in an observational study. Participants wore WST biosensors during sleep and reported their daily activities. An at-home luteinizing hormone (LH) test was used to confirm ovulation. WST was recorded across 437 cycles (mean cycles/participant = 3.21, S.D. = 2.25). We tested the relationship between the fertile window and WST temperature shifts, using the BBT three-over-six rule. A sustained 3-day temperature shift was observed in 357/437 cycles (82%), with the lowest cycle temperature occurring in the fertile window 41% of the time. Most temporal shifts (307/357, 86%) occurred on ovulation day (OV) or later. The average early-luteal phase temperature was 0.33°C higher than in the fertile window. Menstrual cycle changes in WST were impervious to lifestyle factors, like having sex, alcohol, or eating prior to bed, that, in prior work, have been shown to obfuscate BBT readings. Although currently costlier than BBT, the present study suggests that WST could be a promising, convenient parameter for future multiparameter fertility awareness methods.
Bone HealthPeak Bone Mass and Ovulation ProtectionBone Accrual ImpactProgesterone Bone Formation
Open Access
How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. Main Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
Malaria is prevalent in Nigeria, and artemether + lumefantrine (artemisinin-based combination therapy [ACT]) is drug of choice in treatment of uncomplicated cases. ACT is contraindicated in early pregnancy. They release-free radicals that can compromise female fertility. Infertility and its associated complications such as miscarriages, abnormal gestation, and unstable marriages seem to be on the increase. This study aims at evaluating the effect of ACT on female fertility. The significance of this research is to draw the attention of fertility care givers to this possible cause of infertility and fertility challenges. Creighton Model FertilityCare System and NaProTECHNOLOGY are simply technologies that can be used to assess female fertility. They are used in this study to assess the effect of ACT administered at different stages of menstrual cycles of three selected fertile adult females. The results are interpreted on the background of standard Creighton model chart. This study has shown that ACT has a significant fertility deteriorating effect on the women. It caused ovulation defect and diagnosed as partial rupture syndrome in the very cycle of use and in the first cycle after use. It also significantly reduced cervical mucus production and significantly reduced luteal phase progesterone production with an associated significant increase of luteal phase estrogen production. ACT use as antimalarial may be a possible cause of infertility and fertility challenges in women.
Fertility AwarenessMenstrual CycleDiagnostics
Open Access
An affordable, user-friendly fertility-monitoring tool remains an unmet need. We examine in this study the correlation between pulse rate (PR) and the menstrual phases using wrist-worn PR sensors. 91 healthy, non-pregnant women, between 22-42 years old, were recruited for a prospective-observational clinical trial. Participants measured PR during sleep using wrist-worn bracelets with photoplethysmographic sensors. Ovulation day was estimated with "Clearblue Digital-Ovulation-urine test". Potential behavioral and nutritional confounders were collected daily. 274 ovulatory cycles were recorded from 91 eligible women, with a mean cycle length of 27.3 days (±2.7). We observed a significant increase in PR during the fertile window compared to the menstrual phase (2.1 beat-per-minute, p < 0.01). Moreover, PR during the mid-luteal phase was also significantly elevated compared to the fertile window (1.8 beat-per-minute, p < 0.01), and the menstrual phase (3.8 beat-per-minute, p < 0.01). PR increase in the ovulatory and mid-luteal phase was robust to adjustment for the collected confounders. There is a significant increase of the fertile-window PR (collected during sleep) compared to the menstrual phase. The aforementioned association was robust to the inter- and intra-person variability of menstrual-cycle length, behavioral, and nutritional profiles. Hence, PR monitoring using wearable sensors could be used as one parameter within a multi-parameter fertility awareness-based method.
Menstrual CycleFunctional Hypothalamic AmenorrheaHypothalamic CausesAmenorrhea-Related Bone Loss
The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.
To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.
The topic of how the menstrual cycle is a vital sign which could signal pathophysiologic process has received considerable attention in the past decade. The current recommendations of various academic groups will be discussed as well as the FertilityTMM Care method of charting and the Naprotechnology approach to evaluating abnormalities of the menstrual cycle. Two clinical scenarios seen in adolescent medicine, PCOS and AUB, will be analyzed looking at the pathophysiology of these clinical scenarios and their management. The approach will be one that conducts an evaluation to try to find the underlying problem and aims to restore the normal physiology of the menstrual cycle.
The American Academy of Pediatrics, the American College of Obstetrics and Gynecology and the New York Academy of Sciences have published academic statements during the past ten years emphasizing the need for providers to teach patients how to chart and the important clinical ramifications of using this charting as a vital sign. In 2006 the American Academy of Pediatrics published in the Pediatrics Journal a "Menstruation Using the Menstrual Sign as a Vital Sign." In 2015, the American College of Obstetrics and Gynecology published a Committee Opinion emphasizing the need to teach women the charting of their menses and the important pathophysiologic process that could be detected with the charting.
Menstrual CyclePMS Diagnosis and TreatmentPMDD ManagementLuteal Phase Symptoms
Premenstrual disorders affect up to 12% of women. The subspecialties of psychiatry and gynecology have developed overlapping but distinct diagnoses that qualify as a premenstrual disorder; these include premenstrual syndrome and premenstrual dysphoric disorder. These conditions encompass psychological and physical symptoms that cause significant impairment during the luteal phase of the menstrual cycle, but resolve shortly after menstruation. Patientdirected prospective recording of symptoms is helpful to establish the cyclical nature of symptoms that differentiate premenstrual syndrome and premenstrual dysphoric disorder from other psychiatric and physical disorders. Physicians should tailor therapy to achieve the greatest functional improvement possible for their patients. Select serotonergic antidepressants are first-line treatments. They can be used continuously or only during the luteal phase. Oral contraceptives and calcium supplements may also be used. There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy.
Although a fragility fracture family history (FFFH+) has repeatedly been shown to be associated with lower bone mineral density (BMD), its relationship to human BMD change is unclear. Animal research, however, documented that different purebred strains within rodent species have wide ranges in rates of bone acquisition during growth as well as in change post-ovariectomy. Our objective was to compare the rate of premenopausal spinal trabecular BMD change between women with and without a general family history of fragility fracture. Participants and methodsHealthy premenopausal community women participated in prospective observational studies at two academic Vancouver, Canada (n = 66) and Munich, Germany (n = 20). The primary outcome was annual spinal BMD change, measured by quantitative computed tomography (QCT). The two studies employed similar methodologies for assessing QCT and FFFH. Volunteer community participants had a mean age of 36.0 (SD, 6.9) years, body mass index 22.5 (2.4) and baseline QCT of 150.2 (22.5) mg/cm3 trabecular bone. The rates of BMD change - 3.5 (5.1)/year Vancouver, - 2.0 (3.4)/year Munich (95 % - 3.9, 0.9). Over a third of the women (31 of the 86, 36 %) reported FFFH+. Those with and without a FFFH were similar in demographics, nutrition, exercise, menstrual cycle and luteal phase lengths and physiological measures (serum calcium, osteocalcin and estradiol). However, women with FFFH+ lost FFFH+, - 4.9 (5.0), FFFH-, - 2.2 (4.4) mg/cm3/year (95 % CI diff - 0.7 to - 4.8, F1.83 = 7.88, p = 0.006). FFFH+ explained 7.7 % of the variance in QCT volumetric trabecular spinal bone change/year in these healthy premenopausal women. This study shows for the first time that having a history of a fragility fracture in a family member is associated with a greater rate of premenopausal spinal trabecular bone loss.
The aim of this study was to evaluate the association between menstrual cycle characteristics in early life and adulthood and fecundability. Pregnancy Study Online (PRESTO) is an Internet-based preconception cohort study of pregnancy planners from the United States and Canada. During the preconception period, we enrolled 2189 female pregnancy planners aged 21-45 years who had been attempting conception for ≤6 cycles. Women self-reported menstrual cycle characteristics via an online baseline questionnaire, and pregnancy status was ascertained through bimonthly follow-up questionnaires. Proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Compared with usual menstrual cycle lengths of 27-29 days, cycle lengths of <25 (FR = 0.81, 95% CI: 0.54-1.22) and 25-26 days (FR = 0.92, 95% CI: 0.75-1.14) were associated with reduced fecundability. Compared with women who reached menarche at the age of 12-13 years, those who reached menarche at <12 years had reduced fecundability (FR = 0.87, 95% CI: 0.76-0.99). Women whose cycles never regularized after menarche (FR = 0.93, 95% CI: 0.81-1.06) had slightly reduced fecundability compared with women whose cycles regularized within 2 years of menarche. Bleed length and heaviness of bleeding were not appreciably associated with fecundability. Menstrual cycle characteristics, specifically cycle length and age at menarche, may act as markers of fertility potential among pregnancy planners.
Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.
Johnson KA et al., 2016·Pharmacoepidemiol Drug Saf
The purpose of this study is to characterize the patterns of medication intake in healthy, reproductive-age women not using hormonal contraception. Two hundered fifty-nine healthy, premenopausal women (18-44 years of age) enrolled in the BioCycle Study (2005-2007) were followed over two menstrual cycles. Women were excluded if they were currently using oral contraceptives or other chronic medications. Over-the-counter and prescription medication use among participants was evaluated daily throughout the study via a diary assessing type of medication, dosage, units, and frequency. Medications were categorized as allergy, antibiotics, central nervous system (CNS), cold and cough, gastrointestinal, musculoskeletal, and pain medication based on primary active ingredient. Medication use within each category was assessed across standardized 28-day cycles to evaluate differences in use across cycle phases (i.e., early, middle, and late). Medication use was reported by 73% of participants. The most and least frequently used medications, respectively, were pain (69%) and musculoskeletal medications (1%). Pain, CNS, and antibiotic medication use varied significantly across the cycle, with pain and CNS medication more frequently reported during menses and antibiotics more frequently during the luteal phase. Allergy, cold and cough, gastrointestinal, and musculoskeletal medication use did not vary across the cycle. Patterns of medication use among reproductive age women vary across the menstrual cycle for certain types of medications, particularly in pain (e.g., Ibuprofen), antibiotics (e,g, Amoxicillin), and CNS (e.g., Adderall) medications. Future studies involving use of these types of medication in premenopausal women may need to consider the relationship of their use to the menstrual cycle.
Non-sexually active adolescents are currently treated with combined hormonal contraception (CHC) for common experiences (e.g., cramps, acne) and serious problems (e.g., hypothalamic amenorrhea, heavy menstrual flow) for which it is not indicated, is ineffective, and is likely to cause negative long-term reproductive and bone effects. The importance to a woman's health of adolescent reproductive/bone maturation is described. Evidence is also provided to show the association of CHC use by adolescents with subfertility and inadequate bone growth. Ibuprofen is safer and more effective for cramps and heavy flow; cyclic progesterone builds bone in amenorrhea. In summary, a common, unscientific medical "habit" is compromising long-term reproductive and bone health in adolescents.
Contraception/ComparisonAdolescent UsePharmaceutical EthicsAdolescent Bone Density
Here I respond to Akers, Dhar, and Shah's (2016), Stubbs's (2016), Olshansky's (2016), and Kissling's (2016) commentaries on the article (Prior, 2016) in which I expressed concerns about the potential adverse long-term reproductive and bone health effects on normal adolescents’ maturation related to use of combined hormonal contraceptives (CHC) for contraception and/or treatment. Although Akers et al. (2016) take exception, the precautionary principle on which medical/pharmaceutical ethics is based challenges us to show that CHC is officially indicated and effective in randomized, double-blind, placebo-controlled trials with adolescents. Those who support current practices are obligated to provide young patients and their parents with evidence from large, population-based, prospective studies (or meta-analyses of longitudinal data) that adolescents who have used CHC develop the same menstrual cycle/ovulatory function, fertility, and reproductive lifespan and similar bone density and strength as peers who did not use CHC. Without this information there can be neither reproductive justice (Kissing, 2016), nor true choice. Why is this minimal, expected scientific data not available? It is likely that authors of practice guidelines for adolescent CHC contraceptive use and who advocate its “non-contraceptive benefits” have pro-estrogen cultural biases or conflicts of interests due to pharmaceutical industry connections. I agree with Olshansky (2016) that we should listen to adolescents’ concerns and use evidence-based and safe treatments for milder heavy bleeding and cramps. For heterosexual adolescents seeking contraception, we can suggest and explain the use of safer, yet effective, nonhormonal strategies, such as the copper IUD or a barrier plus full-dose vaginal spermicide.
Journal of Pharmaceutical Research International (Issn: 2456-9119) is dedicated to publish high quality papers in all areas of pharmaceutical Science including pharmaceutical drugs, community pharmacy, hospital pharmacy, clinical pharmacy, compounding pharmacy, consultant pharmacy, internet pharmacy, veterinary pharmacy, nuclear pharmacy, military pharmacy, pharmacy informatics, pharmaceutics, medicinal chemistry, pharmacognosy, pharmacotherapy, pharmacodynamics, pharmacokinetics, clinical pharmacology, neuropharmacology, psychopharmacology, pharmacogenetics, pharmacogenomics, pharmacoepidemiology, toxicology, theoretical pharmacology, posology, pharmacognosy, behavioral pharmacology, environmental pharmacology, medicine development and safety testing, drug legislation and safety, pharmaceutical microbiology, pharmaceutical molecular biology, pharmaceutical biotechnology. The journal also encourages the submission of useful reports of negative results. This is a quality controlled, OPEN peer reviewed, open access INTERNATIONAL journal.
Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of αto γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.
Body LiteracyMenstrual Cycle as Vital SignMenstrual EvaluationAdolescent Reference Ranges
Despite variations worldwide and within the U.S. population, median age at menarche has remained relatively stable-between 12 years and 13 years-across well-nourished populations in developed countries. Environmental factors, including socioeconomic conditions, nutrition, and access to preventive health care, may influence the timing and progression of puberty. A number of medical conditions can cause abnormal uterine bleeding, characterized by unpredictable timing and variable amount of flow. Clinicians should educate girls and their caretakers (eg, parents or guardians) about what to expect of a first menstrual period and the range for normal cycle length of subsequent menses. Identification of abnormal menstrual patterns in adolescence may improve early identification of potential health concerns for adulthood. It is important for clinicians to have an understanding of the menstrual patterns of adolescent girls, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate the adolescent girl patient. By including an evaluation of the menstrual cycle as an additional vital sign, clinicians reinforce its importance in assessing overall health status for patients and caretakers.
Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case-control studies. This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self-reported and ultrasound examination-based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self-reported and ultrasound examination-based gestational age were compared with women with a deviation of 7 days or less. Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001). Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome.
Although habitual low-to-moderate alcohol intake has been linked with reduced all-cause mortality and morbidity, the effect of recent alcohol intake on female reproductive function has not been clearly established. We assessed the relation between acute alcohol consumption, reproductive hormones, and markers of menstrual cycle dysfunction including sporadic anovulation, irregular cycle length, luteal phase deficiency, long menses, and heavy blood loss.
A total of 259 healthy, premenopausal women from Western New York were followed for ≤2 menstrual cycles (2005-2007) and provided fasting blood specimens during ≤8 visits/cycle and four 24-h dietary recalls/cycle. Linear mixed models were used to estimate associations between previous day's alcohol intake and hormone concentrations, whereas Poisson regression was used to assess RR of cycle-average alcohol intake and menstrual cycle function. For every alcoholic drink consumed, the geometric mean total and free estradiol, total and free testosterone, and luteinizing hormone were higher by 5.26% (95% CI: 1.27%, 9.41%), 5.82% (95% CI: 1.81%, 9.99%), 1.56% (95% CI: 0.23%, 2.90%), 1.42% (95% CI: 0.02%, 2.84%), and 6.18% (95% CI: 2.02%, 10.52%), respectively, after adjustment for age, race, percentage of body fat, perceived stress, pain-medication use, sexual activity, caffeine, and sleep. Binge compared with nonbinge drinking (defined as reporting ≥4 compared with <4 drinks/d, respectively) was associated with 64.35% (95% CI: 18.09%, 128.71%) and 63.53% (95% CI: 17.41%, 127.73%) higher total and free estradiol. No statistically significant associations were shown between cycle-average alcohol intake and menstrual cycle function. Although recent moderate alcohol intake does not appear to have adverse short-term effects on menstrual cycle function, including sporadic anovulation, potential protective and deleterious long-term effects of alterations in reproductive hormones on other chronic diseases warrant additional investigation.
Menstrual CycleEndocrine CausesProlactin and Thyroid ScreeningMenstrual Dysfunction
To evaluate the prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding (AUB) compared with matched controls. In 2013-2014, an observational study of women with AUB (group A) and women with regular menstruation (group B) was undertaken at one center in Egypt and one in the United Arab Emirates. Eligible women were aged 20-35 years and were not obese. Participants underwent clinical examinations, vaginal ultrasonography, office hysteroscopy (in selected cases), and measurement of hormone levels. Hyperprolactinemia was present in 17 (16.2%) of 105 patients in group A and 4 (3.2%) of 125 patients in group B (P=0.009). In group A, a high thyroid-stimulating hormone (TSH) level was observed in 8 (7.6%) patients and low levels of free triiodothyronine/thyroxine were found in 5 (4.8%) patients, compared with 2 (1.6%) patients and 1 (0.8%) patient in group B (P=0.012 and P=0.008, respectively). Polymenorrhea was the most frequent presentation of AUB (n=60 [57.1%]). Five (29.4%) patients with hyperprolactinemia had galactorrhea. In group A, 8 (47.1%) patients with a high TSH had hyperprolactinemia, whereas 1 (1.1%) patient with a high TSH had a normal prolactin value (P=0.008). Screening by evaluating prolactin and thyroid hormone levels is recommended for all patients with AUB, even in the absence of galactorrhea.
Ovulatory menstrual cycles are essential for women's fertility and needed to prevent bone loss. There is a medical/cultural expectation that clinically normal menstrual cycles are inevitably ovulatory. Currently within the general population it is unknown the proportion of regular, normal-length menstrual cycles that are ovulatory. Thus, the objective of this study was to determine the population point prevalence of ovulation in premenopausal, normally menstruating women. The null hypothesis was that such cycles are ovulatory. This is a single-cycle, cross-sectional, population-based study-a sub-study of the HUNT3 health study in the semi-rural county (Nord Trøndelag) in mid-Norway. Participants included >3,700 spontaneously (no hormonal contraception) menstruating women, primarily Caucasian, ages 20-49.9 from that county. Participation rate was 51.9%. All reported the date previous flow started. A single, random serum progesterone level was considered ovulatory if ≥9.54 nmol/L on cycle days 14 to -3 days before usual cycle length (CL). Ovulation was assessed in 3,168 women mean age 41.7 (interquartile range, [IQR] 36.8 to 45.5), cycle length 28 days (d) (IQR 28 to 28) and body mass index (BMI) 26.3 kg/m2 (95% CI 26.1 to 26.4). Parity was 95.6%, 30% smoked, 61.3% exercised regularly and 18% were obese. 1,545 women with a serum progesterone level on cycle days 14 to -3 were presumed to be in the luteal phase. Of these, 63.3% of women had an ovulatory cycle (n = 978) and 37% (n = 567) were anovulatory. Women with/ without ovulation did not differ in age, BMI, cycle day, menarche age, cigarette use, physical activity, % obesity or self-reported health. There were minimal differences in parity (96.7% vs. 94.5%, P = 0.04) and major differences in progesterone level (24.5 vs. 3.8 nmol/L, P = 0.001). Anovulation in a random population occurs in over a third of clinically normal menstrual cycles.
The onset of puberty has been a fascinating topic for reproductive endocrinologists for decades; however, its underlying physiological mechanisms have remained elusive until recently. The discovery and understanding of the effects exerted by the peptide hormone kisspeptin have shed light on this research area. This review is aimed to discuss the functions of kisspeptin, with special focus on its role in the onset of puberty and in the ovulatory mechanism. The points under discussion are (1) the characteristics of kisspeptin and its receptor, (2) the relevance of this hormone and its interaction with leptin in the onset of puberty, (3) the role of kisspeptin in the ovulatory mechanism based on its differential expression at hypothalamic nuclei, which is modulated by sex steroid hormones, and (4) the clinical relevance of kisspeptin and its antagonists in new therapeutic strategies for the treatment of various reproductive pathologies. All of this explains the revolution that kisspeptin has caused among researchers working in the field of gynecological endocrinology and reproductive biology.
Menstrual CycleReproductive Endocrinology
Open Access
Does use of commonly used over-the-counter (OTC) pain medication affect reproductive hormones and ovulatory function in premenopausal women? Few associations were found between analgesic medication use and reproductive hormones, but use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for potential confounders. Analgesic medications are the most commonly used OTC drugs among women, but their potential effects on reproductive function are unclear. STUDY DESIGN, SIZE, The BioCycle Study was a prospective, observational cohort study (2005-2007) which followed 259 women for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS, SETTING, Two hundred and fifty-nine healthy, premenopausal women not using hormonal contraception and living in western New York state. Study visits took place at the University at Buffalo. Main During study participation, 68% (n = 175) of women indicated OTC analgesic use. Among users, 45% used ibuprofen, 33% acetaminophen, 10% aspirin and 10% naproxen. Analgesic use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for age, race, body mass index, perceived stress level and alcohol consumption (OR 0.36 [0.17, 0.75]). Results remained unchanged after controlling for potential confounding by indication by adjusting for 'healthy' cycle indicators such as amount of blood loss and menstrual pain during the preceding menstruation. Moreover, luteal progesterone was higher (% difference = 14.0, -1.6-32.1, P = 0.08 adjusted) in cycles with follicular phase analgesic use, but no associations were observed with estradiol, LH or FSH. LIMITATIONS, Self-report daily diaries are not validated measures of medication usage, which could lead to some classification error of medication use. We were also limited in our evaluation of aspirin and naproxen which were used by few women. The observed associations between follicular phase analgesic use and higher progesterone and a lower probability of sporadic anovulation indicate that OTC pain medication use is likely not harmful to reproduction function, and certain medications possibly improve ovulatory function. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). The authors have no conflicts of interest to disclose.
Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest fiber (per g), 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.
Ovulation occurs on 1 day during each menstrual cycle (even if multiple follicles are involved), and the several days preceding ovulation are when intercourse is most likely to result in pregnancy. Collectively, the potentially fertile days up to and including the day of ovulation are called the “fertile window” (1). Since the 1930s, several biomarkers of the fertile window have been investigated for the purposes of empowering women and couples seeking to use fertility-awareness based methods or natural family planning to avoid pregnancy, as well as to expand understanding of human reproductive physiology.
To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression. A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 ± 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (<16, no depressive symptoms [92%] vs. ≥ 16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation. No significant associations were identified between depressive symptoms and reproductive hormone levels (all P > .05) or the odds of sporadic anovulation (adjusted odds ratio, 1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption. Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression.
Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women? Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women. Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation. STUDY DESIGN, SIZE, We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007. PARTICIPANTS/MATERIALS, SETTING, Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle. Main Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03). LIMITATIONS, Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential. This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare.
To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses.
Prospective cohort study.
Western New York. PATIENT(S): Two hundred fifty-nine healthy, regularly menstruating women followed for one (n=9) or two (n=250) menstrual cycles (2005-2007). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of sporadic anovulatory cycles identified using 11 previously defined algorithms that use E2, P, and LH concentrations. RESULT(S): Algorithms based on serum LH, E2, and P levels detected a prevalence of anovulation across the study period of 5.5%-12.8% (concordant classification for 91.7%-97.4% of cycles). The prevalence of anovulatory cycles varied from 3.4% to 18.6% using algorithms based on urinary LH alone or with the primary E2 metabolite, estrone-3-glucuronide, levels. CONCLUSION(S): The prevalence of anovulatory cycles among healthy women varied by algorithm. Mid-cycle LH surge urine-based algorithms used in over-the-counter fertility monitors tended to classify a higher proportion of anovulatory cycles compared with luteal-phase P serum-based algorithms. Our study demonstrates that algorithms based on the LH surge, or in conjunction with estrone-3-glucuronide, potentially estimate a higher percentage of anovulatory episodes. Addition of measurements of postovulatory serum P or urine pregnanediol may aid in detecting ovulation.
We investigated whether sexual activity was associated with reproductive function in the BioCycle Study, a prospective cohort study that followed 259 regularly menstruating women aged 18 to 44years for one (n=9) or two (n=250) menstrual cycles in 2005-2007. Women were not attempting pregnancy nor using hormonal contraceptives. History of ever having been sexually active was assessed at baseline and frequency of sexual activity, defined as vaginal-penile intercourse, was self-reported daily throughout the study. Serum concentrations of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were measured up to 8times/cycle. Sporadic anovulation was identified using peak progesterone concentration. Linear mixed models were used to estimate associations between sexual activity and reproductive hormone concentrations and generalized linear models were used to estimate associations with sporadic anovulation. Models were adjusted for age, race, body mass index, perceived stress, and alcohol consumption and accounted for repeated measures within women. Elevated concentrations of estrogen (+14.6%, P<.01), luteal progesterone (+41.0%, P<.01) and mid-cycle LH (+23.4%, P<.01), but not FSH (P=.33) or testosterone (P=.37), were observed in sexually active women compared with sexually inactive women (no prior and no study-period sexual activity); sexually active women had lower odds of sporadic anovulation (adjusted odds ratio=0.34, 95% 0.16-0.73). Among sexually active women, frequency of sexual activity was not associated with hormones or sporadic anovulation (all P>.23). Findings from our study suggest that ever having been sexually active is associated with improved reproductive function, even after controlling for factors such as age.
Hyperandrogenism is a hallmark of polycystic ovary syndrome (PCOS) in women with irregular menses, yet the relationship between androgens and ovarian dysfunction remains poorly understood in eumenorrheic women. The objective of the study was to evaluate whether sporadic anovulation was associated with higher T and anti-müllerian hormone (AMH; marker of ovarian follicle count) concentrations in eumenorrheic women.
This was a prospective cohort study from 2005 to 2007.
The study was conducted at the University of Buffalo in western New York state. A total of 259 eumenorrheic women without a self-reported history of infertility, PCOS, or other endocrine disorder participated in the study. Total T and AMH were measured five to eight times per cycle for one (n = 9) or two (n = 250) cycles per woman (n = 509 cycles) with timing of menstrual cycle phase assisted by fertility monitors. Anovulatory cycles were defined biochemically by progesterone and LH concentrations. Repeated-measures ANOVA was conducted on log-transformed data with adjustment for age. Compared with ovulatory cycles (n = 467), sporadic anovulatory cycles (n = 42) had marginally higher total and significantly higher free T [mean 23.7 ng/dL (95% confidence interval [CI] 21.4-26.3) vs 21.6 ng/dL (95% CI 20.9-22.3), P = .08, and 0.36 ng/dL (95% CI 0.33-0.40) vs 0.32 ng/dL (95% CI 0.31-0.33), P = .02, respectively] during menses and also throughout the luteal phase (P < .01 for all). Women with higher T had elevated AMH concentrations, increased reporting of a history of acne requiring medical treatment, but not increased hirsutism. Mechanisms of androgen-related ovulatory dysfunction that characterize PCOS in women with menstrual disturbances may occur across a continuum of T concentrations, including in eumenorrheic women without clinical hyperandrogenism.
Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women. We assessed the prevalence and overlap of two established short luteal phase duration less than10 days (clinical LPD) and suboptimal luteal progesterone of 5 ng/mL or less (biochemical LPD) and their relationship with reproductive hormone concentrations.
Design, Setting, We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles. Among ovulatory cycles with recorded cycle lengths (n = 463), there were 41 cycles (8.9%) with clinical LPD, 39 cycles (8.4%) with biochemical LPD, and 20 cycles (4.3%) meeting both criteria. Recurrent clinical and biochemical LPD was observed in eight (3.4%) and five (2.1%) women, respectively. Clinical and biochemical LPD were each associated with lower follicular estradiol (both P ≤ .001) and luteal estradiol (P = .03 and P = .02, respectively) after adjusting for age, race, and percentage body fat. Clinical, but not biochemical, LPD was associated with lower LH and FSH across all phases of the cycle (P ≤ .001). Clinical and biochemical LPD were evident among regularly menstruating women. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (ie, clinical LPD), indicating that clinical and biochemical LPD may reflect different underlying mechanisms. Identifying ovulation in combination with a well-timed luteal progesterone measurement may serve as a cost-effective and specific tool for LPD assessment by clinicians and researchers.
The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age. Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22). The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.
To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake. High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, -10.6 to -2.5) and luteal phase progesterone (-22.1%; -36.2 to -4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4). High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women.
Transient exposures may influence fertility and early embryonic development. To assess the time of conception in vivo and conduct concurrent biomonitoring, ovulation must be identified prospectively. We report on the development and validation of a simple, prospective method, the Peak Day method, to determine likely day of ovulation based upon daily observations of cervical fluid. We recruited 98 women to learn the Peak Day method from a brochure, 26 of whom concurrently used the method with blinded daily urine hormone monitoring (estrone glucuronide and luteinizing hormone). All women were instructed to complete an exposure questionnaire immediately upon identifying ovulation. Briefly, the exposure questionnaire captured time-varying and transient exposures such as medication use, water consumption, and amount of sleep. We assessed timely completion of the exposure questionnaire, agreement of women's estimated day of ovulation (EDO) and the EDO by expert review, and agreement between the EDO by expert review and by blinded urine monitoring. Of 147 cycles evaluated, women selected an EDO in 130 (88%) and subsequently completed the periovulatory exposure questionnaire in 122 (94%) cycles. Of the 26 cycles evaluated with blinded hormonal monitoring, the Peak Day "best quality" algorithm, based upon cervical fluid, identified ovulation ± 3 days of the urine monitor in 24 cycles (92%). With simple written instructions, women can identify an estimated day of ovulation and perform periovulatory exposure assessment. The Peak Day method is highly cost-effective and could be applied by researchers to target periconceptional or very early developmental stage exposure assessment.
Over 100 million women currently use oral contraceptive pills (OCPs) worldwide. However, little is known about the effects of OCPs on arterial stiffness and hemodynamics. Furthermore, whether arterial stiffness and hemodynamics vary throughout the natural menstrual cycle remains controversial. Herein, we estimated the effect of the natural menstrual cycle and OCP use on arterial stiffness and hemodynamics. Healthy, nonsmoking women, aged 18-30 years, were recruited if they had regular menstrual cycles and never used OCPs (OCP nonuser group), or were using low-dose OCPs for at least 6 months (OCP user group). Using applanation tonometry, three assessments of arterial stiffness and central and peripheral hemodynamics were performed during the early follicular (days 3-6), late follicular (days 14-16), and luteal (days 22-26) phases. Within group and between group comparisons were performed using general linear models. Sixty women (21.7 ± 2.8 years) were recruited. Compared with OCP nonusers, OCP users had significantly increased aortic and peripheral SBPs during the active OCP use, but not during the inert tablet phase. No differences in arterial stiffness were noted. OCP use was associated with significant increases in aortic and peripheral blood pressures, but not with increased arterial stiffness. Given the widespread OCP use, future longitudinal studies are needed to confirm our findings and assess the long-term effect of OCPs on arterial stiffness and hemodynamics.
To assess the association of total isoflavone intake with ovulatory function, including sporadic anovulation in healthy premenopausal women.
Prospective cohort study.
University. PATIENT(S): Participants included 259 healthy regularly menstruating women aged 18-44 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of E2, free E2, P, LH, FSH, and SHBG and sporadic anovulation in healthy premenopausal women. RESULT(S): Isoflavone intake was not associated with E2, free E2, P, LH, and FSH concentrations. Consumption in the highest quartile (Q4: 1.6-78.8 mg/d) was significantly associated with greater SHBG concentrations (β = 0.09; 95% confidence interval [CI] 0.02-0.16), compared with the first quartile (Q1: 0.0-0.3 mg/d). CONCLUSION(S): Isoflavone intake was not associated with sporadic anovulation (Q4 vs. Q1: odds ratio 0.87, 95% CI 0.32-1.66). Dietary isoflavone intake among young premenopausal women was not related to sex hormone concentrations or anovulation, but was associated with minimally increased SHBG concentrations. These results suggest potential endocrine effects with no subsequent effects on ovulation, easing concerns regarding their impacts on fertility.
Menstrual CycleSubclinical AnovulationPremenopausal Bone LossBone Formation Role
Subclinical ovulatory disturbances (anovulation or short luteal phases within normal-length menstrual cycles) indicate lower progesterone-to-estrogen levels. Given that progesterone plays a bone formation role, subclinical ovulatory disturbances may be associated with bone loss or less than expected bone gain. Our purpose was to perform a meta-analysis of prospective studies in healthy premenopausal women to determine the overall relationship of subclinical ovulatory disturbances to change in bone mineral density. Two reviewers independently identified from serial literature searches 6 studies a 2-year study in 114 young adult women, 2006-2009, Vancouver, Canada; a 2-year study in 189 premenopausal women, 2000-2005, Toronto, Canada; a single-cycle study in 14 young women, 1996-1997, Melbourne, Australia; an 18-month study in 53 women, 1990-1995, Santa Clara, California; a 4-year study in 27 women, 1988-1995, Vancouver, Canada; and a 1-year study in 66 women, 1985-1988, Vancouver, Canada. This meta-analysis included a combined sample size of 473 observations in 436 premenopausal women studied over 1-4 years and aged 14-47 years. The percentage of women with ovulatory disturbances varied significantly from 13% to 82%. Women with more frequent ovulatory disturbances had more negative percentage changes in spine bone mineral density (weighted mean difference = -0.86; P = 0.040) for random-effects analysis. There was significant heterogeneity among these 6 studies (I(2) = 80%). In summary, these data show that regularly menstruating women with more frequent ovulatory disturbances experience more negative changes in bone (approximately -0.9% per year). These cycles with silent estrogen/progesterone imbalance may be clinically important.
What are the characteristics of, and how variable are, individual normal menstrual cycle profiles of excretion rates for the urinary metabolites oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG)? There is a continuum of menstrual cycle profiles that differ from standard textbook profiles but which can be understood simply in terms of growth, atresia and ovulation of ovarian follicles. Point-of-care assays with the Ovarian Monitor pre-coated assay tubes, using urine samples diluted to a constant volume per unit time, give laboratory accurate clinical data for individual menstrual cycles. Lay operators can perform the point-of-care assay system at home to achieve reliable and reproducible results, which can be used for natural family planning. STUDY DESIGN, SIZE, This prospective study involved 62 women, with normal menstrual cycles, Palmerston North, New Zealand, Sydney, Australia and Santiago, Chile. The study lasted 3 years. PARTICIPANTS/MATERIALS, SETTING, Women collected daily urine samples and determined their E1G and PdG rates with a pre-coated enzyme assay system known as the Ovarian Monitor. For two cycles, the assays were repeated in a study centre and the results were averaged to give 113 individual menstrual cycles for analysis. The cycles were displayed individually in a proprietary database program. MAIN The individual normal hormonal profiles were more complex than the classic composite curves for 40% of the cycles. Of 113 ostensibly normal cycles, only 91 were potentially fertile and 22 had some luteal phase defect. The oestrone glucuronide and PdG excretion rates were reliable and informative in the non-invasive elucidation of ovulation and ovarian function for both simple and complex profiles. Daily monitoring revealed the variability of normal menstrual cycle profiles. The LH peaks were variable and ambiguous markers for ovulation. LIMITATIONS, The study consisted of cycles only from women with regular cycles of 20-40 days duration. All the women were intending to avoid a pregnancy during the study thus the limits of the fertile window were not tested. The principles established in this study should apply to cycles of any length. All peaks in oestrone glucuronide excretion should be tested by concurrent measurements of PdG, which gives a positive indication of the fate of the follicle it represents. The Ovarian Monitor provides a useful addition for practitioners of natural family planning. STUDY FUNDING/COMPETING INTEREST(S): Financial support for this study was obtained from the UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (HRP). D.G.C. is currently employed by and holds stock in Manawatu Diagnostics Ltd, a company in the development phase of a potentially competing product. The remaining authors have nothing to declare.
Urinary hormonal markers may assist in increasing the efficacy of Fertility Awareness Based Methods (FABM). This study uses urinary pregnanediol-3a-glucuronide (PDG) testing to more accurately identify the infertile phase of the menstrual cycle in the setting of FABM. Secondary analysis of an observational and simulation study, multicentre, European study. The study includes 107 women and tracks daily first morning urine (FMU), observed the changes in cervical mucus discharge, and ultrasonography to identify the day of ovulation over 326 menstrual cycles. The following (A) use of the daily pregnandiol-3a-glucuronide (PDG) test alone; (B) use of the PDG test after the first positive urine luteinizing hormone (LH) kit result; (C) use of the PDG test after the disappearance of fertile type mucus. (1) one day of PDG positivity; or (2) waiting for three days of PDG positivity before declaring infertility. After the first positivity of a LH test or the end of fertile mucus, three consecutive days of PDG testing over a threshold of 5μg/mL resulted in a 100% specificity for ovulation confirmation. They were respectively associated an identification of an average of 6.1 and 7.6 recognized infertile days. The results demonstrate a clinical scenario with 100% specificity for ovulation confirmation and provide the theoretical background for a future development of a competitive lateral flow assay for the detection of PDG in the urine.
Initial evaluation of the patient with acute abnormal uterine bleeding should include a prompt assessment for signs of hypovolemia and potential hemodynamic instability. After initial assessment and stabilization, the etiologies of acute abnormal uterine bleeding should be classified using the PALM-COEIN system. Medical management should be the initial treatment for most patients, if clinically appropriate. Options include intravenous conjugated equine estrogen, multi-dose regimens of combined oral contraceptives or oral progestins, and tranexamic acid. Decisions should be based on the patient's medical history and contraindications to therapies. Surgical management should be considered for patients who are not clinically stable, are not suitable for medical management, or have failed to respond appropriately to medical management. The choice of surgical management should be based on the patient's underlying medical conditions, underlying pathology, and desire for future fertility. Once the acute bleeding episode has been controlled, transitioning the patient to long-term maintenance therapy is recommended.
Progesterone with its anti-seizure effect plays a role in the pathophysiology of catamenial epilepsy which affects 31-60% of epileptic women. In this study, an attempt to treat women suffering from catamenial epilepsy with progesterone, as an adjuvant drug, was made. The treatment was given to 36 women aged 20-40 years (mean 30.75±6.05) with seizures in the entire second half of the menstrual cycle, who were found to have low serum levels of progesterone on days 22, 27, 28 of the cycle in comparison with a control group of healthy women. The patients were administered progesterone in a daily dose of 50 mg on days 16-25 of each cycle. The serum levels of antiepileptic drugs were assayed. The period of progesterone therapy ranged from 3 to 45 months (17.7 on average). Three patients were free of secondary generalized seizures, and one--of simple partial seizures. A decline in the frequency of primary and secondary generalized seizures by 20-96% (55.9% on average) was accomplished in 18 patients (primary generalized by 20-96%--54.7% on average, and secondarily generalized by 38-85%--59% on average). A decline in the frequency of complex partial seizures by 38-87% (63.1% on average) was achieved in 15 women. In 1 patient, the frequency of myoclonic seizures decreased by 46%. There was no improvement in 5 women (3 patients with generalized, 1 with complex partial and 1 with simple partial seizures). An exacerbation of seizure frequency occurred in 5 patients. Adverse effects were not found in any of the subjects. The average concentrations of antiepileptic drugs during hormonal therapy were in the therapeutic range. Progesterone combined with antiepileptic therapy was well tolerated and resulted in a significant reduction of seizure frequency in majority of patients with catamenial epilepsy.
Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease.
Obesity and high body mass index (BMI) are known to be risks for anovulation and infertility. Little is known about how BMI levels affect parameters of the menstrual cycle. The purpose of this study was to determine the influence of BMI on parameters of the menstrual cycle and the likelihood for ovulation. The participants in this study were 244 women between the ages of twenty and fifty-four (mean thirty years) who charted from one to thirty-six menstrual cycles (mean seven cycles) for a total of 2,035 cycles. Urinary luteinizing hormone (LH) threshold tests were used to estimate the day of ovulation and the lengths of the follicular and luteal phases. The 244 participants were classified as normal weight with a BMI of 18.5-24.9 kg/m2 (N = 141), overweight with a BMI of 25-29.9 kg/m2 (N = 67), and obese with a BMI of 30 kg/m2 or greater (N = 36). One-way ANOVA indicated that there was a significant difference between groups in length of the luteal phase (F = 4.62, p < 0.01) and length of menses (F = 3.03, p < 0.05). Odds ratio indicated that the combined obese and overweight group was 34 percent less likely to have a positive detected urinary LH surge. We concluded that obesity might contribute to infertility by shortening the luteal phase and decreasing the probability of ovulatory menstrual cycles.
Reproductive EndocrinologyMenstrual Cycle
Open Access
Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons). The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. Cancer Research UK.
Menstruation has many of the features of an inflammatory process. The complexity and sequence of inflammatory-type events leading to the final tissue breakdown and bleeding are slowly being unravelled. Progesterone has anti-inflammatory properties, and its rapidly declining levels (along with those of estrogen) in the late secretory phase of each non-conception cycle, initiates a sequence of interdependent events of an inflammatory nature involving local inter-cellular interactions within the endometrium. Intracellular responses to loss of progesterone (in decidualized stromal, vascular and epithelial cells) lead to decreased prostaglandin metabolism and loss of protection from reactive oxygen species (ROS). Increased ROS results in release of NFκB from suppression with activation of target gene transcription and increased synthesis of pro-inflammatory prostaglandins, cytokines, chemokines and matrix metalloproteinases (MMP). The resultant leukocyte recruitment, with changing phenotypes and activation, provide further degradative enzymes and MMP activators, which together with a hypoxic environment induced by prostaglandin actions, lead to the tissue breakdown and bleeding characteristic of menstruation. In parallel, at sites where shedding is complete, microenvironmentally-induced changes in phenotypes of neutrophils and macrophages from proto anti-inflammatory, in addition to induction of growth factors, contribute to the very rapid re-epithelialization and restoration of tissue integrity.
Menstrual bleeding patterns are considered relevant indicators of reproductive health, though few studies have evaluated patterns among regularly menstruating premenopausal women. The authors evaluated self-reported bleeding patterns, incidence of spotting, and associations with reproductive hormones among 201 women in the BioCycle Study (2005-2007) with 2 consecutive cycles. Bleeding patterns were assessed by using daily questionnaires and pictograms. Marginal structural models were used to evaluate associations between endogenous hormone concentrations and subsequent total reported blood loss and bleeding length by weighted linear mixed-effects models and weighted parametric survival analysis models. Women bled for a median of 5 days (standard 1.5) during menstruation, with heavier bleeding during the first 3 days. Only 4.8% of women experienced midcycle bleeding. Increased levels of follicle-stimulating hormone (β = 0.20, 95% 0.13, 0.27) and progesterone (β = 0.06, 95% 0.03, 0.09) throughout the cycle were associated with heavier menstrual bleeding, and higher follicle-stimulating hormone levels were associated with longer menses. Bleeding duration and volume were reduced after anovulatory compared with ovulatory cycles (geometric 29.6 vs. 47.2 mL; P = 0.07). Study findings suggest that detailed characterizations of bleeding patterns may provide more insight than previously thought as noninvasive markers for endocrine status in a given cycle.
Physical activity (PA) is an important modifiable risk factor for both bone mineral density (BMD) and body mass index (BMI). However, BMI is itself strongly predictive of BMD. Our aim was to determine the association between PA and BMD, with consideration of BMI as a potential mediating factor. The Canadian Multicentre Osteoporosis Study (CaMos) is a population-based prospective cohort study of Canadian women and men. PA was determined from interviewer-administered questionnaires at baseline and Year 5 and summarized as daily energy expenditure in total metabolic equivalents of the task multiplied by minutes/day (MET*m/d). Height, weight, and total hip and lumbar spine BMD were measured at baseline and Year 5. General linear models assessed relationships between PA and BMD, both cross-sectionally (baseline PA with baseline BMD) and longitudinally (average PA and change in PA with change in BMD). BMI was considered as a mediating factor. Potential confounders included age, center, education, caffeine intake, alcohol exposure, smoking history, history of weight-cycling, age at menarche, past use of oral contraceptives, history of >3 months missed menstruation, menopausal status, and antiresorptive use, as relevant. The study included 2855 men and 6442 women. PA was inversely associated with BMI at baseline, and an increase in PA between baseline and Year 5 was associated with a decrease in BMI, with 0.41 (95% CI: 0.22, 0.60) kg/m(2) loss per 1000 MET*m/d increase (in men) and 0.40 (95% CI: 0.23, 0.57) kg/m(2) loss per 1000 MET*m/d increase (in women). BMI was strongly associated with BMD, both cross-sectionally and longitudinally. However, increased PA was associated with a small increase in total hip BMD, 0.004 (95% CI: 0.000-0.008) g/cm(2) per 1000 MET*m/d (in men) and 0.003 (95% CI: 0.000-0.007) g/cm(2) per 1000 MET*m/d (in women). Average PA was associated with an increase in lumbar spine BMD in women, but not in men; it was not associated with change in total hip BMD in either sex. Increased PA is associated with an increase in BMD and a concomitant decrease in BMI. These findings suggest that population-level interventions to increase PA would favorably impact bone and other health outcomes.
Fertility AwarenessUrinary Hormone MetabolitesHome-Based Hormone TestingEstrogen and Progesterone Profiles
The UNDP/WHO/World Bank/Special Programme of Research, Development and Research Training in Human Reproduction (Geneva) set up a study to determine whether it is feasible for women to monitor their ovarian activity reliably by home testing. Daily self-monitoring of urinary hormone metabolites for menstrual cycle assessment was evaluated by comparison of results obtained with the Home Ovarian Monitor by untrained users both at home and in study centres. Women collected daily data for urinary estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) for two cycles, then the procedure was repeated in the women's local centre (in Chile, Australia or New Zealand) giving a total of 113 duplicate cycles. The tests were performed without the benefit of replicates or quality controls. The home and centre cycles were normalized and compared to identify assay errors, and the resulting home and centre menstrual cycle profiles were averaged. Reliable mean cycle profiles were obtained with the home and centre excretion rates agreeing to within 36 ± 21 nmol/24 h for E1G and 0.77 ± 0.28 µmol/24 h for baseline PdG values (1-5 µmol/24 h). The cycles had a mean length of 28.1 ± 3.1 days (n = 112; 5th and 95th 24 and 35 days, respectively), a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n = 106; 5th and 95th 11 and 17 days), calculated from the day of the LH peak. The study confirmed that the Ovarian Monitor pre-coated assay tubes worked well even in the hands of lay users, without standard curves, quality controls or replicates. Point-of-care monitoring to give reliable fertility data is feasible.
Menstrual CycleReproductive Endocrinology
Open Access
We report menstrual and mid-cycle patterns of self-reported "fluid retention" in 765 menstrual cycles in 62 healthy women. Self-reported "fluid retention," commonly described as bloating, is one element of the clinical assessment and diagnosis of premenstrual symptoms. These daily diary data were collected as part of an observational prospective one-year study of bone changes in healthy women of differing exercise characteristics. Ovulation was documented by quantitative basal temperature analysis, and serum estradiol and progesterone levels were available from initial and final cycles. Fluid retention scores (on a 0-4 scale) peaked on the first day of menstrual flow (mean ± 0.9 ± 0.1), were lowest during the mid-follicular period, and gradually increased from 0.22 ± 0.05 to 0.50 ± 0.09 over the 11 days surrounding ovulation. Mid-cycle, but not premenstrual, fluid scores tended to be lower in anovulatory cycles (ANOVA P = 0.065), and scores were higher around menstruation than at midcycle (P < 0.0001). Neither estradiol nor progesterone levels were significantly associated with fluid retention scores. The peak day of average fluid retention was the first day of flow. There were no significant differences in women's self-perceived fluid retention between ovulatory and anovulatory cycles.
Fertility AwarenessHormonal IndicatorsFollicular DevelopmentBiomarker-Based Methods
Open Access
El objetivo de este artículo es revisar los principales conceptos en la literatura acerca de la ventana de la fertilidad en pacientes con ciclos menstruales normales. El énfasis principal del artículo se ha dirigido al análisis de la teoría de Brown de la ovulación, revisar conceptos básicos de la ovulación, secreción y metabolismo de la hormona folículo estimulante, y al estudio clínico, ecográfico y bioquímicos del desarrollo folicular de la ventana de la fertilidad. Este artículo también repasa los biomarcadores clínicos y los diferentes metabolitos endocrinos que delimitan en la fase fértil del ciclo. Se revisan diferentes estudios en los cuales las valoraciones en suero y orina de los esteroides sexuales, han corroborado tener una correlación directa para enmarcar el período fértil. Actualmente tienen relevancia estos conocimientos en diferentes grupos de interés, sobre todo en mujeres con un alto nivel de motivación interesadas en el reconocimiento de su fertilidad, las cuales pueden beneficiarse mediante la aplicación de conocimientos técnicos actuales que detectan la ventana fértil. También estos conocimientos suelen cobrar importancia en aquellas personas que pertenecen a programas de regulación de la fertilidad (PRF), con intención de distanciar un embarazo, o de reconocer el periodo fértil del ciclo para conseguir un embarazo espontáneamente, o mediante programas de NaProTecnología. Otros grupos de interés, son aquellos en los cuales no se tiene experiencia en cursos de PRF, pero desean mejorar sus conocimientos en el reconocimiento de la fertilidad por medio de una breve entrevista, o por medio de cursos de orientación familiar.
Reproductive EndocrinologyMenstrual Cycle
Open Access
In the modern environment one is exposed to various stressful conditions. Stress can lead to changes in the serum level of many hormones including glucocorticoids, catecholamines, growth hormone and prolactin. Some of these changes are necessary for the fight or flight response to protect oneself. Some of these stressful responses can lead to endocrine disorders like Graves' disease, gonadal dysfunction, psychosexual dwarfism and obesity. Stress can also alter the clinical status of many preexisting endocrine disorders such as precipitation of adrenal crisis and thyroid storm.
Reproductive EndocrinologyAdolescent Brain DevelopmentNeurocognitive FunctionPuberty and Development
Neurophysiological and behavioral development is particularly complex in adolescence. Youngsters experience strong emotions and impulsivity, reduced self-control, and preference for actions which offer immediate rewards, among other behavioral patterns. Given the growing interest in endocrine effects on adolescent central nervous system development and their implications on later stages of life, this article reviews the effects of gonadal steroid hormones on the adolescent brain. These effects are classified as organizational, the capacity of steroids to determine nervous system structure during development, and activational, the ability of steroids to modify nervous activity to promote certain behaviors. During transition from puberty to adolescence, steroid hormones trigger various organizational phenomena related to structural brain circuit remodelling, determining adult behavioral response to steroids or sensory stimuli. These changes account for most male-female sexual dimorphism. In this stage sex steroids are involved in the main functional mechanisms responsible for organizational changes, namely myelination, neural pruning, apoptosis, and dendritic spine remodelling, activated only during embryonic development and during the transition from puberty to adolescence. This stage becomes a critical organizational window when the appropriately and timely exerted functions of steroid hormones and their interaction with some neurotransmitters on adolescent brain development are fundamental. Thus, understanding the phenomena linking steroid hormones and adolescent brain organization is crucial in the study of teenage behavior and in later assessment and treatment of anxiety, mood disorders, and depression. Adolescent behavior clearly evidences a stage of brain development influenced for the most part by steroid hormones.
Contraception/ComparisonCognitive EffectsHormones and CognitionNeurocognitive Function
Cognitive abilities, such as verbal fluency and mental rotation, are most sensitive to changes in sex steroids but poorly studied in the context of hormonal contraceptive usage. Therefore, we investigated the performance of mental rotation and verbal fluency in young (21.5±1.8 years) healthy oral contraceptive (OC) users (23 women) and non-users (20 women) during the follicular, ovulatory and luteal phases of the menstrual cycle. Salivary 17β-estradiol, progesterone and testosterone levels were assayed to evaluate hormonal differences between groups and the phases of the menstrual cycle. To assess the effects of progestins having androgenic/anti-androgenic properties, OC users were subdivided into the third and new generation OC users. In addition, positive and negative affects as factors possibly affecting cognitive performance were evaluated. Salivary 17β-estradiol and progesterone levels were significantly lower in hormonal contraception users. Level of salivary testosterone was slightly lower in the OC users group with significant difference only during ovulatory phase. Naturally cycling women performed better on verbal fluency task as compared to OC users. Subjects who used the third generation (androgenic) OCs generated significantly fewer words as compared to new generation (anti-androgenic) OC users and non-users. The third generation OC users demonstrated significantly longer RT in MRT task as compared to non-users. The MRT, verbal fluency and mood parameters did not depend on the phase of menstrual cycle. The parameters of the PANAS (Positive and Negative Affect Schedule) scales did not differ between OC users and non-users. Our findings show that hormonal contraception has an impact on verbal and spatial abilities. Different performances between users of oral contraceptives with androgenic and anti-androgenic properties suggest an essential role for the progestins contained in OCs on cognitive performance.
Nassaralla CL et al., 2011·J Womens Health (Larchmt)
Menstrual cycle function may continue to be altered after discontinuation of oral contraceptives (OC). Few studies have been published on the effects of recent OC use on menstrual cycle parameters; none have examined characteristics of the menstrual flow or the quality of cervical mucus. The purpose of this retrospective matched cohort study is to assess biomarkers of the menstrual cycle after discontinuation of OCs. Among a sample of women who daily recorded observations of menstrual cycle biomarkers, 70 women who had recently discontinued OCs were randomly matched by age and parity with 70 women who had not used OCs for at least 1 year. Outcomes investigated included overall cycle length, length of the luteal phase, estimated day of ovulation, duration of menstrual flow, menstrual intensity, and mucus score. Differences between recent OC users and controls were assessed using random effects modeling. Recent OC users had statistically significantly lower scores for mucus quality for cycles 1 and 2. Additionally, OC users had a later estimated day of ovulation that was statistically significant in cycle 2 and a decreased intensity of menstrual flow that was significant in the first four cycles (difference = -0.48 days). In random effects modeling, all these parameters were significantly different for the first six cycles combined. Menstrual cycle biomarkers are altered for at least two cycles after discontinuation of OCs, and this may help explain the temporary decrease in fecundity associated with recent OC use.
Jerilynn C Prior et al., 2011·Front Biosci (Schol Ed)
Perimenopause, rather than a time of declining estrogen, is characterized by three major hormonal changes that may begin in regularly menstruating erratically higher estradiol levels, decreased progesterone levels (in normally ovulatory, short luteal phase or anovulatory cycles), and disturbed ovarian-pituitary-hypothalamic feedback relationships. Recent data show that approximately a third of all perimenopausal cycles have a major surge in estradiol occurring de novo during the luteal phase. This phenomenon, named "luteal out of phase (LOOP)" event, may explain a large proportion of symptoms and signs for symptomatic perimenopausal women. Large urinary hormone data-sets from women studied yearly over a number of years in the Study of Women Across the Nation (SWAN) and in the Tremin data will eventually provide a more clear prospective understanding of within-woman hormonal changes. Predicting menopause proximity with FSH or Inhibin B levels is documented to be ineffective. Anti-Mullerian hormone levels may prove predictive. Finally, there is an urgent need to change perimenopause understandings, language and therapies used for midlife women's symptoms to reflect these hormonal changes.
Bone HealthBone RemodelingSkeletal ImpactBone Physiology
Women's menstrual cycles and bone remodeling are linked in part by their co-dependency on the stressand resource-associated variables that govern both of their cyclical natures. Therefore, it is not surprising that evolution has resulted in the same signaling molecules and pathways that regulate normal ovarian function to be involved in bone remodeling and turnover. This review will first provide an overview of the normal menstrual cycle, its modification by age and ovulatory disturbances, and how it parallels bone remodeling. Epidemiological and clinical evidence will be presented that link bone remodeling, strength, and fractures with women's history of reproductive and menstrual cycle characteristics. This combined evidence will then be presented alongside a synthesis of current concepts derived from basic science investigations focused on understanding the molecular mechanisms underlying the influence of ovarian factors on bone physiology. Osteoporosis is a significant source of morbidity for older women. The data presented in this review suggest that a woman's reproductive cycle and ovulatory characteristics foreshadow the future health of her bones. More importantly, identifying the key mechanisms underlying reproductive and bone health would not only provide essential preventative strategies, but may also uncover attractive targets for the treatment of osteoporosis.
There are many types of ovarian activity that occur in women. This review provides information on the relationship between the hormone values and the degree of biological response to the hormones including the frequency and degree of uterine bleeding. The continuous process is termed the 'Continuum' and is thus similar to other processes in the body. This review draws on information already published from monitoring ovarian activity by urinary oestrogen and pregnanediol measurements using timed 24-h specimens of urine. Much of the rationalization was derived from 5 to 6 year studies of girls progressing from childhood to adulthood, women progressing through menopause, and the return of fertility post-partum. During these times, all the reported types of ovarian activity were encountered. All cycle types can be understood in terms of steps in the normal maturation of fertility at the beginning of reproductive life, its return post-partum and its demise at menopause. Each step merges into the next and therefore the sequence is termed the 'Continuum'. Unpredictable movement from fertile to infertile types and back can occur at any time during reproductive life. Stress is a major causative factor. Hormonal definitions for each step, the relevance of the various cycle types in determining fertility and in the initiation of uterine bleeding and the roles of the pituitary hormones in causing them, are presented. The findings explain the erratic fertility of women and why ovulation is not always associated with fertility. They provide an understanding of the various types of ovarian activity and their relation to pituitary function, fertility and uterine bleeding.
We estimated peak bone mass (PBM) in 615 women and 527 men aged 16 to 40 years using longitudinal data from the Canadian Multicentre Osteoporosis Study (CaMos). Individual rates of change were averaged to find the mean rate of change for each baseline age. The age range for PBM was defined as the period during which bone mineral density (BMD) was stable. PBM was estimated via hierarchical models, weighted according to 2006 Canadian Census data. Lumbar spine PBM (1.046 ± 0.123 g/cm(2)) occurred at ages 33 to 40 years in women and at 19 to 33 years in men (1.066 ± 0.129 g/cm(2)). Total hip PBM (0.981 ± 0.122 g/cm(2)) occurred at ages 16 to 19 years in women and 19 to 21 years in men (1.093 ± 0.169 g/cm(2)). Analysis of Canadian geographic variation revealed that the levels of PBM and of mean BMD in those over age 65 sometimes were discordant, suggesting that PBM and subsequent rates of bone loss may be subject to different genetic and/or environmental influences. Based on our longitudinally estimated PBM values, the estimated Canadian prevalences of osteoporosis (T-score < -2.5) were 12.0% (L(1)-L(4)) and 9.1% (total hip) in women aged 50 years and older and 2.9% (L(1)-L(4)) and 0.9% (total hip) in men aged 50 years and older. These were higher than prevalences using cross-sectional PBM data. In summary, we found that the age at which PBM is achieved varies by sex and skeletal site, and different reference values for PBM lead to different estimates of the prevalence of osteoporosis. Furthermore, lack of concordance of PBM and BMD over age 65 suggests different determinants of PBM and subsequent bone loss.
Research MethodologyCost-Effective Participant EnrollmentObservational Study DesignWomen's Health Research Methods
Battistella E et al., 2010·J Womens Health (Larchmt)
We address the crucial and challenging task of anticipating the resources needed to recruit eligible participants for research. We provide our analysis of various recruitment strategies and their cost-effectiveness in our experience in enrolling 610 women for an observational study on ovulation. We assess the cost-effectiveness and success of multiple recruitment strategies we employed and provide the estimated cost of labor and materials for each. At enrollment, all participants were asked an open-ended question about how they learned about the study. No financial compensation was provided, but participants received personal hormonal analysis results on completion. Of the 610 enrolled women, 552 provided information on how they learned about the study. The total cost of recruitment was $7645.11, which includes 183 staff hours. The average recruitment cost per participant was $12.53 (ranging from $0 to $118.63). The two methods with the lowest total costs resulted in enrollment of 48% of the recruitment goal using only 0.3% of the budget. In contrast, the two methods with the highest total costs produced 13% of the participants needed but consumed over 72% of the budget. Low-cost methods are a viable, practical source for attracting healthy women for observational research. Investigators are encouraged to track sources of recruitment and analyze their data at regular intervals during the recruitment phase. Sharing comprehensive recruitment data will assist other researchers to better estimate the resources needed to meet their enrollment goal, leading to more efficient use of time and funding.
The objectives of the study were to develop bone mineral density (BMD) reference norms and BMD Z-scores at various skeletal sites, to determine whether prior fracture and/or asthma were related to BMD, and to assess possible geographic variation of BMD among Canadian youth aged 16-24 yr. Z-Scores were defined as the number of standard deviations from the mean BMD of a healthy population of the same age, race, and sex. Z-Scores were calculated using the reference sample defined as Canadian Caucasian participants without asthma or prior fracture. Reference standards were created for lumbar spine (L1-L4), femoral neck, total hip, and greater trochanter, by each year of age (16-24 yr), and by sex. The Z-score norms were developed for groups noted earlier. Mean Z-scores between the asthma or fracture subgroups compared with the mean Z-scores in the reference sample were not different. There were minor differences in mean BMD across different Canadian geographic regions. This study provides age, sex, and skeletal site-specific Caucasian reference norms and formulae for the calculation of BMD Z-scores for Canadian youth aged 16-24 yr. This information will be valuable to help to identify individuals with clinically meaningful low BMD.
The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [χ(2)(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 ± 0.59) and black (pH 4.7 ± 1.04) women as compared with Asian (pH 4.4 ± 0.59) and white (pH 4.2 ± 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.
Menstrual CycleSubclinical AnovulationOvulatory Disturbance EffectsStress and Ovulation
Cross-sectional studies have found associations among elevated cognitive dietary restraint (CDR), increased ovulatory disturbances, and lower bone mass, possibly mediated by cortisol. To determine whether healthy young women with higher CDR have more menstrual cycles with subclinical ovulatory disturbances (SOD), elevated 24-h urinary free cortisol (UFC), and less positive 2-yr areal bone mineral density change (Delta-aBMD). DESIGN, SETTING, We conducted a 2-yr longitudinal study of 123 healthy, community-dwelling, nonobese, regularly menstruating women aged 19-35 yr. Key variables were Three Factor Eating Questionnaire Restraint score, percent of cycles with anvoluation and/or luteal phase length <10 d (%SOD), UFC, and Delta-aBMD at the lumbar spine (L1-L4), total hip, and whole body. Anthropometrics, general stress, physical activity, and energy intake were measured. Adjusting for potential confounders, differences were examined by general linear modeling using median split of CDR score and %SOD. Women with higher CDR had higher %SOD (56 vs. 34%, P < 0.001) and higher UFC (28.0 vs. 24.0 microg/d, P = 0.021). Delta-aBMD did not differ by CDR. Women with higher %SOD had less positive Delta-aBMD at L1-L4 (0.7 vs. 1.9%, P = 0.034) and hip (-0.6 vs. 0.9%, P = 0.001), and higher CDR score (8.7 vs. 7.1, P = 0.04). Physical activity, general stress, body mass index, and energy intake did not explain differences by CDR or %SOD. UFC was not associated with %SOD or Delta-aBMD. Women with more frequent SOD reported higher CDR and experienced less positive Delta-aBMD. Although women with higher CDR had higher UFC, the mechanism linking CDR, SOD, and aBMD is not clear.
Menstrual CycleSubclinical AnovulationOvulatory Disturbance EffectsBasal Body Temperature
Cognitive dietary restraint (CDR) of limiting food intake to achieve/maintain a perceived ideal body weight. The objective of this 2‐yr prospective study was to determine if women with higher CDR have more subclinical ovulation disturbances (SOD; anovulation or luteal phase <10 d), elevated cortisol excretion and less positive changes in areal bone mineral density over two years (ΔaBMD). Participants were 123 healthy, non‐obese, regularly menstruating women aged 19–35. Annually participants completed questionnaires (Three Factor Eating Questionnaire, physical activity, general stress, dietary intake), anthropometrics and 24‐hr urine collections for measurement of 24‐hr urinary free cortisol (UFC). At baseline and final follow‐up, dual energy x‐ray absorptiometry scans measured ΔaBMD at the lumbar spine (L1‐4), hip and total body. Quantitative waking temperature was used to determine SOD frequency. SOD correlated positively with CDR and inversely with hip ΔaBMD but not with UFC. CDR and UFC were not associated with each other or ΔaBMD. Women with higher CDR had more SOD. Women with more SOD had less positive ΔaBMD and higher CDR. Physical activity, general stress, body mass and energy intake did not explain differences by CDR or SOD. In conclusion, CDR was the only study variable associated with SOD which was associated with less positive ΔaBMD. Canadian Institutes of Health Research 79563.
: Canadian Institute of Health Research
Physicians and menstruating women often ask pharmacists for recommendations about menstrual cycle–related problems. Progesterone and medroxyprogesterone may provide physiology-based treatment, but official indications in menstruating women in Canada are minimal. To describe pharmacists' responses to vignette-based questions about the treatment of common clinical problems in menstruating women and review evidence-based therapies. A pharmacist interviewer administered an 11-item questionnaire to a random sample of community pharmacists. Questions were based on clinical vignettes in adolescent, preand perimenopausal women and related to heavy flow, polycystic ovary syndrome, premenopausal osteoporosis, perimenopausal night sweats and side effects/contraindications for estrogens and progesterone/progestins. The participation rate was 58%, including equal numbers of male and female pharmacists. Seventy-two percent indicated that they would treat menorrhagia in an anemic 13-year-old with oral contraceptives — 21% would recommend ibuprofen and 86% iron. Half recommended that a 35-year-old smoker with heavy flow and acne stop oral contraceptives, but the other 50% recommended a switch to an oral contraceptive with cyproterone. For premenopausal osteoporosis, the majority recommended calcium and vitamin D, but 53% endorsed oral contraceptives — only 7% suggested cyclic medroxyprogesterone. For night sweats, the majority recommended progesterone/progestin in a regularly menstruating 42-year-old woman. Estrogens are contraindicated with past thrombosis and/or breast cancer family history, and they could cause nausea; 50% of pharmacists also attributed these adverse effects to progesterone/progestins. Community pharmacists vary widely in their treatment choices for common preand perimenopausal women's menstrual cycle–related problems. The evidence in support of most recommendations is minimal or lacking.
Harvey AT et al., 2009·J Psychosom Obstet Gynaecol
We examined the cyclicity of negative mood relative to ovulation and ovulation disturbances in Menstrual Cycle Diary(c) data collected daily during a 1-year study of ovulation, exercise, and bone change. A validated quantitative basal temperature-based methodology was used to determine the onset of the luteal phase. 'Feeling depressed', 'feeling anxious', and 'feeling angry/frustrated' were scored on a scale of 0 (absent) to 4 (very intense). Mood scores were examined over two 15-day intervals centered on either ovulation/midpoint, or on the onset of flow. Data were available from 765 cycles of 62 healthy and initially ovulatory women with a mean age of 33.9 +/- 5.4 years. Of 739 cycles that could be classified, 532 (72%) were normally ovulatory, 185 (25%) were ovulatory with a short (<10 day) luteal phase, and 22 (3%) were anovulatory. Minor cyclic mood changes were present in both ovulatory and anovulatory menstrual cycles. In anovulatory cycles, mood tended to be more variable but less negative, with a time course that differed from that in ovulatory cycles. Mood scores did not differ based on luteal phase length or with hormone levels. Patterns and mechanisms of mood change in very symptomatic women appear to be essentially amplifications of normal experiences.
Fertility AwarenessBasal Body TemperatureTemperature Analysis MethodsProgesterone Confirmation Methods
Jennifer L Bedford et al., 2009·Eur J Obstet Gynecol Reprod Biol
To assess computerised least-squares analysis of quantitative basal temperature (LS-BT) against urinary pregnanediol glucuronide (PdG) as an indirect measure of ovulation, and to evaluate the stability of LS-QBT to wake-time variation. Cross-sectional study of 40 healthy, normal-weight, regularly menstruating women aged 19-34. Participants recorded basal temperature and collected first void urine daily for one complete menstrual cycle. Evidence of luteal activity (ELA), an indirect ovulation indicator, was assessed using Kassam's PdG algorithm, which identifies a sustained 3-day PdG rise, and the LS-QBT algorithm, by determining whether the temperature curve is significantly biphasic. Cycles were classified as ELA(+) or ELA(-). We explored the need to pre-screen for wake-time variations by (A) all recorded temperatures, (B) wake-time adjusted temperatures, (C) temperatures within 2h of average wake-time, and (D) expert reviewed temperatures. Relative to PdG, classification of cycles as ELA(+) was 35 of 36 for LS-QBT methods A and B, 33 of 34 (method C) and 30 of 31 (method D). Classification of cycles as ELA(-) was 1 of 4 (methods A and B) and 0 of 3 (methods C and D). Positive predictive value was 92% for methods A-C and 91% for method D. Negative predictive value was 50% for methods A and B and 0% for methods C and D. Overall accuracy was 90% for methods A and B, 89% for method C and 88% for method D. The day of a significant temperature increase by LS-QBT and the first day of a sustained PdG rise were correlated (r=0.803, 0.741, 0.651, 0.747 for methods A-D, respectively, all p<0.001). LS-QBT showed excellent detection of ELA(+) cycles (sensitivity, positive predictive value) but poor detection of ELA(-) cycles (specificity, negative predictive value) relative to urinary PdG. Correlations between the methods and overall accuracy were good and similar for all analyses. Findings suggest that LS-QBT is robust to wake-time variability and that expert interpretation is unnecessary. This method shows promise for use as an epidemiological tool to document cyclic progesterone increase. Further validation relative to daily transvaginal ultrasound is required.
PCOSAbnormal Uterine BleedingIrregular Bleeding Causes
Open Access
Abnormal uterine bleeding imposes major medical, social and financial problems for women, their families and the health services. Abnormal uterine bleeding refers to the regularity, frequency, duration and volume of bleeding. Irregular menstrual bleeding is most common at the extremes of reproductive life, in the initial 12-18 months after menarche and 5-6 years before the menopause begins. In Australia, the estimated cost of investigating and managing heavy menstrual bleeding alone is approximately AUS $6 million per annum. This article addresses the common causes of irregular bleeding in preand peri-menopausal women and presents an investigational approach.
The copper intrauterine device (IUD) can cause side effects in some women; increased uterine bleeding and pain may cause early removal. Because of simplified reporting from previous research, little is known about how side effects might change over time. This is a secondary analysis of a prospective study of 1947 first-time copper IUD users. Over a 1-year period, we collected detailed information on side effects and looked for trends using generalized mixed-effects regression modeling. During menses, most bleeding and pain side effects were found to decrease over time (p<.05). During intermenstrual intervals, overall spotting and pain complaints remained unchanged, but the number of days with these problems increased (p<.05). Serious side effects that prompted either a clinic visit or IUD removal had varied patterns over time, depending on the type of problem. Side effects from the copper IUD can be troubling for both user and clinician. Some problems improve over time, while others do not. This information may be helpful in counseling women who are considering IUD use and current users who are contemplating IUD removal due to side effects.
Menstrual CycleEvolutionary Function of MenstruationEndometrial DecidualizationMenstrual Preconditioning Theory
Menstruation is widely viewed as serving no purpose other than to reinitiate the endometrial cycle in the absence of pregnancy. Yet, it is striking that cyclic endometrial decidualization followed by menstrual shedding is confined to the few species, including human beings, where placenta formation entails deep trophoblast invasion of maternal tissues and its vasculature. Both menstruation and pregnancy are inflammatory conditions that cause a degree of physiological ischemia-reperfusion tissue injury, albeit much more so in pregnancy. Thus, the emergence of cyclic menstruation may not have been an evolutionary coincidence but serves to protect uterine tissues from the profound hyperinflammation and oxidative stress associated with deep placentation, a process known as preconditioning. The concept of menstrual preconditioning provides a novel paradigm for understanding how reproductive disorders impact on pregnancy outcome. For example, endometriosis could be viewed as a disorder of exaggerated menstrual preconditioning that confers protection against placentation-related disorders, such as preeclampsia.
To assess the amount of variability in ovarian follicular growth rate and maximum follicular diameter related to different centers, women and cycles of the same women in a multicenter observational study of follicular growth. Secondary analysis of a prospective cohort study from eight centers in Europe. There were 533 ultrasound examinations in 282 cycles of 107 women with normal fertility. A random effects model with center, woman and cycle as hierarchical units of variation was used to analyze mean follicular diameter on days preceding ovulation. Follicular growth did not differ by center. There was homogenous growth across women and cycles, and the maximum follicular diameter before ovulation varied substantially across cycles but not across women. Many (about 40%) women had small maximum follicular diameter on the day before ovulation (<19 mm). Pre-ovulatory cycle length was not related to maximum follicular diameter. In normal fecundity, there is a substantial variation in maximum follicular diameter from cycle to cycle based on variation in the duration of follicular development, but the variation could not be explained by different characteristics of different women. Explanation of variation in follicular growth has to be found on the cycle level.
Menstrual CycleSecular TrendsBMI and Metabolic AssociationsPuberty Timing
Studies from around the world indicate a trend toward younger ages of menarche. The extent of this trend in the Canadian population is unknown, and the relationship to later-life health indicators has not yet been fully elucidated. The objective of this study is to estimate the trend in age at menarche (AAM) in the Canadian population and evaluate the relationship between AAM and adult body mass index (BMI). Our data source was a nationally representative survey (the Canadian Community Health Survey, 2.2), and analyses included 8080 women, aged 15 and older, who self-reported AAM. Height and weight were measured by the interviewers for the calculation of current BMI. We modeled the secular trend in AAM over time, and the relationship between current BMI and AAM. We found a statistically significant decline in AAM in successive age cohorts, indicating a 0.73-year (8.8-month) decrease in AAM between the oldest and youngest age cohorts in the sample. A 1-year increase in AAM was associated with a decrease in mean BMI of approximately 0.5 kg/m(2), after adjustment for covariates. A current age-AAM interaction term was nonsignificant, indicating that the relationship was stable throughout increasing temporal separation from puberty. The observed trend toward earlier menarche could be an indicator of a change in insulin-related metabolism, possibly mediated by behavioral and environmental variables. This study suggests that AAM may be an important clinical and public health indicator of susceptibility to overweight and obesity and attendant morbidity.
Menstruation is the cyclic, orderly sloughing of the uterine lining on account of the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. There is a tendency among parents and clinicians to view oligo-amenorrhea as a normal variant in the teen years. In fact, the 95th percentile for the time interval between cycles is 90 days. Thus, it is abnormal for an adolescent to be amenorrheic for greater than 3 months, even in the early gynecologic years. Identification of abnormal menstrual patterns throughout adolescence may permit early identification of potential health concerns for adulthood. Few problems in gynecologic endocrinology are as complex or challenging to the clinician as amenorrhea. However, thorough evaluation of menstrual cycle disorders in adolescence provides a window of opportunity for early diagnosis and treatment of conditions affecting the hypothalamic-pituitary-ovarian (HPO) axis. Here we discuss a systematic approach to the evaluation and treatment of amenorrhea in adolescents who do not have androgen excess. There is strong evidence that estrogen deficiency is a risk factor for later development of osteoporosis and hip fracture. Delay in the evaluation and treatment of disordered menses in some cases may contribute to reduced bone density. Both patients and clinicians need to view the ovary as an important endocrine organ that helps maintain health, especially bone health.
To determine the effect of luteinized unruptured follicle (LUF) cycles on frozen thawed embryo transfer (FET).
A retrospective analysis comparing the clinical outcomes after FET among 144 cases of luteinized unruptured follicle (LUF) cycles and 866 cases of ovulation cycles.
Reproductive medical center, Beijing China. Chinese infertile women who underwent FET. None. Clinical pregnancy rate (PR), implantation rate. The implantation rate, clinical pregnancy rate, on-going pregnancy rate and live birth rate in LUF group were 12.76% (49/384), 27.78% (40/144), 24.31% (35/144) and 19.44% (28/144), respectively, and in ovulation group, 14.74% (332/2251), 31.29% (271/866), 28.29% (245/866) and 22.23% (193/866), respectively (p > 0.05). LUF does not affect the clinical outcomes of FET. Patients of LUF should be included in FET treatment.
Reproductive EndocrinologyEpilepsy and Reproductive HormonesInadequate Luteal PhaseCatamenial Epilepsy
We aimed to evaluate the effect of epilepsy on the reproductive hormones levels among female patients, and to investigate the frequency of catamenial pattern of seizures. A total of 42 female patients with epilepsy and 21 healthy females (control group) were included. Subjects were at least 2 years postmenarche with regular cycles. Symptoms of premenstrual syndrome (PMS) were assessed using calendar of premenstrual experience scoring. Patients were evaluated for catamenial pattern of seizures. Levels of FSH, LH, estradiol (E), and progesterone (P) were assessed for all subjects in the three phases of the cycles. Pelvi-abdominal ultrasound was performed near time of ovulation, to follow up size of mature follicle. Symptoms of PMS were not different in patients and controls, or in patients with and those without catamenial tendency. In both perimenstrual (M) and midluteal phases, FSH and P levels were lower and E/P ratio higher in patients group. There was a catamenial pattern of seizures in 31% of patients (53.8% M C(1); 46.15% inadequate luteal phase C(3)pattern). Patients with C(3)pattern showed lower P levels in the midluteal phase compared to patients with noncatamenial pattern, to those with C(1)pattern or to controls. Patients with C(1)pattern had lower P levels than controls in the M phase. There was evident disruption in the reproductive hormones in female patients with epilepsy with lower FSH and P levels and higher E/P ratio. A total of 31% of patients showed catamenial pattern of seizures (C(1)and C(3)patterns) that was significantly related to P withdrawal.
Fertility AwarenessFertile Window EstimationVariability and DurationE3G and LH Detection
The purpose of this study was to determine the variability in length of the fertile phase of the menstrual cycle with 140 participants who produced 1,060 cycles with an electronic hormonal fertility monitor. The length of the fertile phase, as defined by the first day with a threshold level of urinary E3G and ending with a second day above a threshold of LH, varied from <1 to >7 days, with the most frequent length being 3 days.
Bone HealthHIV-Associated Bone DiseaseOligomenorrheaPopulation-Based Assessment
This Canadian study of bone health showed that HIV+ women were more likely to have had fragility fractures (OR 1.7) but had BMD values that were not different than women from a national population-based cohort.
Given that 17.5 million women globally are HIV-infected and living longer on anti-retroviral therapy (ART+), it is essential to determine whether they are at risk for osteoporosis as is currently assumed. Assessment of osteoporosis risk factors and lifetime low-trauma (fragility) fracture history used a common interviewer-administered questionnaire and phantom-adjusted bone mineral density (BMD). This study compared HIV+ Canadian women with ageand region-matched control women (1:3) from a national population-based study of osteoporosis. One hundred and thirty-eight HIV+ women (100 ART+, 38 ART-) were compared with 402 controls. There were no differences in age (37.7 vs. 38.0 years), BMI (25.0 vs. 26.2), family history of osteoporosis, exercise history, alcohol or calcium intakes, age at menarche, oral contraceptive use or parity. HIV+ cases included more Aboriginal and Black women (12.5% and 16.2 vs. 2% and 1%, respectively), smoked and used injection drugs (53%) more, were more often treated with glucocorticoids, had oligomenorrhea, and reported 10-kg weight cycling. Significantly more HIV+ women reported lifetime fragility fractures (26.1% vs. 17.3; OR 1.7, 95% CI 1.1, 2.6). HIV+ and control spine 1.0 +/- 0.12 vs.1.0 +/- 0.14 g/cm(2) (diff. 0.0, 95% CI -0.27, 0.27) or total femur 0.91 +/- 0.15 vs. 0.93 +/- 0.12 g/cm(2) (diff 0.02, 95% CI +0.005, -0.045). HIV+ women reported significantly more past osteoporotic fractures than population-based controls despite normal BMD. Research is needed to assess bone microarchitecture and develop a reliable fracture risk assessment tool for HIV+ women.
Hormone-based contraceptives affect mood in healthy women or in women with premenstrual dysphoric disorder (PMDD). No study has yet examined their association with mood in women with major depressive disorder (MDD). The purpose of this study was to determine whether estrogen-progestin combination or progestin-only contraceptives are associated with depression severity, function and quality of life, or general medical or psychiatric comorbidity in women with MDD. This analysis focused on a large population of female outpatients less than 40 years of age with non-psychotic MDD who were treated in 18 primary and 23 psychiatric care settings across the US, using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Baseline demographic and clinical information was gathered and compared between three combination (estrogen-progestin)(N=232), progestin-only (N=58), and no hormone treatment (N=948). Caucasians were significantly more likely to use combined hormone contraception. Women on progestin-only had significantly more general medical comorbidities; greater hypersomnia, weight gain and gastrointestinal symptoms; and worse physical functioning than women in either of the other groups. Those on combined hormone contraception were significantly less depressed than those with no hormone treatment by the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated. The combined hormone group also demonstrated better physical functioning and less obsessive-compulsive disorder (COCD) comorbidity than either of the other groups. Synthetic estrogen and progestins may influence depressive and physical symptoms in depressed women.
Body LiteracyMenstrual Cycle as Vital SignAdolescent Menstrual PatternsMenstrual Assessment
Young patients and their parents often are unsure about what represents normal menstrual patterns, and clinicians also may be unsure about normal ranges for menstrual cycle length and amount and duration of flow through adolescence. It is important to be able to educate young patients and their parents regarding what to expect of a first period and about the range for normal cycle length of subsequent menses. It is equally important for clinicians to have an understanding of bleeding patterns in girls and adolescents, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate young patients' conditions appropriately. Using the menstrual cycle as an additional vital sign adds a powerful tool to the assessment of normal development and the exclusion of pathological conditions.
In the discussion of biologic differences between male and female fertility (April 6 issue),1 Federman states that women are fertile for only 12 hours each month. Although the egg is viable for 12 hours or less, the window of fertility in women is approximately five to six days in each menstrual cycle,24 depending on the presence of estrogenic cervical mucus that maximizes the storage, survival, and transport of sperm until ovulation.4,5 Dr. Stanford rightly calls attention to the elegant estrogen-dominated events that precede ovulation and that favor passage of sperm through the cervix . . .
The concept of the ovarian cycle as a continuum considers that all types of ovarian activity encountered during the reproductive life are responses to different environmental conditions in order to ensure the health of the woman. During the normal ovulatory cycle, a series of sequential events have to occur in a highly synchronized manner. Fertility awareness is useful in helping women to identify the different stages of their reproductive life cycle. Fertility awareness is also a valuable tool in helping women to identify gynecological disorders. Persistence of irregularities within the mucus patterns and the menstrual cycle should be of concern to women presenting with these problems. These irregularities may be due to obstetrical, endocrine, gynecological or iatrogenic disorders. Insight into early pregnancy complications, ovulatory dysfunction and pelvic inflammatory disease can be ascertained from abnormalities within the menstrual cycle and mucus pattern. Thus, fertility awareness will also enable the recognition and early treatment of several metabolic, endocrine and infectious diseases.
Menstrual CyclePhase Length DistributionOvulation Day EstimationElectronic Fertility Monitors
Fehring RJ et al., 2006·J Obstet Gynecol Neonatal Nurs
To determine variability in the phases of the menstrual cycle among healthy, regularly cycling women.
A prospective descriptive study of a new data set with biological markers to estimate parameters of the menstrual cycles. One hundred forty one healthy women (mean age 29 years) who monitored 3 to 13 menstrual cycles with an electronic fertility monitor and produced 1,060 usable cycles of data. Variability in the length of the menstrual cycle and of the follicular, fertile, and luteal phases, and menses. The estimated day of ovulation and end of the fertile phase was the peak fertility reading on the monitor (i.e., the urinary luteinizing hormone surge). Mean total length was 28.9 days (SD = 3.4) with 95% of the cycles between 22 and 36 days. Intracycle variability of greater than 7 days was observed in 42.5% of the women. Ninety-five percent of the cycles had all 6 days of fertile phase between days 4 and 23, but only 25% of participants had all days of the fertile phase between days 10 and 17. Among regularly cycling women, there is considerable normal variability in the phases of the menstrual cycle. The follicular phase contributes most to this variability.
The purpose of this review is to put into a useful clinical context the changing over time of basic ovarian-pituitary-hypothalamic relationships during perimenopause. "Perimenopause" means changes in ovarian hormones, feedback relationships, and clinical experiences beginning in women ages 35-50 with regular flow and ending 1 yr after the final menstrual flow. A key observation must be explained--estradiol levels are increased in perimenopause. Inhibin B levels are lower and activin may be higher in midlife, menstruating women. These changes probably cause higher follicular phase FSH levels--"endogenous ovarian hyperstimulation" results. The positive estradiol feedback on LH is also disturbed--midcycle LH peaks and mid-luteal slow-frequency, high-amplitude LH pulses are less frequent. In addition to higher levels, estradiol receptors may increase in tissues of symptomatic women. Despite hyperstimulation of follicles, progesterone levels and luteal phase lengths are paradoxically decreased--reasons probably include LH peak disruptions and estrogen-stimulated greater corticotrophin-mediated reproductive suppression. In summary, disturbed feedback relationships causing higher and unpredictable estrogen and lower progesterone levels occur throughout perimenopause, especially during regular cycles. Prospective, population-based research is needed to systematically relate these feedback hormonal changes to clinical characteristics and to allow a diagnosis of perimenopause in regularly cycling midlife women.
Menstrual CycleUltrastructureScanning Electron MicroscopyCervical Mucus Patterns
Two main types of cervical mucus have been described oestrogenic and progestative. Each category shows diverse morphological and functional features from the reproductive point of view. Traditionally, this change has been approached by analysing morphological patterns. In fact, a mesh model has been described for cervical mucus, structurally composed of fibrillar subunits with a parallel orientation, together with another model in a characteristic network shape with canalicular units, but the real model is not clear. The objective of our work was to study the different morphological structures of the mucus, as related to the day of follicular rupture (considered as day 0) determined by ultrasound. Cervical mucus samples were obtained from the cervical canal with an ASPIRETTEtrade mark from day -4 to day +1 of the menstrual cycle. Samples were fixed and dried by critical point. The ultrastructure was examined with scanning electron microscopy. The presence of three types of oestrogenic and one type of progestative cervical mucus was confirmed in this period. Our paper shows different types of ultrastructure in the oestrogenic mucus in relation to ovulation, which would help to understand the interaction between male gametes and cervical mucus in migration through the female genital tract.
Menstrual CycleRespiratory FunctionEstradiol and ProgesteroneRepeated Measures
Catherine J Bacon et al., 2005·Respir Physiol Neurobiol
To determine whether lung transfer factor for carbon monoxide (T(L(CO))) alters during menstrual phase and if steroid hormone levels relate to these changes, T(L(CO)) and T(L(CO)) adjusted for both alveolar volume (T(L)/V(A)) and haemoglobin concentration, were measured at five predefined and hormonally confirmed menstrual phases in 13 women. No difference between phases was observed in T(L(CO)) or adjusted values. Moreover, there was no association between the maximal change in oestradiol, progesterone, progesterone ratio and the change in T(L(CO)) measured at the same time. When the first five chronological measurements, regardless of the menstrual phase at which they were measured, were analysed, T(L(CO)) changed significantly (p<0.05) with a maximal change between the first and fourth test (-2.69+/-2.53, 95% confidence interval). Although these results indicate that the first in a series of T(L(CO)) measurements may be higher, we found neither menstrual cycle phase nor ovarian hormone-related changes in T(L(CO)), and conclude that its adjustment for menstrual phase may not be necessary.
Reproductive EndocrinologyMenstrual CycleFertility Awareness
Open Access
Our recent study showed a dose-response relationship between environmental tobacco smoke (ETS) and the risk of early pregnancy loss. Smoking is known to affect female reproductive hormones. We explored whether ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. We prospectively studied 371 healthy newly married nonsmoking women in China who intended to conceive and had stopped contraception. Daily records of vaginal bleeding, active and passive cigarette smoking, and daily first-morning urine specimens were collected for up to 1 year or until a clinical pregnancy was achieved. We determined the day of ovulation for each menstrual cycle. The effects of ETS exposure on daily urinary PdG and E1C levels in a +/-10 day window around the day of ovulation were analyzed for conception and nonconception cycles, respectively. Our analysis included 344 nonconception cycles and 329 conception cycles. In nonconception cycles, cycles with ETS exposure had significantly lower urinary E1C levels (beta = -0.43, SE = 0.08, p < 0.001 in log scale) compared with the cycles without ETS exposure. There was no significant difference in urinary PdG levels in cycles having ETS exposure (beta = -0.07, SE = 0.15, p = 0.637 in log scale) compared with no ETS exposure. Among conception cycles, there were no significant differences in E1C and PdG levels between ETS exposure and nonexposure. In conclusion, ETS exposure was associated with significantly lower urinary E1C levels among nonconception cycles, suggesting that the adverse reproductive effect of ETS may act partly through its antiestrogen effects.
Contraception/ComparisonExtended Use SafetyRisks and EvidenceContraceptive Safety
For many years, individual women and doctors have experimented with extending the duration of active oral contraceptive (OC) pills between pill-free intervals (long OC) to control menstruation. The U.S. approval of an OC with 84 active days and 7 pill-free days in 2003 has attracted considerable media attention. In this review we consider the published evidence on the effectiveness, side effects, and risks of menstrual suppression with long OC. We performed a systematic review of published literature on long OC, up to April 2003. Ten papers were located; two were randomized trials comparing long OC to standard OC; the remaining studies were single-group observational studies. Women on long OC schedules had fewer days of scheduled bleeding during days without pills but more days of unscheduled bleeding and spotting than those on standard OC. These problems were worse for women new to OC and diminished over time. Women on long OC were more likely to discontinue due to poor control of bleeding; women on standard OC were more likely to stop because of problems with headaches. Women on long OC and standard OC both showed increases in physiological factors related to clotting, with a nonsignificant tendency for those on long OC to be more affected. No studies considered the effects of long OC on breast tissue, breast density, endometrial safety, or adolescent maturation and reproductive development. No systematic data were available on the return to reproductive function and fertility after taking long OC. There were no placebo-controlled trials and no information on how long OC compares to normal, unmedicated menstrual cycles. Therefore we believe scientific evidence for safety of long OC use is presently lacking.
The rise in FSH (FSHr) that leads to the recruitment of a cohort of follicles during the menstrual cycle occurs during the luteal-follicular transition, however, it is unclear whether it consistently occurs on one particular day, or is subjected to reproductive ageing. We determined the FSHr in 836 complete menstrual cycles from 102 women with regular menses using an algorithm, and additionally compared the relative variation in FSH during the last 14 days of the cycle. Possible effects of reproductive ageing on the onset of FSHr were also investigated. The day of FSHr follows a normal distribution with a median value of -4 (relative to first day of menses), mean -4.1 and SD 2.1. Analysis of the relative changes in FSH during the last 14 days of the cycle revealed the first significant rise on day -4 (P=0.0033), coinciding with the first significant drop in estrogens (P=0.0002). No effect of chronological age, or initial FSH levels, on FSHr was found, however, there was an inverse relationship between total follicular phase length (from day of FSHr to LH peak) and initial FSH levels (P<0.0001). The initial FSH rise in the cycle occurs consistently 4 days before menses, is related to a drop in estrogen levels, and is not affected by reproductive ageing.
Baerwald et al. (1) proposed a new model for ovarian follicular development in the human menstrual cycle. They showed additional waves of follicular development in the follicular and luteal phase of normal ovulatory cycles. Although no additional ovulation was observed, the authors speculated that the anovulatory follicles from the additional waves of follicular development may be able to ovulate in the presence of an additional LH surge.
Fertility AwarenessScientific FoundationsBiophysical Properties and Mucus TypingHormonal and Ultrasound Correlation
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
The CREIGHTON MODEL FertilityCare System (CrMS) rests on a decades-long body of research demonstrating that cervical mucus functions as a physiologically regulated biological valve, opening predictably at the periovulatory estrogen rise and closing in the post-Peak phase. Chapter 15 of Hilgers (2004) synthesizes hormonal, ultrasound, cytologic, and biophysical evidence to establish that a woman's external observation of her Peak Day reliably identifies the fertile window, and documents the system's effectiveness data for both achieving and avoiding pregnancy across a five-study meta-analysis of nearly 1,900 couples.
Thomas W. Hilgers, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Medical protocols in NaProTECHNOLOGY are cycle-phase-targeted regimens — covering ovulation induction, luteal phase hormonal support, hyperprolactinemia management, thyroid optimization, and pre-conceptual supplementation — derived from the biomarker-defined diagnosis rather than empirical stimulation. Consolidating these protocols in a single reference enables practitioners to apply evidence-based, individualized treatment sequences that address root hormonal pathology while supporting natural conception.
Fertility AwarenessAchieving- and Avoiding-Related BehaviorUse TaxonomyPregnancy Classification
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Chapter 13 of Hilgers' NaProTECHNOLOGY textbook establishes a clinical behavioral taxonomy unique to the Creighton Model FertilityCare System, distinguishing between achieving-related and avoiding-related use based on whether a couple's actions increase or decrease the probability of conception. The chapter argues that a "taking a chance" mindset is inherently contraceptive in psychology and must be replaced with intentional, education-grounded behavior that reflects a couple's genuine family planning goals.
Women's HealthEndometrial Cancer Risk and DetectionBreast Cancer Hormonal AssociationsOvarian Cancer Early Detection
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Chapter 34 of Hilgers (2004) examines how NaProTechnology cycle charting may identify women at elevated risk endometrial, breast, and ovarian. The chapter presents clinical case series and a small prospective study suggesting that observable cycle biomarkers, particularly patterns indicating suboptimal luteal-phase function, may precede diagnosis and could inform earlier evaluation, while calling explicitly for further research to validate these findings.
Menstrual CycleAbnormal Uterine BleedingCREIGHTON MODEL SystemLuteal Phase Dysfunction
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Unusual uterine bleeding -- including premenstrual spotting, tail-end brown bleeding, mid-cycle intermenstrual bleeding, and heavy menses -- is evaluated in NaProTECHNOLOGY through prospective CrMS charting combined with cycle-phase-targeted estradiol and serial post-Peak progesterone profiles, which typically reveal luteal phase deficiency, follicular estradiol insufficiency, or anovulation as the primary etiology. Treatment is etiology-directed cooperative progesterone replacement for luteal defects, follicular support or ovulation induction for follicular phase insufficiency, and fertility-sparing surgical correction for structural pathology such as endometriosis, polyps, or fibroids, without routine recourse to contraceptive suppression.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
A CrMS-synchronized hormone sampling protocol is detailed in which progesterone, estradiol, and other reproductive hormones are drawn at cycle-phase-specific time points defined by the charted Peak Day rather than by fixed cycle day, producing a targeted hormone profile that accurately reflects luteal and follicular function. This Peak Day-referenced approach substantially improves the diagnostic sensitivity for luteal phase deficiency, follicular dysfunction, and other endocrine abnormalities that fixed-day sampling routinely misclassifies.
Bone HealthReproductive EndocrinologyFertility AwarenessNaProTECHNOLOGY
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Chronic anovulation and progesterone or estradiol deficiency identified through CrMS charting represent periods of suboptimal bone accrual in women of reproductive age, because both estradiol and progesterone contribute to skeletal maintenance -- estradiol through suppression of osteoclast activity and progesterone through osteoblast stimulation. NaProTECHNOLOGY uses longitudinal CrMS records of ovulatory status and hormone profiles as a bone-health risk screen, guiding cycle-synchronized bioidentical hormone replacement to restore normal estrogen-progesterone balance and potentially mitigate progression toward osteoporosis in women with chronic cycle-based endocrine deficiencies.
NaProTECHNOLOGYFamily Practice ModelFertilityCare Practitioner and OB/GYN ConsultCreighton Model Charting and Timed Hormone Profiling
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Family physicians trained in NaProTECHNOLOGY serve as primary coordinators of medical management — prescribing targeted hormone support, monitoring biomarker trends, and triaging surgical referrals — within a collaborative care model. Their longitudinal relationship with patients and ability to integrate reproductive medicine into whole-person primary care is a structural advantage of the NaProTECHNOLOGY delivery system over specialist-only models.
NaProTECHNOLOGYCPRT and CERTProgesterone and Estradiol SupportPeak Day Ovulation Timing
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Cooperative progesterone and estrogen replacement therapy administers bioidentical hormones in precise synchrony with the woman's CrMS-identified Peak day -- beginning progesterone at P+2 or P+3 and continuing through the luteal phase -- to augment deficient corpus luteum output rather than override the cycle with suppressive dosing. Serial serum progesterone across post-Peak days guides dose titration, and the approach is applied to luteal phase deficiency, recurrent miscarriage, premenstrual syndrome, and postpartum depression while preserving ovulatory function and fertility.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Physiological and psychological stress disrupts hypothalamic GnRH pulsatility via CRH-cortisol pathways, producing downstream impairments in LH and FSH secretion that manifest as anovulation, delayed ovulation, follicular phase prolongation, or luteal phase deficiency -- all of which are documented cycle-by-cycle on the CrMS chart. NaProTECHNOLOGY addresses stress-induced HPO axis dysfunction by identifying the specific cycle-level disorder through charting and targeted hormone profiling, then applying cycle-appropriate ovulation induction and cooperative hormone support alongside correction of the underlying physical or psychological stressor.
Oral contraceptives are commonly used by women athletes. However, their effect on athletic performance is unclear. To examine the effects of a moderate dose, triphasic oral contraceptive on measures of athletic performance in highly trained women athletes. This is a double blind, placebo controlled trial in 14 women with ovulatory menstrual cycles and maximal aerobic capacity (VO(2)MAX) >/==" BORDER="0">50 ml/kg/min. Four measures of athletic VO(2)MAX, anaerobic capacity (anaerobic speed test), aerobic endurance (time to fatigue at 90% of VO(2)MAX), and isokinetic strength (Cybex II dynamometer). Height, weight, and six skinfold measurements were also recorded. All these observational tests were completed during both the follicular and mid-luteal phases of an ovulatory menstrual cycle. Cycle phases were confirmed by assaying plasma oestradiol and progesterone. Participants were subsequently randomly assigned to either a tricyclic oral contraceptive or placebo and retested in identical fashion (oral contraceptive phase). Absolute and relative changes in VO(2)MAX from follicular to oral contraceptive phase decreased in the oral contraceptive group by 4.7%, whereas the placebo group showed a slight increase (+1.5%) over the same time period. Two of the women taking oral contraceptive had decreases of 4 and 9 ml/kg/min. In contrast, most women in the placebo group improved or maintained VO(2)MAX. There was also a significant increase in the sum of skinfolds in women taking oral contraceptive compared with those taking placebo (p<0.01). There were no significant changes in other physiological variables (maximum ventilation, heart rate, respiratory exchange ratio, packed cell volume) or measures of performance (anaerobic speed test, aerobic endurance, isokinetic strength) as a function of oral contraceptive treatment. The decrease in VO(2)MAX that occurs when oral contraceptive is taken may influence elite sporting performance in some women. Further studies are required to determine the mechanisms of this change.
Perimenopause/MenopauseVasomotor and Breast Tenderness CyclicityBasal Body Temperature MethodsDaily Perimenopause Diary
The purpose was to explore cyclicity of breast tenderness and vasomotor symptoms in menstruating mid-life women using the Daily Perimenopause Diary. Untreated mid-life women from a convenience sample completed the Daily Perimenopause Diary for clinical (n = 14) or research (n = 10) assessments. Breast tenderness, sleep disturbance and day and night vasomotor intensity were rated on a 0-4 scale with vasomotor number as a count. Daily oral temperature data were analyzed using the Quantitative Basal Temperature algorithm to assess ovulation and estimate luteal phase length. Analysis of variance tested cyclicity using the mean of three 3-day windows (during flow, at mid-cycle and premenstrually). Ninety-eight complete flow-to-flow diaries (from 24 women, mean age 47 years, cycle length 27 +/- 6.4 (standard deviation) days) were available, with quantitative temperature data for 60 cycles in 16 women. Of assessed cycles, 90% were ovulatory; 25% had luteal phases < 10 days. Breast tenderness was maximal in the premenstrual window overall (p < 0.0001) and in the ovulatory subset. Night sweats were maximal premenstrually (p = 0.0035) except in anovulatory cycles. Daytime flushes were not cyclic (p = 0.1333) except in ovulatory cycles (p = 0.031). Daily Perimenopause Diaries from mid-life women show premenstrual increases in breast tenderness and night sweats.
SurgeryTiming and OutcomesSurgical RecurrenceSurgical Implications
In vitro studies demonstrated that implantation on membranes (peritoneum, amniotic membranes) can take place if there are defects on the surface of the membranes. If these mechanisms play a role for the development of endometriosis in vivo, then patients with surgical treatment of peritoneal endometriosis in the luteal phase must have a high recurrence rate. Retrospective analysis of operation charts and follow-up data. Department of gynecology, in a hospital-based endometriosis treatment center. PATIENT(S): Two hundred twenty premenopausal women. INTERVENTION(S): Laparoscopic treatment for peritoneal endometriosis, stage I and II by revised American Society for Reproductive Medicine guidelines. MAIN OUTCOME MEASURE(S): During the follow-up period of 2 years, symptoms and gynecological and sonographic findings were documented. In case of suspected recurrence a repeat laparoscopy with biopsy was performed to prove the recurrent endometriosis macroscopically and histologically. RESULT(S): The total recurrence rate after 2 years was 9.6%. The recurrence rate of group III (15%) was twice as high as those of group I (7%) and group II (8%), as indicated by subjective complaints, clinical findings, macroscopy, and histology; no differences were found between groups I and II. CONCLUSION(S): Endoscopic surgery for the treatment of peritoneal endometriosis should not be performed in the luteal phase.
This study examined pain sensitivity and pain modularity mechanisms (e.g., beta-endorphin levels, blood pressure) in women with premenstrual dysphoric disorder (PMDD; n = 27) and healthy controls (n = 27) during the follicular and luteal phases of the menstrual cycle. Physiological measures were taken during rest and ischemic pain testing. In both cycle phases, PMDD women (a) displayed lower resting cortisol and beta-endorphin levels and (b) exhibited shorter pain threshold and tolerance times and greater pain unpleasantness ratings during pain. PMDD women also reported greater pain unpleasantness and intensity and had lower beta-endorphin levels in their luteal phase and tended to display higher blood pressure levels at rest and during pain testing. Results suggest that endogenous opioids may be pathophysiologically relevant to PMDD and that the hypothalamic-pituitary-gonadal axis may modulate pain sensitivity in PMDD.
To describe severity of emotional and physical symptoms in a large diverse sample; to examine demographic, health status, and behavioral correlates of symptom severity; and to describe use of medications and alternative remedies for premenstrual symptoms. A total of 1194 women, ages 21-45, selected from members of a large northern California health maintenance organization, completed daily ratings of symptom severity for two menstrual cycles. An empirically derived algorithm defined symptom severity groups as minimal (n = 186), moderate (n = 801), severe (n = 151), or premenstrual dysphoric disorder (n = 56). Symptom severity as a continuous variable was defined by the two-cycle mean symptom ratings in the luteal phase. Demographic, health status, and behavioral factors and use of treatments for premenstrual symptoms were assessed by self-report. Luteal phase symptom-specific ratings were generally significantly greater in the premenstrual dysphoric disorder group than in the other groups (P <.001). Symptom severity score increased with each comorbidity and decreased with each year of age. Symptom severity was also inversely associated with oral contraceptive use (emotional symptoms) and better perceived health (physical symptoms). Hispanics reported greater severity of symptoms, and Asians less, relative to whites. Use of herbal and nutritional supplements for premenstrual symptoms steadily increased from 10.8% in the minimal group to 30.4% in the premenstrual dysphoric disorder group (P <.01). The degree of premenstrual symptom severity varies in the population, is relatively constant within each woman over two consecutive cycles, particularly for emotional symptoms, and is influenced by age, race/ethnicity, and health status.
To assess the reliability and factor structure of the Calendar of Premenstrual Experiences (COPE) in premenstrual syndrome (PMS) patients. Healthy women diagnosed with PMS (N = 215) completed daily diaries assessing 22 PMS behavioral and physical symptoms over two consecutive months. Internal consistency (alpha) was high (.93-.94) for the COPE total score and behavioral subscale score and moderately high (.79) for the physical subscale score. Test-retest correlations produced lower estimates of reliability (.55-.59). Four factors, accounting for 64% of the total variance, mood symptoms, somatic/cognitive symptoms, appetitive symptoms and fluid retention symptoms. Symptom reports increased in consecutive luteal phases for three of the four factors; however, the factor structure remained consistent in consecutive months. The COPE diary is a reliable instrument for identifying fluctuations in behavioral and physical symptoms during the luteal phase, and PMS symptoms can be reliably conceptualized within four factors. Symptom expression may increase in response to daily self-monitoring.
PregnancyUltrasound vs LMP DatingClassification and PrevalenceVariability in Ovulation Timing
Early ultrasound scanning estimation of gestational age is known to increase the reported preterm delivery rate (<37 completed weeks) compared with estimation by date of the last normal menstrual period, but it is unclear how this systematic difference arises. This study was a hospital-based study of 44,623 women who delivered a live-born or stillborn infant between January 1, 1978, and March 31, 1996, and who had both last normal menstrual period-based and early (usually at 16-18 weeks) ultrasound scan-based gestational age estimates. Cross-classification of the 2 estimates by completed weeks was used to examine the direction and magnitude of the differences between them and to compare the resulting classifications of preterm birth. The early ultrasound scan-based gestational age distribution was shifted uniformly to the left (ie, lower gestational age) relative to the last normal menstrual period gestational age distribution; the early ultrasound scan-based preterm delivery rate was 9.1%, which was 19.5% (n = 659 births) higher than the 7.6% rate by last normal menstrual period (P <.0001). The last normal menstrual period estimate exceeded the early ultrasound scan estimate far more often than the reverse, up to and including early ultrasound scan estimates of 40 weeks. No concentration of 4-week discrepancies was observed in either direction, as would be expected with random or systematic errors in recall of the last normal menstrual period. The absolute number of births at 37 to 39 weeks of gestation (by last normal menstrual period) that were reclassified as preterm (n = 1206 births) was much higher than the number of preterm births at 34 to 36 weeks of gestation that were reclassified as term (n = 581 births). The net increase of 625 preterm births (from 581 to 1206 births) that resulted from reclassification of births at 37 to 39 last normal menstrual period weeks accounted for 95% of the total 659-birth increase in early ultrasound scan-based preterm births at all last normal menstrual period gestational ages. Early ultrasound scanning reduces the gestational age estimate across the entire gestational age range; early ultrasound scan-based reclassification of gestational age results in a substantial increase in the prevalence of preterm births. Small downward reclassifications exceed upward reclassifications of similar magnitude, which is consistent with previous reports that delayed (>14 days) ovulation is more frequent than early (<14 days) ovulation.
Perimenopause/MenopauseLuteal Phase DefectsEstradiol and Progesterone in PerimenopauseDisturbances in Perimenopause
Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels occur during perimenopause. These ovarian changes may be causally related to lower inhibin production but the dynamic prospective inter-relationships within women are not well documented. This review will first define perimenopause and then explore the limited published data on ovulatory characteristics in perimenopause. In addition, it will report preliminary prospective observational data on menstrual cycles and ovulation in initially ovulatory women followed through the perimenopause. Prospective data suggest that ovulation disturbances begin early in perimenopause and increase with irregular cycles. Combined with higher oestradiol levels they may cause menorrhagia. It is not yet known whether disturbances of ovulation relate to bone loss in perimenopausal, as in premenopausal, women. It is also not known whether progesterone therapy can effectively counteract the end organ (breast, endometrial, brain) effects of higher/erratic oestradiol levels and effectively treat perimenopausal vasomotor and other symptoms.
To determine whether a new monophasic oral contraceptive containing drospirenone/ethinyl estradiol reduces premenstrual symptoms. In an open-label study measuring intrasubject changes in premenstrual symptoms and comparing effects between women who were new users of oral contraceptives and those who switched from previous contraceptives, ethinyl estradiol (30 micrograms) and drospirenone (3 mg) were administered for 13 menstrual cycles to 326 healthy women aged 18-35 years. Subjects completed the 23-item Women's Health Assessment Questionnaire at baseline and at the end of the sixth cycle. At the end of cycle 6, premenstrual and menstrual symptom scores on the negative affect and water retention scales were reduced significantly relative to baseline, as was increased appetite during the premenstrual and menstrual phases. Similar improvements were seen among new users of hormonal contraceptives and those who switched from previous contraceptives. Impaired concentration scale scores were not significantly reduced from baseline, and assessments of undesired hair changes and feelings of well-being did not change appreciably. An oral contraceptive containing drospirenone/ethinyl estradiol may reduce the premenstrual symptoms of negative affect, water retention and increased appetite.
Menstrual CyclePMDD and Depression RiskPremenstrual Dysphoric DisorderPMDD Diagnostic Validity
Investigators examined whether premenstrual dysphoric disorder (PMDD) poses a risk for major depressive disorder (MDD). In an initial study, women rated premenstrual symptoms and functional impairment daily for two menstrual cycles. A semistructured diagnostic interview was given to obtain psychiatric histories and differentiate PMDD from premenstrual exacerbations of other disorders. Participants in this pilot study were eight women with PMDD and a random subgroup without PMDD (n = 9) initially. Another semistructured interview was given to diagnose psychiatric disorders occurring during a two-year follow-up interval. In all, seven of the eight women with PMDD developed MDD within two years, including all those who had never had MDD before. The odds that a woman with PMDD developed MDD were 14 times the odds that a woman without PMDD developed MDD ( p <.05). Premenstrual dysphoric disorder may be a prodrome of or causal risk factor for MDD. Preliminary evidence for the diagnostic validity of PMDD is provided.
This study examined changes in the luteal vasculature throughout the menstrual cycle and during simulated pregnancy with human chorionic gonadotrophin (HCG) in the human. Endothelial cell and pericyte area were assessed by quantitative immunocytochemistry for CD34 and alpha-smooth muscle actin respectively, taking into consideration the dynamics of lutein cell hypertrophy and atrophy throughout the cycle and after HCG treatment. Endothelial cell proliferation was detected by Ki-67/CD34 dual staining and a proliferation index was obtained. The molecular regulation of angiogenesis was studied by examining changes in vascular endothelial growth factor (VEGF) immunostaining. The early luteal phase is associated with intense angiogenesis, as indicated by high endothelial cell proliferation, and by the mid-luteal phase a mature vasculature was apparent, as shown by maximal endothelial cell and pericyte areas. During the late luteal phase, decreased endothelial proliferation, endothelial cell and pericyte area indicated vascular regression. HCG treatment induced a second burst of total and endothelial cell proliferation and a concomitant increase in endothelial cell and pericyte areas. VEGF protein was expressed throughout the luteal phase and a significant increase was found after HCG treatment. Luteal rescue with HCG is associated with a second wave of angiogenesis and vascular stabilization.
Perimenopause/MenopauseSTRAW Staging SystemDefinition and StagingStaging Criteria
Women have twice the incidence of major depression compared with men. They are prone to develop episodes of depression during times of reproductive hormonal change at puberty, with use of oral contraceptives, during the premenstrual phase of the menstrual cycle, postpartum and during the perimenopause (see ). describes the variety of disturbances in biological rhythms observed in mood disorders. In this report, we describe the chronobiological disturbances observed in female-specific mood disorders, namely, premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. We hypothesize that changing reproductive hormones, by affecting the synchrony or coherence between components of the circadian system, may alter amplitude or phase (timing) relationships and thereby contribute to the development of mood disorders in predisposed individuals.
To evaluate the efficacy of progesterone and progestogens in the management of premenstrual syndrome. Systematic review of published randomised, placebo controlled trials. 10 trials of progesterone therapy (531 women) and four trials of progestogen therapy (378 women). Proportion of women whose symptoms showed improvement with progesterone preparations (suppositories and oral micronised). Proportion of women whose symptoms showed improvement with progestogens. Secondary analysis of efficacy of progesterone and progestogens in managing physical and behavioural symptoms. Overall standardised mean difference for all trials that assessed efficacy of progesterone (by both routes of administration) was -0.028 (95% confidence interval -0.017 to -0.040). The odds ratio was 1.05 (1.03 to 1.08) in favour of progesterone, indicating no clinically important difference between progesterone and placebo. For progestogens the overall standardised mean was -0.036 (-0.014 to -0.060), which corresponds to an odds ratio of 1.07 (1.03 to 1.11) showing a statistically, but not clinically, significant improvement for women taking progestogens. The evidence from these meta-analyses does not support the use of progesterone or progestogens in the management of premenstrual syndrome.
Fertility AwarenessBiomarker ComparisonUltrasound and Hormonal IndicesCervical Mucus and Urinary Hormones
To improve prediction of ovulation in normal cycles. Collection of women's characteristics and their menstrual cycles. Monitoring and analysis of time relationships between several transvaginal ultrasonography, cervical mucus, basal body temperature, urinary luteinising hormone, and ratio of urinary oestrogen to progesterone metabolites. Each of eight natural family planning clinics was to study 12 women for at least three cycles. One hundred and seven normally fertile and cycling women aged 18 to 45. Daily measurements of urinary luteinising hormone, follicle stimulating hormone, oestrone-3-glucuronide and pregnanediol-3alpha-glucuronide. Basal body temperature recording and cervical mucus checking. Transvaginal ultrasound examination of the ovaries. Delays between the expected day of ovulation according to the luteinising hormone peak or to ultrasound evidence and the expected days according to the other indices of ovulation. Ultrasonography was able to show evidence of ovulation in 283 out of 326 cycles. The average time lag between luteinising hormone peak and ultrasound evidence was less than one day (+0.46) but premature and late luteinising hormone-expected date of ovulation were observed in nearly 10% and 23% of cycles, respectively. Basal body temperature rise was observed in 98% of cycles. Cervical mucus peak symptom, rapid drop in the ratio of urinary metabolites, and luteinising hormone initial rise were all close to ultrasonographic evidence in more than 72% of cycles. For accuracy and practical reasons, the cervical mucus peak symptom, the ratio of urinary metabolites and luteinising hormone initial rise might be better indices of ovulation than the luteinising hormone peak.
To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. Clinical research center in an academic medical institution. PATIENT(S): Seventy-seven women > or =18 years old with time since menarche > or =5 and < or =25 years were recruited by advertisement. INTERVENTION(S): Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. MAIN OUTCOME MEASURE(S): Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. RESULT(S): Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. CONCLUSION(S): The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.
Bone HealthDietary RestraintSubclinical AnovulationMetabolic Factors
Women with high scores for dietary restraint have been found to have higher 24-h urinary cortisol excretion and a higher prevalence of subclinical ovulatory disturbances, both of which may be risk factors for bone loss. The purpose of this study was to explore relationships between dietary restraint and bone health in regularly menstruating young women. 62 women (age: 21.7 +/- 2.5 yr) had body composition and total body and lumbar spine bone mineral density (BMD) and content (BMC) assessed using dual-energy x-ray absorptiometry. Dietary restraint was assessed using the restraint subscale from the Three-Factor 29 women had low restraint (LR; restraint score 0--5), 33 had high restraint (HR; restraint score 13--21). Exercise (h x wk(-1)) was assessed by questionnaire on two occasions. LR and HR women were similar in age and body composition (fat mass = 15.0 +/- 4.7 kg, lean mass = 40.9 +/- 4.9 kg), but HR women exercised more (3.4 +/- 1.7 vs 2.2 +/- 1.8 h x wk(-1), P < 0.05). Exercise was correlated with BMD and BMC, and when it was included as a covariate, total body BMC was significantly lower in HR than LR women. In multiple regression analysis, weekly hours of exercise and restraint score were significant predictors of total body BMD and BMC. The observations of this cross-sectional study suggest that high levels of cognitive dietary restraint, or associated factors such as higher cortisol, may attenuate the positive effects of exercise on bone in young women.
Bone HealthPubertal Bone Mineral AcquisitionGrowth and DevelopmentCalcium Intake and Bone Density
This 2-year prospective study examined associations among bone mineral acquisition and physical, maturational, and lifestyle variables during the pubertal transition in healthy girls. Forty-five girls, initially 10.5+/-0.6 years, participated. Body composition and bone mineral content (BMC) at the spine and total body (TB) were assessed at baseline and annually thereafter using dual-energy X-ray absorptiometry (DXA). Nutrient intakes were assessed using 3-day diet records and a calcium food frequency questionnaire (FFQ), physical activity by questionnaire, sexual maturation using Tanner's stages of breast and pubic hair maturation, growth by height and weight, and eating attitudes using the children's Eating Attitudes Test (Children's EAT). Mean children's EAT subscale scores (dieting, oral control [OC], and bulimia) were stable over time. Median split of OC subscale scores was used to form high and low OC groups. Groups had similar body composition, dietary intake, activity, and Tanner stage at baseline and 2 years. Using height, weight, and Tanner breast stage as covariates, girls with low OC scores had greater TB BMC at baseline (1452+/-221 g vs. 1387+/-197 g; p = 0.030) and 2 years (2003+/-323 g vs. 1909+/-299 g; p = 0.049) and greater lumbar spine (LS) BMC at 2 years (45.2+/-8.8 g vs. 41.2+/-9.6 g; p = 0.042). In multiple regression analysis, OC score predicted baseline, 2 years, and 2-year change in TB and spinal BMC, contributing 0.9-7.6% to explained variance. Calcium intake predicted baseline, 2 years, and 2-year change in TB BMC, explaining 1.6-5.3% of variance. We conclude that both OC and habitual calcium intake may influence bone mineral acquisition.
This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.
To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. General medicine community clinics. 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.
Cognitive dietary restraint, assessed by the Three-Factor Eating Questionnaire restraint subscale, is associated with subclinical menstrual cycle disturbances. This association may be mediated by stress-activated cortisol release. We assessed whether 24-h urinary cortisol excretion differs between women with high and low restraint scores.
Participants (aged 21.6+/-2.5 y; n = 62) with normal-length menstrual cycles and high (n = 33) or low (n = 29) restraint scores completed a questionnaire describing weight history, dietary practices, and exercise. Cortisol, calcium, and creatinine were measured in urine collected over 24 h on a day when all food and beverages were provided and measured. Previously, 3-d food records and anthropometric measurements were obtained. Age, height, weight, body mass index, and length of menstrual cycle were similar between groups. The reported amount of exercise was higher (3.4+/-1.7 compared with 2.2+/-1.8 h/wk; P<0.05) and energy intakes (assessed from 3-d and 24-h food records) were lower in the highthan in the low-restraint group. Ratios of urinary cortisol (nmol) to creatinine (mmol) were higher in the high-restraint than in the low-restraint group (42.9+/-12.9 compared with 36.3+/-8.9; P<0.05), whereas ratios of urinary calcium (mmol) to creatinine were lower (0.3+/-0.1 compared with 0.4+/-0.2; P<0.05) in the high-restraint group. Urinary cortisol was not associated with exercise, nutrient intakes, or anthropometric measurements. High dietary restraint scores are associated with urinary cortisol, a biological marker of stress, and high cortisol excretion may affect bone health. Our results suggest that further research is warranted to clarify these associations and to determine whether they persist over time.
To provide specific estimates of the likely occurrence of the six fertile days (the "fertile window") during the menstrual cycle.
Prospective cohort study. 221 healthy women who were planning a pregnancy. The timing of ovulation in 696 menstrual cycles, estimated using urinary metabolites of oestrogen and progesterone. The fertile window occurred during a broad range of days in the menstrual cycle. On every day between days 6 and 21, women had at minimum a 10% probability of being in their fertile window. Women cannot predict a sporadic late ovulation; 4-6% of women whose cycles had not yet resumed were potentially fertile in the fifth week of their cycle. In only about 30% of women is the fertile window entirely within the days of the menstrual cycle identified by clinical guidelines-that is, between days 10 and 17. Most women reach their fertile window earlier and others much later. Women should be advised that the timing of their fertile window can be highly unpredictable, even if their cycles are usually regular.
Selective serotonin-reuptake inhibitors (SSRIs) are increasingly being used as first-line therapy for severe premenstrual syndrome (PMS). We undertook a meta-analysis on the efficacy of SSRIs in this disorder. We searched medical and scientific databases, approached pharmaceutical companies, and reviewed citations of relevant articles to identify 29 studies of the use of SSRIs in PMS. 14 were excluded (no placebo group, preliminary report of included trial, or low quality). 15 randomised placebo-controlled trials were included. Information on study design, participants, drugs used and dosing regimens, outcome measures, side-effects, and sources of funding was extracted. Standardised mean differences between treatment and placebo groups were calculated to obtain an overall estimate of efficacy. The primary outcome measure was a reduction in overall PMS symptoms. The primary analysis included data on 904 women (570 assigned active treatment and 435 assigned placebo, including 101 in crossover trials). The overall standardised mean difference was -1.066 (95% CI -1.381 to -0.750), which corresponds to an odds ratio of 6.91 (3.90 to 12.2) in favour of SSRIs. SSRIs were effective in treating physical and behavioural symptoms. There was no significant difference in symptom reduction between continuous and intermittent dosing or between trials funded by pharmaceutical companies and those independently funded. Withdrawal due to side-effects was 2.5 times more likely in the active-treatment group than in the placebo group. SSRIs are an effective first-line therapy for severe PMS. The safety of these drugs has been demonstrated in trials of affective disorder, and the side-effects at low doses are generally acceptable.
Sveinsdóttir H et al., 2000·Acta Obstet Gynecol Scand
The prevalence of significant symptom change (symptom cyclicity) prospectively rated over multiple menstrual cycles has not been established in a non-clinical population. Seventy-three women charted 57 symptoms over 2-6 menstrual cycles each. Symptoms, and summarized symptom scores within seven symptom groups, were tested for changes between the follicular phase and the luteal phase of each cycle. Recurrent symptom cyclicity over multiple cycles within individuals was ascertained and the stability between cycles of mean symptom scores for both the follicular phase and the luteal phase. Forty-five percent of the participants experienced cyclicity over multiple cycles in at least one symptom and 23% in at least one symptom group. Eighteen percent of the participants consistently reported a higher symptom score during the luteal phase compared to the follicular phase (a PMS-like pattern) in all symptoms in which they experienced a change. The remaining 27% experienced a varying direction of change in the same symptom between cycles, or consistently experienced a lower symptom score during the luteal phase (a reverse PMS-like pattern) of the cycles they charted. Recurrent cyclicity was experienced by 16% of the participants in one symptom; in two symptoms by 15%; in 3 8 symptoms by 14%; in one symptom group by 19% and in two symptom groups by only 4% of participants. Average symptom severity did not vary significantly between cycles. Due to the varied direction of symptom severity change over multiple cycles, prospective daily ratings are necessary to achieve a true picture of menstrual related symptom cyclicity in the general population.
PregnancyLast Menstrual Period ReliabilityStillbirth and Preterm BirthPregnancy Dating Implications
To estimate the risk of adverse outcomes in women whose first day of the last menstrual period (LMP) was unreliable. Among 20,244 singleton pregnancies with measurements of biparietal diameter between 12 and 22 weeks' gestation, LMP was registered as unreliable in 3775 (18.6%) and reliable in 16,469 (81.4%). Adverse outcomes were defined as spontaneous or missed abortions after 12 weeks' gestation, stillbirth or postnatal death within 1 year, preterm birth, birth weight less than 2500 g, and low birth weight (LBW) for gestation (lower than 22% below sex-specific expected weight). Logistic regression analysis and Kaplan-Meier survival analysis were used to analyze the risk of adverse outcomes. The risk of death was doubled in pregnant women with unreliable LMPs compared with those with reliable LMPs (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.5, 2.6). This risk was highest with respect to stillbirth (OR 2.7; 95% CI 1.7, 4.3). The risks of preterm birth, LBW, and LBW for gestation were also significantly increased (ORs 1.5, 1.4, and 1.2; 95% CIs 1.3, 1.7; 1.2, 1.6; and 1. 0, 1.4, respectively). An unreliable LMP is associated with increased risk of adverse outcomes, especially fetal death.
Fertility AwarenessStandard Days MethodTheoretical EffectivenessIdentification Methods
A significant number of women worldwide use periodic abstinence as their method of family planning. Many of them use some type of calendar-based approach to determine when they should abstain from unprotected intercourse to avoid pregnancy; yet they often lack correct knowledge of when during their menstrual cycle they are most likely to become pregnant. A simple method of natural family planning (NFP) based on a fixed formula to define the fertile window could be useful to these women. This article reports the results of an analysis of the application of a fixed formula to define the fertile window. A large existing data set from a World Health Organization study of the Ovulation Method was used to estimate the theoretical probability of pregnancy using this formula. Information about the variable probability of pregnancy on different cycle days relative to ovulation also was considered in the analysis. Results suggest that a fixed formula in which days 8-19 of the menstrual cycle are considered to be the fertile window would provide the appropriate basis of a simple, effective, family planning method.
Exercise is understood to exert positive effects on bone. However cancellous bone has not been shown to increase with exercise. Previous results of our 1-yr observational prospective study in ovulatory women related 20% of the change in cancellous spinal bone mineral density (BMD), measured by quantitative computed tomography (QCT), to luteal phase length (the time from ovulation to menstruation, LL). The 66 women who documented exercise daily included normally active women (N = 23) and those who ran consistently or were increasing running in preparation for a marathon (N = 43). Exercise did not affect BMD change in the women as a whole. We re-evaluated those data to determine whether exercise-related effects on spinal cancellous BMD change in regularly cycling premenopausal women were related to ovulatory characteristics. The potential relationship of exercise to BMD change was reanalyzed by stratifying women into tertiles according to average LL documented by quantitative basal temperature analysis. Repeated-measures ANOVA indicated independent positive effects of both luteal length (P = 0.001) and activity (P = 0.041). The 11 runners with LL > 10.9 d had a nonsignificant 0.5% increase in lumbar BMD while the 15 who averaged short LL (<9.9 d) experienced a significant 3.6% loss. In the runners as a group, however, kilometers run per week was negatively related to BMD change throughout (r = -0.347, P = 0.024). These data are the first to indicate that, in women with regular cycles, luteal length and exercise independently and positively affect change in spinal cancellous BMD.
Menstrual CycleCycle Length VariabilityMenstrual Cycle BiomarkersProspective Cohort Study
To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. Prospective follow-up study. Healthy couples recruited throughout Denmark. PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity. CONCLUSION(S): The mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.
A case-control study was conducted to determine whether menstrual and gynecologic abnormalities precede the onset of chronic fatigue syndrome (CFS) in women with this disorder to a greater extent than that observed among healthy controls. We identified 150 women who met the 1988 Centers for Disease Control criteria for CFS from the Brigham and Women's Hospital Cooperative CFS Research Center. A comparison group of 149 women being seen for nongynecologic conditions were selected from the waiting area of the Brigham and Women's Hospital Internal Medicine outpatient department. Women with and without CFS completed self-administered questionnaires on menstrual, reproductive, and medical history. Women with CFS reported increased gynecologic complications and a lower incidence of premenstrual symptomatology. After adjustment for age, a somewhat greater number of cases compared with controls self-reported irregular cycles, periods of amenorrhea, and sporadic bleeding between menstrual periods. Factors suggestive of abnormal ovarian function--such as a history of polycystic ovarian syndrome, hirsutism, and ovarian cysts--were reported more often in CFS cases compared with controls. Frequent anovulatory cycles due to ovarian hyperandrogenism (PCOS) or hyperprolactinemia may increase risk for CFS through loss of the potential immunomodulatory effects of progesterone in the presence of continued estrogen production. We hypothesize that frequent anovulatory cycles due to PCOS and/or hyperprolactinemia may explain the increased reporting of gynecologic complications and the lower reported premenstrual symptomatology observed in women with CFS.
I. Introduction II. Defining the Perimenopause III. Classic Studies of the Perimenopause A. Historical studies B. Early reports of women’s experiences in the perimenopause C. Early prospective menstrual cycle interval and basal temperature documentation IV. Prospective Epidemiological Studies of the Perimenopause A. Manitoba Project on Women and Their Health in the Middle Years B. Massachusetts Women’s Health Study C. Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study V. Systematic Studies of the Endocrinology of the Perimenopause A. Cross-sectional (single-cycle) hormonal studies in the perimenopause B. Prospective ovarian hormonal levels in the perimenopause VI. Histological Studies of Ovarian Changes Across the Lifespan VII. Physiological Studies of Changing Ovarian Hormones in Women in Their Forties and Fifties A. Folliculogenesis and ovarian hyperstimulation for in vitro fertilization (IVF) B. Inhibin physiology in women over forty VIII. Hypotheses to Explain Perimenopausal Endocrinology A...
Bone HealthDiet and NutritionVegetarian Diet EffectsCross-Sectional Comparison
To compare spinal bone mineral density (BMD) and 1-year BMD change between premenopausal vegetarian and nonvegetarian women.
Cross-sectional comparison of spinal BMD at baseline and prospective comparison of a subsample.
A western Canadian metropolitan area. Healthy vegetarian (n = 15 lacto-ovo-vegetarian, n = 8 vegan) and nonvegetarian (n = 22) women aged 20 to 40 years, with regular menstrual cycles and stable body weight completed baseline measurements. Twenty of these women (6 lacto-ovo-vegetarian, 5 vegan, 9 nonvegetarian) participated in repeat measurements at approximately 13 months. Descriptive statistics, independent sample and paired t tests, 1-way analysis of variance, correlation analysis, and stepwise multiple regression were used to compare groups and to assess associations with BMD. At baseline, subjects were 27.2 +/- 5.1 years old. Vegetarians had lower body mass index (21.1 +/- 2.3 vs 22.7 +/- 1.9, P < .05) and percent body fat (24.0 +/- 5.5% vs 27.4 +/- 5.1%, P < .05); they also tended to have lower BMD (1.148 +/- 0.111 g/cm2 vs 1.216 +/- 0.132 g/cm2, P = .06), although this was not apparent with weight as a covariate (P = .14). Baseline BMD was predicted by vitamin B-12 intake and total body fat (R2 = .24, P = .001). Participants in the follow-up differed only in their being older than nonparticipants. Over 1 year, mean BMD increased significantly (1.1%): by diet group, nonvegetarians' BMD increased but vegetarians' BMD was unchanged. No other monitored variables were associated with BMD change. Vegetarian women should be aware of links between low BMD and low body weight/body fat, and should maintain adequate intakes of nutrients believed to affect BMD.
Menstrual CycleMineral and Electrolyte ChangesEffects on Mineral MetabolismMagnesium and Calcium
To determine the serum concentrations of the sex steroid hormones with respect to the concentrations of the biologically active fractions of magnesium and calcium during the different phases of the menstrual cycle. Controlled clinical study. An academic research environment. PATIENT(S): Six parous and four nulliparous healthy cycling female volunteers. MAIN OUTCOME MEASURE(S): Concentrations of the sex steroid hormones estrogen, progesterone, and testosterone as well as the ionized Ca and Mg levels were measured in the serum of normal cycling women the menstrual, early follicular, late follicular, ovulatory (ovulatory/early luteal), and luteal phases. RESULT(S): In each woman, there was a comparatively high ionized Mg level coincident with the early follicular phase, a statistically significant decrease in ionized Mg around the time of ovulation, a significant decrease in ionized and total Mg when the serum progesterone concentration peaked, and a significant increase in the serum Ca2+/Mg2+ ratio at both the ovulatory and luteal phases. In addition, a decrease in ionized Mg was found with increased testosterone levels. CONCLUSION(S): Healthy women of reproductive age demonstrate recurring cycling of ionized Mg and cyclic alterations in the ionized Ca to Mg ratio in their serum. The changes in serum concentrations of these important physiologically active cations, in the range at which they occur, can affect such entities as the vasculature, synaptic transmission, and excitation-secretion coupling and thus can produce the well-known premenstrual syndromes during the luteal phase in women who are somewhat deficient in Mg or in those who have an unusually increased Ca2+/Mg2+ ratio.
To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). Prospective study. The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.
To evaluate the expression of alpha6 and beta4 integrin subunits on surface and glandular endometrium throughout the menstrual cycle and during early pregnancy. Second Department of Obstetrics and Gynecology, University of Catania, Catania, Italy. PATIENT(S): Thirty-two women. Nineteen of the women regularly menstruated in different phases of the cycle, and 13 were in the sixth to ninth week of gestation and required voluntary abortion. INTERVENTION(S): Endometrial specimens collected during endometrial biopsy, hysterectomy, or voluntary abortion. MAIN OUTCOME MEASURE(S): Immunohistochemical staining for alpha6 and beta4 integrin subunits in endometrial tissues. RESULT(S): Both subunits (poorly expressed in preimplantation days) reached a significant peak on the endometrial surface during the implantation window, which tended to disappear in the postimplantation phase. On glandular endometrium they exhibited an opposite trend, showing high levels in the preimplantation and postimplantation days, whereas their expression decreased during the implantation window. The two subunits tended to disappear in early pregnancy. CONCLUSION(S): alpha6 and beta4 integrin subunits are uniformly distributed and highly expressed on the endometrial surface during the implantation window; they decreased dramatically in the postimplantation phase. These results could suggest involvement of integrin-extracellular matrix components in blastocyst-endometrium interaction during the early stages of implantation.
The symptoms of women with premenstrual syndrome improve in response to suppression of ovarian function, although these women have no evidence of ovarian dysfunction. We undertook a study to determine the role of estrogen and progesterone in this syndrome. We first studied the effect of ovarian suppression with leuprolide, an agonist analogue of gonadotropin-releasing hormone, or placebo on symptoms in 20 women with the premenstrual syndrome. Ten women whose symptoms improved during leuprolide treatment were given estradiol and progesterone in a double-blind, crossover design, each for four weeks, during continued leuprolide administration. Women without premenstrual syndrome (normal women) participated in a similar protocol. Outcomes were assessed on the basis of daily self-reports by the patients and biweekly rater-administered symptom-rating scales. The 10 women with premenstrual syndrome who were given leuprolide had a significant decrease in symptoms as compared with base-line values and with values for the 10 women who were given placebo. The 10 women with premenstrual syndrome who were given leuprolide plus estradiol or progesterone had a significant recurrence of symptoms, but no changes in mood occurred in 15 normal women who received the same regimen or in 5 women with premenstrual syndrome who were given placebo hormone during continued leuprolide administration. In women with premenstrual syndrome, the occurrence of symptoms represents an abnormal response to normal hormonal changes.
Menstrual CycleDiagnosis and TreatmentPharmacotherapyInternational Surveys
To investigate and compare the diagnoses and treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) from the perspectives of psychiatrists and obstetricians/gynecologists (OB/GYNs) in Japan. Between December 2021 and February 2022, a web-based survey was conducted among the members of the Japanese Association of Neuro-Psychiatric Clinics. Data from 262 psychiatrists who responded to the aforementioned survey were compared with data from 409 OB/GYNs from a survey conducted in 2021 among members of the Japanese Society of Obstetrics and Gynecology. Overall, 79.8% of psychiatrists and 97.3% of OB/GYNs were involved in practicing PMS/PMDD diagnosis and treatment. Most psychiatrists believed that PMS should be treated by OB/GYNs (74.4%) and PMDD by psychiatrists (75.6%). Only vague medical interviews were conducted by 86.6% of psychiatrists, and only 9.7% maintained a two-cycle symptom diary. Psychiatrists mostly prescribed selective serotonin/serotonin and noradrenaline reuptake inhibitor (SSRI/SNRI) continuous dosing (91.1%), followed by Kampo medicines, especially Kamishoyosan (73.3%); only 2.8% chose oral contraceptive pills, unlike OB/GYNs, while SSRI continuous (32.8%) and luteal phase dosing (20.6%) and Kampo medicine (42.1%) were the most common first-line treatments. Lifestyle guidance was prescribed by 63.6% of psychiatrists, followed by cognitive behavioral therapy (13.8%) and the symptom diary observation method (11.1%), which were similar to OB/GYNs' choices. Many Japanese psychiatrists and OB/GYNs do not base PMS/PMDD diagnoses on prospective monitoring methods using specific diagnostic criteria and therefore do not provide evidence-based treatment. Moreover, a tendency of being biased toward treatments in which the department specialized was observed.
Herbal and related remedies are becoming increasingly popular in the United States. Although some of these products have been promoted as panaceas with little scientific data to support their use, clinical data are starting to accumulate showing the benefit of specific products. For the herbal products, English translation of the German Commission E monographs greatly increases the availability of credible information. Under the 1994 Dietary Health Supplement and Education Act, these products are considered as dietary supplements rather than drugs; regulation by the Food and Drug Administration is therefore limited. This lack of regulation has contributed to drug misadventures; such adverse events should be reported to the MedWatch program of the Food and Drug Administration. One suggestion to improve the status of these products in the United States would be to adopt the German philosophy that the products be approved as drugs based on absolute proof of safety and reasonable proof of efficacy.
To evaluate the anxiolytic 3alpha-5alpha-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls. Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data. Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 +/- 0.8 versus 7.5 +/- 1.3 ng/mL; P < .04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 +/- 0.3 versus 3.2 +/- 1.3 ng/mL; P < .05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels. Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.
To examine the endometrial effects of three different doses of progesterone administered vaginally. Forty women 25-41 years old deprived of ovarian function received estradiol (E2) for 28 days. From days 15 to 27, a new mucus-like vaginal gel of progesterone was administered every other day, randomly, dosed at 45 mg (group A, n = 14), 90 mg (group B, n = 13), or 180 mg (group C, n = 13). Plasma gonadotropins, estrone, E2, and progesterone were measured. An endometrial biopsy was performed on day 20 (n = 20) or 24 (n = 20) for endometrial dating and for estrogen and progesterone receptor determinations. Plasma estrogen levels were in the menstrual cycle range. Mean progesterone levels were lower in group A (2.4 +/- 0.2 ng/mL) than in group B (3.6 +/- 0.2 ng/mL) or C (3.4 +/- 0.4 ng/mL) (P < .005). Plasma FSH and LH decreased significantly during progesterone treatment. In all groups, we observed secretory transformation in the glands (day 20) and stroma (day 24) and the distribution of estrogen and progesterone receptors seen in normal menstrual cycles. Transvaginal administration of progesterone induced normal secretory transformation of the endometrium despite low plasma levels, suggesting a direct transit into the uterus or "first uterine pass effect."
EndometriosisMenstrual CharacteristicsMenstrual Blood Loss AssessmentHeavy Menstrual Bleeding
To assess menstrual blood loss and other menstrual characteristics prospectively in women with and without endometriosis. Three hundred fifteen premenopausal women undergoing laparoscopy for various reasons were asked to complete a pictorial blood loss assessment chart devised by Higham et al to evaluate menstrual flow on which the monthly score has been demonstrated to correlate directly with uterine blood loss measured by the alkaline hematin method. In addition, cycle length and flow duration were recorded. The women also were asked to grade dysmenorrhea severity using a 100-mm visual analogue and a 0-3-points verbal rating scale. One hundred sixty-three women had endometriosis, and 152 did not. The latter group comprised 59 women with a normal pelvis, 36 with nonendometriotic ovarian cysts, 29 with chronic pelvic inflammatory disease, and 28 with miscellaneous conditions. The median [interquartile range] pictorial blood loss assessment chart score was 110 [66.5-156.5] in women with endometriosis and 84 [56-129] in those without the disease (P = .007); 87 out of 163 (53%) women with endometriosis had a menstrual chart score equal to or greater than 100 compared with 56 out of 152 (37%) of those without (chi 2(1) = 8.02, P = .005; difference = 16%, 95% confidence interval, 6%, 28%). Menstrual flow duration was slightly longer in women with endometriosis (mean difference, 0.33 days). Dysmenorrhea visual analogue and verbal rating scores were significantly higher in the endometriosis than the nonendometriosis group. According to a visual chart, women with endometriosis had heavier menstrual flow and a significantly higher rate of abnormal menstrual scores that those without the disease.
Menstrual CycleThyroid-Related Menstrual DisturbancesEffects on MenstruationThyroid Dysfunction and Anovulation
Both hyperand hypothyroidism may result in menstrual disturbances. In hyperthyroidism, amenorrhea was described as early as 1840 by von Basedow. The most common manifestation is simple oligomenorrhea (decreased menstrual flow). Anovulatory cycles are very common. Increased bleeding may occur, but is rare in hyperthyroidism. Nowadays hyperthyroidism is diagnosed earlier than it once was, and so the clinical picture is generally milder. So, menstrual disorders are less common than in previous series. In a recent paper, 21.5% of 214 patients had disturbances in their cycle, compared to 50% in some older series. In hypothyroidism, on the contrary, polymenorrhea (increased menstrual bleeding) is more common. Defects in hemostasis may contribute to this. Anovulation may be represent. Fertility is reduced in both hyperand hypothyroidism, and the outcome of pregnancy is more often abnormal than in euthyroid women. It is of interest that in juvenile hypothyroidism precocious puberty has been described. This is probably due to a "spillover" effect TSH,
Menstrual CycleBone Mineral ChangesOral Contraceptives and ProgesteroneTreatment Outcomes
The objectives of this study were to assess (1) whether treatment with oral contraceptives, in comparison with medroxyprogesterone and placebo, improved bone mineral in women with hypothalamic amenorrhea and (2) whether treatment with medroxyprogesterone, in comparison with placebo, improved bone mineral in women with hypothalamic oligomenorrhea. The study was a randomized, controlled clinical trial. Twenty-four white women, aged 14 to 28 years, with hypothalamic amenorrhea or oligomenorrhea were prospectively enrolled for a 12-month intervention period. Amenorrheic subjects were randomized to receive oral contraceptives, medroxyprogesterone, or placebo. Oligomenorrheic subjects were randomized to receive medroxyprogesterone or placebo. Bone mineral was measured by dual-energy x-ray absorptiometry at baseline and at 6 and 12 months. In amenorrheic subjects spine and total body bone mineral measurements at 12 months were greater in the oral contraceptive group than in the medroxyprogesterone and placebo groups when baseline bone mineral measurements, body weight, and age were controlled for (p < or = 0.05). There were no differences in hip bone mineral calcium and bone mineral density measurements at 12 months among the three groups. In oligomenorrheic subjects there was no detectable improvement in bone mineral associated with medroxyprogesterone use. This study supports the hypothesis that oral contraceptive use in women with hypothalamic amenorrhea will improve lumbar spine and total body bone mineral.
Bone HealthOvulation InteractionBone Mineral DensitySkeletal Effects
Petit MA et al., 1997·Medicine & Science in Sports & Exercise
Current concepts suggest that normal estrogen levels are necessary for exercise to have an osteogenic effect on bone. In a population of running and sedentary women Prior et al. (NEJM, 1990) have shown that consistent ovulation is necessary to prevent spinal cancellous bone loss. Change in spinal bone mineral density was measured by quantitative computed tomography (QCT) in running and sedentary women over one year, along with prospective documentation of dietary, menstrual cycle, hormonal, and exercise variables. Of the 66 women studied only 12 remained ovulatory throughout the year. Forty-two women were runners of which 6 were consistently ovulatory. We hypothesized that ovulation would interact with an exercise effect on cancellous bone. Analysis of the 42 runners showed an average loss in bone of 1.8%. Luteal phase index (r = 0.509) and average progesterone (r = 0.381) were correlated with change in QCT, but not estrogen, calcium, or any other hormonal, dietary, or morphometric variable. There was a negative association between change in QCT and number of km run/week (r = -0.319). In the 12 consistently ovulatory women, average cancellous bone increased in runners(≈2%) and decreased in nonrunners (N) by ≈1% (seefig.). These data are the first to show an increase in purely cancellous bone with moderate levels of aerobic activity. The results suggest that the presence of consistently ovulatory cycles, and thus progesterone in addition to estrogen, may be necessary for an osteogenic effect of low impact exercise (running) on cancellous bone.
Reproductive EndocrinologyLuteal Phase Defect DiagnosisTransvaginal Color DopplerCorpus Luteum Function
Kupesic S et al., 1997·Eur J Obstet Gynecol Reprod Biol
To evaluate intraovarian resistance index (RI) in 47 healthy fertile volunteers with ovulatory cycles, 28 patients with luteal phase defect (LPD) and four patients with luteinized unruptured follicle (LUF Sy). Transvaginal color Doppler assessment of the follicular and corpus luteum blood flow and plasma progesterone (P) levels were obtained in each patient. Significantly higher intraovarian artery RI (< 0.001) was obtained for LPD group than for controls during the luteal phase. In the control group both follicular and corpus luteum RI were significantly lower (P < 0.001) on the dominant side, while in LPD group no difference (P > 0.05) between the sides occurred. Mean P levels were significantly lower (P < 0.001) in the LPD group (6.9 +/- 2.3 ng/ml) than in controls (24.1 +/- 11.4 ng/ml). In all the LPD patients histopathology revealed delayed endometrial pattern, while normal endometrial dating was found in all the evaluated patients form the control group (n = 15). In the patients with LUF Sy (n = 4) similar RI values were obtained in the follicular and corpus luteum phase. There was no difference between the sides in terms of the intraovarian RI, while subnormal values of P were obtained in all the examined patients (14.1 +/- 6.2 ng/ml). Transvaginal color Doppler may predict the function capacity of the corpus luteum.
The Couple to Couple League (CCL) is pleased that an article and an editorial in the December 1995 issue of the well-respected New England Journal of Medicine confirm that natural family planning (NFP) has value and is scientifically based, a fact the CCL has known for many years. The research covered in the article entitled Timing of Sexual Intercourse in Relation to Ovulation found that the only fertile days were the five days before ovulation and the day of ovulation itself. Most conceptions (76.4%) occurred during the day of and the first and second days before ovulation. CCL's slide showing the extent of the fertile time reflects the data of the report, but also includes the possibility of a second ovulation occurring within 24 hours of the first ovulation. The study found that women conceived in only 37% of cycles in which intercourse took place during the six-day fertile period. This rate is not much different than that claimed by a NFP physician many years ago (about 30%). The study showed the highest conception probability to be when the couple had sexual intercourse every day during the fertile period (37% vs. 33% for every other day). CCL advises couples to abstain until the fertile period then follow one coital frequency period during one cycle (e.g., every day) and the other pattern the next cycle (e.g., every other day). The study refuted claims that the timing of coitus relative to ovulation was not associated to the sex of the baby and that aging sperm do not reduce the viability of the fetus and/or cause birth defects. In fact, aging sperm rarely fertilize the ovum. The only way to positively detect ovulation is seeing the ovum burst out of the ovary. Hormone analyses of blood or urine and observations of cervical mucus and basal body temperature allow an estimate of the day of ovulation. NFP is not based on detecting ovulation but on identifying the limits of the fertile period.
Bone HealthOvulatory DisturbancesSubclinical DefectsBone Metabolism
Healthy premenopausal women with regular cycles are believed to be increasing or maintaining bone density. However, few studies have prospectively documented spinal cancellous bone, the bone that changes rapidly in response to reproductive hormones, in this population. Furthermore, our previous one-year study documented that 24% of the one-year bone change by quantitative computed tomography (QCT) was related to subclinical ovulatory disturbances (short luteal phase and non-ovulation) in the presence of regular menstrual cycles. The purpose of this study was to document the cancellous bone change over five years in this initially ovulatory, premenopausal cohort of 66 healthy women. Thirty-seven women, who continued to be premenopausal and have regular cycles, completed this five-year study. Those enrolled differed only by being older and weighing less than those who could not be contacted (n = 19) or who declined to participate (n = 10). Documentation of current ovulatory characteristics was obtained for at least three cycles in 27 women. At the five-year assessment, the volunteers were 40.6 (range 26-47) years old, weighed 58.5 (41-77) kg, and were 160.9 (149-174) cm in height. All were premenopausal, healthy, nonsmokers with regular menstrual cycles (mean 27.7, range 24-33 days). Six women with intervening events (such as pregnancy or use of oral contraceptives) had interval (12 to 60 months) QCT changes similar to the remaining 31 (-7.98 vs. -4.92 mg/cm, p = 0.1, respectively). Mean five-year QCT was 143.0 +/- 20.2 mg/cm, whereas the initial mean value was 151.9 +/- 20.1 mg/cm. Significant QCT loss over five years (-8.9 +/- 6.2 mg/cm) (95% Cl -6.9 to -11.0) correlated with QCT change in the first year (r = 0.629, p < 0.001). First-year change was not related to the subsequent four-year interval change (r = -0.056, p = 0.74), however. Five-year QCT change was not related to age, weight, osteoporosis family history, estimated calcium intake, or exercise, but did correlate with year one luteal index (luteal/cycle length) (r = 0.339, p = 0.043). Significant cancellous spinal bone loss occurs in healthy, ovulatory premenopausal women, and is influenced by subclinical disturbances of ovulation.
The relationship between symptoms of premenstrual syndrome (PMS) and serum levels of pregnenolone (Pe), pregnenolone sulfate (PS), 5 alpha-pregnane-3,20-dione (5 alpha-DHP), 3 alpha-hydroxy-5 alpha- pregnan-20-one (5 alpha-THP), LH, 17 beta-estradiol (E2), and progesterone (P) was investigated during 2 consecutive menstrual cycles in 12 patients using daily measurements. Corresponding hormones were also measured during 1 cycle in 8 control women. Pe, PS, 5 alpha-DHP, and 5 alpha-THP showed a significant cyclicity within menstrual cycles and a high rate of correlation with P variation in both PMS patients and controls. No significant difference was found between PMS patients and controls in average serum concentrations of Pe, PS, 5 alpha-DHP, 5 alpha-THP, and LH during the luteal phase, whereas a significantly higher level of E2 and a lower level of P were observed in PMS patients. The variation in symptom scores was compared with that in hormone levels within each woman. The symptom peak showed a delay of 3-4 days after the serum P, Pe, 5 alpha-DHP, and 5 alpha-THP peaks. However, the plasma PS peak appeared on the same day or only 1 day before the symptom peak in PMS patients. When comparing the 2 cycles studied, more negative symptoms occurred in cycles with higher luteal phase E2, Pe, and PS concentrations, whereas higher luteal phase 5 alpha-DHP and 5 alpha-THP concentrations were associated with improved symptom ratings in PMS patients. These results suggest that the mentioned steroids are related to the severity of distressing symptoms in PMS patients.
Fertility AwarenessTiming of IntercourseConception ProbabilityUrinary Hormone Metabolites
The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception, although the actual number of fertile days in a woman's menstrual cycle is uncertain. The timing of intercourse may also be associated with the sex of the baby. We recruited 221 healthy women who were planning to become pregnant. At the same time the women stopped using birth-control methods, they began collecting daily urine specimens and keeping daily records of whether they had sexual intercourse. We measured estrogen and progesterone metabolites in urine to estimate the day of ovulation. In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated, as indicated by increases in the urinary concentration of human chorionic gonadotropin around the expected time of implantation. Two thirds (n = 129) ended in live births. Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. There was no evident relation between the age of sperm and the viability of the conceptus, although only 6 percent of the pregnancies could be firmly attributed to sperm that were three or more days old. Cycles producing male and female babies had similar patterns of intercourse in relation to ovulation. Among healthy women trying to conceive, nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation. For practical purposes, the timing of sexual intercourse in relation to ovulation has no influence on the sex of the baby.
Menstrual CycleHypothalamic Amenorrhea TreatmentOpioid Antagonist TherapyNaltrexone for Amenorrhea
To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.
Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.
Reproductive EndocrinologyNeurological ApplicationsEpilepsy and SeizuresProgesterone Clinical Trials
This open trial assessed the effects of adjunctive progesterone therapy on seizure frequency in 25 women with catamenial exacerbation of complex partial (CPS) and secondary generalized motor (SGMS) seizures. Progesterone was well tolerated by 23 of the 25 women and had readily reversible dose-related side effects of asthenia and emotional depression in two. Eighteen women (72%) experienced a decline in seizure frequency during a 3-month treatment period compared with the 3 months prior to therapy (p < 0.01). Average daily CPS frequency declined by 54% (p < 0.01), SGMS by 58% (p < 0.02).
To explore the pulsatile-release characteristics of LH and P in women with premenstrual syndrome (PMS) compared with age-matched phase-matched controls. Prospective, repeated measures, two-group study. Human volunteers in an academic research environment. Six women with rigorously defined prospectively determined PMS; six age-matched phase-matched controls. Frequency, amplitude, concentration, and coincident pulsatile release characteristics of LH and P at three symptom-related points of the luteal phase. No significant between-group differences in frequency, amplitude, or concentration were found. In pooled data, significant coincident pulsing between LH and P was demonstrated. The length of time between LH and P pulses systematically increased across the luteal phase, a finding not previously reported. In the PMS group only, significant coincident pulsing occurred at an unexpected zero time lag on the symptom-onset sampling day. A progressively increasing coupling interval may reflect the gradual decline of the corpus luteum. Presence of a zero time lag between LH and P at symptom onset in women with PMS may indicate an aberrance in corpus luteum response to LH stimulation.
To determine the effectiveness of oral micronized progesterone, alprazolam, and placebo in premenstrual syndrome (PMS) treatment and the effect of clinical contact on treatment responses. Randomized, double-blind, placebo-controlled 3-month parallel treatment arms with flexible dosage and with the length of clinical contact randomized within each treatment group. University hospital PMS medical treatment outpatient program in obstetrics/gynecology department. Among volunteers for PMS treatment, 444 were evaluated and 185 meeting defined PMS criteria were randomized to treatment; treatment data are available for 170. There were no medical withdrawals for adverse events. A double-blinded protocol in which 300 mg of oral micronized progesterone, 0.25 mg of alprazolam, or placebo was administered four times a day from day 18 of the menstrual cycle through day 2 of the next cycle, including taper. The mean daily dose at the third treatment was 1760 mg of progesterone or 1.5 mg of alprazolam. Subjects were randomized to brief (< 20 minutes) or extended (50 minutes) visits. Daily symptom report (DSR) scored for total DSR symptoms, four DSR factors. Alprazolam was significantly better than placebo or progesterone for total premenstrual symptoms and DSR factors of mental function, pain, and mood. Thirty-seven percent of the alprazolam group experienced a 50% reduction in total DSR scores. There were no clinically significant withdrawal symptoms when alprazolam administration was restricted to the luteal phase. Oral micronized progesterone therapy was no better than placebo. Brief vs extended visits had no effect on treatment outcome. Treatment response was associated with severity of premenstrual symptoms at baseline but with no other diagnostic variables. Alprazolam has a role in PMS treatment and offers a therapy limited to the luteal phase. Oral micronized progesterone is ineffective for PMS.
Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria. The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle. Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P < 0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P < 0.001). Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.
Menstrual CycleExercise and Athletic PerformanceFollicular vs Luteal PhasePhysical Performance
The purpose of this study was to examine the effects of menstrual cycle phase on four selected indices aerobic capacity, anaerobic capacity, isokinetic strength, and high intensity endurance. Sixteen eumenorrheic women (VO2max > or = 50 ml.kg-1.min-1) were tested during the early follicular (F) and midluteal (L) phases of the menstrual cycle. Cycle phases were confirmed by serum estradiol and progesterone assays. No significant differences were observed between F and L tests in weight, percent body fat, sum of skinfolds, hemoglobin concentration, hematocrit, maximum heart rate, maximum minute ventilation, maximum respiratory exchange ratio, anaerobic performance, endurance time to fatigue (at 90% of VO2max), or isokinetic strength of knee flexion and extension. Both absolute and relative VO2max, however, were slightly lower in L than in F (F = 3.19 +/- 0.09.min-1, L = 3.13 +/- 0.08.min-1, P = 0.04; and F = 53.7 +/- 0.9 ml.kg-1.min-1, L = 52.8 +/- 0.8 ml.kg-1.min-1, P = 0.06). These results suggest that the cyclic increases in endogenous female steroid hormones of an ovulatory menstrual cycle may have a slight, deleterious influence on aerobic capacity, with potential implications for individual athletes. Nevertheless, the cycle phase did not impact significantly on the majority of the other performance tests and cardiorespiratory variables measured in this study.
We compared energy and macronutrient intakes across the menstrual cycle in participants (n = 42) in a study that assessed the frequency of ovulatory disturbances in regularly cycling vegetarians and nonvegetarians. Women kept daily basal body temperature records for six consecutive menstrual cycles and provided 3-d diet records near the beginning, middle, and end of different cycles. On completion of the study, temperature records were quantitatively analyzed to determine whether cycles were ovulatory, and if so, the date the luteal phase began. Diet records kept near the beginning and end of cycles were matched with temperature analysis results, and women were grouped according to whether the end-of-cycle record was kept during the luteal phase of an ovulatory cycle (group 1, n = 29), or during an anovulatory cycle or before luteal phase onset of a short luteal phase cycle (group 2, n = 13). Group 1 had higher energy intakes during the luteal than during the follicular phase (9.27 +/- 2.69 vs 8.01 +/- 2.36 MJ/d, P < 0.0001), whereas intakes of group 2 did not differ across the cycle (7.91 +/- 2.18 vs 8.20 +/- 1.48 MJ/d, NS). Both groups' macronutrient intakes were similar in records kept near the beginning and end of cycles. Documentation of ovulation is necessary in studies assessing premenopausal women's energy intakes.
The present study extends a previous report of lower plasma ACTH levels in women with premenstrual syndrome (PMS) compared with asymptomatic controls. Plasma levels of estradiol and progesterone were measured daily in 10 women with confirmed PMS and 8 asymptomatic women. Daily symptom reports were maintained during the same menstrual cycle. Both estradiol and progesterone levels were consistently, but not significantly, higher throughout the cycle in PMS subjects compared with controls. From the follicular to the early luteal phase, estradiol levels were significantly higher in a previously defined PMS subgroup 2 with more severe symptoms throughout the cycle compared with both the less severe PMS subgroup 1 and controls. Progesterone levels were significantly and positively correlated with PMS symptoms along the entire menstrual cycle, preceding the symptoms by 5-7 days. These preliminary results provide support for the hypothesis that the presence of progesterone at early luteal phase levels is required for PMS symptoms to occur.
Ovulatory function was prospectively assessed over 6 mo in 23 vegetarians and 22 nonvegetarians with clinically normal menstrual cycles. Subjects were 20-40 y of age, of stable weight (body mass index, in kg/m2, of 18-25), on current diets for > or = 2 y, and not using oral contraceptives. Quantitative analysis of basal body temperature records classified cycles as normally ovulatory, short luteal phase (< 10 d), or anovulatory. Subjects completed the Three-Factor Eating Questionnaire (subjects completed the Three-Factor Eating Questionnaire (subscales for restraint, hunger, and disinhibition) and kept three 3-d food records. Vegetarians had lower BMIs (21.1 +/- 2.3 vs 22.7 +/- 1.9, P < 0.05), percentage body fat (24.0 +/- 5.5% vs 27.4 +/- 5.1%, P < 0.05), and restraint scores (6.4 +/- 4.4 vs 9.5 +/- 3.7, P < 0.05). Mean cycle lengths were similar, but vegetarians had longer luteal phase lengths (11.2 +/- 2.6 vs 9.1 +/- 3.8 d, P < 0.05). Cycle types also differed (chi 2 = 9.64, P < 0.01): vegetarians had fewer anovulatory cycles (4.6% vs 15.1% of cycles). Compared with those with restraint scores below the median, highly restrained women had fewer ovulatory cycles (3.6 +/- 2.3 vs 5.0 +/- 1.4, P < 0.05) and shorter mean luteal phase lengths (7.4 +/- 4.1 vs 10.7 +/- 3.1 d, P < 0.05). We conclude that ovulatory disturbances and restrained eating are less common among vegetarians, and that restraint influences ovulatory function.
To assess the efficacy of alprazolam in the treatment of two groups of patients diagnosed with late luteal phase dysphoric disorder (LLPDD). The first group met only the diagnostic criteria for LLPDD. The second group experienced LLPDD and mild symptoms of anxiety and depression during the follicular phase. A double-blind, placebo-controlled crossover design was used. Patients were treated with alprazolam and placebo for 3 months each and completed daily measures of anxiety, tension, depression, irritability, and feelings of being out of control. The response to alprazolam differed significantly by group. For the first group, alprazolam (0.25 mg three times a day) relieved the severity of tension (P = .001), irritability (P = .005), anxiety (P = .008), and feelings of being out of control (P = .012) more than placebo. Few side effects were reported; the incidence (P = .001) and severity (P = .001) of side effects were dose-related. Alprazolam and placebo did not differ for the second group, and the incidence and severity of side effects were unrelated to dose. Alprazolam benefits women diagnosed solely with LLPDD. It is not recommended for patients who experience LLPDD as well as symptoms of mild anxiety or depression during the follicular phase.
To determine the ability of luteal phase length determined by basal body temperature (BBT) pattern and a midluteal serum progesterone level to predict the result of an endometrial biopsy in a subsequent cycle. We performed a retrospective analysis of 141 women with a history of infertility who were being evaluated for luteal function. The luteal phase length determined from a BBT chart of one menstrual cycle was compared to a single midluteal serum progesterone level from a second menstrual cycle. These findings were compared to a luteal phase endometrial biopsy performed in a third menstrual cycle. Subjects were divided into four groups depending upon luteal phase length (normal 11 or more days) and serum progesterone level (normal at least 10 ng/mL). The four groups were designated "normal," "short luteal phase," "low progesterone," and "abnormal," depending upon the results of the two tests. The frequency of in- and out-of-phase endometrial biopsy results in the four groups was compared. There was no difference in the occurrence of an in- or out-of-phase endometrial biopsy when the four groups were compared. Neither luteal phase length nor a single midluteal serum progesterone level was predictive of subsequent in-phase or out-of-phase endometrial biopsy.
Menstrual CycleMineral DeficiencyEtiologyTrace Element Assessment
We measured plasma Cu. Zn and Mg levels in 40 women suffering from premenstrual tension syndrome (PMTS) and in 20 control subjects by atomic absorption spectrophotometer. Mean plasma Cu, Zn and Mg levels, the Zn/Cu ratio were 80.2 +/- 6.00 micrograms/dl, 112.6 +/- 8.35 micrograms/dl, 0.70 +/- 0.18 mmol/l, and 1.40 +/- 0.10 in the PMTS group; and 77.0 +/- 4.50 micrograms/dl, 117.4 +/- 9.50 micrograms/dl, 0.87 +/- 0.10 mmol/l, and 1.51 +/- 0.05 in the control group respectively. The mean Mg level and the Zn/Cu ratio were significantly lower in PMTS patients than in the control group. Plasma Mg and Zn levels were diminished significantly during the luteal phase compared to the follicular phase in PMTS group. Mg deficiency may play a role in the etiology of PMTS.
Menstrual CycleBone LossProgesterone TherapyBone Density Effects
Bone loss occurs in young women who experience amenorrhea or ovulatory disturbances. The purpose of this study was to determine whether bone loss could be prevented by simulating a more normal hormonal pattern, using treatment with cyclic medroxyprogesterone, with or without calcium supplementation, in physically active women with disturbed menstruation.
This study was a 1-year randomized, double-blind, placebo-controlled trial. Women who were stratified by menstrual cycle disturbance were randomized into four groups. The outcome variable was the change in spinal bone density measured by dual energy techniques.
A large metropolitan area. Sixty-one healthy, normal-weight physically active premenopausal women aged 21 to 45 years who experienced amenorrhea, oligomenorrhea, anovulation, or short luteal phase cycles completed the study. Therapies were cyclic medroxyprogesterone (10 mg/day for 10 days per month) and calcium carbonate (1,000 mg/day of calcium) (A) (n = 16) cyclic medroxyprogesterone plus calcium carbonate; (B) (n = 16) cyclic medroxyprogesterone with calcium placebo; (C) (n = 15) placebo medroxyprogesterone with active calcium; or (D) (n = 14) both medroxyprogesterone and calcium placebos. The initial bone density (mean = 1.12 g/cm2) did not differ by group (P = 0.85). The 1-year bone density change was strongly related to treatment with medroxyprogesterone (P = 0.0001) and weakly to calcium (P = 0.072) treatment. Bone density increased significantly (+1.7% +/- 0.5%, +/- SEM, P = 0.004) in the medroxyprogesterone-treated groups (A and B), did not change in the calcium-treated group (C) (-0.7% +/- 0.6%, P = 0.28), and decreased on both placebos (D) (-2.0% +/- 0.6%, P = 0.005). Cyclic medroxyprogesterone increased spinal bone density in physically active women experiencing amenorrhea or ovulatory disturbances. POTENTIAL Amenorrhea, oligomenorrhea, anovulation, and short luteal phase cycles are common in premenopausal women and associated with spinal bone loss occurring at a stage of life when bone density would normally be stable or increasing. This controlled trial shows a significant gain in bone in women in the cyclic medroxyprogesterone intervention group, whereas those subjects in the placebo group lost bone. Calcium supplementation appeared to be helpful but did not reach statistical significance. The implications of these findings for the prevention of osteoporosis warrant further investigation.
To establish age-stratified reference values for salivary luteal P levels. One hundred thirty-six regularly menstruating women (18 to 48 years of age), screened for weight, exercise, and steroid medication use, collected daily saliva samples for one complete menstrual cycle. Luteal P levels were measured by 3H-RIA, and data were aligned by day of next menstrual onset. Means (+/- 1 SD range) and percentiles, calculated using both untransformed and log transformed data, were calculated for each luteal day and for indices of luteal P production. Reference values for salivary daily luteal P levels and indices of luteal P are presented for three age groups (18 to 24 years, 25 to 39 years, and 40 to 48 years). The age-stratified reference values presented here can be used, without collateral clinical procedures, to assess salivary luteal P levels. Salivary monitoring is ideally suited for research and long-term clinical observation, but the characteristics of salivary P data may limit the usefulness of these values for individual diagnosis.
Perimenopause/MenopauseMenstrual Cycle Effects on BoneMenstrual DisturbancesBone Metabolism
We assessed the relationship between dietary restraint and menstrual cycle characteristics in 27 ovulatory women, previous participants in a longitudinal study of spinal cancellous bone mineral density (BMD). Subjects completed the restraint scale of the Three Factor Eating Questionnaire, recorded basal temperature and exercise for at least three menstrual cycles, and completed a 3-d food record. Cycle lengths of women in the upper and lower tertiles of scores for restraint were similar [27.8 +/- 1.0 (mean +/- SE) vs 27.6 +/- 0.8 d], but luteal phase length was shorter in the former group (8.6 +/- 0.9 vs 10.8 +/- 0.5 d, P < 0.05). Age, body mass index, percent body fat, waist-hip ratio, reported energy intake, and activity were similar between groups. Because the previous longitudinal study found associations between ovulatory disturbances and bone loss, we assessed spinal BMD using dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). BMD of women in upper and lower restraint tertiles, respectively, DXA, 1.15 +/- 0.05 vs 1.20 +/- 0.06 g/cm2; and QCT, 140 +/- 7 vs 133 +/- 7 mg/cm3. Additional prospective studies, however, appear warranted. In conclusion, this study's results provide evidence that high dietary restraint is associated with a shortened luteal phase length.
Menstrual CycleDietary InfluencesLignans and Hormonal EffectsNutritional Interventions
Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean +/- SEM, 12.6 +/- 0.4 vs. 11.4 +/- 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.
Women diagnosed as suffering from premenstrual syndrome and symptom free controls were compared on hormonal parameters, glucose tolerance, mineralocorticoids, cholesterols, triglycerides, apolipoprotein (a), magnesium and calcium in the follicular and luteal phases of the menstrual cycle. The effect of treatment with essential fatty acids on the biochemical variables was also evaluated in a randomized, double-blind crossover design. The results showed that the hormonal and biochemical profiles of women with PMS and symptom free controls were markedly similar, except for aldosterone which was lower in the follicular and luteal phases and cholesterol which was higher in the follicular phase in women with PMS. No effects of treatment with essential fatty acids were found for any of the biochemical variables studied.
Premenstrual syndrome (PMS) is a menstrual cycle-related disorder of mood and behavior with unknown etiology and lack of evidence of endocrine imbalances. The absence of menstrual cyclicity eliminates PMS symptoms, and cyclic gonadal changes appear necessary but not sufficient cause for behavioral symptoms in predisposed women. As there are many depressive symptoms in PMS, we focused on the neuroendocrine characteristics of depression, primarily hypothalamic-pituitary-adrenal hyperactivity, and investigated plasma adrenocorticotropin (ACTH) and cortisol levels in the menstrual cycle. Blood samples were drawn daily from ten patients with PMS and eight asymptomatic control subjects who also reported symptoms daily throughout one menstrual cycle. The ACTH levels were significantly lower in patients with PMS compared to control subjects in the luteal phase. Two PMS subgroups were identified by cluster analysis applied to symptom scores. Plasma ACTH levels of PMS Cluster 1 subjects were significantly lower compared to controls. The ACTH levels of PMS Cluster 2 subjects were nearly identical to controls. These preliminary results suggest distinct hormonal subgroups in the heterogeneous PMS population and support further study of ACTH as a biological correlate of PMS.
Delangue AF, 1993·Soins Gynecol Obstet Pueric Pediatr
The Billings method, or cervical mucus method, is a natural family planning method developed during the 1970s by the Australian physicians John and Evelyn Billings. The method requires periodic abstinence during the periods recognized as fertile according to the characteristics of the mucus. The method can be used to avoid pregnancy or to favor it through identification of the day of maximum fecundity. The method does not alter the natural rhythms of the body or entail unpleasant side effects. At the beginning of the menstrual cycle, the cervix is closed by a mucus plug and the sperm survive less than two hours in the acidic environment of the vagina. Several days before ovulation, the cervix begins to secrete mucus that will protect the sperm from the acidity of the vagina and permit their passage to the uterus. Thus protected, the sperm can survive up to four days. Mucus at this stage has an elastic quality. After ovulation, the mucus thickens and becomes increasingly impenetrable to sperm. It feels sticky and gelatinous. The Billings method requires observation of the sensation of wetness or dryness and the characteristics of the mucus. Each evening the woman should note that day's observations on a chart. The "peak day" is the last day of elastic mucus that gives a sensation of wetness. The peak day is the most visible sign of ovulation and can be recognized only on the next day. The three days following the peak day are considered fertile, because ovulation can occur up to 48 hours after the peak and the ovum can survive up to 24 hours. If the Billings method is used to avoid pregnancy, intercourse should be avoided during menstruation as the appearance of mucus may be masked in a short cycle. Intercourse is permissible in the evening of every second day until the appearance of the mucus.
Menstrual CycleBiochemical PropertiesCervical Mucus and Sperm InteractionSperm Migration Patterns
Cervical mucus is produced throughout the menstrual cycle. Sperm migration, however, is possible only during the periovulatory period of the cycle. Cervical mucus is also produced during the amenorrhoeic post-partum period. Post-partum mucus is very similar to luteal phase mucus except that it can allow sperm migration. In this study, mucus samples obtained from all these periods were classified according to their capacity to allow sperm migration. The biochemical characteristics of mucus samples that did (peri-ovulatory and 40% of post-partum samples) and did not (luteal and 60% of post-partum samples) allow sperm migration were then compared. Mucus samples with positive sperm migration showed the highest percentage of water and lowest protein and glycoprotein concentration (per ml of mucus). In addition, post-partum mucus samples with positive sperm migration showed lower concentrations of proteins and glycoproteins than post-partum mucus samples that did not allow sperm migration. However, the amount of glycoproteins per mg of protein was similar between post-partum samples that were positive and negative for sperm migration. These data suggest that the carbohydrate composition of the glycoproteins is playing a key role in the ability of cervical mucus to accept spermatozoa.
Reproductive EndocrinologyGrowth Factor RegulationProgesterone Action on EndometriumEndometrial Decidualization
Endometrial stromal cells undergo decidual transformation, in response to epidermal growth factor (EGF) and progesterone. Since insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) are believed to be involved in endometrial differentiation, and insulin regulates IGFBP production in a variety of cells, we have investigated the modulatory roles of EGF, progesterone, and insulin on IGFBP secretion by long term cultures of human endometrial stromal cells. Without insulin, the principal IGFBP secreted into conditioned medium, detected by Western ligand blotting, was a 28-kilodalton (kDa) IGFBP, identified by immunoprecipitation as IGFBP-1. This was observed only when the stromal cells were decidualized. With increasing insulin, IGFBP-1 decreased to undetectable levels. Concomitantly, IGFBP-2 increased, as did a 24-kDa IGFBP (believed to be IGFBP-4) and a 28-kDa IGFBP, shown to be a glycoprotein by endoglycosidase sensitivity (and believed to be glycosylated IGFBP-4). In the nondecidualized state, insulin increased the secretion of IGFBP-3, IGFBP-2, and the 24-kDa IGFBP, which were slightly inhibited by EGF and relatively unaffected by progesterone alone. In the absence of insulin, progesterone weakly stimulated IGFBP-1 secretion, which increased markedly when the cells were decidualized by combined treatment with EGF and progesterone. These data show that IGFBP-3, IGFBP-2, IGFBP-1, and presumably IGFBP-4 and its glycosylated form are differentially regulated by peptide and steroid hormones in endometrial stromal cells and that their regulation is a function of stromal differentiation.
Although its etiology is unknown, it has been hypothesized that premenstrual syndrome (PMS) is linked to a deficiency of central serotoninergic activity. In the present study, we evaluated the effect of fluoxetine, a specific serotonin uptake inhibitor, on PMS symptoms. Following extensive screening, including several psychological inventories, eight women with severe persistent PMS participated in a 6-month double-blind, placebo-controlled, crossover study which included three months each of daily fluoxetine 20 mg or placebo, administered in a randomized order. Symptoms were evaluated using the Calendar of Premenstrual Experiences and other psychometric measures. Compared with placebo, treatment with fluoxetine was associated with an improvement in PMS symptoms as judged by highly significant decreases in behavioral (P less than .005), physical (P less than .05), and total (P less than .005) Calendar of Premenstrual Experiences scores; Beck Depression Inventory scores (P less than .005); Profile of Mood States subscales scores including depression (P less than .005), tension (P less than .005), and anger (P less than .01); and State-Trait Anxiety Inventory scores. The use of fluoxetine was associated with a greater mean reduction in behavioral (75%) than in physical scores (40%), with a mean decrease in total Calendar of Premenstrual Experiences scores of 62%, which rendered these scores similar to follicular phase values. Thus, the luteal phase symptomatology of PMS was effectively abolished. At this dose, no significant side effects or complications were noted during treatment. Fluoxetine appears to be a highly effective, well-tolerated treatment for the psychological and physical symptoms accompanying severe PMS.
Reproductive EndocrinologyExercise-Induced AmenorrheaProgesterone and Bone MetabolismLuteal Phase Deficiency in Athletes
A physically active and athletic lifestyle is not only a healthy but a fulfilling choice for women. Although there is extensive literature on 'athletic amenorrhoea' which implies that exercise causes loss of the menstrual cycle, there is inadequate scientific evidence for a causal relationship. The reproductive system adapts to environmental, nutritional, emotional and physical stressors or 'threats' by downward adjustment towards the premenarcheal pattern. The hormonal milieu of this adaptation is low gonadal steroid and high glucocorticoid levels which synergistically increase the risk for a negative bone balance. Athletic women may become amenorrhoeic if reproductive immaturity, emotional stress and undernutrition coexist with increasing exercise loads. Treatment for athletic women with menstrual cycle changes requires that hypothalamic stressors be identified and decreased. In addition, as progesterone deficiency (from disorders of ovulation, whether flow is regular or absent) is the most prevalent menstrual cycle change, treatment with medroxyprogesterone on days 16 to 25 of their cycle will not only provide regular flow (if estrogen levels are sufficient) but will also promote increased bone density.
Natural family planning (NFP) is based on the knowledge *largely nonexistent) of a women as to whether she is in her fertile period or not. In contrast to the calendar method, the Billings method consists of observing bodily functions, whereby women learn about the fertile and infertile period during the menstrual cycle. This method is very safe as long as the woman has been instructed thoroughly. The Pearl index (the number of pregnancies/100 woman years) can be 1. In a Swedish province, 7/1000 population used this method and had an abortion rate of .5/1000, a fact contradicting the allegation of mass abortion as a result of the method. Only well-trained NFP instructors can teach women, and at the University of Umea such training has been available for some years. The biological basis of the Billings method rests on the fact that every release of an egg is preceded by a ripening process of a follicle in the ovary. This follicle secretes increasing amounts of estrogen which stimulates the cervix to produce secretions for the sperm. Right before ovulation, the follicle reduces estrogen production and noradrenaline takes over, stimulating the peak-day secretion (P-secretion) for further selection of sperm. Ovulation usually occurs on the peak day, which is the day of maximum fertility and the last day of mucous symptoms. For 3 days after peak day until menstruation, the risk of becoming pregnant diminishes successively until it is as low as after sterilization. The instructor is trained to recognize and overcome certain factors that make it more difficult to identify the mucous symptoms, such as the previous use of oral contraceptives, certain illnesses, drugs, and life styles. NFP can also be used for attaining pregnancy by identifying the peak day; women with premenstrual syndrome can calculate when their symptoms start, and sportswomen can predict the time of their menstruation. NFP is fascinating when it is compared to other methods because of its human dimension, and there is still a great deal to be learned about it.
The premenstrual syndrome (PMS) has been proposed to result from excessive exposure to and/or withdrawal of brain opioid activity during the luteal phase. Because hypothalamic opioids are believed to modulate GnRH secretion, in part under the influence of ovarian steroids, we performed longitudinal studies of gonadotropin and ovarian steroid secretion across ovulatory, symptomatic cycles of 17 PMS patients and 8 normal volunteers. Pulsatile LH secretion was measured every 10 min for 8 hr at times when central opioid activity was expected to be low (early follicular phase), high (mid-luteal phase; ML), and declining (late luteal phase). In both subject groups, a cycle-phase effect was observed for LH pulse frequency (p = < 0.001) and amplitude (p = 0.002), and for the transverse mean concentrations of LH (p = 0.05), FSH (p < = 0.001), estradiol (E2) (p = < 0.001) and progesterone (P) (p = < 0.001). ML P secretion in PMS patients was pulsatile, and mean concentrations (over 30-60 min) were similar to those of normal controls. The changes in pulsatile LH secretion across the cycle were not different in the PMS patients compared to the normal women, though mean FSH in the ML phase was higher in the PMS group (p = < 0.05). The similar changes in luteal LH pulse frequency fail to provide evidence that GnRH secretion is impaired, thus challenging the view that the neuroregulation of the menstrual cycle in women with PMS is markedly altered.
Menstrual CycleHormonal PathophysiologyFemale Androgen ExcessAndrogen Assessment in PMS
Serum levels of progesterone, total testosterone, free testosterone, androstenedione (A2), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone binding globulin (SHBG) were measured in the follicular phase, around ovulation, and in the luteal phase of 11 women with severe premenstrual irritability and dysphoria and in 11 age-matched controls with no premenstrual complaints. Serum levels of free testosterone were significantly higher in the subjects with premenstrual syndrome (PMS) than in the controls in the luteal phase (p < 0.01), the follicular phase (p < 0.05), and around ovulation (p < 0.01). DHEA levels were significantly higher in the PMS subjects, as compared to controls, around ovulation (p < 0.05), while 17-OHP levels were higher in the PMS women in the luteal phase (p < 0.05). With respect to the other steroids measured, as well as SHBG, no differences between PMS subjects and controls were found. These results indicate a possible involvement of androgens in the pathophysiology of premenstrual irritability and dysphoria.
Reproductive EndocrinologyInhibin and ActivinNeuroendocrine ControlParacrine Signaling
It has become apparent in recent years that regulation of the ovulatory cycle cannot be accomplished solely through the mediation of the two pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Within the last decade, discoveries of additional regulatory mechanisms involved in the neuroendocrine control of the events of the ovulatory cycle have provided new insight into the control of this complex biological phenomenon (127). Among the most interesting of these discoveries are …
To characterize the extent and sources of imprecision in histologic dating of the endometrial biopsy. Duplicate endometrial biopsies from 25 women were dated by five evaluators on two separate occasions to evaluate the overall precision of the measure. Using variance component analysis, estimates of intrauterine, intraevaluator, and interevaluator variability were determined. Samples were obtained during outpatient fertility testing. Evaluators were colleagues at the same institution. PATIENTS, Women presenting with infertility undergoing routine evaluation. None. Variability in histologic dating of the endometrium. Inconsistencies between evaluators accounted for 65% of the observed variability, whereas 27% was because of inconsistencies in duplicate readings by the same evaluator. Regional differences in the uterus accounted for only 8% of the total variability. The overall error from these sources have the potential to result in a substantial false-positive rate for diagnosis of luteal phase defect.
Endovaginal sonography of the endometrium demonstrates characteristic findings throughout the menstrual cycle. To correlate these findings with histologic criteria for normal endometrial development, we compared endometrial biopsies with ultrasonographic findings. Nineteen cycles were monitored in 18 women with ovarian failure whose endometrial cycles were induced exogenously by sequential transdermal 17 beta-estradiol (E2) and intramuscular progesterone. These subjects underwent ultrasonography of the endometrium prior to the day of progesterone initiation (luteal day +1) and continuing throughout the mid-secretory phase. On luteal day +1, ultrasonography characteristically demonstrated a multilayered endometrium consisting of a hyperechoic perimeter (endometrial-myometrial interface), a hypoechoic inner layer, and a hyperechoic midline (luminal interface). By luteal day +7, a gradual increase in echogenicity of the inner layer was detected, while the inner myometrium remained hypoechoic. Eleven of 19 cycles demonstrated a completely hyperechoic endometrium on luteal day +7 and also demonstrated normal stromal development on endometrial biopsies. Three patients who had endometrial biopsies consistent with their chronological development failed to demonstrate a hyperechoic endometrium by luteal day +7. All five biopsies that were histologically out of phase were detected by ultrasonography. Thus, ultrasonography demonstrated a sensitivity of 100% and a specificity of 62% for the detection of histologically normal endometrial development. Endometrial thickness could not be used to discriminate between biopsies that were normal (13 +/- 1.0 mm) and those out of phase (13.8 +/- 1.8 mm). Endometrial histology demonstrated asynchrony of glands and stroma in nine cases in which ultrasonography correlated with stromal, but not with glandular dating, suggesting that the increased echogenicity may reflect stromal edema.(ABSTRACT TRUNCATED AT 250 WORDS)
Women with luteal phase deficiency have been shown to have an increased frequency of luteinizing hormone pulses in the early follicular phase of the menstrual cycle. Because progesterone is known to modulate luteinizing hormone secretion, it has been hypothesized that the decreased progesterone secretion in a previous luteal phase deficiency cycle could lead to the abnormal luteinizing hormone secretory pattern in the ensuing early follicular phase. With the possibility that the higher luteinizing hormone pulse frequency might lead to another deficient luteal phase, it becomes conceivable that luteal phase deficiency could be self-perpetuating. To test this hypothesis, luteal phase deficiency was induced in six normal women by decreasing luteinizing hormone support of the corpus luteum with a gonadotropin-releasing hormone antagonist Nal-Glu, administered twice daily beginning in the midluteal phase after a control cycle. During the antagonist-treated luteal phase, each subject met the predetermined criteria for induced a 33% or greater decrease in integrated progesterone from the control cycle and an integrated progesterone level less than 100 ng/ml per day. Luteinizing hormone secretion patterns were determined by frequent blood sampling performed every 10 minutes for 12 hours in the early follicular phase of the control cycle and the cycle after antagonist administration. Daily luteal progesterone levels were measured in the control, treatment, and posttreatment cycles. Each volunteer served as her own control. Standard parameters were compared between the control and posttreatment pulse studies (1) luteinizing hormone pulse frequency was 9.5 +/- 1.0 vs 10.0 +/- 0.9 pulses/12 hours, control vs posttreatment, respectively, p = 0.5; (2) luteinizing hormone pulse amplitude was 11.0 +/- 1.3 vs 12.0 +/- 2.2 ng/ml, p = 0.6; and (3) luteinizing hormone mean level was 19.4 +/- 2.3 vs 22.2 +/- 3.3 ng/ml, p = 0.1. Corpus luteum function was also compared between the control and posttreatment cycles. Luteal phase length was 13.7 +/- 0.6 vs 12.7 +/- 0.6 days, p = 0.08. Integrated progesterone values were 136.9 +/- 12.9 vs 130.5 +/- 11.3 ng/ml per day, p = 0.5. Therefore no discernible abnormalities in early follicular luteinizing hormone secretions or corpus luteum secretion of progesterone occurred after an induced luteal phase deficiency cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomiphene, constitute rational and effective adjuncts to therapy.
Fertility and the mechanism of ovulation is complex. The processes of fertilization and ovulation are described in this report. Information includes a description of the natural indicators of fertility and infertility, the cervical mucus pattern, and the Guidelines for the Billings Ovulation Method. The ovarian monitor which provides for the measurement of ovarian hormones (estrone glucuronide (EIG) and pregnanediol glucuronide (PdG) in a timed specimen of urine is also described. The cervical mucus pattern method measures ovarian hormones and fertility. No more than 2% of women who have been taught the Ovulation Method and performed the charting would need to use the Ovarian Monitor. It is commonly used to assure that the women's observations and interpretations are correct when there is a strong desire to either achieve or postpone pregnancy. For research, the monitor is useful in accurately measuring the timing of ovulation within the phase of potential fertility during the cycle and the changing probabilities of conception on days within the fertile period. The limits of the fertilizing life span of sperm can be measured as well as the factors which influence this life span. The day of maximum fertility, the correlation of the mucus pattern with fertility and time of ovulation, and assessment of conception cycles are measurable. Diagnostic information can be gleaned which will help to explain bleeding patterns, particularly around menopause, where fluctuating ovarian hormonal levels influence unexplained bleeding patterns. The Monitor can be useful as a test for pregnancy in measurement of high PdG and E1G levels. Four phases are identified for interpreting 1) the E1G and PdG levels are declining during the beginning of menstruation to reach a constant level (20-60 nmol/24 hours and .9 - 3.3 mcmol/24 hours); 2) rising E1G values and low PdG values and changing mucus pattern of the preovulatory cycle; 3) the ovulatory phase of peak E1G values (150-450 nmol/24 hours) followed by a distinct fall and the beginning of a rise in PdG values and the Peak of the mucus pattern; and 4) the luteal phase of rising PdG (9-36 mcmol/24 hours), and rising E1G values (100-400 nmol/24 hours) to maximum, and then falling before menstruation.
beta-Endorphin has a role in the regulation of the normal menstrual cycle and possibly in the onset of puberty. We have reviewed the evidence pointing to an alteration in this neuropeptide that may contribute to the pathogenesis of various reproductive dysfunctions. Elevated or high levels of beta-endorphin have been associated with exercise-associated amenorrhea, stress-associated amenorrhea, and polycystic ovarian syndrome. Depressed or low levels of beta-endorphin have been associated with PMS and menopause. Alterations in the levels of beta-endorphin may change the pulsatile release of GnRH via noradrenergic and/or dopaminergic pathways. We have primarily focused on beta-endorphin as representative of the endogenous opioid peptides, but other opioid peptides may also contribute to the pathogenesis of various types of reproductive dysfunction. Perhaps it will become possible to characterize and hone our understanding of the function of beta-endorphin and the other substances composing the endogenous opioid peptides. A better understanding of their role in physiological as well as pathophysiological processes may allow for the development of rational approaches to the treatment of specific disorders pertaining to reproduction. Many questions remain unanswered. what is the precise mechanism of action by which beta-endorphin exerts its influence on pulsatile GnRH release? Is there a functional relationship between CNS and peripheral (serum) levels of beta-endorphin? Are the detected changes in beta-endorphin levels merely associated, or are they a cause of a particular disorder? Since it took almost 40 years between the time prostaglandins were first discovered and eventual realization of their clinical application, it may take some time before the beta-endorphin story is complete.
The notion of an oscillator or signal generator in the central nervous system that controls the rhythmic release of GnRH and, thereby, the pulsatile secretion of the gonadotropic hormones, originated in the finding of strikingly abrupt and rhythmic fluctuations in the concentration of LH in the plasma of ovariectomized monkeys. These oscillations had a period of about one hour when blood samples were obtained at 10 to 20 minute intervals.I
These surprising observations were presaged by reports of seemingly random, major fluctuations in plasma gonadotropin concentrations in gonadectomized monkeys" and rats as well as in women.' In these earlier studies, the sampling intervals employed were never less than one hour and unable, therefore, to reveal the orderly, rhythmic events that occur with frequencies of one event per hour or more.
In the original study describing pulsatile LH secretion in ovariectomized monkeys the possibility was considered that the circhoral discharges of LH may be initiated by autoregulatory mechanisms involving long or short feedback loops, but the more likely view that these discharges were due to intermittent signals from the central nervous system unrelated to circulating LH levels that resulted in putative increments in GnRH release was favored. Nevertheless, the possible role of autoregulatory mechanisms in the control of pulsatile LH secretion was repeatedly considered,6 but finally laid to rest in the relatively recent past.7Conversely, the view that each pulse of LH released from the pituitary gland is the consequence of a bolus of GnRH secreted into the pituitary portal system has been unequivocally upheld by the demonstration of synchronous increments of GnRH assessed in the pituitary portal circulation and of LH measured in samples of peripheral blood obtained simultaneously.s, 9 In any case, the phenomenon of pulsatile gonadotropic hormone secretion was rapidly extended to most vertebrate species studied in this regard, including our own, and forms the basis of an increasingly voluminous, rapidly expanding literature.
Bone HealthOvulatory DisturbancesSubclinical AnovulationLuteal Phase Deficiency
Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary. We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases. The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups. Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Progesterone is the most widely used treatment for premenstrual syndrome. To answer definitely the question of whether progesterone suppositories are effective for the treatment of premenstrual syndrome, a randomized, placebo-controlled, double-blind crossover study of 168 women, receiving progesterone in doses of 400 and 800 mg or placebo, was carried out. Premenstrual symptoms were not significantly improved by progesterone compared with placebo in any measure used in the study, including daily symptom reports maintained throughout treatment, clinician evaluation of improvement, and patient global reports of symptoms severity, relief, and disruption of daily activity. No symptom cluster or individual symptom differed significantly between progesterone and placebo treatment. These treatment results were not significantly affected by fluctuations in response during the placebo washout period, pretreatment levels of depression or anxiety at either postmenstrual or premenstrual times, or any of 19 other background, medical history, or symptom variables examined individually as covariates with treatment.
In order to delineate factors contributing to variation in hormone levels, progesterone and prolactin (PRL) levels from 28 normal women, obtained daily during one menstrual cycle and every 20 minutes during a midluteal 24-hour admission in a subgroup of five subjects, provided a data base for analysis of these variables. Pulsatile analysis of the 24-hour data was conducted using an adaptive-threshold algorithm, and normal reference ranges were generated from randomly selected daily hormone values. Our data verify that inherent variation can significantly alter single random serum levels of reproductive hormones. These variations included menstrual cycle day, circadian influence, pulsatile secretion, assay error, and biologic heterogeneity. Besides the expected day-to-day change in progesterone levels during the luteal phase, seven of ten women exhibited a significant circadian variation in progesterone; however, the time of day of the peak level was not consistent among women. Prolactin levels did not demonstrate any clinically relevant change over the menstrual cycle, but did have a consistent circadian pattern (nocturnal rise) over the 24-hour study period. Pulsatile variation occurred in both progesterone and PRL levels during the 24-hour admission. Five different reference ranges were generated from randomly selected single daily values from the 28 normal menstrual cycles. Although the mean levels calculated for each reference range were similar, the reference ranges demonstrated considerable variation due to the random sampling. In the five progesterone reference ranges, the lower limit of the range varied from 2.7-6.1 ng/mL, whereas the upper limit varied from 24.2-42.1 ng/mL.(ABSTRACT TRUNCATED AT 250 WORDS)
Menstrual CycleLength Determination MethodsQuantitative AnalysisBBT Validation Against LH Peak
Basal temperature data are known to provide unreliable assessments of luteal phase length when they are evaluated by qualitative, visual-pattern methods. This study of 24 cycles in 24 women compared the serum LH peak day with the luteal phase onset day determined by three quantitative a) a new computerized least mean square method developed by the authors; b) the mean temperature method reported by Vollman; and c) a computerized version of the World Health Organization cumulative sum method of Royston. The luteal phase onset day determined by the three quantitative basal temperature methods, (a, b, and c) correlated well with the midcycle LH peak (r = 0.879, 0.891, and 0.791, respectively, all p less than 0.001). The cumulative sum method, however, was only able to analyze 19/24 cycles. The mean delay between the LH peak day and the luteal phase onset day determined by thermal shift was 2.4 +/- 1.5, 2.7 +/- 1.4, and 4.1 +/- 2.0 d (mean +/- SD), respectively. The mean temperature method, but not the other two methods, showed an increasing delay between the LH peak day and the thermal shift day with longer follicular phase lengths. Rectal and oral temperature data from the same cycle give identical luteal onset days when analyzed by the least mean square and mean temperature methods, but discrepant days by the cumulative sum analysis. The least mean square technique is a reliable and precise method for population documentation of luteal phase lengths.
Menstrual CycleGlucose and Insulin DynamicsMetabolic EvaluationCarbohydrate Metabolism
Three-hour oral glucose tolerance tests were performed on days 5 and 25 of ovulatory menstrual cycles in 26 women. The women were divided into normal (n = 9) and premenstrual syndrome (PMS) (n = 17) categories. Ovulation was confirmed by basal body temperature records and plasma progesterone levels. There were no statistically significant changes in the plasma glucose or insulin levels between the two tests in either group. Except for a higher two-hour plasma insulin concentration on the day 5 test in normal women, no statistically significant carbohydrate differences were noted between the groups. The data suggest that alterations in carbohydrate metabolism are not important in PMS.
Bone HealthProgesterone Bone EffectsProgesterone PhysiologyOvulatory Cycle Bone Impact
Experimental, epidemiological, and clinical data indicate that progesterone is active in bone metabolism. Progesterone appears to act directly on bone by engaging an osteoblast receptor or indirectly through competition for a glucocorticoid osteoblast receptor. Progesterone seems to promote bone formation and/or increase bone turnover. It is possible, through estrogen-stimulated increased progesterone binding to the osteoblast receptor, that progesterone plays a role in the coupling of bone resorption with bone formation. A model of the interdependent actions of progesterone and estrogen on appropriately-"ready" cells in each bone multicellular unit can be tied into the integrated secretions of these hormones within the ovulatory cycle. Figure 5 is an illustration of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a stylized ovulatory cycle. Increasing estrogen production before ovulation may reverse the resorption occurring in a "sensitive" bone multicellular unit while gonadal steroid levels are low at the time of menstrual flow. The bone remodeling unit would then be ready to begin a phase of formation as progesterone levels peaked in the midluteal phase. From this perspective, the normal ovulatory cycle looks like a natural bone-activating, coherence cycle. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling. Much further data are needed about the interrelationships between gonadal steroids and the "life cycle" of bone. Feldman et al., however, may have been prophetic when he commented; "If this anti-glucocorticoid effect of progesterone also holds true in bone, then postmenopausal osteoporosis may be, in part, a progesterone deficiency disease."
Reproductive EndocrinologyLH and FSH RegulationGnRH Antagonist EffectsHormonal Dynamics
To examine the differential regulation of glycoprotein hormone secretion from the gonadotrope by GnRH, the Nal-Glu GnRH antagonist was administered to euthyroid women in the early follicular phase (days 1-5) of the menstrual cycle, and the results compared to previous studies with the Nal-Arg GnRH antagonist. After a 4-h period of baseline sampling at a frequency of every 10 min, a single sc dose of the GnRH antagonist was administered to each subject. Frequent sampling continued for 8 h, followed by hourly sampling for a further 16 h. LH, FSH, and free alpha-subunit were measured serially in assays with high specificity. There was a 90% concordance of LH and free alpha-subunit pulses during the baseline sampling period. Pulsatile secretion of LH and free alpha-subunit was immediately abolished at the highest dose of the Nal-Glu antagonist for at least 8 h. The maximum percent suppression of LH after administration of the Nal-Glu GnRH antagonist was 70 +/- 4%, 80 +/- 4%, and 83 +/- 1% at doses of 15, 50, and 150 micrograms/kg, respectively, compared to 51 +/- 10%, 70 +/- 5%, and 69 +/- 5% at doses of 50, 150, and 500 micrograms/kg Nal-Arg antagonist. Decreases in FSH were 28 +/- 2%, 32 +/- 7%, and 39 +/- 2%, with increasing doses of the Nal-Glu antagonist compared with 25 +/- 6%, 17 +/- 6%, and 28 +/- 4% reductions at increasing doses of the Nal-Arg antagonist. Free alpha-subunit decreased 22 +/- 4%, 23 +/- 4%, and 28 +/- 3% at increasing doses of the Nal-Glu antagonist and 12 +/- 4%, 27 +/- 4%, and 30 +/- 7% with increasing doses of the Nal-Arg antagonist. For the Nal-Glu antagonist, suppression of LH was greater than that of FSH and free alpha-subunit at all doses (P less than 0.001), while FSH suppression was greater than that of free alpha-subunit at the highest dose only (P less than 0.05). For the Nal-Arg antagonist, LH suppression was greater than that of FSH or free alpha-subunit at all doses (P greater than 0.01), and FSH suppression exceeded that of free alpha-subunit at the 50 micrograms/kg dose. Suppression of LH was greater with the Nal-Glu antagonist than with the Nal-Arg antagonist at doses of 50 and 150 micrograms/kg (P less than 0.05), and FSH suppression was greater with the Nal-Glu antagonist at 150 micrograms/kg (P less than 0.01), while the degrees of maximum suppression were similar for the two different GnRH antagonists for free alpha-subunit.(ABSTRACT TRUNCATED AT 400 WORDS)
Menstrual CycleLuteal Phase Defect EtiologyNormal Follicular DevelopmentLuteal Phase Dating
Luteal phase defect (LPD) accounts for a significant proportion of reproductive disorders, however its etiology is still debated. A prospective study was performed on 37 ovulatory women to determine whether LPD can occur in cycles characterized by completely normal folliculogenesis. Criteria for normal a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presence of a dominant follicle that disappeared, an increase of serum progesterone, and normal serum levels of prolactin, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and LH. Thirty of 37 women fulfilled the above mentioned strict criteria and underwent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographic parameters of folliculogenesis and ovulation. Women with delayed endometrial development demonstrated slightly longer follicular phases (17.0 +/- 1.1 versus 14.5 +/- 0.3 days). Perfectly normal follicular and periovulatory events may be followed by deficient luteal phases.
The recurrent deficiency of progesterone (P) secretion by the corpus luteum has been associated with infertility and habitual abortion and given the clinical diagnosis of luteal phase deficiency (LPD). There is evidence that both follicular and luteal phase abnormalities can result in LPD cycles. In this study we have examined reproductive hormone levels and preovulatory follicular size in women with LPD (n = 10). For the purposes of this study, LPD was determined by an endometrial biopsy in the studied cycle that was more than 2 days out of phase. These biopsies were performed in women with infertility or habitual abortion who exhibited an out of phase biopsy in a prior cycle. The control group consisted of 28 normal women. Daily serum levels of the following hormones were LH and FSH [immuno- and bioactive (LH-immuno and LH-bio)], P, estradiol (E2), and inhibin. The LPD women exhibited significant decreases in integrated luteal phase levels of inhibin [10,615 +/- 898 vs. 13,560 +/- 662 (U/L).days; P less than 0.02] and E2 [5,015 +/- 275 vs. 6,435 +/- 393 (pmol/L).days (1366 vs. 1753 (pg/mL).days); P less than 0.05] in addition to the expected decrease in P [280 +/- 23 vs. 420 +/- 23 (nmol/L).days (88 vs. 132 (ng/mL).days); P less than 0.01]. On days 6-11 after the LH surge (day 0), there was a significant (P less than 0.05) decrease in mean LH-bio levels in LPD compared with those in normal women (146 +/- 26 vs. 212 +/- 24 micrograms/L). The midcycle LH surge was deficient in LPD when both LH-immuno [482 +/- 30 vs. 672 +/- 43 (micrograms/L).days; P less than 0.01] and LH-bio [1711 +/- 179 vs. 2248 +/- 226 (micrograms/L).days; P less than 0.05] levels were compared with normal values. When comparing the follicular phase in LPD with that in normal women, similar follicle size, peak and integrated E2 levels, and mean LH and FSH (immuno and bio) levels were found. The only follicular phase abnormality noted in this study was decreased mean levels of serum inhibin in the early and midfollicular phases (221 +/- 19 vs. 308 +/- 25 U/L; P less than 0.01). In this group of women with LPD, low levels of inhibin in the follicular phase were consistent with the concept of a defect in function of the preovulatory follicle, possibly as a result of previously described defects in gonadotropin secretion in this condition.(ABSTRACT TRUNCATED AT 400 WORDS)
Sixty-three endometrial biopsies were dated histologically by using the standard criteria on two separate occasions by the same observer. Overall, it was found that exact agreement occurred in 15 (24%), but disagreement of more than 2 days occurred in 6 (10%). The proportion of exact agreement in the first half of the luteal phase (32%) was found to be significantly higher (P less than 0.05) than that in the second half of the luteal phase (9%). In a separate part of the study, 27 women had two endometrial biopsies, each performed in a separate cycle. The within-subject between-cycle variation of the results of endometrial dating (exact 4%, disagreement of more than 2 41%) was found to be significantly different from intraobserver variation (P less than 0.01 for both). The amount of intraobserver variation suggests that the traditional dating criteria are not precise enough to quantify corpus luteum function in the second half of the luteal phase, whereas the amount of within-subject between-cycle variation implies that the result of endometrial dating in one cycle cannot be used reliably to predict that of another cycle.
Reproductive EndocrinologyOvarian-Pituitary AxisGonadotropin RegulationMaturation and Shedding
The relationship between asymptomatic bacteriuria and prematurity/low birth weight (LBW) is still a controversial issue, despite many studies. Meta-analysis, a research tool designed to analyze and combine the results of previous studies, may resolve this discrepancy among contradictory results of clinical trials. The purpose of this study was to examine the relationship between asymptomatic bacteriuria and preterm delivery/LBW using meta-analysis. Reports from the literature were classified according to study design into cohort or randomized-treatment control trials. Meta-analysis of cohort studies showed that untreated asymptomatic bacteriuria during pregnancy significantly increased rates of LBW and preterm delivery. Nonbacteriuric patients had only about two-thirds the risk (typical relative risk = 0.65; 95% confidence interval 0.57, 0.74) of LBW and half the risk (typical relative risk = 0.50; 95% confidence interval 0.36, 0.70) of preterm delivery of those with untreated asymptomatic bacteriuria. These reduced risks correspond to a 3.4 (confidence interval 1.8, 5.0) percentage-point difference in LBW and a 3.8 (1.1, 6.4) percentage-point difference in preterm delivery. The analysis of randomized clinical trials showed that antibiotic treatment significantly reduced the risk of LBW (typical relative risk = 0.56; 95% confidence interval 0.43, 0.73), with a substantial reduction of 6.4 (confidence interval 3.3, 9.5) percentage points in the rate of LBW. We conclude that clinical and epidemiologic evidence indicates a strong association between untreated asymptomatic bacteriuria and LBW/preterm delivery and that antibiotic treatment is effective in reducing the occurrence of LBW.
Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.
Menstrual CycleExercise-Associated AmenorrheaLH PulsatilityCortisol and Reproductive Function
The functional integrity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes was assessed by determining pulsatile LH, ACTH, and cortisol secretion during the early follicular phase in athletic women with regular menstrual cycles (CA; n = 9), athletic women with amenorrhea (AA; n = 9), and regularly cyclic sedentary women (CS; n = 8). The CA and AA women were not significantly different in body composition, exercise training, psychometric tests, or dietary consumption. The CA women had shorter luteal phases (P less than 0.05) and lower urinary excretion of pregnanediol glucuronide than the CS women. In the AA women, urinary estrone glucuronide, pregnanediol glucuronide, and LH excretion were low throughout a 30-day period. The CA women had a 24-h pattern of pulsatile LH secretion characterized by reduced frequency (P less than 0.05) and increased amplitude (P less than 0.05), yielding an overall increased 24-h mean level (P less than 0.05), but interpulse intervals similar to those in the CS women. During sleep, LH pulse frequency slowed in the CS and CA women, while pulse amplitude increased and the mean serum LH level decreased in both groups. The AA women had even fewer pulses (P less than 0.05) of normal amplitude occurring at much more variable (P less than 0.01) interpulse intervals. Sleep-associated changes in LH pulsatility were absent. Responses to a 10-microgram bolus GnRH dose revealed blunted (P less than 0.05) FSH release in CA and augmented (P less than 0.05) LH release in AA women. The groups did not differ in any 24-h ACTH pulse pattern parameter or in cortisol pulse frequencies. Yet, early morning (0200-0800 h) serum cortisol levels were higher (P less than 0.05) in both groups of athletes, and this elevation was extended through the day (0800-2000 h; P less than 0.001) and evening (2000-0200 h; P less than 0.05) in the AA women. The plasma ACTH and serum cortisol responses to bolus human CRH administration were blunted in the CA and AA women [change from baseline (delta) in ACTH, P less than 0.05 and P less than 0.01; delta cortisol, P less than 0.01 and P less than 0.01, respectively], but adrenal sensitivity (delta cortisol/delta ACTH ratio) was increased (P less than 0.05). The plasma ACTH and serum cortisol responses to meals also were blunted in the athletic groups (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)
PregnancyExercise During PregnancyExercise-Associated AmenorrheaPhysical Activity and Reproduction
Two runners who were not aware they had conceived continued their intense running regimens during the first and second trimesters of pregnancy. Both women assumed that their amenorrhea was due to endurance training. When their pregnancies were diagnosed, both women markedly reduced their training mileage during the third trimester because they feared that intense exercise might harm the fetus. Retrospective data were collected on their antenatal and intrapartum courses. Both women delivered healthy infants of normal weight. Although these two cases suggest that strenuous anaerobic exercise during pregnancy is not harmful, more studies are needed to determine if these cases are isolated.
Reproductive EndocrinologyLuteinized Unruptured FollicleAnovulation MechanismsFollicle Rupture and Luteinization
DlJ. ring the last stage of puberty, the hypothalamic-pituitary-ovarian axis acquires the ability to respond to high levels of estradiol; this results in a sharp increase in the pituitary output of luteinizing hormone (LH). It is believed that within a mature follicle, the LH surge triggers a complex set of events that results in two apparently ovulation and luteinization. The term ovulation will imply rupture of the follicular wall and release of an oocyte, whereas luteinization will imply the morphologic and biochemical shift in the …
Twenty women with the diagnosis of premenstrual syndrome (PMS) participated in a double-blind, placebo-controlled, crossover study to evaluate the efficacy of naltrexone, an oral opiate antagonist. This study was designed to test the hypothesis that inhibition of opiate withdrawal would aid in the treatment of PMS. The subjects received either placebo or naltrexone from days 9-18 of the cycle for three consecutive cycles. The mean scores of the three day-25 Menstrual Distress Questionnaires of 16 patients on naltrexone were compared with the mean scores of the same patients on placebo. Scores were at least ten points lower on naltrexone in 11 patients and at least ten points higher on naltrexone in two patients. Score changes of less than ten points were noted in the other three patients. The mean scores dropped 28 points on naltrexone (P = .016). The general acceptability of naltrexone was good, with side effects including nausea, decreased appetite, and dizziness. These results suggest that naltrexone alleviates many PMS symptoms and may be an effective treatment for this syndrome.
Pulsatile administration of gonadotrophin releasing hormone (GnRH) is a very effective treatment for induction of ovulation in hypothalamic amenorrhoea (HA). Thirty-seven women have been treated for a total of 117 cycles which resulted in 42 pregnancies--four treatment failures occurred. If these cycles are excluded, the 42 pregnancies were obtained within 2.3 cycles. One twin pregnancy occurred and no hyperstimulation was observed. The treatment was administered intravenously with a dosage schedule based on the grading of HA. We concluded that pulsatile GnRH was safe and very successful in induction of pregnancy in HA. Other indications (polycystic ovary syndrome and luteal phase defect) remain much less suitable for this treatment.
The authors studied the effects of clonidine on a subgroup of women who had symptoms associated with premenstrual syndrome; the subgroup comprised 24 women aged 19 to 41 years who had "moderate" to "severe" cyclic decreases in beta-endorphin levels. All of the women received clonidine and placebo in a double-blind cross-over design that spanned four menstrual cycles. Clonidine was significantly (p less than .05) more effective than placebo in reducing symptoms.
Hammarbäck S et al., 1988·Acta Obstet Gynecol Scand
A treatment with the GnRH-agonist, buserelin, was given intranasally in a dosage of 400 micrograms once daily, to induce anovulation in 26 women with premenstrual tension syndrome; 23 patients completed the study course. The design was double-blind and cross-over. Daily symptom ratings were made for two pretreatment, diagnostic cycles and continued for up to six cycles or 6 months. The rating scale used was an earlier described visual analogue scale. Blood samples for estradiol and progesterone radio-immunoassay were taken once weekly throughout the study. Results show beneficial effects of both placebo and GnRH-agonist, compared with the pretreatment situation. The GnRH-agonist was, however, significantly better than placebo. At the end of the treatment periods the patients while still taking placebo, still showed cyclical symptom changes, whereas during the GnRH-agonist treatment the cyclical changes had disappeared. The results indicate that a factor from the corpus luteum must be involved in the etiology of cyclical mood changes. The results also show that inhibition of ovulation by mean of GnRH-agonists is one possible way to treat premenstrual tension syndrome.
A variety of hypotheses have been proposed to explain the premenstrual syndromes. These hypotheses serve as rationales for an equally diverse range of proposed treatments. To investigate these hypotheses, we obtained multiple blood samples across the menstrual cycle in women with well-characterized menstrually related mood disorder and in control subjects. No diagnosis-related differences were observed in the levels or patterns of secretion of progesterone, estradiol, follicle-stimulating hormone, luteinizing hormone, testosterone-estradiol-binding globulin, dehydroepiandrosterone sulfate, dihydrotestosterone, prolactin, or cortisol. Our data suggest that premenstrual syndrome does not represent a simple hormonal deficiency and that the cited rationales for several of the proposed treatments are of questionable merit.
Reproductive EndocrinologyLuteal Cell SteroidogenesisProgesterone and Estradiol ProductionCorpus Luteum Function
Enriched small and large cell fractions were prepared from mature corpora lutea from 15 women in the midluteal phase by enzymatic dissociation, followed by Percoll gradient centrifugation. The steroidogenic function of each cell type was assessed by measuring the gonadal steroids released into the incubation medium. The large cell fraction was estimated to be 97% pure, with minimal contamination by small cells, whereas the small cell fraction was approximately 68% pure, being contaminated with 10% large cells and 22% nonsteroidogenic cells. In the unstimulated state, large cells were approximately 2-fold more potent in progesterone formation and aromatase activity, but only half as potent in androstenedione and testosterone formation as an equal number of small cells. When stimulated with hCG, the small cells responded with significant increases in progesterone, androstenedione, and testosterone release, but the large cells did not. Both cell types secreted estrone and 17 beta-estradiol in the presence of androgen substrate, but the addition of FSH significantly stimulated aromatization only in large cells. Thus, small and large human luteal cells have steroidogenic properties similar to those exhibited by follicular thecal and granulosa cells, respectively.
In order to evaluate the relationship between the urinary luteinizing hormone (LH) surge as detected by the OvuSTICK (Monoclonal Antibodies, Inc., Mountain View, CA) method and daily cervical mucus parameters, ten spontaneously ovulating women undergoing infertility evaluation were followed during their cycles with twice daily urinary LH testing as well as daily ultrasound, mucus evaluation, and hormonal assays of serum LH, progesterone (P), and estradiol (E2). Maximal cervical mucus scores, as determined using a modified Insler score, were noted to coincide consistently with the urinary LH surge as detected by twice daily testing and to precede ultrasound evidence of ovulation by 0 to 24 hours. Mucus scores rapidly declined in the 24-hour period following the urinary LH surge. Detection of the urinary LH surge may therefore help identify that period of time during which cervical mucus parameters are optimal and therefore facilitate the timing of artificial insemination, intercourse, or postcoital testing.
CommentThis case fits the criteria for mania listed by the Diagnostic and Statistical Manual of Mental Disorders (3rd edition) and the ninth revision of the International Classification of Diseases.The association of mania and myxoedema must be very rare, and we can find no other reported case. 1-5The two usual psychiatric syndromes seen in myxoedema are, firstly, confusion and cognitive impairment resembling dementia, sometimes with clouding of consciousness; and, secondly, depressed mood with paranoid delusional ideas and often hallucinations.' 2 Irritability and violence are reported only in association with paranoid cases.2Our patient showed no psychiatric disorder until further metabolic disturbance was superimposed on his thyroid deficiency.After surgery he had a mental disturbance which may have been mild hypomania, which suggests that he may have been particularly susceptible to develop a mental disturbance from metabolic abnormality as an expression of his genetic predisposition indicated by the positive family history.We thank Professor J T Silverstone for his help and advice in preparing this report.
Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.
Whole-blood serotonin levels in 14 subjects with well documented premenstrual syndrome and 13 age-matched controls were compared. Serotonin levels of premenstrual syndrome subjects were significantly lower during the last ten days of the menstrual cycle. No significant differences were noted in levels of serum estradiol and progesterone. Decreased serotonin is known to be associated with depression in humans, and nonhuman primates have exhibited abnormal behavioral profiles when given serotonin antagonists. The present observation suggests that the physiologic basis of premenstrual syndrome involves an alteration in serotonin metabolism.
Endometrial biopsies from 90 women with regular menstrual cycles and a hormonal profile compatible with normal luteal function were morphometrically assessed using 11 different indices and the results were plotted in 48-hour periods around the day of the luteinizing hormone (LH) surge (LH +/- 0). The endometrial dating reached its highest significance from days LH -3/-2 to days LH +7/+8, when the changes occurred with a high degree of regularity regardless of the length of the preovulatory and postovulatory phases. It is proposed therefore that the dating of the endometrium should be related to the LH surge rather than to the "ideal" 28-day cycle. The results also seem to suggest the existence of a regulatory mechanism for the synchronization of follicular maturation and midcycle endometrial development. Further study of the factors involved in this mechanism may result in a better understanding of certain forms of unexplained infertility.
A double-blind controlled study of the effects of vitamin B6 supplementation on premenstrual symptoms was conducted. Fifty-five women who reported moderate to severe premenstrual mood changes participated in the study. Symptoms were monitored prospectively through daily home record-keeping over a one-month baseline period followed by two months of treatment. Subjects were randomly assigned to receive daily supplements of 150 mg of vitamin B6 or placebo over the entire two-month treatment period. Analysis of covariance suggested that even though vitamin B6 may improve premenstrual symptoms related to autonomic reactions (eg, dizziness and vomiting) and behavioral changes (eg, poor performance and decreased social activities), a significant amount of physical and affective symptomatology remained during the premenstrual phase. In light of recently reported, potentially toxic effects of low doses of vitamin B6, our results call for caution in using this therapy for premenstrual symptoms.
A double-blind, placebo-controlled, randomized multiple crossover study was designed to determine the effectiveness of alprazolam in the treatment of premenstrual syndrome. Patients maintained daily diaries of 22 premenstrual symptoms for one pretreatment control cycle and four treatment cycles. Alprazolam 0.25 mg or placebo was administered three times daily from cycle day 20 until the second day of menstruation, at which time the dosage was tapered by one tablet per day to minimize withdrawal effects. The results of the clinical trial indicate that alprazolam is significantly more effective than placebo in relieving the severity of premenstrual nervous tension, mood swings, irritability, anxiety, depression, fatigue, forgetfulness, crying, cravings for sweets, abdominal bloating, abdominal cramps, and headache. The low incidence of side effects makes alprazolam an acceptable treatment for premenstrual syndrome for those women unresponsive to other therapies.
Exercise is commonly listed as a remedy for the premenstrual syndrome (PMS), although no study has proven that it is an effective therapy. Numerous reports have suggested that exercise is associated with improved mood and symptoms. In those reports, however, the diagnosis of PMS was not clearly documented, nor was the exercise carefully controlled. Preliminary evidence suggests that exercise training in ovulatory, sedentary women and intensified training in women athletes decrease mild premenstrual symptoms. Although conditioning exercise is associated with short luteal phase and anovulatory cycles, decreases in mild premenstrual symptoms occur prior to menstrual cycle changes. Controlled studies of PMS and exercise training may not only document an effective, nonpharmacologic therapy for PMS but also clarify the hormonal etiology of this complex biobehavioral phenomenon.
Menstrual CycleExercise EffectsExercise-Induced AdaptationPhysical Training
Reproductive change during conditioning exercise (physical training provides a model of hypothalamic adaptation to alterations in the external and internal environment. Parallels exist between the reproductive changes with exercise and those occurring with physical illness, undernutrition and psychological trauma. Although menstrual cyclicity may be disrupted in younger women, luteal phase shortening, anovulation and decreased premenstrual symptoms within normal ovulatory cycles are the most frequent observations noted. Baseline LH, prolactin and oestradiol tend to be lower, and other hormones unchanged, in trained women. Testosterone may be decreased within the normal range in men. Recent evidence shows that LH pulse frequency, amplitude and area under the LH curve are decreased in both female and male runners. Interrelationships between increases in central dopamine, endorphin and probably some hypothalamic message(s) relating to nutritional state appear to modulate these reproductive changes. The clinical and therapeutic response to reproductive alterations in the context of exercise differs when these are seen as adaptive and not as disease processes (Prior and Vigna, 1985b).
Plasma beta-endorphin (beta-EP), beta-lipotropin (beta-LPH), and cortisol concentrations were measured by perimenstrual period in 11 patients affected by premenstrual syndrome (PMS) and in 8 asymptomatic healthy volunteers. Blood samples were collected every 2 to 3 days, for 1 month, starting from midcycle. The Menstrual Distress Questionnaire (MDQ) was administered during the testing period. Plasma beta-LPH and cortisol levels remain stable during the perimenstrual period, in both controls and PMS patients. On the contrary, PMS patients showed a decrease of plasma beta-EP in the week preceding menses and during the first days of menstrual flow. Beta-EP values of PMS patients regain normal levels during the next follicular phase. No changes of beta-EP levels were recorded in asymptomatic women. MDQ scores revealed that PMS patients complained of water retention, pain discomfort, and mood swings. The transient and reversible decrease of plasma beta-EP in PMS patients near to and at menses remains to be clarified.
Six months of exercise training was associated with decreased premenstrual symptoms in two groups of women. There was no change in symptoms in nontraining women. Eight sedentary (ST) women increased running from 0 to 76 +/- 26 km/cycle (mean +/- standard deviation) over 6 months and seven runners (MT) trained for a marathon (42.2 km). Six normally active, nontraining (C-NT) women kept their activity constant. Each subject completed monthly intensity-graded questionnaires or kept daily symptoms diaries concerning premenstrual symptoms. All monitored basal body temperature, weight, and exercise. Gonadal steroids were measured in ST women. For ST subjects, breast (P = 0.005), fluid (P = 0.01), and personal stress (P = 0.025) decreased. MT women experienced decreased fluid (P = 0.034) and depression (P = 0.014). Anxiety tended to decrease (P = 0.087). ST and MT subjects experienced decreases in premenstrual symptoms without documented hormonal, menstrual cycle, or weight changes. These symptom changes appear to be the earliest evidence of the effects of conditioning exercise on the reproductive system.
Reproductive EndocrinologyGnRH PulsatilityRegulation of SecretionGnRH Pulse Generator
Reproductive function in humans changes markedly during life and is usually divided into four stages. During the initial stage, which begins early in fetal life and ends in infancy, gonadotropins and gonadal steroids are secreted at levels similar to those seen in early and mid-adolescence. In the second stage, which lasts from infancy through the first decade of life, reproductive function first regresses and then becomes quiescent. Puberty, the third stage, is heralded by a nocturnal increase in the secretion of gonadotropins and sex steroids. This nocturnal predominance gradually diminishes and disappears during the fourth stage — adulthood. In men, . . .
Reproductive EndocrinologyProgesterone and Cancer RiskHormonal Risk FactorsHormone Levels and Disease
Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.
The use of mefenamic acid in the treatment of premenstrual syndrome (PMS) was investigated in 15 women over six menstrual cycles. A randomized, double-blind, cross-over, placebo-controlled design was used to overcome the methodologic criticisms of other medication trials in this condition. Mefenamic acid significantly improved many of the physical, mood, and performance symptoms associated with PMS. The physical symptoms that showed marked improvement were fatigue, headache, and general aches and pains (P less than .001). Most mood symptoms were improved, the most significant being freedom from mood swings (P less than .005).
Rigorous criteria were used to select women with severe premenstrual syndrome for inclusion in an 8-month double-blind placebo-controlled clinical trial of progesterone vaginal suppositories. Following a control month without treatment, progesterone (200 mg in polyethylene glycol base) or placebo was self administered twice daily by vaginal suppository for a minimum of 12 days before the onset of menstruation for 3 months. Crossover to the opposite medication for a further 3 months was followed by a final control cycle without treatment in month 8. Physician contact was minimized throughout the study to avoid any possible positive effects of psychological support which may have confounded past investigations. Detailed self-report questionnaires were completed every 3 days for the duration of the study. Although the attrition rate was high, 20 women completed the trial and their records are analyzed here. The results of this trial indicate that the response to vaginal progesterone in these dosages is, at best, marginal and not significantly different from response with placebo use.
The first study was done in which vaginal hormonal cytograms were correlated with cervical mucus symptoms as charted by women using the ovulation method of natural family planning. Daily vaginal smears obtained by 67 women during 78 menstrual cycles provided the basis of the study. The women had used the ovulation method for at least three cycles and were not breast-feeding. All vaginal smears examined cytologically had a microbiologic diagnosis of lactobacilli. All the vaginal hormonal cytograms revealed ovulatory-type patterns. Karyopyknotic index (KPI) peak correlated with peak mucus day +/-2 days in 74, or 94.9%, of the cases, with a mean of peak mucus at +0.14 days. The average number of mucus days prior to the KPI peak was 6.1. Seven women also provided daily blood specimens for bioassay of luteinizing hormone (LH). KPI peaked with a mean of 0.7 days after the LH peak.
Prior JC et al., 1986·Eur J Appl Physiol Occup Physiol
Conditioning exercise decreased premenstrual symptoms during 3 months of a prospective controlled training study. Eight women with normal ovulatory menstrual cycles began a running exercise training programme while completing intensity-graded questionnaires concerning molimina. Six sedentary control women followed the same protocol for 3 months but did not exercise. Oral basal temperatures evaluated by mean temperature analysis were obtained for all cycles. Exercise distance and time, average exercise heart rate, basal and maximal heart rate and body weights were recorded prospectively and evaluated during the control (0) and 3rd month of the study. Mid-luteal phase progesterone and estrogen levels were sampled during the analyzed cycles for the exercise group. Molimina did not change over 3 months time in the control group. The exercise group, after increasing distance run to 51.0 +/- 18.1 km/cycle at 3 months, showed decreases in overall molimina (scores on a 9-point scale) 6.5 +/- 1.8 to 3.5 +/- 0.9, p less than 0.01). Breast symptoms decreased from 8.3 +/- 0.7, p less than 0.005. Fluid symptoms also decreased from 7.3 +/- 1.8 to 5.5 +/- 0.9, p less than 0.025. Menstrual cycle intervals, luteal lengths, body weights and mid-luteal estrogen and progesterone levels were normal and unchanged. Moderate exercise training without major weight, hormonal or menstrual cycle alteration significantly decreased premenstrual symptoms.
Menstrual CycleCervical MucusClinical OutcomesProfessional Training
To determine whether changes in circulating levels of neuropeptides are associated with symptoms of premenstrual syndrome (PMS), 20 women with the diagnosis of PMS and 20 asymptomatic subjects were studied. The premenstrual beta-endorphin levels were significantly lower in PMS patients (P = 0.0001). The decrease in beta-endorphin levels during the luteal phase, compared with the follicular phase, in PMS patients was also significant (P = 0.0002). Neurotensin, human pancreatic peptide, vasoactive intestinal polypeptide, gastrin, and bombesin-like immunoreactivity levels did not reveal significant changes between days 7 and 25 in patients with PMS.
Gonadal steroids are altered by the reproductive system's adaptation to conditioning exercise. Contraceptive options for the athletic woman include all measures appropriate for the sedentary woman. Barrier methods (always with spermicidal jelly) are the preferred choice. The cardiovascular risks, decreased aerobic performance, and shorter time to muscular exhaustion related to oral contraceptives make this a less desirable option. Potential complications from the steroid changes low oestrogen and progesterone with risk of loss of trabecular bone and early osteoporosis, and absent progesterone with low normal oestrogen levels associated with risk of endometrial or breast cancer. Therapeutic options for the amenorrhoeic or young athlete include supplemental oral calcium, cyclic oral progesterone, or possibly cyclic physiological oestrogen and progesterone. The anovulatory (usually older) athlete with regular menses needs cyclic progesterone. Medroxyprogesterone 10mg on days 16 to 25 of the cycle or for 10 days monthly can potentially prevent endometrial and breast cancer, give predictable cycles, improve trabecular bone balance and stimulate the return of ovulatory cycles. A practical approach to anovulatory infertility in the athlete includes a 10% reduction in exercise intensity and/or an increase in percentage body fat to 18 to 20%. Cyclic vaginal progesterone (25mg bid) can then treat short luteal phase cycles. With improved understanding of the hormonal adaptations to conditioning exercise, we will be better able to outline contraceptive and therapeutic options in the future.
A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos's menstrual distress questionnaire, Beck et al's depression inventory, Spielberger et al's state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.
InfertilityDiagnosis and AssessmentEndometrial Biopsy HistologyProgesterone Insufficiency
Endometrial biopsy specimens were obtained from 107 normally menstruating infertile women 2 to 3 days before the anticipated onset of menses and were day-dated according to histologic criteria. A simultaneous blood sample was obtained for measurement of progesterone (P) and beta-subunit of human chorionic gonadotropin. Of 98 biopsies which could be accurately dated, 56 were in-phase (IP) and 42 were out-of-phase (OOP). Mean serum P levels were significantly lower in women with OOP biopsies undertaken more than 4 days before the onset of menses. A sharp decline in serum P levels was observed in women with IP but not OOP biopsies, so that on the final premenstrual day serum P levels were significantly higher than normal in women with OOP biopsies. Pregnancy continued without interruption in two of six patients who underwent biopsy in the cycle of conception. One patient had an ectopic pregnancy; and the three remaining pregnant patients, all with subnormal P values, aborted. The study suggests that there is a high frequency of minor abnormalities in luteal function in normally menstruating, infertile women for whom tubal and male factors were normal. The frequency of subclinical pregnancy (2 of 107) was lower than anticipated from earlier studies.
Serum hormone concentrations were determined at intervals during the last 17 days of the menstrual cycle in 35 patients with premenstrual tension (PMT) and 11 control subjects without symptoms. The maximum mean concentration of oestradiol occurred 17 days before menstruation in the patients and 14 days before in the controls. The maximum concentrations of progesterone were similar in the two groups but the mean concentrations rose earlier in the cycle in the patients with PMT. These results suggested that the patients tended to ovulate earlier in the cycle than the controls and on the basis of the ovulatory surge in gonadotrophins two groups could be identified, group A who showed signs of ovulation 14 days or less before menstruation (17 patients, 9 controls) and group B who ovulated more than 14 days before menstruation (18 patients, 2 controls). There were no significant differences between the groups in prolactin, thyroid stimulating hormone or testosterone levels, but cortisol concentrations were uniformly higher in both groups of patients compared with those in the controls. Follicular growth was assessed with ultrasound in 18 patients and 16 control subjects. Mean follicular diameters were significantly lower in the patients than in the control group at the time of ovulation. Oestradiol determinations done at the same time correlated with the diameters and were also significantly lower in the patient group. The results suggest that ovulation tends to occur prematurely in women with PMT.
Menstrual CycleAnovulation and Luteal DefectsMenstrual DysfunctionReproductive Impact
Sonographic criteria of endometrial tissue were obtained following serial observations in normally ovulating women, and a prospective identification of a specific phase was made in those with regular menstrual cycles. This may be the first report of endometrial tissue characterization. Clinical management of infertility and monitoring of follicular growth will thus be facilitated.
Plasma and erythrocyte magnesium were measured in 105 patients with premenstrual syndrome (PMS) using a simple atomic absorption spectroscopy method. The erythrocyte magnesium concentration for the patients with PMS was significantly lower than that of a normal population. The plasma magnesium did not show this difference. The significance of this apparent cellular deficiency of magnesium is discussed.
Fifteen women with moderate to severe premenstrual symptoms, defined and graded according to a recently developed scoring system, took part in a double blind study of the effect of progesterone on premenstrual symptoms. The dosage was 100 mg progesterone twice daily delivered in vaginal pessaries. The women were improved with a statistically significant decrease in their scores by progesterone as well as by placebo treatment. There was no statistically significant difference between the two regimes.
Blood and urine specimens from 27 premenopausal breast cancer patients and 62 healthy controls have been compared with respect to concentration of testosterone and progesterone in blood and of testosterone and androstanediol in urine, measured in the luteal phase of the menstrual cycle. There was a strong positive association between the concentration of the two androgens, either in blood or urine, and breast cancer risk. A strong association was also observed with decreasing levels of progesterone. The association was statistically significant (p for trend less than 0.01) for each hormone; the rate ratios were 10.2 for serum testosterone (highest category), 5.6 for serum progesterone (lowest category), 8.4 for urinary testosterone (highest category), and 5.2 for androstanediol (highest category). The rate ratio for women presenting both high serum testosterone and low progesterone was 21.8 (4.1 to 116.1). Considering the exposure to at least one of three androgens at the highest level and low progesterone, the rate ratio was as high as 90.2 (8.2 to 989.7). This study provides evidence for the hypothesis that increased androgenic activity is an important risk indicator for breast cancer, particularly when associated with anovulation, as indicated by low serum progesterone level.
Menstrual CyclePathophysiologyDiagnosis and Classification
Pulsatile secretion of LH in women has been shown to vary during the menstrual cycle. LH pulse frequency during the luteal phase is markedly reduced compared to that in the follicular phase. The objectives of the present study were to determine if similar changes in pulsatile LH secretion occur in the monkey, and whether endogenous opiates are involved in producing these changes. In order to document if LH pulse frequency is reduced in the nonhuman primate luteal phase, serial blood samples were collected from 10 rhesus monkeys at 15-min intervals for 6 h at 3 different times of the luteal phase (early, mid-, and late). This pattern of secretion was contrasted to that observed during the ensuing early follicular phase. LH pulse frequency during the luteal phase was significantly reduced compared to the early follicular phase. Mean pulse frequency (+/- SE) was 0.84 +/- 0.16 pulses/6 h in the luteal phase vs. 2.99 +/- 0.58 pulses/6 h in the early follicular phase. When endogenous opioid activity was blocked during the luteal phase by a 5-h continuous infusion of naloxone (2 mg/h), an opiate antagonist, LH pulse frequency was increased to 2.48 +/- 0.25 pulses/5 h. This frequency was markedly different from the frequency of 0.85 +/- 0.17 pulses/5 h observed in the control period which immediately preceeded the naloxone infusion. The mean amplitude of the LH pulses in the luteal phase, which was significantly greater than that observed in the early follicular phase (20.9 +/- 1.9 ng/ml and 11.7 +/- 0.3 ng/ml) was not affected by naloxone (23.5 +/- 2.4 ng/ml vs. 25.3 +/- 1.9 ng/ml). Infusion of naloxone for longer periods (9 h) in 3 additional monkeys caused an increase in LH pulse frequency which was maintained in 2 of the monkeys, whereas the third animal exhibited only an acute response (a single pulse). These results indicate that the reduction in LH pulse frequency that occurs in the luteal phase of the rhesus menstrual cycle is an event in which endogenous opiates participate. Our previous finding that beta-endorphin release from neurons in the median eminence is stimulated during the luteal phase of the monkey, together with the present results, suggest that beta-endorphin functions as a modulator of pulsatile LH secretion in the primate menstrual cycle.
Fertility AwarenessUltrastructureScanning Electron MicroscopyCervical Mucus Changes
Interesting data on infertile human membranous mucus compared with infertile filamentous mucus have emerged from previous studies using scanning electron microscopy (SEM). The aim of this study was to obtain more information about the infertility of membranous mucus being independent of ovarian hormone stimulus. All different types of mucus, progressively secreted during the menstrual cycle by endocervical muciparous cells, were collected from the cervical canal of a fertile woman with a long menstrual cycle and specifically with a long infertile preovulatory period. The most significant results concern the identification of the cycle phase characterized by the presence of membranous mucus alone, i.e. the infertile preovulatory phase and the hormonal bases of membranous mucus infertility. The conclusion is reached that each ovarian hormone pattern stimulates the secretion of a specific type of mucus during the menstrual cycle.
Blood was found in the peritoneal fluid in 90% of women with patent tubes at laparoscopy during perimenstrual time. If the fallopian tubes were occluded, then only 15% of patients had evidence of blood in the pelvis. Also, 90% of patients with endometriosis and eight of nine women on oral contraceptives had bloody fluid during the menstrual period. The present observations indicate that retrograde menstruation through the fallopian tubes into the peritoneal cavity is a very common physiologic event in all menstruating women with patent tubes.
Normal probability plots were used to assess the homogeneity of a population of 327 luteal phases from apparently ovulatory menstrual cycles. The length of the luteal phase was defined as the interval (in days) following but not including, the luteinizing hormone peak, up to and including the day before onset of menstruation. A small sub-set of the population consisted of cycles with abnormally short luteal phases but the majority of the data followed a normal frequency distribution which gave a mean (+/- SD) for normal luteal phase length of 14.13 (+/- 1.41) days. It was estimated that all cycles with a luteal phase less than or equal to 9 days were abnormal, and that 74%, 22% and 2% respectively of cycles with luteal phases of 10, 11 and 12 days were also abnormal. The total incidence of short luteal phases defined as above was 5.2%.
The pattern of episodic gonadotropin release was studied in 15 normal female volunteers during the luteal phase of the menstrual cycle with 24 h of blood sampling for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 10-min intervals. Six subjects (two in the early, two in the mid-, and two in the late luteal phase) also had each of these specimens processed for progesterone levels. A progressive slowing of LH pulsations was present across the luteal phase with the mean LH pulse frequency declining from 15.2 pulses/24 h in the early to 8.4/24 h in the late luteal phase. A trend towards reduction in the amplitude of LH pulses was also observed (12.3 +/- 2.2 SD mIU/ml in the early vs. 8.6 +/- 3.4 mIU/ml in the late luteal phase; NS). In addition, LH pulses of heterogeneous amplitude were identified during the same 24-h study. The mean +/- SD of the larger and of the smaller LH pulses was 16.9 +/- 4.7 and 2.3 +/- 1.0 mIU/ml, respectively (P less than 0.001). While the slowing of the frequency of all LH pulses correlated well (r = 0.80, P less than 0.001) with the day of the luteal phase and poorly with the actual plasma progesterone levels, the incidence of the small LH pulses was highest in the mid-luteal phase and correlated well with the mean progesterone plasma levels (r = 0.63, P less than 0.01). In the early luteal phase, the pattern of progesterone secretion was stable over the 24-h studies and showed no relationship to episodic LH release. In contrast, in the midand late luteal phase, plasma progesterone concentrations rapidly fluctuated during the 24-h studies from levels as low as 2.3 to peaks of 40.1 ng/ml, often within the course of minutes. Progesterone increments closely attended episodes of LH release, as documented by the significant (P less than 0.05) cross-correlation between LH and progesterone levels, at time lags of 25-55 min. The results of this study indicate (a) the frequency of pulsatile release of LH declines progressively and correlates well with the duration of exposure to progressively and correlates well with the duration of exposure to progesterone; (b) the amplitude of LH pulses varies with the appearance of an increased percentage of smaller pulses correlating well with the acute level of progesterone; (c) in the early luteal phase, the pattern of progesterone secretion is stable; (d) in the midand late luteal phase, progesterone secretion is episodic, and correlates with LH pulsatile release; and (e) single progesterone estimations in the midand late luteal phase do not accurately reflect corpus luteum adequacy.
By studying the changes of microscopic and ultramicroscopic structure of cervical mucus and the corresponding changes of ovarian hormone levels throughout the cycle, a close correspondence was found between micro and ultramicrostructures. The optical structure of non canalized mucus and the electronic features of membranous mucus maintained a similarly unvaried morphology in spite of the striking changes in hormonal levels during the cycle. On the contrary, a varied morphology corresponding to the changes of cyclic levels of ovarian hormones was observed in the optical structure of canalized mucus and in the electronic features of filamentous mucus. Therefore, whatever its micro or ultramicroscopic features, the dehydrated mucus showed two components, one dependent and the other independent of ovarian hormones. A similar conclusion has also been reached for fresh mucus components.
Reproductive EndocrinologyHypothalamic Control of Menstrual CycleOpioid Peptide ModulationGnRH Pulse Regulation
Thirty-one women with severe premenstrual syndrome had low sex hormone binding globulin (SHBG) binding capacities 30.2 +/- 9.4 nmol DHT bound/l. The SHBG binding capacities rose when they were treated with three different doses of progesterone. On 400 mg (17 women) SHBG level was 45.11 +/- 11.80. On 800 mg (8 women) SHBG binding capacity rose to 64.75 +/- 14.30 and on the six women who took 1200 mg progesterone daily SHBG binding capacity was 78.5 +/- 23.10. These results are discussed.
In women with premenstrual syndrome, negative changes start soon after ovulation gradually increasing as the corpus luteum develops, and reach a maximum during the last 5 days of the luteal phase. They decline rapidly once menstruation starts, disappearing within one or two days of ovarian steroids reaching baseline levels. Positive moods are at maximum when preovulatory estradiol reaches its peak. A comparison of hormone levels in women with high and low degrees of cyclical mood change showed no difference in progesterone, estradiol, testosterone, or androstenedione.
This is a survey of 14 placebo-controlled studies regarding the treatment of premenstrual symptoms with bromocriptine. There is no substantial support that bromocriptine is an effective drug in the premenstrual syndrome as an entity. Symptoms such as irritability, depression, and anxiety were not significantly improved during treatment with bromocriptine compared to placebo treatment. Bromocriptine appears to be the treatment of choice in premenstrual mastodynia if the dosage of bromocriptine is at least 5 mg daily. Bromocriptine may therefore have a place in selected cases of the premenstrual syndrome with associated mastodynia.
A prospective study is presented in order to determine the frequency of the luteinized unruptured follicle (LUF) in a population of 66 regularly cycling women. They were monitored by daily ultrasound for a total of 183 cycles, and the LUF was detected in 9 cycles, giving an incidence of 4.9%. The results of daily changes of luteinizing hormone, estradiol, and progesterone provide support for the thesis that the LUF behaves steroidogenically as a corpus luteum and that the luteal phase duration is normal. Continued monitoring in 35 cycles revealed a recurrence in only one case during a fourth subsequent cycle. Thus, the findings indicate that the LUF is a sporadic and infrequent phenomenon. It is therefore an uncommon cause of infertile cycles in potentially fertile women and represents a biologic variable rather than a syndrome. Based on ultrasonic and endocrine observations, a mechanism is proposed for the resolution of the LUF.
Basal body temperature (BBT) charts from three menstrual cycles of 20 normal women and 20 women with biopsy-proven luteal phase defect (LPD) were reviewed. Mean luteal phase length in the normal women was 13.4 days, and that of the women with LPD was 11.8 days (P less than 0.05). Six (30%) of the LPD patients had luteal phases of less than 11 days according to BBT, and five of these patients had severely out-of-phase endometrial biopsies. None of the normal patients had luteal phases of less than 11 days. There was no significant difference in the mean rate of postovulatory BBT rise between the two groups. It is suggested that the slope of postovulatory temperature shift is not helpful in the diagnosis of LPD but that evidence of a luteal phase of less than 11 days on BBT does indicate a high likelihood of LPD.
Daily estimations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone were made in the serum of eight infertile patients from day 1 through the follicular phase during menstrual cycles before and after tamoxifen therapy. Tamoxifen therapy was found to shorten the follicular phase from 15.4 +/- 0.8 days (mean +/- standard error of the mean) to 14.0 +/- 0.6 days (difference not significant) and to lengthen the luteal phase from 12.8 +/- 0.4 days to 14.1 +/- 0.8 days (P less than 0.05). The mean estradiol concentration in the eight patients during tamoxifen treatment cycles rose on day 8 (3 days after starting tamoxifen treatment) and increased significantly (P less than 0.05) from day 10 to midcycle. The integrated follicular phase estradiol concentration in the tamoxifen treatment cycle increased to 2450.1 +/- 208.1 pg/ml/cycle, and was significantly higher (P less than 0.025) than that in the nontreatment cycle. In contrast, the concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin during the follicular phase and at the midcycle peak of tamoxifen treatment cycles were not significantly different from those of the nontreatment cycle. These results suggest that the mechanism of tamoxifen in improving folliculogenesis may involve a direct action on the ovary without intervention of the hypothalamic-pituitary system.
Thirteen women with luteal phase defects (LPD) confirmed by endometrial biopsies and 14 with histologically normal endometria were studied for early follicular and midfollicular phase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and for midluteal phase progesterone, estrogen, testosterone, and prolactin levels. The results showed that the women with LPD had significantly lower FSH levels and FSH/LH ratios in the early and midfollicular phases. LH levels, however, were similar in the LPD and normal women. During the midluteal phase, the LPD women showed significantly lower levels of progesterone and estrogen and normal levels of testosterone and prolactin. These findings reaffirm the prevailing concept that events surrounding follicular growth and development can indeed influence the quality of that cycle's corpus luteum. Furthermore, LPD as a result of hyperprolactinemia appears to be a different entity from that due to inadequate follicular phase FSH.
A group of 22 women with anovulatory cycles was treated with tamoxifen in 46 cycles. We elucidated daily hormone profiles in 5 of the 33 tamoxifen-induced ovulatory cycles in order to make a comparison with those found in 5 normal cycles. Serum follicle-stimulating hormone and luteinizing hormone (LH) rose during or a few days after the tamoxifen therapy, and thereafter serum estradiol levels rose gradually over the normal ranges during the follicular phase and reached an extremely high preovulatory peak which triggered an LH surge. This increased estradiol production exerted its usual negative feedback on LH secretion. Following ovulation, serum progesterone rose and fell in a manner similar to that in the normal cycles, with occasional values that exceeded the normal range. The endocrine significance of these findings is discussed.
Reproductive EndocrinologyNutritional EtiologyClassification and SubgroupsVitamin and Mineral Therapy
The premenstrual symptom complex many women experience in a moderate to severe form can be divided into four subgroups. Because there is more than one syndrome and nervous tension is one of the most common symptoms, the term premenstrual tension syndromes (PMTS) is used. The most common subgroup, PMT-A, consists of premenstrual anxiety, irritability and nervous tension, sometimes expressed in behavior patterns detrimental to self, family and society. Elevated blood estrogen and low progesterone have been observed in this subgroup. Administration of vitamin B6 at doses of 200-800 mg/day reduces blood estrogen, increases progesterone and results in improved symptoms under double-blind conditions. Women in this subgroup consume an excessive amount of dairy products and refined sugar, and progesterone may be of value in them. The second-most-common subgroup, PMT-H, is associated with symptoms of water and salt retention, abdominal bloating, mastalgia and weight gain. The severe form of PMT-H is associated with elevated serum aldosterone. Vitamin B6 at high dosage suppresses aldosterone and results in diuresis and clinical improvement. Vitamin E helps the breast symptoms. Methylxanthines and nicotine should be curtailed and sodium limited to 3 gm/day. PMT-C is characterized by premenstrual craving for sweets, increased appetite and indulgence in eating refined sugar followed by palpitation, fatigue, fainting spells, headache and sometimes the shakes. PMT-C patients have increased carbohydrate tolerance and low red-cell magnesium. Adequate magnesium replacement results in improved glucose tolerance tests and decreased PMT-C symptoms. Deficiency of the prostaglandin PGE1 may also be involved in PMT-C. PMT-D is the least common but most dangerous because suicide is most frequent in this subgroup. The symptoms are depression, withdrawal, insomnia, forgetfulness and confusion. In ten PMT-D patients the mean blood estrogen was lower and the mean blood progesterone higher than normal during the midluteal phase. Elevated adrenal androgens are observed in some hirsute PMT-D patients. Two PMT-D patients with normal blood progesterone and estrogens had high lead levels in hair tissue and chronic lead intoxication. This subgroups needs careful medical attention when the symptoms are severe. Therapy should be individualized according to the results of the evaluation.
One hundred thirty-seven premenopausal women with premenstrual tension underwent laparoscopy for bleeding, pain and/or infertility. Endometriosis was the associated gynecologic disease observed most frequently (66 patients). Other associated disorders were primary dysmenorrhea (31), poststerilization syndrome (24), chronic pelvic inflammatory disease (8) and leiomyoma uteri (8). Screening for prolactin and thyroid-stimulating hormone in patients with galactorrhea (74) revealed one patient with pituitary microadenoma and two with primary hypothyroidism. The midluteal progesterone levels were significantly decreased, whereas the midluteal estradiol 17 beta levels were significantly elevated. Because of the frequent association of premenstrual tension with other gynecologic diseases, screening for premenstrual tension in all premenopausal women is recommended.
Body LiteracyNursing and MidwiferySympto-Thermal MethodCycle Interpretation and Signs
All forms of birth control require some motivation, and motivation calls for understanding. If a woman learns to interpret her own cycles, her understanding of her body will be enhanced, and this could have benefits in all aspects of her fertility control. Professional nurses and health visitors are frequently expected to explain the intrigues of the menstrual cycle whether it be in family planning clinics, on gynecology wards, or in a client's home. When information about the monthly cycle is linked with the signs women observe in their own bodies, knowledge will result. With accurate knowledge about the span of the fertile phase, it should be within most women's grasp to control their own fertility, whether they use this knowledge alone or together with some mechanical contraceptive method. The endocrine hormones which control each menstrual cycle come from the pituitary gland and the ovaries, and they work in a feedback system, triggering each other. The start of the cycle is day 1 of the period when the pituitary gland starts the production of follicle stimulating hormone (FSH). This is taken in the bloodstream to the ovary where, as its name implies, it stimulates the ripening of follicles, each of which contains an egg cell. Operating in a feedback system, estrogen is carried back to the pituitary gland where it then causes a lessening in the production of FSH and stimulates the release of the luteinizing hormone (LH). LH proceeds back to the ovary and together with estrogen suppresses the growth of all the follicles except one, which then matures to release an egg at ovulation. If the egg is not fertilized, the pituitary gland detects the high level of progesterone and ceases production of LH, which causes the corpus luteum to die away. The 1st phase of the cycle leading up to ovulation is known as the follicular phase, and its length can vary considerably from month to month. The 2nd phase, leading up to menstruation, is the luteal phase, and its length does not vary more than 12-16 days, normally 14. There are 3 main observations daily temperature; the cervical mucus; and a "calendar" assessment, and after a few months the likely course of the cycle is evident. Each of these 3 ways of interpreting cycles are reviewed in detail. If the motivation and understanding is there, most women can become adept at reading the signs each month. While still learning, it is important to seek advice from those who understand the methods and can ensure accurate interpretation. Encouraging women to discover how their bodies work is not aimed at discouraging the use of mechanical or chemical contraceptive methods. It is simply a way to enhance a woman's understanding of her body which could bring her positive physical and emotional benefits. Practically, if more women could read their body cycles, there would most likely be an increase in motivation to use contraception and an associated reduction in unwanted pregnancies.
DiagnosticsCervical MucusProtocolProfessional Training
Van der Meer YG et al., 1983·Journal of Psychosomatic Obstetrics & Gynecology
A double-blind cross-over placebo controlled trial was carried out to compare progesterone 200 mg with a placebo, both given in rectal suppositories, in 20 patients with the pre-menstrual syndrome (PMS). Each kind of suppository was used twice daily from mid-cycle to the onset of menstruation during two successive cycles. Six patients did not complete the trial. Daily scores for a number of psychological and somatic symptoms were recorded by the participants. Mean symptom scores in the last seven days of the pre-menstruum did not differ significantly between the two treatment periods. The participants did not express a significant preference for the progesterone therapy. Mean blood levels of FSH, oestradiol, prolactin and LH, determined on the first day of menstruation did not differ between the two periods of treatment. Side effects, in the form of electrolyte abnormalities or hepatic or renal function disturbances, were not seen. In this trial, progesterone 200 mg twice daily by the rectal route was not more effective than the placebo.
Journal Article THE NEUROENDOCRINOLOGY OF OPIOID PEPTIDES Get access ASHLEY GROSSMAN, BA BSc MRCP, ASHLEY GROSSMAN, BA BSc MRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for Oxford Academic PubMed Google Scholar LESLEY H REES, MD MSc MRCPath FRCP LESLEY H REES, MD MSc MRCPath FRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for Oxford Academic PubMed Google Scholar British Medical Bulletin, Volume 39, Issue 1, 1983, Pages 83–88, //doi.org/10.1093/oxfordjournals.bmb.a071796 01 March 1983
Menstrual CycleNutritional TreatmentVitamin E SupplementationDose-Response Studies
In a double-blind, randomized dose-response study, 75 women with benign breast disease were administered a written questionnaire in which they scored the severity of premenstrual syndrome (PMS) symptoms before and after two months of treatment with placebo or alpha-tocopherol (150, 300, or 600 IU/day). Controlling for age and pretreatment scores, alpha-tocopherol had a significantly greater effect than placebo, improving three of the four classes of PMS symptoms. These findings suggest that vitamin E supplementation may be of value in women with severe PMS symptoms.
Fertility AwarenessStructural Changes and HormonesCervical Mucus MorphologyCervical Mucus Observation
In studying the structural changes of human cervical mucus during the ovulatory cycle, they have been observed to be directly related to ovarian hormone changes. Mucus structural changes, if taken according to their sequence during the cycle, clearly express the anatomic and functional events occurring in the ovary. If each structure is considered separately, only the mucus of the preovulatory period can be considered an indication of the corresponding ovarian processes, presenting peculiar morphologic characteristics. The observation of a similar morphologic appearance in the mucus of the early follicular and luteal phases leads one to believe, in spite of the influence of totally different hormone levels, in the likely existence of a mechanism of interference between estrogens and progesterone during the postovulatory period of the cycle.
Menstrual CycleBeta-EndorphinMenstrual Cycle RoleEndorphin and Cycle Dynamics
The possibility that beta-endorphin, an endogenous opiate, is involved in the regulation of the menstrual cycle was examined. Daily serum beta-endorphin levels, in conjunction with luteinizing hormone, progesterone, and 17 beta-estradiol were measured during 26 hormonally normal menstrual cycles. Twenty-one cycles showed a preovulatory peak and postovulatory trough of beta-endorphin, 2 cycles had a postovulatory peak, and 3 had a postovulatory peak with sustained elevation. The raw data were standardized by conversion to "Z-scores," and the composite values were computed for each of the three classes described above. Significance within these three classes was assessed using a one-way analysis of variance with an F-ratio at 95% confidence limits. The composite plot of the 26 cycles showed a statistically significant preovulatory peak occurring 2 days prior to the luteinizing hormone surge and a postovulatory trough of beta-endorphin 5 days later. These results suggest that beta-endorphins play a significant role in the neurochemical mechanisms of gonadotropin release.
Whereas follicle rupture never occurred before the 37th hour after an ovulatory stimulus (either the onset of the LH surge or hCG administration) in control patients, ovulation was observed at 26 to 36 h in women submitted to ultrasonography during the late follicular phase. Premature ovulation was observed in 5 out of 23 and 8 out of 19 cycles when ultrasonography occurred during the 3 days preceding or in the 36 h following ovulatory stimulus. This as yet unexplained observation leads us to reconsider the advisability of ovarian scan during the late follicular phase of the menstrual cycle.
The human individual responds as an entire organism to the effect of endurance training. Exercise physiologists have long documented cardiovascular, musculo-skeletal and metabolic effects of conditioning. Only recently are we beginning to understand that there are hormonal and hypothalamic changes which occur with conditioning. These hormonal changes probably serve similar adaptive functions as do the other conditioning responses. Careful controlled studies need to be performed of individuals prior to, early in conditioning, and following extended periods of conditioning looking at hypothalamic function, body morphometric characteristics, psychiatric and psychological testing and menstrual cycle data in order to better understand hormonal conditioning. When hormone changes occurring with endurance training are approached in this light, the complex inter-related alterations will begin to form a pattern. Further studies are needed to document the dynamic and reversible nature of these hormonal adaptations.
Concentrations of beta-endorphin were measured in the venous effluent of the hypothalamus (hypophyseal portal blood) at various phases of the menstrual cycle and after ovariectomy in rhesus and pigtailed monkeys. In the rhesus, beta-endorphin concentrations were high during the mid- to late follicular phase [737 +/- 256 pg/ml (mean +/- SE)] and the luteal phase (1675 +/- 1108) of the menstrual cycle, but were undetectable (less than 133) at menstruation. Concentrations were also high in pigtailed monkeys during stages of the menstrual cycle other than at menstruation (4870 +/- 1090 pg/ml), but undetectable (less than 133) 4--12 months after ovariectomy. These results indicate that beta-endorphin concentrations in hypophyseal portal blood are related to menstrual cycle events, probably changes in ovarian steroids; this in turn suggests that beta-endorphin may participate in the ovarian feedback regulation of gonadotropin secretion.
Fourteen normal women (self-selected from 180 women enrolled) in a marathon training clinic kept basal body temperature (BBT), mileage, and weight records for 48 cycles before the marathon. Age 20-45, gynecologic age greater than 5 years, no hormone use, or weight change in 3 months. The women were 35.2 +/- 5.6 years in age, 22.6 +/- 5.1 years gynecologic age, runners of 4.1 +/- 2.5 years with premenstrual symptoms, previous pregnancy 4/14, no infertility and 2/14 remote amenorrhea. BBT records were obtained and analyzed by Vollman's criteria (1977). There was no weight loss. 32/48 cycles were biphasic but only 16 were normal in the length of the premenstrual phase (PreM = luteal, nl 10 - 16 d) with a mean of 11.1 +/- 1.2 days. The other 16 biphasic cycles had short PreM phase of 6.4 +/- 1.8 days. Monophasic (M = anovulatory) cycles occurred in 16/48 records. Cycles which were abnormal (Short PreM and M) differed only in that usual run length was longer (9.6 - 9.9 miles) than in normal cycles (7.9 +/- 2.4 miles). Marathon training may be associated with normal length but M and short PreM type cycles.
Hormonal profiles were obtained throughout 26 conception cycles and 27 non-conception control cycles. The pregnancies followed treatment (clomiphene or bromocriptine) in 12 women but were spontaneous in the remaining 14. No sustained significant difference between the various types of conception cycle was found for LH, FSH, oestradiol or progesterone concentrations. Prolactin concentrations varied widely, suggesting that mean cycle prolactin concentrations ranging from 45 to 760 mi.u./l are compatible with conception. Although there were no significant differences in progesterone secretion within the conception cycles, there were highly significant differences between the conception cycles and the non-pregnant control cycles. Mean progesterone concentrations in the conception group were higher (P less than 0.005) than those in the control women over Days 3-8 following the LH peak. This difference could only be partly accounted for by heterogeneity within the control group (15-20% of the control cycles had low progesterone concentrations and were probably subfertile. It is suggested that the higher conception cycle progesterone concentrations during the early part of the luteal phase may constitute a preimplantation component of the maternal recognition of pregnancy in women.
Fertility AwarenessOvulation Method (Billings)Comparison of NFP MethodsCervical Mucus
Past practices of Natural Family Planning (NFP) have 1) calendar rhythm in which a constant mathematical relationship was calculated between the day of ovulation and the beginning of the succeeding menstrual period, 2) temperature rhythm in which sexual intercourse is permitted by observing that the basal body temperature rises at the time of ovulation, 3) a combination of calendar and temperature rhythm methods, 4) paper test strips which measure glucose and electrolytes in vaginal secretions, 5) electronic devices of various sorts which record changes in the potentials of the pelvic organs at the time of ovulation, and 6) recent developments in computer technology which measure a number of variables. All of these techniques depend upon the identification of the fertile and infertile periods of the menstrual cycle. More recent studies by the World Health Organization have analyzed the teaching phase of NFP and the effectiveness phase of NFP using the detection of ovulation by following changes in the quality of cervical mucus. These studies tested 869 women with varied backgrounds in 5 countries. The data support the fact that many motivated women can detect ovulation reasonably accurately by following changes in their cervical mucus (the Billings method), although teaching time and motivation are considerable. Long-term and detailed data are necessary to determine the value of these methods. The advantage of NFP is the avoidance of drugs and devices. Disadvantages are that demands are placed on the sex life of couples, and there are associations between failures and increased rates of congenital abnormalities.
Fertility AwarenessPostovulatory Infertility IdentificationPeak Mucus Symptom ResearchCervical Mucus and Ovulation
The estimated time of ovulation (ETO) was correlated with the day of defined postovulatory infertility in 66 hormonally normal menstrual cycles from 24 subjects for each of 15 different natural family planning methodologies. Inherent weaknesses were identified in methods based upon calendar calculations or basal body temperature only. These weaknesses could be removed for the basal body temperature-only methods if symptoms, especially the peak mucus symptom, were added to the temperature records. However, the peak mucus symptom alone had the greatest precision of all methods studied. No advantage could be identified in combining the basal body temperature with the peak symptom.
Sex hormone binding globulin (SHBG) binding capacity was measured in 50 women with severe premenstrual syndrome and 50 age-matched controls. The binding capacity was significantly lower (P = 0.001) in the patients. This finding suggests that the levels of SHBG binding capacity could be useful in the diagnosis and may help to explain the aetiology of the premenstrual syndrome.
Several periovulatory symptoms sometimes used in natural family planning are correlated with the estimated time of ovulation in 23 subjects and 64 hormonally normal menstrual cycles. The data suggest that intermenstrual pain may not be due to 1 specific cause but rather to several related factors. As a symptom of ovulation, intermenstrual pain was more specific than lower backache, abdominal bloating, and intermenstrual bleeding nonetheless, intermenstrual pain has a broad periovulatory association. The most reproducible and predictable sign of this series appeared to be the postovulatory occurrence of breast tenderness.
DiagnosticsOvarian Ultrasound MonitoringFollicular Development TrackingSonographic Methods
Serial sonographic examinations were performed on 15 volunteers five days during the expected midcycle. The 75 sonographic studies were evaluated in a nonbiased manner, and the following 1) the presence or absence of a follicle within the ovary; 2) if present, the average dimension of the follicle; 3) the ability to delineate both ovaries; and 4) the presence of associated changes, such as involution of the follicle, echogenic texture within the follicle, or fluid in the cul-de-sac. The sonographic findings were correlated with serial leutinizing hormone (LH) assays as well as basal body temperature charts. As defined in the study, the correlation between the sonographic findings and hormonal determination were considered excellent in 70% of the cases, good in 20%, and poor in 10%. Both ovaries were delineated in 73% of the examinations performed, thus substantiating the ability of sonography to detect maturing ovarian follicles.
27 healthy young Italian women were studied to evaluate their ability to identify symptomatically the potentially fertile phase of the menstrual cycle by self observation of their cervical mucus pattern as described in the Ovulation Method Billings. The women's observations were correlated with daily plasma levels of FSH, LH, estradiol-17 beta and progesterone. Ovulation was considered to occur on the day following the LH peak. The hormonal assays revealed that 2 of the 34 cycles studied were anovulatory. 24 of the 27 subjects in the study group demonstrated their ability to recognize the onset of the mucus discharge and the peak symptom from the first cycle after teaching, another two from the second cycle. The only other subject contributed an anovulatory cycle in which the hormonal assay confirmed the accuracy of her mucus observations. In the study, the mean interval between the time of ovulation as assessed and the peak symptom recorded by the subjects was 0.0 days, with a range from -2 to +1 days. The mean time interval from the first recorded symptom to the estimated day of ovulation was 6.0 days, with a range from 3 to 10 days. The study shows that young Italian women can be taught to recognize their cervical mucus pattern as described in the Ovulation Method Billings. The accuracy of their observations is demonstrated by the hormonal assays. The study also confirms the conclusion reached in earlier similar studies that there is a direct correlation between the cervical mucus symptom and the potentially fertile phase of the cycle. Research is currently being conducted on a larger number of couples employing the Ovulation Method Billings to actually regulate their fertility.
Reproductive EndocrinologyOpioid Regulation of GonadotropinsLH PulsatilityGnRH Regulation
To test the postulate that endogenous opioid peptides may be involved in the neuroendocrine mechanisms controlling the frequency and amplitude of LH pulses, saline and an opioid receptor antagonist, naloxone, were infused sequentially, each for 6-h intervals, in six normal cycling women during the luteal phase of the menstrual cycle. During naloxone infusion (1.6 mg/h), there was a significant (P less than 0.01) increase in both the frequency and amplitude of LH pulses compared to those in saline controls. FSH pulses were not discernible in individual subjects; however, a significant increment in FSH levels occurred concomitantly with the increase in LH. These data strongly suggest that endogenous opiates, through an inhibition of hypothalamic LRF, participate in the endocrine events leading to the low frequency of episodic LH secretion characteristic of the luteal phase of the human menstrual cycle.
In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.
Fertility AwarenessBiological BasisSperm TransportEstradiol and Progesterone
The fertile period of the human menstrual cycle consists of those days on which sexual intercourse can result in a pregnancy. Its duration is determined by the functional life span of the gametes within the female reproductive tract. Various mechanisms control gamete transport and survival in the reproductive tract of the human female. The ovarian hormones estradiol and progesterone have an important role in regulating these mechanisms. The nature of cervical mucus and its governing influences on sperm transport and survival following coitus are of prime importance in defining the fertile days of the menstrual cycle. Man's early concepts of the fertile period were often based on erroneous theories of the female reproductive cycle. It is only since the late 1920's that a true understanding of ovulation and the menstrual cycle has evolved. Current approaches in natural family planning to recognizing the fertile and infertile days of the menstrual cycle are discussed and evaluated.
Fertility AwarenessCervical Mucus ObservationBiomarker of FertilityMucus Pattern Recognition
The ovulation method provides a woman with an awareness of her cervical mucus pattern. This enables her to mark the beginning and end of the fertile phase of the cycle as well as the time of maximum fertility. Not only is the time of ovulation located but also there is recognition of infertility in the absence of ovulation. The key to understanding is the concept of the basic infertile pattern which precedes the commencement of follicular development; the key to successful use is competent teaching. After preliminary considerations on the fertile phase the determination of ovulation and the aspect of periodic abstinence two basic studies comparing clinical and hormonal observations are reviewed showing how accurately the cervical mucus reflects ovarian activity. Understanding the basic infertile pattern and the two sets of rules (the early day rules and peak rule identifying respectively the beginning and end of the fertile period) is basic to the application of the ovulation method. Criteria for the ideal family planning method and the importance of quality teaching are presented. Two problems requiring attention in NFP are restrictive terminology in data collection and a lack of fully developed and positive approach to periodic abstinence.
The luteinized unruptured follicle syndrome is a frequent phenomenon, occurring in half of our women with regular cycles and infertility. Progesterone concentrations and 17 beta-oestradiol concentrations were assayed in peritoneal fluid of women during the luteal phase. Up to day 20 of the cycle, the concentrations were significantly higher in women with an ovulation stigma than in women without an ovulation stigma on their corpus luteum. The range of concentrations was sufficiently different in the early luteal phase to be used diagnostically, the only limitation being the presence of a cystic corpus luteum. We suggest that the assay of progesterone and 17 beta-oestradiol in peritoneal fluid should be done in all women with infertility and biphasic basal body temperature charts in order to diagnose the luteinized unruptured follicle syndrome.
Healthy volunteers with regular ovarian function, women taking oral contraceptives, and infertile patients being treated with clomiphene were studied longitudinally from day 7 of the cycle to menstruation. The main objective was to determine whether ovulation or failure to ovulate could be detected accurately by the use of ultrasound. The ovaries were scanned with a Kretz Combison 100 sector scanner every 1 to 3 days for morphologic changes consistent with follicle development, ovulation, and development of the corpus luteum. The morphologic changes were correlated with daily urinary hormone profiles. The estimated times of ovulation according to ultrasound and luteinizing hormone peak overlapped by 24 hours in 19 of 23 normal cycles and in 5 of 6 cycles of patients treated with clomiphene. Both techniques indicated that three of three women taking oral contraceptives did not ovulate. The ultrasound studies indicated a wide range in the diameter of the preovulatory follicle, which precludes follicular diameter as a single index for prediction of ovulation. However, by measuring the maximal diameter of the follicle and observing the morphologic changes within the ovary from follicle to corpus luteum, it was possible to detect ovulation in more than 80% of cycles studied. This technique was found to be quick, inexpensive, and efficient.
In rhesus monkeys with hypothalamic lesions (which appear to abolish the endogenous production of gonadotropin-releasing hormone), normal ovulatory mestrual cycles were reestablished by an unvarying, long-term replacement regimen consisting of one intravenous pulse of synthetic gonadotropic-releasing hormone per hour. This finding is in accord with the hypothesis that the pattern of pituitary gonadotropin secretion throughout the menstrual cycle (basal secretion interrupted, once every 28 days on the average, by a preovulatory surge) is not directed by alterations in hypothalamic gonadotropin-releasing hormone secretion but by the ebb and flow of ovarian estrogens acting directly on the pituitary gland.
Fertility AwarenessOvulation DetectionTemperature-Based Ovulation EstimationHormonal Correlation with BBT
Four points on the basal body temperatures (BBT) curve have been correlated with the estimated time of ovulation (ETO), as determined by indirect hormonal parameters, in 74 menstrual cycles from 24 subjects. Only 10 of 66 hormonally
The volume of peritoneal fluid was measured after laparoscopic aspiration in 303 women. Contamination with blood was estimated at 4.2 per cent by haemoglobin assay. In 120 women with regular menstrual cycles, the volume of peritoneal fluid increased progressively during the follicular phase, was highest during the early luteal phase (20.0 +/- 6.3 ml) and declined thereafter. In 89 women with moderate and mild endometriosis the amounts of peritoneal fluid were similar, but 9 women with severe endometriosis had lower (P less than 0.05) volumes during the luteal phase. Women with inactive ovaries had uniformly low 4.2 +/- 2.3 ml in 31 women taking combined oral contraceptive pills; 4.7 +/- 5.8 ml in 17 women taking 5 mg of lynoestrenol daily and 1.2 +/- 1.9 ml in 20 postmenopausal women with an inactive endometrium. In contrast, two postmenopausal women with proliferative endometrium had 7 and 10 ml of peritoneal fluid. Women with active ovaries, 5 with absent or distally occluded Fallopian tubes and 7 without a uterus had normal amounts of peritoneal fluid. The volume of peritoneal fluid was not affected by pelvic varicose veins, a visible corpus luteum or an ovulation stigma. Peritoneal fluid appears to be predominantly an ovarian exudate, neither an exudate from the pelvic peritoneum nor a tubal secretion.
Fertility AwarenessCycle Day VariabilityTiming and PredictionOvulation Timing
It is commonplace for gynecologists to refer to "midcycle" ovulation of women. This concept has often led to the routine diagnosis of ovulatory status on day 14 of what is expected to be a 28-day menstrual cycle. For example, the postcoital test in an infertile patient, or intercourse to achieve pregnancy in a normally fertile patient, is often timed around day 14 under the assumption that ovulation is occurring then. Advocates of natural family planning (NFP) have criticized the concept of "midcycle" ovulation, because their clinical experience suggests that the natural irregularity of menstrual-cycle length militates against ovulation's occurring with any great frequency on day 14.
This report analyzes the relationship of day 14 and the actual midcycle of the menstrual cycle to each other and to indirect hormonal parameters that more directly estimate the time of ovulation.
In this report, the ultrastructure of eM was studied by cryo-scanning electron microscopy (cryo-scan), which enabled us to observe the sample while it still contained water. … It was then placed in a specially made chamber which was part of the cryo-scanning electron microscope model JSM-50A (JEOL, Tokyo). The eM was examined after etching and coating with gold. A human cervical mucus specimen as observed by cryo-scan. The 3-dimensional netlike structure was characteristic (original magnification x 10,000).
Patients with premenstrual syndrome recorded their symptoms daily using menstrual distress questionnaires. These were analysed by a least mean square method of fitting sine waves. After recording an untreated cycle, patients were given progesterone 200 mg b.d. and placebo in a double-blind crossover manner; 75 per cent of patients were then given progesterone 400 mg b.d. and placebo in a similar manner. Treated cycles were rated by both daily menstrual distress questionnaires and retrospective self-assessment. Both rating methods showed there was no significant difference between progesterone and placebo in reducing symptoms of premenstrual syndrome, and in the majority of cases placebo was more effective, although never significantly so.
Daily (12-hour) urine collections taken throughout the menstrual cycle were obtained from 30 young women who by genetic analysis were at risk for familial breast cancer, and from 30 control women carefully matched for age, height, and reproductive history. Steroids in the urine were extracted by glucuronidase hydrolysis, and the primary glucocorticoid, androgen, and estrogen hormones and their metabolites were measured by radioimmunoassay. Highly significant differences were observed only in the case of estrone and estradiol, with the high-risk subjects exhibiting lower values that the controls. This endocrine abnormality in young women at risk for breast cancer may be a potential discriminant for identifying women at risk for the disease in the population at large.
Fertility AwarenessClinical IndicatorsProgesterone CriteriaBasal Body Temperature
This study was designed to test the assumption that women with regular menstrual cycles and premenstrual symptoms are ovulatory. 40 women aged 20-40 years were selected as probably ovulatory on the basis of their recent histories of regular menstrual cycles consistently accompanied by premenstrual molimina. Each subject recorded menses and (BBT) basal body temperature for 1-3 consecutive menstrual cycles during which luteal phase serum (P) progesterone concentrations were determined by radioimmunoassay. All subjects were rated ovulatory or anovulatory by each of several espoused P criteria which confirmed 39/40 subjects (98%) to be ovulatory by a 3 ng/ml criterion; 38/40 subjects (95%) by a 5 ng/ml criterion; and 36/40 (90%) by a 15 ng/ml criterion. Thus P measurements confirmed the clinical impression of ovulation in 90-98% of subjects depending on which P criterion was selected. BBT correlated well with P measurements in that 61/66 cycles (92%) displayed a biphasic BBT pattern 2/66 cycles (3%) displayed a monophasic BBT pattern and 3/66 cycles (5%) were uninterpretable. Only 1 subject was not ovulatory in either of 2 consecutive cycles by even the most liberal P criterion and both cycles were abnormally long and would have been suspected of being anovulatory on clinical grounds. We conclude that patients presenting with a history of regular menstrual cycles accompanied by premenstrual molimina are identifiable as ovulatory without the necessity of measuring luteal phase serum P concentrations. (Authors modified)
12 normal ovulatory women were studied during 17 menstrual cycles. The first day on which the women had increasing quantities of 0.1 ml or more clear cervical mucus (IQCCM) was closely related to the time of ovulation as monitored by basal body temperature and radioimmunoassay of serum-luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. The results show that the time of ovulation can be predicted clinically without specialized tests by observing the day of onset of IQCCM.
The only way to be sure of avoiding pregnancy is for a couple to abstain from sexual intimacy during the fertile phase of the woman's cycle. Billings showed by reference to hormonal parameters that after competent instruction in the ovulation method women can identify the fertile phase of their cycle. If abstinence during the fertile phase is replaced by coitus combined with barrier methods, the pregnancy rate will be higher. The hormonal monitoring has revealed that the Peak Symptom as defined in the ovulation method is the most accurate biological marker of the time of ovulation. The cervical mucus pattern reflects the estrogen levels during follicular ripening from its commencement, and the Peak Symptom reflects a sharp cut-off effected by the elevation of the progesterone level at the time of ovulation. This means that once the mucus begins to be observed as a warning of the approach of ovulation, the woman needs to follow the changing characteristics on a daily basis in order to be certain that she recognizes ovulation.
The observation of the "Peak" mucus symptom in women using the ovulation method of natural family planning has been correlated with the estimated time of ovulation, as evaluated by indirect hormonal parameters. In 65 cycles of the 73 studied in 24 patients, there was hormonal confirmation of ovulation; in eight cycles, anovulation or luteal dysfunction was suspected. In the 65 normal cycles, 64 exhibited a Peak symptom. In those cycles, ovulation was estimated to occur from 3 days before to 3 days after the Peak symptom with a mean of 0.31 days before the Peak symptom. In 95.4% of these cycles, ovulation was estimated to occur from 2 days before to 2 days after the Peak symptom. The variation between cycles of the same patient ranged from 0 to 4 days with a mean of 1.8 days. The beginning of the mucus symptom preceded the estimated time of ovulation by an average of 5.9 days.
The only way to be sure of avoiding pregnancy is for a couple to abstain from sexual intimacy during the fertile phase of the woman's cycle. Billings showed by reference to hormonal parameters that after competent instruction in the ovulation method women can identify the fertile phase of their cycle. If abstinence during the fertile phase is replaced by coitus combined with barrier methods, the pregnancy rate will be higher. The hormonal monitoring has revealed that the Peak Symptom as defined in the ovulation method is the most accurate biological marker of the time of ovulation. The cervical mucus pattern reflects the estrogen levels during follicular ripening from its commencement, and the Peak Symptom reflects a sharp cut-off effected by the elevation of the progesterone level at the time of ovulation. This means that once the mucus begins to be observed as a warning of the approach of ovulation, the woman needs to follow the changing characteristics on a daily basis in order to be certain that she recognizes ovulation.
Reproductive EndocrinologyOpioid Effects on GonadotropinsNeuroendocrine RegulationRat Reproductive Endocrinology
A study was made of the effects on the preovulatory surges of LH and FSH exerted by morphine sulfate (M) administered at 1400 h on proestrus, the beginning of the critical period for gonadotropin release in cycling rats in our colony. Various doses of M were given ip and jugular venous blood was collected under ether anesthesia for radioimmunoassay of plasma levels of LH and FSH. To verify ovulation, oviducts were examined the following day for the presence of ova. A high dose of M (60 mg/kg) totally abolished the LH surge and partially prevented the FSH surge while completely blocking ovulation. With intermediate doses of M (20-30 mg/kg) about half of the rats showed undiminished elevations of plasma LH at 1800 h and complete ovulation the next morning, whereas the other half revealed almost total blockade of LH release and no ovulation. Following a low dose of M (10 mg/kg) a small but significant (P < 0.05) augmentation of LH levels was observed in two of three experiments and all animals receiving this dose ovulated. Pretreatment with naloxone (10 mg/kg) did not itself affect LH or FSH release or ovulation but reversed the effect of the high dose of M and permitted complete ovulation. At 1800 h the pituitaries of control and Mblocked rats responded about equally to exogenous LHRH (100 ng iv) in 15 min increments of plasma LH and FSH and all of the rats ovulated. A timecourse study indicates that the onset of the LH surge may be somewhat delayed but the amplitude was undiminished following administration of a low dose of M. These findings indicate that M exerts dose-dependent effects on the preovulatory discharge of pituitary gonadotropins in the cycling rat.
Fertility AwarenessStatistical AnalysisMucus Pattern CharacterizationCycle Data Analysis
The plasma concentrations of oestrone, oestradiol-17β and progesterone, and the urinary excretion of oestrone, oestradiol-17β, oestriol and pregnanediol have been determined in normal Japanese and British adolescent, pre-menopausal, menopausal and post-menopausal women.
The amounts of plasma oestrogen in British and Japanese women were not significantly different except in the adolescent group. In this latter category the mean level of plasma oestrone and oestradiol-17β in the luteal phase was significantly higher in Japanese compared with British women. The mean excretion of urinary oestrogens in the two races was similar for all age groups studied, as was plasma progesterone and urinary pregnanediol.
The mean ratio of oestriol to oestrone and oestradiol-17β for Japanese was higher than that for British women in the two pre-menopausal groups, although the difference was not statistically significant. The difference in the incidence rates of breast cancer in Britain and Japan does not appear to be related to differences in plasma levels of oestrogens or progesterone.
Progesterone, at five times normal 24 h endogenous production rates, was administered daily to 37 rats over Days 2 to 10, 11 to 17 or 2 to 21 term is Day 23. Peanut oil, the vehicle, was administered alone to 18 control rats over Days 2 to 21. The effect of treatment on fetal, placental and corpus luteal weights was examined on Day 22 of gestation. The administration of progesterone had no apparent effect on the maternal weight gain with pregnancy, myometrial, fetal or placental weights. No external malformations or abnormalities of the internal genitalia were detected in any of the fetuses examined. The mean number of dead fetuses per litter, 0.72 ± 0.19 (SEM) in the control rats, was significantly increased to 1.57 ± 0.34 and 2.25 ± 0.54 in rats treated with progesterone over Days 11 to 17 and 2 to 21 respectively. Male fetuses were about 7.4 percent heavier than female fetuses in the control rats but this difference was significantly less in rats treated with progesterone over Days 11 to 17(3.4 percent). Progesterone treatment had no apparent effect on the mean corpus luteal weight per rat. Over all groups combined, the mean corpus luteal weight was negatively related to the number of corpora lutea per rat. This relationship was unlikely to have been due to local nutritional or overcrowding factors since there was no apparent relationship between corpus luteal weight and the number of corpora lutea in the one ovary.
Androstenedione, testosterone, progesterone and human chorionic gonadotrophin (HCG) in plasma and total oestrogens, luteinizing hormone (LH) and HCG in urine were measured in five women during conceptual cycles and in early pregnancy. There were increased levels in plasma and urine of all the hormones measured between 12 to 48 days after ovulation except progesterone. The concentration of this hormone in plasma decreased during this time. The possible sources of these hormones in early pregnancy are discussed.
Reproductive EndocrinologyGnRH ResponseEstradiol Effects on GonadotropinsHormonal Regulation
This study was designed to investigate the effect of varying concentrations of estradiol, administered to normal women, upon the gonadotropin response to synthetic gonadotropin-releasing hormone (GnRH or LRF). Beginning at 4 pm on the first day of the menstrual cycle, 19 studies were performed in subjects who received injections of estradiol benzoate (E2B every 12 h for 6 days). Concentrations of E2B administered (mug/kg/12 h) 0.3, 0.6, 1.25, 2.5, 3.75, and 5.0. Mean serum estradiol concentrations achieved at these respective concentrations of E2B were 43, 53, 91, 145, 195, and 305 pg/ml. Twelve h after the last E2B injection, an intravenous bolus of 100 mug GnRH was administered. Gonadotropin response to this dose of GnRH after E2B was compared with each subject's response in the early follicular phase of a previous (control) cycle during which no exogenous estradiol was administered.
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.
Reproductive EndocrinologyAnovulationBreast Cancer Hormonal AssociationsLuteal Phase Deficiency
Swain MC et al., 1974·J Obstet Gynaecol Br Commonw
The luteal phase plasma progesterone levels of 341 control patients were compared with those in 25 patients with early and 12 patients with advanced breast cancer. There was a significant increase of ovulatory failure and luteal deficiency in patients with advanced breast cancer.
Reproductive EndocrinologyLuteal Phase DeficiencyOligomenorrhea Hormonal ProfileHormonal Evaluation of Ovulatory Dysfunction
The irregular menses experienced by obese and/or hirsute women were studied by daily measurement of serum LH, FSH, estradiol (E2) and progesterone (P). During 8 cycles of 24 to 157 days, each episode of menstrual bleeding was preceded by hormonal evidence of follicular maturation and corpus luteum formation. The premenstrual fluctuations of LH and E2 were not different from those observed in normal cycles. Although the luteal phase was of more than 10 days' duration, progesterone secretion was subnormal during each cycle. Serum FSH was low throughout the time preceding the LH/FSH surge. These data suggest that inadequate corpus luteum progesterone secretion may be characteristic of the menstrual cycles in oligomenorrheic, obese infertile women.
Plasma concentration of estrogen and progesterone were measured during the last 6 days of the menstrual cycle in women with premenstrual tension, and compared with a group of healthy women. Those women with anxiety as the main symptom (PMT-a) had significantly higher estrogen levels on days 5-2 before the onset of menstruation. On days 6-4 they had lower levels of progesterone. Estrogen-progesterone ratios were significantly higher on days 6-3 before menstruation. The PMT-a group also showed increases in body wt. during the last days of the menstrual cycle.
Ten ovulating women were studied to assess the interrelationships of various systemic, hormonal, and reproductive tract changes during normal menstrual cycles. Samples of blood, 24 hour urine specimens, vaginal smears, and cervical mucus were obtained every 2 days preand post-menstrually and daily in mid-cycle. Endometrial biopsies were performed at the onset of or immediately before menstruation, and the basal body temperature was recorded. Data for 10 cycles were fed into a computer, and mean reciprocal relationships were determined. (1) All endometrial biopsies reflected the late secretory phase; (2) there was a simultaneous mid-cycle surge of luteinizing hormone (LH) and folliclestimulating hormone (FSH), and serum concentrations of FSH and LH were significantly lower in the luteal phase compared to the follicular phase; (3) urinary peaks of estrone, estradiol and total estrogens occurred on the day before and that of estriol occurred on the day of the LH surge; (4) serum progesterone began to rise just before the LH peak, reached a high level 7 days after the LH peak, declined precipitately on Day 9, and rose again on Day 10, to decrease slowly until the onset of menstruation; (5) a significant relationship was observed between the LH peak and the basal body temperature; (6) urinary pregnanediol levels closely paralleled serum progesterone concentrations; (7) vaginal cytology revealed a karyopyknotic index peak the day following the LH peak; (8) properties of cervical mucus showed a remarkable relationship to the ovulatory estrogen peak.
Menstrual CycleHormonal ProfilesAnovulation and PMSPremenstrual Syndrome Etiology
Studies on pituitary and ovarian function as assessed by the urinary output of total gonadotrophic activity, the three classical oestrogens, pregnanediol and, in some cases, testosterone and epitestosterone, were conducted in eight patients suffering from premenstrual tension. Major abnormalities in endocrine function were not a feature of the condition. Ovulation, as judged by pregnanediol assays, was absent in seven out of the fifteen cycles investigated. Contrary to traditional belief, the symptoms of premenstrual tension could exist in the presence of cycles with anovulatory hormonal patterns.
Fertility AwarenessHormonal CorrelationSymptoms and SignsOvulation Detection
From among a group of women with apparently normal menstrual cycles, 7 cycles with short luteal phases were identified. These cycles were characterized by grossly normal FSH and LH patterns although the FSH/LH ratio was below normal. Mean plasma progesterone increased to less than 2 ng/ml shortly after the LH peak; thus, the peak level was lower and the peak occurred earlier than in the normal cycle. Plasma 17-hydroxyprogesterone increased at the time of the LH peak although the mean peak level was only 60% that of normal cycles. There was no secondary increase of 17-hydroxyprogesterone during the luteal phase. These observations are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum formation or function.
Clomiphene citrate [1-p(β-diethylaminoethoxy) phenyl-1,2-diphenyl-2-chloroethylene citrate], because of its ability to induce ovulation, was administered to 26 patients with excessive anovulatory uterine bleeding. Of the 129 menstrual cycles during which the drug was administered, 105 cycles (81.3%) were ovulatory and were followed by normal uterine bleeding. After clomiphene was discontinued, observations made in 52 cycles showed that only 20 (38.4%) were ovulatory
Reproductive EndocrinologyTreatment of AmenorrheaProgestational TherapyHormonal Treatment
Since classical times there has been discussion on the existence or non-existence of variations in libido in women during the menstrual cycle.*This discussion reached its peak in the nineteenth and early part of the present century.The main difference of opinion lay between those who believed that there was increased libido in association with menstruation itself-that is, just before, just after, or during, or various combinations thereof (for example, Campbell, 1891 ; Kossmann, 1903; Havelock Ellis, 1910)-and those who denied the existence of any monthly enhancement of sexual desire in women (for example, Ftirbringer, 1918).The more recent literature continues to show marked differences of opinion.Thus Corner (1952) maintained that libido is maximal just before or just after menstruation, whereas Stopes (1937) considered the monthly rhythm to have two peaks, one just before menstruation and the other at mid-cycle.On the other hand, Eckstein and Zuckerman (1956) stated that " sexual behaviour in women very rarely manifests any rhythmic pattern."However, according to Swyer (1954), " Psychic changes occur throughout the menstrual cycle.So great are the variations in different individuals that generalizations are difficult to draw.Thus, whereas some women lose all or most of their libido during the menstrual period,
Accurate timing of ovulation is especially necessary (1) in artificial insemination in order to avoid wastage of donor semen; (2) in cases where the husband is relatively infertile and it is necessary to conserve his semen. While many physicians rely upon the basal body temperature curve for timing ovulation, the interpretation of such curves is varied. Some physicians believe ovulation occurs prior to the lowest point in the temperature cycle, while others believe that ovulation occurs either at the low point or following the thermal shift. We have been disappointed in our ability to interpret the basal body temperature curve for accurate timing of ovulation, and have placed greater reliance upon concurrent phenomena, such as changes in the quantity and viscosity of cervical mucus and the cyclic changes observed in the vaginal smear. Although the relationship between the occurrence of a profuse, thin cervical mucus discharge and the optimal time of fertility in the human has been recognized for the past century, in our opinion this relationship requires further evaluation.
In his excellent review, "Cervical Cyclic variations and their clinical significance," Shettles quotes Robin who, in 1848, noted the viscous nature of human cervical secretions; and Smith who, in 1865, concluded that conception is most likely when the mucus contents of the cervix are in the most fluid condition. J. Marion Sims, who invented a vaginal speculum and first described the postcoital examination in 1868, observed that the test is positive for motile spermatozoa when the cervical mucus becomes clear and translucent, and about the consistency of the white of egg. Although these observations on human cervical mucus have been well documented, they have been almost disregarded by gynecologists. The significance of the cyclical outpouring of cervical mucus has been rediscovered in the past few years and has aroused great interest in students of sterility.
The optimal time of fertility in domestic animals is the period of heat or estrus. In 1925, Woodman and Hammond showed that during estrus, bovine cervical mucus is fluid and capable of being drawn out into threads, whereas in diestrus the mucus is thick. Seguy and Vimeux, and Seguy and Simonnet called attention to the optimal conditions of longevity of human spermatozoa in the fluid, glairy mucus of the cervix at midcycle. They postulated that these changes in cervical mucus were associated with ovulation and could be compared to the period of estrus in subprimate mammals. They correlated these changes with visual evidence of ovulation at laparotomy. ively, many women observe an increased sticky, mucoid discharge which is typical at midcycle and which is present over a period of days. On occasion this discharge is blood-tinged and may be compared to the distinct bloody mucoid discharge present in the domestic animal "in heat."
This mucus can be seen exuding from the cervix at midcycle and it may be aspirated from the endocervix and actually weighed, as reported by Viergiver and Pommerenke. Clift demonstrated certain rheologic properties of cervical mucus, especially flow elasticity and Spinnbarkeit. Flow elasticity, or elastic recoil of mucus, is measured by an instrument described by Blair. The use of the Blair capillary viscometer is a cumbersome method which we discontinued. We have had no experience with the new modification of the viscometer described by Clift, Glover, and Blair. Spinnbarkeit is easily tested, and we have found it to be a very practical objective method for determining viscosity of cervical mucus. In performing this test (Fig. 1), a vaginal speculum is inserted, exposing the cervix. A glass cannula is inserted into the endocervix and by means of gentle suction, a quantity of endocervical mucus is obtained. This mucus is blown onto a glass slide and a cover slip is placed on it. The mucus adheres to both the slide and the cover slip, and by withdrawing the cover slip, a thread of mucus is formed which can be measured in centimeters (Fig. 2). Usually, the cover slip is withdrawn several times, and the average length of the thread is ascertained. It is our purpose to show the relationship of Spinnbarkeit to other cyclic phenomena occurring during the menstrual cycle, such as basal body temperatures, vaginal smears, quantity of cervical mucus, and longevity of spermatozoa (Fig. 3).
Cervical mucus at midcycle is increased in amount, acellularity, water content, and fluidity. Furthermore, cervical mucus at this time is well supplied with carbohydrate and presumably amino acids. From a teleologic standpoint, we may conclude that because of these characteristics the sperm, on deposition in the vagina, find an environment propitious for their nutrition and migration through the cervical canal.
Reproductive EndocrinologyProgesterone PhysiologyBasal Body TemperatureHormonal Thermoregulation
Of 900 biopsies made with a small suction curet 457 from 329 women were analyzed to show the progression of the endometrium from the high-estrogen early-proliferative phase, immediately following menstruation, through the late proliferation occurring about Day 12 foll owing menstruation. Classifications from Days 14 to 27 are much easier to make because the 1st sign of progestin effect causes significant change. On Day 15 vacuolization of the cytoplasm and beginning migration of the nuclei toward the surface of the cells is seen, leaving a lucid zone underlying the nuclei. On Day 17 this zone is well-marked and the nuclei above it are lining up to lie later each beside the other near the middle of the cell. On Day 19 the row of nuclei has sunk distally near to the base of all the cells. On Day 18 a beginning edema of the stroma is seen, first in patches; by Day 21 it is generalized and the last vestige of the zona pellucida has disappeared. On Day 21 the process of secretion, which began about Day 17, is well advanced. From Day 21 on the signs of hormonal action are seen not primarily in the gla nds but in the stroma and vascular system. Edema has become generalized by Day 21; on Day 23 the stroma cells are larger, more thick-walled, and more numerous; by Day 25 the edema is replaced by masses of contiguous large cells with large pale nuclei and much cytoplasm; and on Day 26 size of the stroma cells has extended so that almost all the interglandu lar cells are contiguous. On Day 27 this solidification of the most sup erficial stroma becomes complete, the glands are widely dilated, the epithelium approaches the cuboidal, the vascular system is highly developed, and the arterioles and venules are engorged with blood. Late on Day 27, just before menstruation, lymphocytes and polymorphonuclear leukocytes appear in great numbers and erythrocytes appear in clumps. T he whole predeciduum is infiltrated, the stroma nuclei become pale, neutrophils appear in large numbers, the tissue disintegrates, and menstruation occurs. Understanding of this normal process can aid in clinical diagnosis of menstrual disorders. A series of biopsies taken with a small surgical curet does little tissue damage and can reveal hormonal imbalance, thin stroma associated with menopause or hypoplastic endometrium, and such pathological conditions as tuberculous endometritis and cancer of the endometrium. In the 3 cases in which a woman with unsuspected early pregnancy was biopsied, no harm was done. This study showed amenorrhea is usually due to deficient follicular development but may be present even if a proliferative endometrium shows a high degree of follicle activity; in the absence of pregnancy there is never a persistent corpus aluteum.
Stein IF et al., 1935·American Journal of Obstetrics and Gynecology
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My attention has been increasingly directed to a large group of women who are handicapped by premenstrual disturbances of manifold nature. It is well known that normal women suffer varying degrees of discomfort preceding the onset of menstruation. Employers of labor take cognizance of this fact and make provision for the temporary care of their employees. These minor disturbances include increased fatigability, irritability, lack of concentration and attacks of pain. In another group of patients, the symptoms complained of are of sufficient gravity to require rest in bed for one or two days. In this group, particularly, pain plays the predominant rôle. There is still another class of patients in whom grave systemic disorders manifest themselves predominantly during the premenstrual period. REPORT OF CASESCase 1. —A young, unmarried woman suffered from frequent convulsive attacks, which later occurred exclusively within ten days preceding menstruation. Neurologic investigation resulted in a diagnosis
Fertility AwarenessOgino MethodEarly ResearchTiming and Prediction