Michels KA et al., 2020·Chronobiol Int·
Open Access
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 difference: -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.
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.
Although maternal nutrition may affect fecundity, associations between preconception micronutrient levels and time to pregnancy (TTP) have not been examined. We assessed the relationship between preconception fat-soluble micronutrient concentrations and TTP among women with 1-2 prior pregnancy losses. This was a prospective cohort study of 1,228 women set within the Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial (United States, 2007-2011), which assessed the association of preconception-initiated daily low-dose aspirin with reproductive outcomes. We measured preconception levels of zeaxanthin, cryptoxanthin, lycopene, αand β-carotene, and αand γ-tocopherol in serum. We used discrete Cox regression models, accounting for left-truncation and right-censoring, to calculate fecundability odds ratios and 95% confidence intervals. The models adjusted for age, body mass index, race, smoking, alcohol, physical activity, income, vitamin use, cholesterol, treatment arm, and study site. Serum α-carotene levels (per log unit (μg/dL) increase, fecundability odds ratio (FOR) = 1.17, 95% confidence interval (CI): 1.00, 1.36) and serum α-carotene concentrations at or above the US average (2.92 μg/dL) versus below the average (FOR = 1.21, 95% CI: 1.02, 1.44) were associated with shorter TTP. Compared with levels below the US average (187 μg/dL), γ-tocopherol concentrations at or above the average were associated with longer TTP (FOR = 0.83, 95% CI: 0.69, 1.00). The potential for these nutrients to influence fecundability deserves further exploration.
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, Duration: 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 numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
Thyroid and Metabolic Function · Insulin and Metabolism
Are maternal preconception lipid levels associated with fecundability?Summary answerFecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels. Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity.Study design, size, durationA secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial. Participants/materials, setting, methodsA total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C Main results and the role of chanceThere were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (For: 0.76, 95% CI: 0.59, 0.97) and 29% (For: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol Limitations, reasons for cautionAlthough the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability. Wider s of the findingsOur results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability.Study funding and competing interest(s)This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist.Trial registration number#NCT00467363.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
Inflammation is linked to causes of infertility. Low-dose aspirin (LDA) may improve reproductive success in women with chronic, low-grade inflammation. To investigate the effect of preconception-initiated LDA on pregnancy rate, pregnancy loss, live birth rate, and inflammation during pregnancy.
Stratified secondary analysis of a multicenter, block-randomized, double-blind, placebo-controlled trial.
Four US academic medical centers, 2007 to 2012. Healthy women aged 18 to 40 years (N = 1228) with one to two prior pregnancy losses actively attempting to conceive. Preconception-initiated, daily LDA (81 mg) or matching placebo taken up to six menstrual cycles attempting pregnancy and through 36 weeks' gestation in women who conceived. Confirmed pregnancy, live birth, and pregnancy loss were compared between LDA and placebo, stratified by tertile of preconception, preintervention serum high-sensitivity C-reactive protein (hsCRP) (low, <0.70 mg/L; middle, 0.70 to <1.95 mg/L; high, ≥1.95 mg/L). Live birth occurred in 55% of women overall. The lowest pregnancy and live birth rates occurred among the highest hsCRP tertile receiving placebo (44% live birth). LDA increased live birth among high-hsCRP women to 59% (relative risk, 1.35; 95% confidence interval, 1.08 to 1.67), similar to rates in the lower and mid-CRP tertiles. LDA did not affect clinical pregnancy or live birth in the low (live birth: 59% LDA, 54% placebo) or midlevel hsCRP tertiles (live birth: 59% LDA, 59% placebo). In women attempting conception with elevated hsCRP and prior pregnancy loss, LDA may increase clinical pregnancy and live birth rates compared with women without inflammation and reduce hsCRP elevation during pregnancy.
Schliep KC et al., 2016·Am J Clin Nutr·
Open Access
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·
Open Access
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.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses? Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses. LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses. STUDY DESIGN, SIZE, Duration: The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses. PARTICIPANTS, SETTING, Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach. Main Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26). LIMITATIONS, Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results. Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest. The trial was registered at ClinicalTrials.gov #NCT00467363. Trial Registration Date: 27 April 2007. DATE OF FIRST PATIENT'S Enrollment: 15 June 2007.
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.
Schliep KC et al., 2015·Am J Clin Nutr·
Open Access
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.
Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA. Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation. Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results. Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos. ClinicalTrials.gov NCT00467363. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
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, Duration: 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 positive associations with fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 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.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
Schisterman EF et al., 2015·J Clin Endocrinol Metab·
Open Access
The objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss.
This was a multicenter, block-randomized, double-blind, placebo-controlled trial. Participants were block-randomized by center and eligibility stratum.
The study was conducted at four U.S.A. medical centers (2007-2012). Participants women aged 18-40 years actively attempting pregnancy, stratified by eligibility criteria: the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss. Daily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy. Time to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured. Of the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (For: 1.28; 95%CI: 1.02, 1.62). Preconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss.
Wong LF et al., 2015·Am J Obstet Gynecol·
Open Access
We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes. A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with a human chorionic gonadotropin-positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n = 677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression. Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 ± 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI ≤3 months as compared to IPI >3 months (adjusted relative risk [aRR], 1.07; 95% confidence interval [CI], 0.98-1.16). Rates were also similar for periimplantation loss (aRR, 0.95; 95% CI, 0.51-1.80), clinically confirmed loss (aRR, 0.75; 95% CI, 0.51-1.10), and any pregnancy complication (aRR, 0.88; 95% CI, 0.71-1.09) for those with IPI ≤3 months as compared to IPI >3 months. Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted.
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, Duration: 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% confidence interval: 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.
Sjaarda LA et al., 2014·J Clin Endocrinol Metab·
Open Access
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.
Schliep KC et al., 2014·J Clin Endocrinol Metab·
Open Access
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 LPD diagnostic criteria: 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, and 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.
Ahrens K et al., 2014·Am J Obstet Gynecol·
Open Access
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.
Filiberto AC et al., 2013·Fertil Steril·
Open Access
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.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
Schisterman EF et al., 2013·Paediatr Perinat Epidemiol·
Open Access
Low-dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves livebirth rates in women with one to two prior losses. We performed a multicentre, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006-12). Eligible women were aged 18-40 years actively trying to conceive, with one to two prior losses. Participants were randomised to receive daily LDA (81 mg/day) or a matching placebo, and all were provided with daily 400-mcg folic acid. Follow-up continued for ≤6 menstrual cycles while attempting to conceive. For those who conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative livebirth rate over the trial period. There were 1228 women randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% more than high school education), and employed (75%) with a household income >$100 000 annually (40%). The characteristics of those in the treatment and placebo arms were well balanced. We describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on livebirth and other pregnancy outcomes in these women.
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 deviation: 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% confidence interval: 0.13, 0.27) and progesterone (β = 0.06, 95% confidence interval: 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 mean blood loss: 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.
Phipps AI et al., 2011·J Natl Cancer Inst·
Open Access
Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers. Using data from 155,723 women enrolled in the Women's Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs). Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10,000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10,000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype. The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further confirmation because the biological mechanisms underlying these differences are uncertain.
Yeung EH et al., 2010·The Journal of clinical endocrinology and metabolism·
Open Access
Conflicting findings have been reported regarding the effect of menstrual cycle phase and sex hormones on insulin sensitivity. The aim was to determine the pattern of insulin resistance over the menstrual cycle and whether variations in sex hormones explain these patterns. The BioCycle study is a longitudinal study that measured hormones at different phases of the menstrual cycle. Participants had up to eight visits per cycle; each visit was timed using fertility monitors to capture sensitive windows of hormonal changes. The study was conducted in the general community of the University at Buffalo (Buffalo, NY). A total of 257 healthy, premenopausal women (age, 27±8 yr; body mass index, 24±4 kg/m2) participated in the study. We measured fasting insulin, glucose, and insulin resistance by the homeostasis model of insulin resistance (HOMA-IR). Significant changes in HOMA-IR were observed over the menstrual cycle; from a midfollicular phase level of 1.35, levels rose to 1.59 during the early luteal phase and decreased to 1.55 in the late-luteal phase. HOMA-IR levels primarily reflected changes in insulin and not glucose. After adjustment for age, race, cycle, and other sex hormones, HOMA-IR was positively associated with estradiol (β=0.082; P<0.001) and progesterone (β=0.025; P<0.001), and inversely associated with FSH (adjusted β=-0.040; P<0.001) and SHBG (β=-0.085; P<0.001). LH was not associated with HOMA-IR. Further adjustment for BMI weakened the association with SHBG (β=-0.057; P=0.06) but did not affect other associations. Insulin exhibited minor menstrual cycle variability. Estradiol and progesterone were positively associated with insulin resistance and should be considered in studies of insulin resistance among premenopausal women.
To test for the possible association of past oral contraceptive (OC) use and incident fracture after menopause.
A prospective cohort of 93,725 postmenopausal women.
Forty Women's Health Initiative (WHI) clinical centers across the United States. PATIENT(S): Ethnically diverse 93,725 volunteer postmenopausal women, 50 to 79 years old. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The main outcome was self-reported incident first fracture assessed prospectively by annual questionnaire. RESULT(S): The adjusted relative hazard (HR) for fracture among past OC users was 1.07 (95% CI, 1.01-1.15). Among women without any postmenopausal hormone treatment, past OC use for < or =5 years led to an HR of 1.15 (95% CI, 1.04-1.27) and for past OC use >5 years led to an HR of 1.09 (95% CI, 0.97-1.23) compared with never users. CONCLUSION(S): This study does not support the idea that past OC use protects against later fracture.