Russo LM et al., 2025·Ecotoxicol Environ Saf·
Open Access
Prior studies have observed impacts of air pollution on semen quality, but timing of exposure during developmental windows of spermatogenesis and impacts of low-to-moderate air pollution is less well understood. We examined the relation between air pollution and semen quality in the Folic Acid and Zinc Supplementation Trial (2013-2018), which enrolled male partners of couples seeking infertility treatment in the Salt Lake City, Utah region (n = 2015). Semen quality parameters were assessed at baseline, 2-, 4-, and 6-months follow-up. Measures of daily air pollutants at each participant's residence were abstracted from Community Multiscale Air Quality models (fine particulate matter: PM2.5, sulfur dioxide, nitrogen dioxide, and ozone: O3), linked to participants' residential addresses, and averaged across the 74-day spermatogenesis window prior to the sample collection date for each study visit, and across four developmental windows of spermatogenesis (mitosis, meiosis I-II, spermiogenesis, and spermiation). Generalized linear mixed models considered four repeated semen sample measures per participant and adjusted for co-pollutants, age, season, and income. In multi-pollutant models, O3 during early-to-mid spermatogenesis (meiosis I+II and spermiogenesis) was related to lower percent normal morphology (% difference -6.73, 95 % CI -9.82, -3.54 and % difference -3.83, 95 % CI -7.51, 0.00, respectively). Additionally, PM2.5 and O3 during late spermatogenesis (spermiation) were associated with lower count and concentration, and PM2.5 with lower progressive motility. These findings suggest that exposure to low-to-moderate levels of air pollution may negatively impact semen quality and indicate that exposure to O3 during meiosis and spermiogenesis may particularly affect normal sperm morphological development.
Purdue-Smithe AC et al., 2022·Am J Clin Nutr·
Open Access
Caffeine is the most frequently used psychoactive substance in the United States and >90% of reproductive-age women report some amount of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-report, which is subject to measurement error and does not account for factors that influence caffeine metabolism. Our objective was to examine associations between preconception serum caffeine metabolites, caffeinated beverage intake, and fecundability. Participants included 1228 women aged 18-40 y with a history of 1-2 pregnancy losses in the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial. We prospectively evaluated associations of preconception caffeine metabolites (i.e., caffeine, paraxanthine, and theobromine) measured from 1191 serum samples untimed to a specific time of day, self-reported usual caffeinated beverage intakes at baseline, and time-varying cycle-average caffeinated beverage intake, with fecundability. Using Cox proportional hazards models, we estimated fecundability odds ratios (FORs) and 95% CIs according to each metabolite. Follow-up was complete for 89% (n = 1088) of participants. At baseline, 85%, 73%, and 91% of women had detectable serum caffeine, paraxanthine, and theobromine, respectively. A total of 797 women became pregnant during ≤6 cycles of preconception follow-up. After adjusting for potential confounders, neither serum caffeine [tertile (T)3 compared with T1 For: 0.87; 95% CI: 0.71, 1.08], paraxanthine (T3 compared with T1 For: 0.92; 95% CI: 0.75, 1.14), nor theobromine (T3 compared with T1 For: 1.15; 95% CI: 0.95, 1.40) were associated with fecundability. Baseline intake of total caffeinated beverages was not associated with fecundability (>3 compared with 0 servings/d adjusted For: 0.99; 95% CI: 0.74, 1.34), nor was caffeinated coffee (>2 compared with 0 servings/d adjusted For: 0.93; 95% CI: 0.45, 1.92) or caffeinated soda (>2 servings/d adjusted For: 0.92; 95% CI: 0.71, 1.20). Our findings are reassuring that caffeine exposure from usual low to moderate caffeinated beverage intake likely does not influence fecundability.This trial was registered at clinicaltrials.gov as NCT00467363.
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; every other day or daily: 2 cycles) and a 28.9% increase in the cumulative pregnancy rate (weekly: 59.9%, every other day: 88.8%; daily: 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.
To estimate the association between physical activity and risk of subclinical and clinical pregnancy loss among women with a history of pregnancy loss.
Prospective cohort study as a secondary analysis of the Effects of Aspirin in Gestation and Reproduction randomized controlled trial of preconception-initiated low-dose aspirin among women with one or two prior pregnancy losses.
Four U.S. clinical centers, 2007-2011. PATIENT(S): Women with confirmed pregnancy (n = 785) as determined from hCG testing in longitudinally collected biospecimens. MAIN OUTCOME MEASURE(S): Subclinical loss of pregnancy detected only by hCG testing and clinically recognized loss. RESULT(S): Among 785 women (mean [SD] age, 28.7 [4.6] years) with an hCG-confirmed pregnancy, 188 (23.9%) experienced pregnancy loss. In multivariable models adjusted for confounders, compared with the first tertile of physical activity (median = 7.7 metabolic equivalent of task hours/week), there was a roughly twofold higher risk of subclinical loss in the second (risk ratio = 2.06; 95% confidence interval, 1.03-4.14) and third tertiles (risk ratio = 1.92; 95% confidence interval, 0.94-3.90), with median metabolic equivalent of task hours/week of 27.8 and 95.7, respectively. No relations were observed between physical activity and clinically recognized loss. CONCLUSION(S): Risk related to physical activity is different for pregnancy failure close to the time of implantation compared with that for later, clinical pregnancy loss. Higher physical activity levels were associated with an elevated risk of subclinical loss (i.e., pregnancies detected only by hCG, n = 55); however, no relationship was observed with clinically recognized loss. Further work is required to confirm these findings, assess generalizability to women without prior losses, and evaluate mechanisms. Ethical Approval: Each participating center's Institutional Review Board approved the study, and participants provided written informed consent. The trial was registered on ClinicalTrials.gov (NCT00467363), and a Data Safety and Monitoring Board provided oversight. : Estimar la asociación entre la actividad física y el riesgo de pèrdida gestacional subclínica y clínica entre mujeres con historia de pèrdida gestacional. DISEÑO:: Estudio prospectivo de cohortes como análisis secundario de un estudio aleatorizado de los efectos de aspirina en la gestación y la reproducción, utilizando bajas dosis de aspirina desde la preconcepción entre mujeres con una o dos pèrdidas gestacionales previas. : Cuatro clínicas en Estados Unidos, entre 2007–2011. : Mujeres con embarazo confirmado (n= 785) determinado por pruebas de hCG en muestras biológicas recogidas longitudinalmente. PRINCIPALES MEDIDAS DE RESULTADO(S):: Pérdida gestacional subclínica detectada sólo por la prueba de hCG y la reconocida clínicamente. : Entre 785 mujeres (media de edad [Deviación standard], 28,7 [4,6] años) con una gestación confirmada con hCG, 188 (23.9%) que tuvieron pérdida gestacional. En un modelo multivariante ajustado para factores de confusión comparado con el primer tercil de actividad física (media= 7,7 equivalentes metabólicos de trabajo horas/semana) hubo un riesgo bruto dos veces mayor de pérdida subclínica en el segundo (relación de riesgo= 2,06; Intervalo de confianza 95%, 1,03–4,14) y el tercer tercil (Relación de riesgo = 1,92 Intervalo de confianza 95%, 0,94–3,9) con una media metabólica equivalente de trabajo horas/semana de 27,8 y 95,7 respectivamente. No hubo relación entre actividad física y pérdidas gestacionales clínicas. : El riesgo asociado a actividad física es diferente para fallo gestacional próximo al momento de la implantación comparado con el más tardío de pérdida gestacional clínica. Niveles mayores de actividad física estuvieron asociados con un riesgo elevado de pérdida subclínica (por ejemplo, embarazos detectados solo por hCG, n=55); sin embargo, no se observó relación con pérdida clínicamente reconocida. Se necesitan más trabajos para confirmar estos hallazgos, evaluando de forma general mujeres sin pérdidas gestacionales previas, y evaluar sus mecanismos. APROBACIÓN ÉTICA:: El comité de revisión institucional de cada centro participante aprobó el estudio y los participantes dieron por escrito su consentimiento informado. El ensayo fue registrado en ClinicalTrial.gov (NCT00467363), y el comité de seguridad y monitorización de los datos dio su aprobación
Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth.Design, setting, and participantsThe Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months.Main outcomes and measuresThe co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and relevanceAmong a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. ClinicalTrials.gov Identifier: NCT01857310.
Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.
Purdue‐Smithe A et al., 2019·Current Developments in Nutrition·
Open Access
The association between caffeine and pregnancy loss remains controversial due to limitations of prior studies such as relying on self-reported intake only, exposure measurement after clinical confirmation of pregnancy, and potential time-varying confounding by nausea/vomiting and lifestyle factors, which may be affected by prior caffeine exposure. Thus, our aim was to evaluate associations of preconception and early pregnancy serum caffeine, paraxanthine, and theobromine, self-reported intake of caffeinated beverages, and risk of pregnancy loss among 1228 reproductive-age women attempting pregnancy in the EAGeR trial during 2007–2011. We estimated HRs and 95% CIs for any pregnancy loss, hCG loss (prior to ultrasound confirmation), and clinical loss (after ultrasound confirmation) according to caffeinated beverage intake and caffeine biomarkers measured at preconception and the 8(th) week of gestation using weighted adjusted Cox proportional hazards models. At preconception, 67%, 28%, and 9% of women reported any intake of caffeinated sodas, coffee, and tea, respectively. Preconception total caffeinated beverage intake of ≥3 vs. 0 cups/day was associated with 85% (95% CI: 1.18, 2.94) higher risk of any pregnancy loss, driven primarily by associations for hCG loss (HR: 2.88 (95% CI: 1.20, 6.91)). Caffeinated soda intake was associated with hCG loss (≥2 vs. 0.2 vs. ≤0.2 ng/mL) at preconception was strongly associated with hCG loss (HR: 4.51 (95% CI: 1.36, 14.91)). Serum caffeine, paraxanthine, and theobromine measured at the 8th week of gestation were not associated with risk of loss. Collectively, these data suggest that caffeine intake prior to pregnancy may increase risk of pregnancy loss, particularly in early gestation. Funding Sources: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD.
Is physical activity (PA) associated with fecundability in women with a history of prior pregnancy loss? Higher fecundability was related to walking among overweight/obese women and to vigorous PA in women overall. PA may influence fecundability through altered endocrine function. Studies evaluating this association have primarily utilized Internet-based recruitment and self-report for pregnancy assessment and have yielded conflicting results. STUDY DESIGN, SIZE, Duration: This is a secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a multisite, randomized controlled trial of preconception-initiated low-dose aspirin. PARTICIPANTS/MATERIALS, SETTING, Healthy women (n = 1214), aged 18-40 and with 1-2 prior pregnancy losses, were recruited from four US medical centers. Participants were followed for up to six menstrual cycles while attempting pregnancy and through pregnancy for those who became pregnant. Time to hCG detected pregnancy was assessed using discrete-time Cox proportional hazard models to estimate fecundability odds ratios (FOR) adjusted for covariates, accounting for left truncation and right censoring. Main The association of walking with fecundability varied significantly by BMI (P-interaction = 0.01). Among overweight/obese women, walking ≥10 min at a time was related to improved fecundability (FOR = 1.82, 95% CI: 1.19, 2.77). In adjusted models, women reporting >4 h/wk of vigorous activity had significantly higher fecundability (FOR = 1.69, 95% CI: 1.24, 2.31) compared to no vigorous activity. Associations of vigorous activity with fecundability were not significantly different by BMI (P-interaction = 0.9). Moderate activity, sitting, and International Physical Activity Questionnaire (IPAQ) categories were not associated with fecundability overall or in BMI-stratified analyses. LIMITATIONS, Some misclassification of PA levels as determined by the short form of the IPAQ is likely to have occurred, and may have led to non-differential misclassification of exposure in our study. Information on diet and change in BMI was not collected and may have contributed to some residual confounding in our results. The generalizability of our results may be limited as our population consisted of women with a history of one or two pregnancy losses. These findings provide positive evidence for the benefits of PA in women attempting pregnancy, especially for walking among those with higher BMI. Further study is necessary to clarify possible mechanisms through which walking and vigorous activity might affect time-to-pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors report no conflicts of interest in this work. #NCT00467363.
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.
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. Clinical ClinicalTrials.gov: NCT00467363.
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.
Vitamin D is associated with markers of ovarian reserve in women of advanced reproductive age and
in vitro
studies suggest that vitamin D may influence anti‐mullerian hormone (AMH). Higher vitamin D levels are also associated with improved IVF outcomes in some studies. However, less is understood regarding associations with ovarian reserve or time to pregnancy among younger women or women without a history of infertility. Our purpose was to assess the relationships between vitamin D and AMH and fecundability among women with proven fecundity.
Secondary analysis of the EAGeR Trial, a multicenter, block‐randomized, double‐blind, placebo‐controlled clinical trial to evaluate the effect of preconception‐initiated daily low dose aspirin on reproductive outcomes in women with a history of pregnancy loss and normal fecundity. Participants were attempting pregnancy, aged 18–40 years, with 1–2 prior pregnancy losses and no history of infertility. We assessed 25‐OH vitamin D and AMH in serum at baseline (not pregnant) among 1185 women. AMH levels were log‐transformed for normality. Linear regression was used to estimate associations between vitamin D and AMH concentrations adjusting for age, body mass index, race, season, physical activity, and number of prior losses. Time to hCG detected pregnancy was assessed using Cox proportional hazard regression models for discrete survival time, accounting for left truncation and right censoring, to estimate fecundability odds ratios (FOR), adjusting for the same factors. A total of 163 women (13.8%) had deficient vitamin D levels (<20 ng/mL). Overall, vitamin D levels were not associated with AMH (percent change −1.6, 95% confidence interval [CI] −5.3%, 2.3% per 10 ng/mL). Vitamin D deficiency was also not associated with AMH (deficient: adjusted geometric mean AMH 2.51, 95% CI 2.20, 2.85 vs. inadequate/sufficient: 2.74, 95% CI 2.60, 2.89). There also were no significant associations observed between overall vitamin D levels or deficiency and fecundability (FOR 1.09, 95% CI 0.84, 1.42 comparing deficient vs. inadequate/sufficient) after adjustment. Vitamin D was not associated with AMH, time to pregnancy, or fecundability among women with proven fecundity. These results suggest that vitamin D is not associated with ovarian reserve or fecundability and that vitamin D supplementation may offer little clinical benefit for improving markers of ovarian reserve and fecundity.
Support or Funding Information
Intramural Research Program, DIPHR, NICHD, NIH
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.
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.