Karen C. Schliep

Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women

STUDY QUESTION Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women? SUMMARY ANSWER Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women. WHAT IS KNOWN ALREADY 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, METHODS 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 RESULTS AND THE ROLE OF CHANCE 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, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTERESTS 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.

Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization

OBJECTIVE To assess the effects of both male and female body mass index (BMI), individually and combined, on IVF outcomes. DESIGN Prospective cohort study. SETTING University fertility center. PATIENT(S) All couples undergoing first fresh IVF cycles, 2005-2010, for whom male and female weight and height information were available (n = 721 couples). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Embryologic parameters, clinical pregnancy, and live birth incidence. RESULT(S) The average male BMI among the study population was 27.5 ± 4.8 kg/m(2) (range, 17.3-49.3 kg/m(2)), while the average female BMI (n = 721) was 25.2 ± 5.9 kg/m(2) (range, 16.2-50.7 kg/m(2)). Neither male nor female overweight (25-29.9 kg/m(2)), class I obese (30-34.9 kg/m(2)), or class II/III obese (≥35 kg/m(2)) status was significantly associated with fertilization rate, embryo score, or incidence of pregnancy or live birth compared with normal weight (18.5-24.9 kg/m(2)) status after adjusting for male and female age, partner BMI, and parity. Similar null findings were found between combined couple BMI categories and IVF success. CONCLUSION(S) Our findings support the notion that weight status does not influence fecundity among couples undergoing infertility treatment. Given the limited and conflicting research on BMI and pregnancy success among IVF couples, further research augmented to include other adiposity measures is needed.

All-Cause and Cause-Specific Mortality after Hypertensive Disease of Pregnancy

OBJECTIVE: To assess whether women with a history of hypertensive disease of pregnancy have increased risk for early adult mortality. METHODS: In this retrospective cohort study, women with one or more singleton pregnancies (1939–2012) with birth certificate information in the Utah Population Database were included. Diagnoses were categorized into gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; and eclampsia. Women with more than one pregnancy with hypertensive disease (exposed) were included only once, assigned to the most severe category. Exposed women were matched one to two to unexposed women by age, year of childbirth, and parity at the time of the index pregnancy. The causes of death were ascertained using Utah death certificates and the fact of death was supplemented with the Social Security Death Index. Hazard ratios for cause-specific mortality among exposed women compared with unexposed women were estimated using Cox regressions adjusting for neonatal sex, parental education, preterm delivery, race–ethnicity, and maternal marital status. RESULTS: A total of 60,580 exposed women were matched to 123,140 unexposed women; 4,520 (7.46%) exposed and 6,776 (5.50%) unexposed women had died by 2012. All-cause mortality was significantly higher among women with hypertensive disease of pregnancy (adjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.57–1.73). Exposed womens greatest excess mortality risks were from Alzheimer disease (adjusted HR 3.44, 95% CI 1.00–11.82), diabetes (adjusted HR 2.80, 95% CI 2.20–3.55), ischemic heart disease (adjusted HR 2.23, 95% CI 1.90–2.63), and stroke (adjusted HR 1.88, 95% CI 1.53–2.32). CONCLUSION: Women with hypertensive disease of pregnancy have increased mortality risk, particularly for Alzheimer disease, diabetes, ischemic heart disease, and stroke.

Is anti-müllerian hormone associated with fecundability? Findings from the EAGeR trial

OBJECTIVE The objective of the study was to evaluate whether anti-Müllerian hormone (AMH) is associated with fecundability among women with proven fecundity and a history of pregnancy loss. DESIGN This was a prospective cohort study within a multicenter, block-randomized, double-blind, placebo-controlled clinical trial ( clinicaltrials.gov , number NCT00467363). SETTING The study was conducted at four US medical centers (2006-2012). PARTICIPANTS Participating women were aged 18-40 years, with a history of one to two pregnancy losses who were actively attempting pregnancy. MAIN OUTCOME MEASURES Time to human chorionic gonadotropin detected and clinical pregnancy were assessed using Cox proportional hazard regression models to estimate fecundability odds ratios (fecundability odds ratios with 95% confidence interval [CI]) adjusted for age, race, body mass index, income, low-dose aspirin treatment, parity, number of previous losses, and time since most recent loss. Analyses examined by preconception AMH levels: low (<1.00 ng/mL, n = 124); normal (referent 1.00-3.5 ng/mL, n = 595); and high (>3.5 ng/mL, n = 483). RESULTS Of the 1202 women with baseline AMH levels, 82 women with low AMH (66.1%) achieved an human chorionic gonadotropin detected pregnancy, compared with 383 with normal AMH (65.2%) and 315 with high AMH level (65.2%). Low or high AMH levels relative to normal AMH (referent) were not associated with fecundability (low AMH: fecundability odds ratios 1.13, 95% CI 0.85-1.49; high AMH: FOR 1.04, 95% CI 0.87-1.24). CONCLUSIONS Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women.

Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study.

BACKGROUND Caffeinated beverages are widely consumed among women of reproductive age, but their association with reproductive hormones, and whether race modifies any such associations, is not well understood. OBJECTIVE We assessed the relation between caffeine and caffeinated beverage intake and reproductive hormones in healthy premenopausal women and evaluated the potential effect modification by race. DESIGN Participants (n = 259) were followed for up to 2 menstrual cycles and provided fasting blood specimens for hormonal assessment at up to 8 visits per cycle and four 24-h dietary recalls per cycle. Weighted linear mixed models and nonlinear mixed models with harmonic terms were used to estimate associations between caffeine and hormone concentrations, adjusted for age, adiposity, physical activity, energy and alcohol intakes, and perceived stress. On the basis of a priori assumptions, an interaction between race and caffeine was tested, and stratified results are presented. RESULTS Caffeine intake ≥200 mg/d was inversely associated with free estradiol concentrations among white women (β = -0.15; 95% CI: -0.26, -0.05) and positively associated among Asian women (β = 0.61; 95% CI: 0.31, 0.92). Caffeinated soda intake and green tea intake ≥1 cup/d (1 cup = 240 mL) were positively associated with free estradiol concentrations among all races: β = 0.14 (95% CI: 0.06, 0.22) and β = 0.26 (95% CI: 0.07, 0.45), respectively. CONCLUSIONS Moderate consumption of caffeine was associated with reduced estradiol concentrations among white women, whereas caffeinated soda and green tea intakes were associated with increased estradiol concentrations among all races. Further research is warranted on the association between caffeine and caffeinated beverages and reproductive hormones and whether these relations differ by race.

Assessment of anovulation in eumenorrheic women: comparison of ovulation detection algorithms

OBJECTIVE To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses. DESIGN Prospective cohort study. SETTING 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.

Characteristics of the Menstrual Cycle After Discontinuation of Oral Contraceptives

BACKGROUND Menstrual cycle function may continue to be altered after discontinuation of oral contraceptives (OC). Few studies have been published on the effects of recent OC use on menstrual cycle parameters; none have examined characteristics of the menstrual flow or the quality of cervical mucus. The purpose of this retrospective matched cohort study is to assess biomarkers of the menstrual cycle after discontinuation of OCs. METHODS Among a sample of women who daily recorded observations of menstrual cycle biomarkers, 70 women who had recently discontinued OCs were randomly matched by age and parity with 70 women who had not used OCs for at least 1 year. Outcomes investigated included overall cycle length, length of the luteal phase, estimated day of ovulation, duration of menstrual flow, menstrual intensity, and mucus score. Differences between recent OC users and controls were assessed using random effects modeling. RESULTS Recent OC users had statistically significantly lower scores for mucus quality for cycles 1 and 2. Additionally, OC users had a later estimated day of ovulation that was statistically significant in cycle 2 and a decreased intensity of menstrual flow that was significant in the first four cycles (difference = -0.48 days). In random effects modeling, all these parameters were significantly different for the first six cycles combined. CONCLUSIONS Menstrual cycle biomarkers are altered for at least two cycles after discontinuation of OCs, and this may help explain the temporary decrease in fecundity associated with recent OC use.

Luteal Phase Deficiency in Regularly Menstruating Women: Prevalence and Overlap in Identification Based on Clinical and Biochemical Diagnostic Criteria

CONTEXT Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women. OBJECTIVE 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 PARTICIPANTS We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles. RESULTS 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). CONCLUSIONS 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.

Sexual activity, endogenous reproductive hormones and ovulation in premenopausal women.

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.

Perceived stress, reproductive hormones, and ovulatory function: a prospective cohort study

Background: Stress has been shown to suppress ovulation in experimental models, but its effect on human reproduction at the population level is unclear. Methods: Healthy women (n = 259), aged 18–44 years from Western New York, were followed for 2 menstrual cycles (2005–2007). Women completed daily perceived stress assessments, a 4-item Perceived Stress Scale (PSS-4) up to 4 times each cycle, and a 14-item PSS at baseline. Mixed model analyses were used to assess effects of stress on log reproductive hormone concentrations and sporadic anovulation. Results: High versus low daily stress was associated with lower estradiol (−9.5% [95% confidence interval (CI) = −15.6% to −3.0%]), free estradiol (−10.4% [−16.5% to −3.9%]), and luteinizing hormone (−14.8% [−21.3% to −7.7%]) and higher follicle-stimulating hormone (6.2% [95% CI = 2.0% to 10.5%]) after adjusting for age, race, percent body fat, depression score, and time-varying hormones and vigorous exercise. High versus low daily stress was also associated with lower luteal progesterone (−10.4% [95% CI = −19.7% to −0.10%]) and higher odds of anovulation (adjusted odds ratio = 2.2 [95% CI = 1.0 to 4.7]). For each unit increase in daily stress level, women had a 70% higher odds of an anovulatory episode (odds ratio = 1.7 [1.1 to 2.4]). Similar but attenuated results were found for the association between the PSS-4 and reproductive hormones, while null findings were found for the baseline PSS. Conclusion: Daily perceived stress does appear to interfere with menstrual cycle function among women with no known reproductive disorders, warranting further research to explore potential population-level impacts and causal biologic mechanisms.