Anne Z. Steiner

Antimüllerian Hormone as a Predictor of Natural Fecundability in Women Aged 30-42 Years

OBJECTIVE: To generate estimates of the association between markers of ovarian aging and natural fertility in a community sample at risk for ovarian aging. METHODS: Women aged 30–44 years with no history of infertility who had been trying to conceive for less than 3 months provided early-follicular phase serum and urine (N=100). Subsequently, these women kept a diary to record menstrual bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. Serum was analyzed for estradiol, follicle-stimulating hormone (FSH), antimüllerian hormone, and inhibin B. Urine was analyzed for FSH and estrone 3-glucuronide. Diary data on menstrual cycle day and patterns of intercourse were used to calculate day-specific fecundability ratios. RESULTS: Sixty-three percent of participants conceived within 6 months. After adjusting for age, 18 women (18%) with serum antimüllerian hormone levels of 0.7 ng/mL or less had significantly reduced fecundability given intercourse on a fertile day compared with women with higher antimüllerian hormone levels (fecundability ratio 0.38; 95% confidence interval [CI] 0.08–0.91). The day-specific fecundability for women with early-follicular phase serum FSH values greater than 10 milli-international units/mL compared with women with lower FSH levels was also reduced, although nonsignificantly (11% of women affected; fecundability ratio 0.44; 95% CI 0.08–1.10). The association with urinary FSH was weaker (27% women affected; fecundability ratio 0.61; 95% CI 0.26–1.26), and the associations for the other markers were weaker still. CONCLUSION: Early-follicular phase antimüllerian hormone appears to be associated with natural fertility in the general population. LEVEL OF EVIDENCE: II

Short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial

OBJECTIVE To examine the short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve when ovarian preservation is planned in view of determining the feasibility of conducting the study on a larger scale. DESIGN Pilot randomized controlled trial. SETTING Tertiary care, academic medical center. PATIENT(S) Thirty premenopausal women aged 18 to 45 years undergoing laparoscopic hysterectomy with ovarian preservation for benign indications from April 2012 to September 2012. INTERVENTION(S) Bilateral salpingectomy (n = 15) versus no salpingectomy (n = 15) at the time of laparoscopic hysterectomy with ovarian preservation. MAIN OUTCOME MEASURE(S) Antimüllerian hormone (AMH) measured preoperatively, at 4 to 6 weeks postoperatively, and at 3 months postoperatively, with operative time and estimated blood loss abstracted from the medical records. RESULT(S) The mean AMH levels were not statistically significantly different at baseline (2.26 vs. 2.25 ng/ml), 4 to 6 weeks postoperatively (1.03 vs. 1.25 ng/ml), or 3 months postoperatively (1.86 vs. 1.82 ng/ml) among women with salpingectomy versus no salpingectomy, respectively. There was also no statistically significant temporal change in the mean AMH level from baseline to 3 months postoperatively (-0.07 vs. -0.08 ng/ml) between the two groups. No difference in operative time (116 vs. 115 minutes) or estimated blood loss (70 vs. 91 mL) was observed. CONCLUSION(S) Salpingectomy at the time of laparoscopic hysterectomy with ovarian preservation is a safe procedure that does not appear to have any short-term deleterious effects on ovarian reserve, as measured by AMH level. Conducting a trial of this nature that is adequately powered with long-term follow-up evaluation would be feasible and is required to definitively confirm these results.

The impact of smoking on antimüllerian hormone levels in women aged 38 to 50 years.

Objective: Smoking is associated with increased follicle-stimulating hormone levels and early menopause. Smoking may directly accelerate ovarian follicular depletion or may act indirectly by increasing the pituitary production of follicle-stimulating hormone. Antimüllerian hormone (AMH), produced by ovarian follicles, is a more direct measure of ovarian reserve. The objective of our study was to determine the extent to which smoking influences ovarian reserve, as measured by AMH levels. Methods: A community sample of 284 women aged 38 to 50 years completed a self-administered questionnaire including a detailed smoking history. Serum AMH levels were measured on day 2, 3, or 4 of the menstrual cycle. The association between AMH and smoking was analyzed using linear regression, adjusting for age and body mass index. Results: Participants aged 38 to 42, 43 to 45, and 46 to 50 years had geometric mean AMH values of 6.7 pM (95% CI, 5.2-8.7 pM), 2.7 pM (95% CI, 1.9-3.8 pM), and 1.3 pM (95% CI, 1.0-1.7 pM), respectively. Current smokers, but not past smokers, had 44% lower AMH values than did the reference group (participants with neither active nor former or passive smoke exposure; P = 0.04). Passive smoking had no effect on AMH values when compared with the reference group (P = 0.55). The impact of smoking on AMH values was not dose dependent based on cigarettes per day (P = 0.08) or pack-years (P = 0.22). Finally, prenatal exposure to smoking (either maternal or paternal) had no impact on AMH levels (P = 0.47 and P = 0.89, respectively). Conclusions: Active smoking, but not former smoking, is associated with decreased AMH values in late-reproductive-age and perimenopausal women, suggesting a possible direct effect of smoking on the depletion of the antral but not primordial follicles. The direct impact of active smoking on AMH levels in younger women requires further investigation.

Antimullerian hormone and obesity: insights in oral contraceptive users

BACKGROUND The study was conducted to examine the impact of oral contraceptives (OCs) on serum antimullerian hormone (AMH) levels by obesity status in reproductive-age women. STUDY DESIGN Ovulatory women, ages 18-35 years, of normal (<25 kg/m(2); n=10) and obese (>30 kg/m(2); n=10) body mass index (BMI) received a low-dose OC (20 mcg ethinyl estradiol/100 mcg levonorgestrel) for two cycles. Serum samples obtained at several time points during active pill use and hormone-free intervals were analyzed for AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and inhibin B. RESULTS AMH levels did not differ by OC cycle day in either BMI group. On average, AMH levels were 34% lower in the obese group (2.9+/-2.1 vs. 4.4+/-1.8 ng/mL, p<.05). Modeling to determine differences in AMH throughout the cycle based on obesity status demonstrated significantly lower levels (p<.05), whereas serum AMH, FSH, LH, estradiol and inhibin B levels revealed no correlations when all time points were included. CONCLUSIONS In reproductive-age women, serum AMH levels do not appear to fluctuate during OC use, but AMH levels are significantly lower in obese women. Lower levels do not appear to be due to differences in gonadotropin levels or ovarian activity.

Optimal timing for elective egg freezing

OBJECTIVE To estimate the optimal age to pursue elective oocyte cryopreservation. DESIGN A decision-tree model was constructed to determine the success and cost-effectiveness of oocyte preservation versus no action when considered at ages 25-40 years, assuming an attempt at procreation 3, 5, or 7 years after initial decision. SETTING Not applicable. PATIENT(S) Hypothetical patients 25-40 years old presenting to discuss elective oocyte cryopreservation. INTERVENTION(S) Decision to cryopreserve oocytes from age 25 years to age 40 years versus taking no action. MAIN OUTCOME AND MEASURE(S) Probability of live birth after initial decision whether or not to cryopreserve oocytes. RESULT(S) Oocyte cryopreservation provided the greatest improvement in probability of live birth compared with no action (51.6% vs. 21.9%) when performed at age 37 years. The highest probability of live birth was seen when oocyte cryopreservation was performed at ages <34 years (>74%), although little benefit over no action was seen at ages 25-30 years (2.6%-7.1% increase). Oocyte cryopreservation was most cost-effective at age 37 years, at

Association of Intrauterine and Early-Life Exposures With Age at Menopause in the Sister Study

28,759 per each additional live birth in the oocyte cryopreservation group. When the probability of marriage was included, oocyte cryopreservation resulted in little improvement in live birth rates. CONCLUSION(S) Oocyte cryopreservation can be of great benefit to specific women and has the highest chance of success when performed at an earlier age. At age 37 years, oocyte cryopreservation has the largest benefit over no action and is most cost-effective.

Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: The Estrogen in the Prevention of Atherosclerosis Trial

Oocytes are formed in utero; menopause occurs when the oocyte pool is depleted. The authors hypothesized that early-life events could affect the number of a womans oocytes and determine age at menopause. To test their hypothesis, the authors conducted a secondary analysis of baseline data from 22,165 participants in the Sister Study (2003-2007) who were aged 35-59 years at enrollment. To estimate the association between early-life events and age at natural menopause, the authors used Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals, adjusting for current age, race/ethnicity, education, childhood family income, and smoking history. Earlier menopause was associated with in-utero diethylstilbestrol exposure (hazard ratio (HR) = 1.45, 95% confidence interval (CI): 1.27, 1.65). Suggestive associations included maternal prepregnancy diabetes (HR = 1.33, 95% CI: 0.89, 1.98) and low birth weight (HR = 1.09, 95% CI: 0.99, 1.20). Having a mother aged 35 years or older at birth appeared to be associated with a later age at menopause (HR = 0.95, 95% CI: 0.89, 1.01). Birth order, in-utero smoke exposure, and having been breastfed were not related to age at menopause. In-utero and perinatal events may subsequently influence age at menopause.

The utility of menstrual cycle length as an indicator of cumulative hormonal exposure.

Objective:To determine if 17β-estradiol increases blood pressure in postmenopausal women. Design:A total of 222 healthy postmenopausal women were randomly assigned to either 1 mg micronized 17β-estradiol daily or placebo for 2 years. Blood pressure measurements were obtained every other month and common carotid artery intima-media thickness measured every 6 months. Statistical analyses comparing longitudinal changes in systolic and diastolic blood pressure between treatment groups used a mixed general linear model including interaction terms to evaluate variations by age or estradiol level. Results:Both placebo and estradiol groups showed small declines in systolic and diastolic blood pressure during the trial among the normotensive subjects and subjects on antihypertensive medications. However, the decline did not differ significantly between the groups. Treatment effects on systolic blood pressure differed significantly by the age of the subject (interaction P value = 0.04) with younger women on estradiol showing on average a rise in systolic blood pressure, and older women a decline. The association between serum estradiol level and systolic blood pressure showed a similar modification with age (P = 0.03). Changes in systolic blood pressure in women on estradiol were positively correlated with intima-media thickness progression (P = 0.03). Conclusions:Overall, 17β-estradiol did not influence changes in blood pressure in normotensive or hypertensive women. The effect of 17β-estradiol treatment on systolic blood pressure may be influenced by a womans age. Estradiol may increase systolic blood pressure in younger postmenopausal women, while having the opposite effect in older postmenopausal women.

A Longitudinal Study of Serum Lipoproteins in Relation to Endogenous Reproductive Hormones during the Menstrual Cycle: Findings from the BioCycle Study

CONTEXT Associations between menstrual cycle length and chronic diseases are hypothesized to be due to differences in underlying hormonal patterns. OBJECTIVE The aim of the study was to evaluate the association between menstrual cycle length and the hormonal profile and anovulation. DESIGN AND SETTING We conducted a prospective cohort study at the University at Buffalo from 2005 to 2007. PARTICIPANTS We recruited 259 healthy, regularly menstruating women aged 18-44 yr. MAIN OUTCOME MEASURES Cycle length was observed for up to two cycles. Serum estradiol, progesterone, LH, and FSH were measured up to eight times per cycle for up to two cycles. RESULTS Women with short cycles (<26 d) had higher FSH concentrations during menses and in the late luteal phase, higher follicular estradiol concentrations, and lower LH concentrations across the cycle. Among women with longer cycles (>35 d), estradiol and LH peaks occurred on average about 3 d later, and FSH peaks about 1 d later compared to women with normal-length cycles. Both short and long cycles, compared with normal-length cycles, had an increased probability of anovulation. In general, per-cycle exposure to hormones was less in short cycles based on the area under the curve, although over time the cumulative exposure to estradiol would be greater for women with short cycles. CONCLUSIONS Short ovulatory cycles were associated with higher follicular phase estradiol, an earlier rise in FSH, and an increased risk of anovulation. These results suggest that menstrual cycle length may be a relevant indicator of estradiol exposure and risk of anovulation among regularly cycling women.

Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age

CONTEXT Exogenous estrogens have been shown to affect the lipid profile, leading to the hypothesis that endogenous estrogens may have similar effects. OBJECTIVE The objective of the study was to evaluate the association between endogenous estrogen and serum lipoproteins across the menstrual cycle. DESIGN This was a prospective cohort study. SETTING The study was conducted at the University at Buffalo, 2005-2007. PARTICIPANTS Participants included 259 healthy, regularly menstruating women aged 18-44 yr. MAIN OUTCOME MEASURES Serum levels of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides measured up to eight times per cycle for up to two cycles were measured. RESULTS Total and LDL cholesterol were lower during the luteal phase as compared with the follicular phase (P < 0.001), and HDL levels were highest around ovulation (P < 0.001). More women were classified above the desirable range (LDL > or =130 mg/dl or total cholesterol > or =200 mg/dl) when measured during the follicular phase. Estradiol was positively associated with HDL in acute effects models [beta = 0.019, 95% confidence interval (CI) 0.015, 0.022] and inversely associated with total (beta = -0.017, 95% CI -0.020, -0.014) and LDL cholesterol (beta = -0.023, 95% CI -0.027, -0.018) and triglycerides (beta = -0.041, 95% CI -0.054, -0.029) in persistent effects models. CONCLUSIONS Endogenous estrogen, like exogenous estrogen, appears to have beneficial effects on the lipid profile. Because lipoprotein cholesterol levels vary across the menstrual cycle, cyclic variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women and in the clinical management of womens cholesterol.