Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities.

Oocyte loss has a significant impact on fertility and somatic health. Yet, we know little about factors that impact this process. We sought to identify genetic variants associated with ovarian reserve (oocyte number as measured by antral follicle count, AFC). Based on recently published genome-wide scans that identified loci associated with age of menopause, we also sought to test our hypothesis that follicle number and menopausal age share underlying genetic associations. We analyzed menopause-related variants for association with follicle number in an independent population of approximately 450 reproductive-aged women of European and African ancestry; these women were assessed for AFC, anthropometric, clinical, and lifestyle factors. One SNP strongly associated with later menopausal age in Caucasian women (+1.07 ± 0.11 years) in previous work was also associated with higher follicle counts in Caucasians (+2.79 ± 1.67 follicles) in our study. This variant is within the Minichromosome Maintenance Complex Component 8 (MCM8) gene, which we found was expressed within oocytes in follicles of the human ovary. In genome-wide scans of AFC, we also identified one marginally genome-wide and several nominally significant SNPs within several other genes associated with follicle number in both ethnic groups. Further, there were overlapping variants associated with multiple ovarian reserve markers (AFC, serum hormone levels, menopausal age). This study provides the first evidence for direct genetic associations underlying both follicle number and menopause and identifies novel candidate genes. Genetic variants associated with ovarian reserve may facilitate discovery of genetic markers to predict reproductive health and lifespan in women.

Genetic variants and environmental factors associated with hormonal markers of ovarian reserve in Caucasian and African American women.

BACKGROUND: The ovarian reserve (number and quality of oocytes) is correlated with reproductive potential as well as somatic health, and is likely to have multiple genetic and environmental determinants. Several reproductive hormones are closely linked with the oocyte pool and thus can serve as surrogate markers of ovarian reserve. However, we know little about the underlying genes or genetic variants. METHODS: We analyzed genetic variants across the genome associated with two hormonal markers of ovarian reserve, FSH and anti-Mullerian hormone, in a reproductively normal population of Caucasian (n = 232) and African American (n = 200) women, aged 25-45 years. We also examined the effects of environmental or lifestyle factors on ovarian reserve phenotypes. RESULTS: We identified one variant approaching genome-wide significance (rs6543833; P= 8.07 × 10⁻8) and several nominal variants nearby and within the myeloid-associated differentiation marker-like (MYADML) gene, that were associated with FSH levels in African American women; these were validated in Caucasian women. We also discovered effects of smoking and oral contraceptive use on ovarian reserve phenotypes, with alterations in several reproductive hormones. CONCLUSIONS: This work is the largest study on ovarian reserve in women of reproductive age and is the only genome-wide study on ovarian reserve markers. The genes containing or near the identified variants have no known roles in ovarian biology and represent interesting candidate genes for future investigations. The discovery of genetic markers may lead to better long-range predictions of declining ovarian function, with implications for reproductive and somatic health.

A characterization of the relationship of ovarian reserve markers with age.

OBJECTIVE: To identify markers of ovarian age that best match the pattern of oocyte loss seen in histology specimens. DESIGN: Cross-sectional study. SETTING: University. PATIENT(S): Caucasian women (n = 252) aged 25-45 years. INTERVENTION(S): none. MAIN OUTCOME MEASURE(S): The relationship between antral follicle count (AFC), antimüllerian hormone (AMH), inhibin B, FSH, and E(2) with age was estimated using the power model, which previously has been shown to most accurately describe oocyte loss in histologic specimens. The power model was fit to each marker and used to compare the rates of change at ages 30 and 40 with the histologic pattern. Among those markers following the pattern, R(2) was used to compare the degree of relationship with age. RESULT(S): Both AMH levels and AFC exhibited significant progressive declines with age. The average rates of loss per year for AFC and AMH were, respectively, -0.57 and -1.09 at age 30, and -1.33 and -3.06 at age 40. FSH, inhibin B, and E(2) did not exhibit progressive rates of change. The R(2) for AFC was 27.3% and for AMH was 22.7%. CONCLUSION(S): Only AFC and AMH follow the pattern of oocyte loss observed histologically. Although AMH may be more cost-effective, AFC is a slightly more accurate noninvasive measure for ovarian aging.

Antral follicle count: absence of significant midlife decline.

OBJECTIVE: To examine the conventional wisdom that declines in antral follicle count accelerate after approximately 37 years of age, which has influenced clinical decision making. We critically examine evidence for this sudden acceleration. DESIGN: Cross-sectional study. SETTING: Academic setting. PATIENT(S): Two hundred fifty-two white women aged 25 to 45 years with regular cycles, a community-based study. INTERVENTION(S): Antral follicle counts were measured by transvaginal ultrasound in early follicular phase. MAIN OUTCOME MEASURE(S): Determination of the rate of antral follicle count decline with age. RESULT(S): The relationship of antral follicle count with age was determined by comparing a linear model with four nonlinear models (biphasic, quadratic, spline, and power). The linear model estimates the follicle decline as 0.97 follicles per year. The biphasic model had estimates of 0.76 follicles per year before 39.6 years of age and 1.92 follicles per year thereafter. At age 35 years the linear, quadratic, broken line, spline, and power models gave estimated declines (respectively) of 0.97, 0.94, 0.76, 0.17, and 0.90 follicles per year. At age 43 years the values were 0.97, 1.51, 1.92, 1.78, and 1.64 follicles per year. The quality of model fit was comparable for all models. CONCLUSION(S): Antral follicle count decline with age in a white population is best described as a gradual acceleration in decline with age. Therefore antral follicle count alone should not be used to determine aggressive treatment because of fear of rapid loss of follicles.