Late maternal menopause is associated with stable anti-Mullerian hormone levels and antral follicle count in daughters during reproductive age

Introduction: Maternal age at menopause is hypothesized to influence daughters’ ovarian reserve. We explored this hypothesis by assessing the ovarian reserve through anti-Müllerian hormone levels (AMH) and antral follicle count (AFC) in healthy women of reproductive age.

Material and Methods: A prospective cohort study of 863 healthy female healthcare workers aged 20–40 years employed at Copenhagen University Hospital. We analysed a subpopulation of women (n = 528) whose mother’s age at natural menopause was known. Data were obtained on menstrual cycle, smoking habits including prenatal smoking exposure, reproductive history, and mother’s age at menopause. On menstrual cycle Day 2–6 plasma hormone levels were assessed and a transvaginal sonography was performed measuring AFC. Women taken a combined oral contraceptive were studied on menstrual cycle Day 2–6 (during withdrawal bleeding). Pregnant women (n = 67) were excluded. Multiple linear regression analyses were performed to investigate the effect of participants’ age and their mother’s age at menopause on AMH levels and AFC with adjustment for use of oral contraceptives, follicle-stimulating hormone levels, participants’ smoking habits and mothers’ smoking habits during pregnancy. All mean values are reported as adjusted with 95%CI.

Results: Participants were stratified into three age groups: 20.0–29.9 years, 30.0–34.9 years and 35.0–39.9 years. Age at maternal menopause was normally distributed (mean age 50.2 years). Based on the age at maternal menopause three groups were defined according to the 10th and the 90th percentile: early maternal menopause (≤ 45 years) (n = 68), normal maternal menopause (46–54 years) (n = 383) and late maternal menopause ( ≥ 55 years) (n = 77). In the group with normal maternal menopause the AMH levels and AFC differed significantly according to participants’ age. Participants aged 20.0–29.9 years, 30.0–34.9 years, and 35.0–39.9 years had adjusted mean AMH levels of 16.6 pmol/L [95%CI 13.5–20.6], 12.4 [10.2–15.1], and 8.5 [7.0–10.5], respectively (p < 0.001) and adjusted mean AFC values of 17.1 [95%CI 14.5–20.2], 14.7 [12.6–17.1], and 10.3 [8.7–12.1], respectively (p < 0.001). In the group with early maternal menopause a significant decrease in AMH level (p < 0.001) and AFC (p = 0.002) was shown when comparing participants aged 20.0–29.9 years with participants aged 30.0–34.9 years. The corresponding adjusted mean AMH levels were 18.6 pmol/L [95%CI 12.4–27.9], 9.2 [6.6–12.7], and 6.9 [5.0–9.4], respectively and the adjusted mean AFC values were 17.7 [95%CI 12.9–24.3], 11.4 [8.8–14.7], and 9.9 [7.7–12.7], respectively. In the group with late maternal menopause no significant differences were seen in AMH levels (p = 0.22) and AFC (p = 0.76) across the three age groups. The corresponding adjusted mean AMH levels were 14.4 pmol/L [95%CI 9.2–22.5], 12.2 [9.1–16.3], and 15.4 [11.1–21.4], respectively, and the adjusted mean AFC values were 14.3 [95%CI 10.0–20.2], 14.4 [11.5–18.2], and 15.1 [11.7–19.5], respectively. Crude and adjusted analyses showed consistent effects of age at maternal menopause on AMH and AFC levels in the daughters. Participants’ smoking habits and mothers’ smoking habits during pregnancy did not infuence AMH levels or AFC.

Conclusions: These cross-sectional data showed that women whose mothers entered menopause at a normal age had the expected decline in ovarian reserve with increasing age. However, women whose mothers entered menopause before the age of 45 years had an early, marked decrease in ovarian reserve. In women whose mothers entered menopause after the age of 55 years, the plasma levels of AMH and the antral follicle count remained stable at least up to 40 years of age, indicating that the ovarian follicular depletion may be postponed in these women. Our data support the hypothesis that hereditary factors have a major impact on the ovarian follicular depletion rate.