Anti-mullerian hormone as predictor for ovarian reserve is associated with age at menopause in Fragile X premutation carriers

Abstract

OBJECTIVE: Carriers of a premutation (repeat length 59-200) in the Fragile X mental retardation (FMR1) gene are known to be at risk for primary ovarian insufficiency (FXPOI). We investigated whether FXPOI is due to low ovarian reserve and/or accelerated decline of ovarian reserve. In addition, we addressed the question whether the levels of anti-Müllerian hormone (AMH) can predict the age at which menopause occurred. DESIGN: Retrospective controlled cohort study. MATERIALS AND METHODS: We determined AMH and follicle stimulating hormone (FSH) levels in blood samples with a 10 year interval (T1 and T2) in 101 women from 46 families with Fragile X syndrome. The levels of premutation carriers (PC) were compared to those of women with a normal repeat length or a full mutation. At T2 40 women were postmenopausal, with time intervals between AMH sample and final menstrual period (FMP) ranging from a few months to 10 years. Statistical multilevel analyses were performed using linear mixed models correcting for age, taking within family and within subject correlations into account. RESULTS: Premutation carriers (n=41) had significantly lower AMH levels (median AMH at T1 for PCs 0.21 ng/ml versus 1.27 ng/ml for control group (n=60), p=0.001), but showed an equal decline in AMH levels (PCs -62.5% versus control group -74.8%) over 10 years (p=0.13). FSH levels were higher (median FSH at T1 for PCs 12.3 IU/l versus control group 8.8 IU/l), but were not elevated (>10 IU/l) until above 40 years of age. Within 7 years until FMP, AMH levels were low and ranged from undetectable (<0.10 ng/ml) to 0.38 ng/ml, while FSH levels ranged from normal (<10 IU/l) to postmenopausal height (>40 IU/l). CONCLUSIONS: Fragile X premutation carriers demonstrate a similar decline in ovarian reserve as women without a risk of diminished ovarian reserve. Therefore, FXPOI may be associated with a predisposition to lower ovarian reserve. AMH levels may serve as a predictor of time until menopause (p=0.048) and, thus, may be useful at an early age.