Polycystic ovary syndrome (PCOS) is characterized by anovulation, elevated levels of circulating androgens and polycystic ovaries. Although the etiology of PCOS is poorly understood, the common denominator is a disturbance in the selection of the dominant follicle. In PCOS women serum Anti-Müllerian Hormone (AMH) levels are elevated. Since AMH reduces FSH sensitivity of growing follicles, the elevated AMH levels in PCOS patients may contribute to the disturbed follicle selection and elevated androgen levels. We investigated the role of AMH signaling in the pathophysiology of PCOS using a genetic approach. The study was approved by the local Medical Ethics Review Committee.
A frequent polymorphism in the AMH gene (AMH Ile49Ser) was studied in a large cohort of PCOS women (n=331). A cohort of 32 normo-ovulatory women and a population-based cohort of 3635 postmenopausal women (the Rotterdam study) served as controls. Genotype and allele frequencies for the AMH Ile49Ser polymorphism were similar in PCOS women and controls (MAF=0.20). However, within the group of PCOS women, carriers of the AMH 49Ser allele had less often polycystic ovaries (OR=0.05, 95% CI=0.010.40, P=0.006) compared to non-carriers. Furthermore, AMH 49Ser allele carriers had lower testosterone and androstenedione levels (nmol/l) compared to non-carriers (1.84±0.08 vs 2.03±0.06, P=0.05, and 11.9±0.4 vs 13.0±0.3, P=0.04, respectively). Serum AMH, FSH, LH and estradiol levels were not different between the genotype groups. Furthermore, in vitro studies demonstrated that the bioactivity of the AMH 49Ser protein is diminished compared to the AMH 49Ile protein (P<0.0001). In conclusion, genetic variants in the AMH gene do not influence PCOS susceptibility. However, the association of the AMH Ile49Ser polymorphism with follicle growth and androgen levels suggests that AMH contributes to the phenotype of PCOS.