Context: The common characteristic of Polycystic Ovary syndrome (PCOS) is a disturbance in the selection of the dominant follicle resulting in anovulation. In PCOS women serum Anti-Müllerian Hormone (AMH) levels are elevated. As AMH decreases FSH sensitivity in mice, the elevated AMH levels may contribute to the disturbed follicle selection in PCOS women.

Objective: To investigate the role of the AMH signaling pathway in the pathophysiology of PCOS using a genetic approach.

Design: The association of the AMH Ile⁴⁹Ser (rs10407022) and the AMH type II receptor -482 A>G (rs2002555) polymorphism with PCOS susceptibility and phenotype was studied in large a cohort of PCOS women.

Setting/ Subjects: 331 women with PCOS, 32 normo-ovulatory controls and 3635 population based controls were included.

Main Outcome Measures: Ovarian parameters, serum AMH, FSH, androgen and estradiol levels were measured.

Results: Genotype and allele frequencies for the AMH Ile⁴⁹Ser and AMHR2 -482 A>G polymorphism were similar in PCOS women and controls. However, within the group of PCOS women, carriers of the AMH ⁴⁹Ser allele had less often polycystic ovaries (92.7% versus 99.5%, P=0.0004), lower follicle numbers (P=0.03) and lower androgen levels compared to non-carriers (P=0.04). In addition, in vitro studies demonstrated that the bioactivity of the AMH ⁴⁹Ser protein is diminished compared to the AMH ⁴⁹Ile protein (P<0.0001).

Conclusions: Genetic variants in the AMH and AMHR2 gene do not influence PCOS susceptibility. However, our results suggest that the AMH Ile⁴⁹Ser polymorphism contributes to the severity of the PCOS phenotype.