A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity

BACKGROUND: Anti-Mullerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. METHODS: In two large population-based cohorts of Dutch postmenopausal women (n=2381 and n=248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type 11 receptor (AMHR2) gene, and natural age at menopause. RESULTS: The AMH Ile(49)Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P=0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P=0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P=0.063). CONCLUSIONS: The observed association of the AMHR2 -482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.