Endocrine Abstracts

Polycystic ovary syndrome (PCOS) is characterized by anovulation, hyperandrogenemia, and polycystic ovaries. Although the etiology of PCOS is poorly understood, the common denominator is a disturbance in the selection of the dominant follicle. TGFβ family members, such as anti-Müllerian hormone (AMH) and bone morphogenetic proteins (BMPs), suppress FSH sensitivity. Therefore their signaling pathway may contribute to the aberrant follicle development in PCOS women. We have investigated the role of ALK2, a type I receptor for AMH and BMPs, in PCOS using a genetic approach.

Seven single nucleotide polymorphisms (SNPs) in the ACVR1 gene, encoding ALK2, were genotyped in a large cohort of Caucasian PCOS women (n=359). A cohort of 30 normo-ovulatory women and a population-based cohort of 3543 postmenopausal women served as controls.

Allele frequencies for the seven ACVR1 tagging SNPs were similar in PCOS women and controls. However, polymorphisms rs1220134, rs10497189 and rs2033962 were associated with AMH levels in PCOS women (P=0.001, 0.002 and 0.007, respectively). For each of these polymorphisms, carriers of the minor allele had respectively 30, 70 and 34% higher AMH levels compared with carriers of the major allele. Polymorphism rs10497189 was also associated with follicle number (P=0.001). Adjustment for follicle number revealed that the association with AMH levels was, in part, independent of follicle number (rs1220134, P=0.007). Consistent with the individual markers in haplotype block 1 (rs1220134 and rs10497189), the haplotypes TT and AC of this block were associated with serum AMH levels (P=0.001 and 0.002, respectively) and follicle number (P=0.01 and 0.001, respectively). No associations were observed between the different ACVR1 genotypes and LH, FSH, androgen and estradiol levels in the PCOS cohort.

In conclusion, genetic variation within ACVR1 is associated with follicle number and AMH levels in PCOS women, suggesting that ALK2 signaling contributes to the disturbed folliculogenesis in PCOS patients.