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A Functional Anti-Müllerian Hormone Gene Polymorphism Is Associated with Follicle Number and Androgen Levels in Polycystic Ovary Syndrome Patients

Department of Internal Medicine (M.E.K., A.G.U., F.H.d.J., A.P.N.T., J.A.V.), Department of Obstetrics and Gynaecology, Division of Reproductive Medicine (J.S.E.L., S.L.F.), and Departments of Epidemiology and Biostatistics (A.G.U.) and Clinical Chemistry (A.G.U.), Erasmus MC, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Jenny A. Visser, Ph.D., Department of Internal Medicine, Room Ee532, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: j.visser{at}erasmusmc.nl.

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. Because AMH decreases FSH sensitivity in mice, the elevated AMH levels may contribute to the disturbed follicle selection in PCOS women.

Objective: The objective of the study was 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 a large cohort of PCOS women.

Setting/Subjects: A total of 331 women with PCOS, 32 normoovulatory 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 AMH type II receptor –482 A>G polymorphism were similar in PCOS women and controls. However, within the group of PCOS women, carriers of the AMH ⁴⁹Ser allele less often had polycystic ovaries (92.7 vs. 99.5%, P = 0.0004), lower follicle numbers (P = 0.03), and lower androgen levels, compared with noncarriers (P = 0.04). In addition, in vitro studies demonstrated that the bioactivity of the AMH ⁴⁹Ser protein is diminished, compared with the AMH ⁴⁹Ile protein (P < 0.0001).

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

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				M. E. Kevenaar, A. P.N. Themmen, A. J. van Kerkwijk, O. Valkenburg, A. G. Uitterlinden, F. H. de Jong, J. S.E. Laven, and J. A. Visser Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome Hum. Reprod., January 1, 2009; 24(1): 241 - 249. [Abstract] [Full Text] [PDF]