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Hum. Reprod. Advance Access originally published online on April 29, 2009
Human Reproduction 2009 24(8):2014-2022; doi:10.1093/humrep/dep113
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome

O. Valkenburg1,5, A.G. Uitterlinden2,3, D. Piersma2, A. Hofman3, A.P.N. Themmen2, F.H. de Jong2, B.C.J.M. Fauser4 and J.S.E. Laven1

1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center, Room HS508, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands 2 Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands 3 Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands 4 Department of Reproductive Medicine and Gynaecology, University Medical Center, Utrecht, The Netherlands

5 Correspondence address. Tel: +31-10-4633571; E-mail: o.valkenburg{at}erasmusmc.nl

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex genetic disorder. Multiple functional polymorphisms have been identified in genes that regulate the hypothalamic–pituitary–gonadal (HPG) axis that regulates ovarian function. The present study aims to examine the influence of genetic variants of the HPG-axis on the severity of clinical features of PCOS and disease susceptibility.

METHODS: We included 518 Caucasian PCOS women and 2996 unselected controls from the general population (the Rotterdam study). Genotype distributions were compared between patients and controls. Subsequently, associations with clinical features of PCOS were studied. Single nucleotide polymorphisms were selected in GnRH (Trp16Ser [rs6185]), the FSH-receptor (FSHR, Ala307Thr [rs6165] and Asn680Ser [rs6166]) and the LH-receptor (18insLQ, Asn291Ser [rs12470652] and Ser312Asn [rs2293275]).

RESULTS: FSHR Ser680 was associated with higher levels of gonadotrophic hormones (FSH: P < 0.01, LH: P = 0.01), and testosterone (P = 0.05) and a higher frequency of hyperandrogenism (P = 0.04). No differences in risk for PCOS in association with the FSH-receptor variants were observed.

CONCLUSION: Genetic variants of the HPG-axis were associated with a modest but significant effect on the phenotype of PCOS. FSHR variants were strongly associated with the severity of clinical features of PCOS, such as levels of gonadotrophic hormones and the presence of hyperandrogenism, but not disease risk.

Key words: polycystic ovary syndrome/FSH receptor/LH receptor/GnRH/polymorphism

Submitted on November 1, 2008; resubmitted on March 25, 2009; accepted on March 30, 2009.


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