title: Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome.
abstract: 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 Ser(680) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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. o.valkenburg@erasmusmc.nl
authors.forename: O
authors.initials: O
authors.lastname: Valkenburg
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: D
authors.initials: D
authors.lastname: Piersma
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: A P N
authors.initials: AP
authors.lastname: Themmen
authors.forename: F H
authors.initials: FH
authors.lastname: de Jong
authors.forename: B C J M
authors.initials: BC
authors.lastname: Fauser
authors.forename: J S E
authors.initials: JS
authors.lastname: Laven
mesh_terms: D000328:Adult; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D020022:Genetic Predisposition to Disease; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006801:Humans; D017588:Hyperandrogenism / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011962:Receptors, FSH / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*; D013739:Testosterone / Q000097:blood
chemical_list: D011962:Receptors, FSH; D011974:Receptors, LH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone