title: Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women.
abstract: BACKGROUND
  Lifestyle parameters, personal history and genetic factors are thought to affect the timing of natural menopause in humans. Based on their biological function, estrogen-metabolizing gene polymorphisms have been regarded as candidate genes for early menopause.
  
  
  METHODS
  In the present cross-sectional, multi-centre study, we analysed nine single nucleotide polymorphisms of six estrogen-metabolizing genes [three estrogen-synthesizing genes, i.e. 17-beta-hydroxysteroid dehydrogenase type 1 (17-beta HSD), cytochrome P-450 (CYP) 17 and CYP19; and three estrogen-inactivating genes, i.e. catechol-O-methyltransferase (COMT), CYP1A1 and CYP1B1] by sequencing-on-chip-technology in 1360 Caucasian women with natural menopause. Women's lifestyle parameters, reproductive and personal histories were ascertained.
  
  
  RESULTS
  Carriage of at least one mutant allele of the CYP1B1-4 Asn453Ser A--> G polymorphism (P = 0.004) and the number of full-term pregnancies (P < 0.001) were found to be independently associated with age at natural menopause. Women with at least one polymorphic allele of CYP1B1-4 experienced natural menopause earlier than non-carriers of the polymorphism [mean (SD) 48.6 (5.0) versus 49.4 (4.3) years]. Women with no, one, two and three or more full-term pregnancies experienced natural menopause at 48.5 (5.0), 48.8 (4.8), 49.5 (4.2) and 49.6 (4.6) years, respectively.
  
  
  CONCLUSIONS
  We present the most comprehensive data on estrogen-metabolizing gene polymorphisms and timing of natural menopause to date. The number of full-term pregnancies and the CYP1B1-4 polymorphism are significant predictors of timing of natural menopause in Caucasian women.
authors.affiliation: Departments of Obstetrics and Gynecology, University of Vienna, Austria. lukas.hefler@meduniwien.ac.at
authors.forename: L A
authors.initials: LA
authors.lastname: Hefler
authors.forename: C
authors.initials: C
authors.lastname: Grimm
authors.forename: G
authors.initials: G
authors.lastname: Heinze
authors.forename: C
authors.initials: C
authors.lastname: Schneeberger
authors.forename: M W
authors.initials: MW
authors.lastname: Mueller
authors.forename: A
authors.initials: A
authors.lastname: Muendlein
authors.forename: J C
authors.initials: JC
authors.lastname: Huber
authors.forename: S
authors.initials: S
authors.lastname: Leodolter
authors.forename: C B
authors.initials: CB
authors.lastname: Tempfer
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D003430:Cross-Sectional Studies; D065633:Cytochrome P-450 CYP1B1; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008019:Life Style; D008593:Menopause / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012044:Regression Analysis; D017584:Reproductive History; D044465:White People / Q000235:genetics*
chemical_list: D004798:Enzymes; D004967:Estrogens; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1