Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women.

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. 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. 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. 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.