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Hum. Reprod. Advance Access published online on March 17, 2005
Human Reproduction, doi:10.1093/humrep/deh848
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© The Author 2005. 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@oupjournals.org
Received October 10, 2004
Revised February 14, 2005
Accepted February 16, 2005

Article

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

L.A. Hefler 1*, C. Grimm 1, G. Heinze 2, C. Schneeberger 1, M.W. Mueller 3, A. Muendlein 3, J.C. Huber 1, S. Leodolter 1, and C.B. Tempfer 1

1 Departments of Obstetrics and Gynecology, Vienna, Austria and
2 , Department ofMedical Computer Sciences, Medical University of Vienna, Vienna, Austria and
3 , Department ofInstitute of Microbiology and Genetics, University of Vienna, Vienna, Austria

* To whom correspondence should be addressed.
L.A. Hefler, E-mail: lukas.hefler{at}meduniwien.ac.at


  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. CONCLUSION: 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.

Keywords: age; estrogen; gene; natural menopause; polymorphism.
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