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Hum. Reprod. Advance Access originally published online on July 18, 2007
Human Reproduction 2007 22(9):2382-2388; doi:10.1093/humrep/dem176
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© The Author 2007. 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

A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity

Marlies E. Kevenaar1,7, Axel P.N. Themmen1, Fernando Rivadeneira1,2, André G. Uitterlinden1,2,3, Joop S.E. Laven4, Natasja M. van Schoor5, Paul Lips6, Huibert A.P. Pols1,2 and Jenny A. Visser1

1 Department of Internal Medicine, Room Ee532, PO Box 2040, Erasmus MC, 3000 CA Rotterdam, The Netherlands 2 Department of Epidemiology and Biostatistics, Erasmus MC, 3000 CA Rotterdam, The Netherlands 3 Department of Clinical Chemistry, Erasmus MC, 3000 CA Rotterdam, The Netherlands 4 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, 3000 CA Rotterdam, The Netherlands 5 Institute for Research in Extramural Medicine, VU University Medical Center, 1081 BT Amsterdam, The Netherlands 6 Department of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands

7 Correspondence address. Tel: +31-10-4087346; Fax: +31-10-4635430; E-mail: m.kevenaar{at}erasmusmc.nl

BACKGROUND: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach.

METHODS: In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause.

RESULTS: The AMH Ile49Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 –482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063).

CONCLUSIONS: The observed association of the AMHR2 –482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.

Key words: anti-Müllerian hormone/menopause/follicle recruitment/polymorphism

Submitted on March 28, 2007; resubmitted on May 1, 2007; accepted on May 21, 2007.


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