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Human Reproduction Update 2005 11(4):357-374; doi:10.1093/humupd/dmi013
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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{at}oupjournals.org

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

D.H. Abbott1,2,4,6, D.K. Barnett1, C.M. Bruns3 and D.A. Dumesic1,5

1National Primate Research Center, Departments of 2 Obstetrics and Gynecology and 3 Medicine, 4 Endocrinology-Reproductive Physiology Training Program, University of Wisconsin, Madison, WI 53715 and 5 Reproductive Medicine and Infertility Associates, Woodbury, MN 55125, USA

6 To whom correspondence should be addressed at: National Primate Research Center, 1223 Capitol Court, Madison, WI 53715, USA. Email: abbott{at}primate.wisc.edu

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

Key words: anovulation / hyperandrogenism / infertility / polycystic ovary syndrome / rhesus monkey


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