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Continuous Administration of a P450 Aromatase Inhibitor Induces Polycystic Ovary Syndrome with a Metabolic and Endocrine Phenotype in Female Rats at Adult Age

Journal article
Authors Manuel Maliqueo
M. Sun
Julia Johansson
Anna Benrick
F. Labrie
Henrik Svensson
Malin Lönn
A. J. Duleba
Elisabet Stener-Victorin
Published in Endocrinology
Volume 154
Issue 1
Pages 434-445
ISSN 0013-7227
Publication year 2013
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 434-445
Language en
Links dx.doi.org/10.1210/en.2012-1693
Subject categories Clinical Medicine

Abstract

Studying the mechanisms for the complex pathogenesis of polycystic ovary syndrome (PCOS) requires animal models with endocrine, reproductive, and metabolic features of the syndrome. Hyperandrogenism seems to be a central factor in PCOS, leading to anovulation and insulin resistance. In female rats, continuous administration of letrozole, a nonsteroidal inhibitor of P450 aromatase, at 400 mu g/d starting before puberty induces hyperandrogenemia and reproductive abnormalities similar to those in women with PCOS. However, despite high circulating testosterone levels, these rats do not develop metabolic abnormalities, perhaps because of their supraphysiological testosterone concentrations or because estrogen synthesis is completely blocked in insulin-sensitive tissues. To test the hypothesis that continuous administration of lower doses of letrozole starting before puberty would result in both metabolic and reproductive phenotypes of PCOS, we performed a 12-wk dose-response study. At 21 d of age, 46 female Wistar rats were divided into two letrozole groups (100 or 200 mu g/d) and a control group (placebo). Both letrozole doses resulted in increased body weight, inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiples cysts, endogenous hyperandrogemia, and lower estrogen levels. Moreover, rats that received 200 mu g/d had insulin resistance and enlarged adipocytes in inguinal and mesenteric fat depots, increased circulating levels of LH, decreased levels of FSH, and increased ovarian expression of Cyp17a1 mRNA. Thus, continuous administration of letrozole, 200 mu g/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome. (Endocrinology 154: 434-445, 2013)

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