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A New Rat Model Exhibiting Both Ovarian and Metabolic Characteristics of Polycystic Ovary Syndrome

Institute of Neuroscience and Physiology, Department of Physiology (L.M., A.H., E.S.-V.), and Institute of Medicine, Department of Molecular and Clinical Medicine (T.L., M.L.), Sahlgrenska Academy, Göteborg University, 405 30 Göteborg, Sweden; Department of Pathology and Cytology (S.C., Z.S.), Akademiska Sjukhuset, 751 85 Uppsala, Sweden; and Department of Pathology, University Clinic Center (Z.S.), Tuzla 75000, Bosnia and Hercegovina

Address all correspondence and requests for reprints to: Elisabet Stener-Victorin, Ph.D. and associate professor, Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, Göteborg University, Box 434, SE-405 30 Göteborg, Sweden. E-mail: elisabet.stener-victorin{at}neuro.gu.se.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a "hyperplastic" theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the syndrome.

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