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

TLDR

Polycystic ovary syndrome is a complex endocrine and metabolic disorder characterized by ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance, yet its etiology remains unclear and treatment is often unsatisfactory. The authors aim to present a novel rat model of PCOS that displays both ovarian and metabolic features of the syndrome. Female rats were administered the nonaromatizable androgen dihydrotestosterone or the aromatase inhibitor letrozole continuously from prepubescence to activate androgen receptors. The DHT-treated rats exhibited irregular cycles, polycystic ovaries with diminished granulosa layers, increased body weight and fat, enlarged mesenteric adipocytes, elevated leptin, and insulin resistance, while letrozole-treated rats were anovulatory with ovarian morphology resembling human PCOS; the study concludes that the letrozole model is best for ovarian studies and the DHT model for both ovarian and metabolic investigations.

Abstract

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.