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

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.

Collaborative work on evaluation of ovarian toxicity 8) Two- or four-week repeated-dose studies and fertility study of Anastrozole in female rats

“…Therefore, the maturation process of large follicles should be a target for aromatase inhibitors. In fact, the same follicular abnormalities as observed in this study were also reported in rats treated with other aromatase inhibitors (Mannerås et al, 2007). Moreover, a preliminary hormone assay using a plasma sample obtained at necropsy was performed and the results showed increased testosterone levels in the 50 mg/kg group of the 2-week study and in the 1 and 50 mg/kg groups of the 4-week study (data not shown).…”

“…In the ovary, aromatase expression is detected in the granulosa cell (Sakurada et al, 2006), and is essential for the maturation of follicles (Britt et al, 2000;Toda et al, 2001). It has been reported that an aromatase inhibitor disturbed the estrous cycle and caused ovarian morphological changes such as follicular cysts in rats after a 90-day infusion (Mannerås et al, 2007), and a 21-day oral administration (Kim et al, 2006). Moreover, an aromatase knock-out female animal was shown to be totally infertile (Toda et al, 2001).…”

Analysis of the vascular responses in a murine model of polycystic ovary syndrome

“…Several experimental animal models for PCOS have been developed through prenatal or postnatal exposure to androgens, but these animal models were mainly used to investigate ovarian and metabolic function and the vascular phenotype was not studied (Manneras et al 2007, Roland et al 2010. In pregnant rats treated with testosterone, increased blood pressure and decreased endothelial function were observed (Chinnathambi et al 2013).…”

Supraphysiological leptin levels shift the profile of steroidogenesis in porcine ovarian follicles toward progesterone and testosterone secretion through increased expressions of CYP11A1 and 17β-HSD: a tissue culture approach

“…Several studies show that prenatal, perinatal, or postnatal androgen exposure in monkeys (Abbott et al 2002), sheep (West et al 2001), rats , Mannerås et al 2007, and mice (Sullivan & Moenter 2004) can induce cyst formation. Exposure of female monkey and sheep fetuses to excess androgen concentrations resulted in an excess of LH and enlarged ovaries that were polyfollicular, anovulatory and hyperandrogenic (Birch et al 2003, Abbott et al 2005.…”