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

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 μg/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 μg/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 μg/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 μg/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome.

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary

“…4 Among the numerous causes hyperandrogenism it is considered a key factor in the origin and maintenance of the changes that occur in women with PCOS. 23 In our material, the reactivity of CYP17A1 in the control group was very weak in granulosa cells, and more pronounced in theca interna cells. It is believed that the theca interna cells that produce androgens act in a paracrine manner in granulosa cells.…”

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

“…Both letrozole and DHT exposure lead to higher pituitary Gnrhr expression (53), which in turn may lead to enhanced GnRH signaling. Increased GnRH pulsatility is a neuroendocrine hallmark of PCOS and favors pituitary synthesis and secretion of LH, leading to elevated LH/FSH ratios (51,54). Although pituitary Gnrhr Lhb, and Kiss1r mRNA was increased, the circulating LH and LH/FSH ratio was not altered in DHT-exposed WT mice (50, 51).…”

A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

“…Recently, a rat model of PCOS using letrozole (LET), a nonsteroidal aromatase inhibitor [27], was shown to exhibit multiple facets of PCOS. This model is based on the finding of lower estrogen/androgen ratios in follicular fluid of PCOS women, suggesting low aromatase activity [28], and the fact that genetic variants of the aromatase gene (CYP19), which converts androgens to estrogen, are associated with the development of PCOS and hyperandrogenism in women [29][30][31][32].…”