Mouse models to study polycystic ovary syndrome: a possible link between metabolism and ovarian function?

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility affecting 6-8% of women worldwide. PCOS is characterized by two of the following three criteria: clinical or biochemical hyperandrogenism, oligo- or amenorrhea, and polycystic ovaries (PCO). In addition, women with PCOS are often obese and insulin resistant, and are at risk for type 2 diabetes and cardiovascular disease. The etiology of PCOS remains unknown. Therefore, several animal models for PCOS have been generated to gain insight into the etiology and development of the PCOS-associated phenotypes. Androgens are considered the main culprit of PCOS, and therefore, androgenization of animals is the most frequently used approach to induce symptoms that resemble PCOS. Prenatal or prepubertal androgen treatment results in many characteristics of human PCOS, including anovulation, cyst-like follicles, elevated luteinizing hormone (LH) levels, increased adiposity, and insulin insensitivity. However, PCOS has a heterogeneous presentation, and therefore it is difficult to generate a model that exactly reproduces the reproductive and metabolic phenotypes observed in women with PCOS. In this review, we discuss several mouse models for PCOS, and compare the reproductive and/or metabolic phenotypes observed in several androgen-induced models as well as in several genetic models.

Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice.

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1(-/-), 5αR2(-/-), and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1(-/-) (but not 5αR2(-/-)) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2(-/-) and 0% of 5αR1(-/-) mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.

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

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of there productive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 mg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significant decrease in acetylcholine-induced aortic relaxations, with no change in calcitonin gene related peptide- or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endothelium dependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients.

Reproductive and metabolic phenotype of a mouse model of PCOS.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive age, is characterized by both reproductive and metabolic features. Recent studies in human, nonhuman primates, and sheep suggest that hyperandrogenism plays an important role in the development of PCOS. We investigated whether chronic dihydrotestosterone (DHT) exposure in mice reproduces both features of PCOS. Such a model would allow us to study the mechanism of association between the reproductive and metabolic features in transgenic mice. In this study, prepubertal female mice received a 90 d continuous release pellet containing the nonaromatizable androgen DHT or vehicle. At the end of the treatment period, DHT-treated mice were in continuous anestrous, their ovaries contained an increased number of atretic follicles, with the majority of atretic antral follicles having a cyst-like structure. Chronic DHT-exposed mice had significantly higher body weights (21%) than vehicle-treated mice. In addition, fat depots of DHT-treated mice displayed an increased number of enlarged adipocytes (P < 0.003). Leptin levels were elevated (P < 0.013), adiponectin levels were diminished (P < 0.001), and DHT-treated mice were glucose intolerant (P < 0.001). In conclusion, a mouse model of PCOS has been developed showing reproductive and metabolic characteristics associated with PCOS in women.