Androgen-induced mouse models of Polycystic Ovary Syndrome (PCOS) — ASN Events

Androgen-induced mouse models of Polycystic Ovary Syndrome (PCOS) (#138)

Aimee SL Caldwell 1 , Linda J Middleton 1 , Charles M Allan 1 , David J Handelsman 1 , Kirsty A Walters 1
  1. Andrology Laboratory, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia

Polycystic ovary syndrome (PCOS) is a frequent cause of female infertility, affecting 5-10% of women worldwide. PCOS is characterised by hyperandrogenism, anovulation, infertility, polycystic ovaries and metabolic abnormalities (insulin resistance, type 2 diabetes and cardiovascular risk). The aetiology of PCOS remains. Several animal models have been developed to study of the cause(s) and pathophysiological mechanisms involved in PCOS. To identify the best mouse model of PCOS we evaluated various postnatal androgen treatments to emulate hyperandrogenism seen in PCOS patients. Three different treatments were evaluated: 1) DHT, a potent non-aromatizable androgen; 2) DHEA, which is elevated in PCOS patients; and 3) Letrozole, a compound which raises endogenous androgens by blocking aromatization of androgens to estrogens. 21 day old mice were treated for 90 days with a sub-dermal implant of DHT, DHEA, Letrozole or a placebo (controls). All DHT mice were acyclic, and displayed an increased body weight (P<0.01) compared to controls. DHT ovaries contained no corpora lutea, indicating anovulation, as well as a significantly higher percentage of unhealthy large antral follicles compared to controls (P<0.05). Inguinal (P ≤ 0.01), parametrial (P<0.05) and retroperitoneal (P≤0.01) fat pad weights were significantly increased, as were blood cholesterol levels (P<0.05) in DHT treated compared to control mice. DHEA-treated mice displayed similar estrous cyclicity to control animals. DHEA ovaries exhibited comparable corpora lutea numbers to control ovaries, but significantly more unhealthy small preantral follicles compared with controls (P=0.05). DHEA treated mice lost weight (P<0.01) but had unchanged fat pad weights and blood cholesterol levels. Letrozole-treated mice exhibited absent or irregular estrous cycling with fewer corpora lutea compared with controls (P<0.01), however, body and fat pad weights as well as blood cholesterol levels remained similar to controls. In conclusion, our results show that postnatal DHT treatment provides more features of the PCOS phenotype with which to study the possible causes and mechanisms of this condition.