The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome (PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed, averaging > 2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined. In order to understand PCOS pathophysiology, its developmental origins, and how to predict and prevent PCOS onset, there is an urgent need for safe and effective markers and treatments. In this review, we detail which animal models are more suitable for contributing to our understanding of the etiology and pathophysiology of PCOS. We summarize and highlight advantages and limitations of hormonal or genetic manipulation of animal models, as well as of naturally occurring PCOS-like females.

Introduction: Polycystic ovary syndrome (PCOS) diagnosis comprises combinations of female hyperandrogenism, menstrual irregularity and polycystic ovaries. While it is a familial and highly prevalent endocrine disorder, progress towards a cure is hindered by absence of a definitive pathogenic mechanism and lack of an animal model of naturally occurring PCOS. Areas covered: These include an overview of PCOS and its potential etiology, and an examination of insights gained into its pathogenic origins. Animal models derived from experimentally-induced hyperandrogenism during gestation, or from naturally-occurring PCOS-like traits, most reliably demonstrate reproductive, neuroendocrine and metabolic pathogenesis. Expert opinion: Genetic studies, while identifying at least 17 PCOS risk genes, account for <10% of women with PCOS. A number of PCOS risk genes involve regulation of gonadotropin secretion or action, suggesting a reproductive neuroendocrine basis for PCOS pathogenesis. Consistent with this notion, a number of animal models employing fetal androgen excess demonstrate epigenetic induction of PCOS-like traits, including reproductive neuroendocrine and metabolic dysfunction. Monkey models are most comprehensive, while mouse models provide molecular insight, including identifying the androgen receptor, particularly in neurons, as mediating androgen-induced PCOS-like programming. Naturally-occurring female hyperandrogenism is also demonstrated in monkeys. Animal models are poised to delineate molecular gateways to PCOS pathogenesis.