Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

ABSTRACT

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.

KEYWORDS:

• Hyperandrogenism
• developmental origin of adult disease
• animal models
• androgen excess
• impaired negative feedback
• infertility
• anovulation
• obesity
• insulin resistance

Article highlights

• Polycystic ovary syndrome (PCOS) is a highly prevalent, familial, hyperandrogenic infertility and cardiometabolic disorder lacking a defined pathogenic mechanism. PCOS risk genes regulate a variety of reproductive, neuroendocrine and metabolic functions, but account for <10% of patients.

• Accumulating evidence from human studies implicates fetal testosterone exposure as an epigenetic contributor to PCOS pathogenesis.

• Fetal female testosterone exposure in a variety of animal models reliably induces PCOS-like phenotypes, with accompanying changes in DNA methylation and microRNA expression implicating altered gene expression related, in part, to PCOS risk genes.

• Recently identified, naturally occurring hyperandrogenic female monkeys express PCOS-like reproductive and neuroendocrine traits, with genital biomarkers indicative of increased exposure to testosterone commencing during fetal life.

• Transgenic mouse models implicate androgen receptors, particularly neuronal androgen receptors, in mediating the majority of testosterone-induced, PCOS-like reproductive, neuroendocrine and metabolic traits.

• Gestational intervention, however, can yield desirable and undesirable outcomes, leaving offspring vulnerable to additional risk for adult disease or altered behavior.

• Early interventions during adolescence, including anti-androgen and insulin sensitizer therapies, hold more promise.

• Recent advances in regulating organ-specific gene expression in mice, as well as gene silencing and gene over-expression in nonhuman primates, promise key refinements in understanding molecular pathogenesis generating PCOS.

Acknowledgments

We thank Marissa Kraynak PhD, Robert Shapiro PhD, Matt Flowers PhD, Emily Greinwald BS, and the Veterinary, Animal, Assays and Pathology Services of the Wisconsin National Primate Research Center for their expert assistance in nonhuman primate studies contributing to this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors were supported in part by NIH grants: P50 HD028934, P50 HD044405, P50 HD071836, P51 ODO11092 and UL1TR001881.