Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome

Abstract

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.

Keywords: adipogenic constraint-induced lipotoxicity; androgen excess; developmental programming; genetic manipulation; naturally hyperandrogenic female monkeys; therapeutic prevention.

Graphical Abstract

Figure 1.

Hypothetical contribution of environmental, epigenetic, and genetic factors in the pathophysiology of PCOS. PCOS is a heterogeneous endocrine disorder and its pathogenesis is poorly understood. Current evidence supports gene-environment interactions and epigenetic regulation in the origins of PCOS. The inherited genetic component appears to span all organ systems and physiological function, with epigenetics capable of modifying the expression patterns of inherited genes. Environmental elements can influence all developmental components by impacting organ systems, physiological function and epigenetic regulation, with population-specific environmental elements thought to bring about ethnic differences in PCOS sub-phenotypes. While substantial gaps in knowledge still exist, further insights into our understanding of genetic and developmental contributions to the etiology of PCOS will significantly improve our ability to diagnose, treat, and prevent PCOS in the future.

Figure 2.

Neuroendocrine mechanisms potentially involved in mediating the development of PCOS. Substantial evidence now supports a key role for the neuroendocrine system in the pathogenesis of PCOS. Panel (A) illustrate rodent and panel (B) primate hypothalamus-pituitary-gonadal feed-back loops. The elevated LH:FSH ratio observed in women with PCOS is likely due to increased activity and secretion from GnRH neurons in the rostral forebrain (mice) and mediobasal hypothalamus (NHP and humans). The resulting increase in LH pulsatility contributes to the development of PCOS ovarian features, including theca cell hyperplasia and elevated androgen production. Impaired gonadal steroid hormone negative feedback sensitivity is indicative of brain specific impairments in the regulation of GnRH neurons. Recent research using animal models has identified that alterations in GABA, KNDy, and AMH brain-specific signaling are likely involved in GnRH neuron hyperactivity in PCOS. In hyperandrogenized PCOS animal models GABA circuit abnormalities develop before PCOS symptoms emerge (97, 158), and adult females exhibit increased GABA transmission to GnRH neurons (93), together with increased innervation to GnRH neurons (95), and yet AR blockade restores normal GABA innervation and transmission (93, 97). KNDy neurons play a key role in pulse generation (159, 160), however, varied subtle and frequently absent differences in the KNDy circuit have been identified in hyperandrogenized PCOS animal models (52, 53, 56, 91, 132, 161, 162). AMH directly stimulates GnRH activity (163) and prenatal maternal AMH excess has been shown to induce PCOS characteristics in mice, including increased GABAergic appositions to GnRH neurons and increased GnRH neuron firing rate in adulthood (107).