Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Abstract

Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

Keywords: adipogenic constraint; androgen excess; developmental programming; infertility; insulin resistance; testosterone-associated traits; transgenerational transmission.

Figure 1

Developmental chronology of experimental manipulations utilized to generate female Indian macaque models for polycystic ovary syndrome (PCOS) and induced phenotypic traits in comparison to naturally occurring hyperandrogenic females. a, positive correlation between circulating T and AGD in High T females, alone; b, only in High T females with circulating T ≥ 2 SD above population mean T; c, <20% of fertilized oocytes reach blastocyst in vitro; d, high circulating T produced by continuous exogenous treatment; e, poor embryo quality contributing to pregnancy failure. References: model #1 [13], model #2 [111], model #3 [100,112], model #4 [111], model #5 [100,112], model #6 [113], model #7 [35,114], model #8 [35,114], model #9 [115,116], model #10 [117], model #11 [118,119,120].

Figure 2

Diagrammatic illustration of commonalities in selected PCOS-like traits exhibited by female Indian macaque models.