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.
Highlights
Polycystic ovary syndrome (PCOS) bestows detrimental life-long consequences on a woman’s health and wellbeing [1,2]
Other causes of hyperandrogenism may contribute to the development or aggravation of polycystic ovary syndrome (PCOS), including LH hypersecretion, adipogenic constraint and obesity leading to compensatory hyperinsulinemia arising from insulin resistance, as well as fetal androgen exposure [3,25,26]
Females exposed to early-to-mid gestation T exhibit diminished oocyte developmental competence and fertilization rates [135], further reducing likelihood of pregnancy. These macaque findings would suggest that women with PCOS, who are seeking infertility treatment, are highly likely to benefit from pre-conception lifestyle, therapeutic or combination therapies in terms of diminished pregnancy complications and healthier babies
Summary
Polycystic ovary syndrome (PCOS) bestows detrimental life-long consequences on a woman’s health and wellbeing [1,2]. Rotterdam criteria recognize four PCOS phenotypes: classic PCOS with (type A) and without (type B) polycystic ovaries, ovulatory PCOS (type C) without intermittent or absent cycles, and “non-hyperandrogenic” PCOS (type D) without high T or excessive body hair [1,3]. The majority of PCOS subjects recruited from local or unselected human populations exhibit the less severe ovulatory or “non-hyperandrogenic” phenotypes (types C and D, respectively) [10] Such distinctions become important when examining PCOS etiopathogenesis since the consequences of pronounced cardiometabolic disease in clinical referral studies may intertwine PCOS consequence with cause, providing less than ideal targets to emulate in animal models seeking foundational mechanisms for novel therapies. AMH level ≥ 10 ng/mL (PCOM); type B, HA + OD; type C, HA + PCOM; type D, OD + PCOM, as described [13]
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