Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys

Abstract

Old World monkeys provide naturally-occurring and experimentally-induced phenotypes closely resembling the highly prevalent polycystic ovary syndrome (PCOS) in women. In particular, experimentally-induced fetal androgen excess in female rhesus monkeys produces a comprehensive adult PCOS-like phenotype that includes both reproductive and metabolic dysfunction found in PCOS women. Such a reliable experimental approach enables the use of the prenatally androgenized (PA) female rhesus monkey model to (1) examine fetal, infant and adolescent antecedents of adult pathophysiology, gaining valuable insight into early phenotypic expression of PCOS, and (2) to understand adult pathophysiology from a mechanistic perspective. Elevated circulating luteinizing hormone (LH) levels are the earliest indication of reproductive dysfunction in late gestation nonhuman primate fetuses and infants exposed to androgen excess during early (late first to second trimester) gestation. Such early gestation-exposed PA infants also are hyperandrogenic, with both LH hypersecretion and hyperandrogenism persisting in early gestation-exposed PA adults. Similarly, subtle metabolic abnormalities appearing in young nonhuman primate infants and adolescents precede the abdominal adiposity, hyperliplidemia, and increased incidence of type 2 diabetes that characterize early gestated-exposed PA adults.These new insights into the developmental origins of PCOS, and progression of the pathophysiology from infancy to adulthood, provide opportunities for clinical intervention to ameliorate the PCOS phenotype thus providing a preventive health care approach to PCOS-related abnormalities. For example, PCOS-like traits in PA monkeys, as in PCOS women, can improve with better insulin-glucose homeostasis, suggesting that lifestyle interventions preventing increased adiposity in adolescent daughters of PCOS mothers also may reduce their risk of acquiring many PCOS-related metabolic abnormalities in adulthood.

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

“…Animal models have shown that prenatal androgen treatment induce accelerations of LH pulsatile release in primates (Abbott et al 2009), sheep (Forsdike et al 2007, Steckler et al 2009), and rodents (Foecking et al 2005), in accordance with the present results. Our observations confirm the concept that an early disturbance due to intrauterine androgen excess reprograms nervous tissue development of the fetus and irreversibly alters neuroendocrine function in female offspring.…”

Prenatal androgen excess programs metabolic derangements in pubertal female rats

“…PNA female nonhuman primates show reproductive and metabolic disturbances such as polycystic ovaries, hyperandrogenism, oligomenorrhea, oligo-or anovulation, and LH hypersecretion, which are consistent with the human PCOS phenotype (Abbott et al 2008a,b). Furthermore, intrauterine androgen exposure in these monkeys leads to the development of insulin resistance associated with visceral adiposity, impaired glucose metabolism, and dyslipidemia (Abbott et al 2009). These observations substantiate the hypothesis that an early perturbation due to in utero androgen excess resets the reproductive and metabolic trajectory of the growing fetus and programs target tissue differentiation and development, supporting a potential role of epigenetics and fetal programming in the pathogenesis of PCOS (Franks 2012).…”

Mammalian foetal ovarian development: consequences for health and disease

“…The origins of PCOS have been proposed to extend back to foetal life. Exposure to androgens during gestation led to the development of PCOS by female rhesus monkeys (Abbott et al 2009), sheep (Veiga-Lopez et al 2008 and rats (Demissie et al 2008), with characteristics similar to those observed in humans. Interestingly, treatment of adult monkeys with androgens in various forms and regimens failed to induce PCOS (Billiar et al 1985).…”

“…The authors postulate that expression of fibrillin 3 at this time may predispose the foetus to develop PCOS in later life. To prevent the propagation of PCOS or metabolic-related disorders from mothers to daughters, interventions to prevent increased weight gain/adiposity during adolescence have been proposed (Abbott et al 2009). …”