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 gestation-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.

Figure 1

Daily oral administration of 3 mg/kg of the insulin sensitizer, pioglitazone, for six consecutive months normalizes ovulatory menstrual cycle duration in adult PA female rhesus monkeys (solid bars) compared to the previous placebo treatment period. On cessation of pioglitazone treatment, menstrual cycle abnormalities returned in PA females. Regular, ovulatory menstrual cycles were displayed by control female monkeys (open bars) throughout. Differences between individual means (+SEM) were determined from univariate F-tests performed after a significant (P<0.05) overall analysis of variance with repeated measures design. Modified from Zhou et al., 2007.

Figure 2

Treatment of two female rhesus monkeys between the ages of 5-12 months with intramuscular testosterone propionate (7.5 mg/kg per week; solid and dashed lines) accelerates growth rate and age at menarche (first menses) compared to untreated female rhesus monkeys (solid circles denote mean values with standard deviations). Reproduced with permission from van Wagenen (1949).