Endocrine Antecedents of Polycystic Ovary Syndrome in Fetal and Infant Prenatally Androgenized Female Rhesus Monkeys1

Abstract

Experimentally induced fetal androgen excess induces polycystic ovary syndrome-like traits in adult female rhesus monkeys (Macaca mulatta). Developmental changes leading to this endocrinopathy are not known. We therefore studied 15 time-mated, gravid female rhesus monkeys with known female fetuses. Nine dams received daily s.c. injections of 15 mg of testosterone propionate (TP), and six received injections of oil vehicle (control) from 40 through 80 days of gestation (term, 165 days; range, +/-10 days). All fetuses were delivered by cesarean section using established methods at term. Ultrasound-guided fetal blood sample collection and peripheral venous sample collection of dams and subsequent infants enabled determination of circulating levels of steroid hormones, LH and FSH. The TP injections elevated serum testosterone and androstenedione levels in the dams and prenatally androgenized (PA) fetuses. After cessation of TP injections, testosterone levels returned to values within the reference range for animals in these age groups, whereas serum androstenedione levels in PA infants were elevated. The TP injections did not increase estrogen levels in the dams or the PA fetuses or infants, yet conjugated estrogen levels were elevated in the TP-injected dams. Serum levels of LH and FSH were elevated in late-gestation PA fetuses, and LH levels were elevated in PA infants. These studies suggest that experimentally induced fetal androgen excess increases gonadotropin secretion in PA female fetuses and infants and elevates endogenous androgen levels in PA infants. Thus, in this nonhuman primate model, differential programming of the fetal hypothalamo-pituitary unit with concomitant hyperandrogenism provides evidence to suggest developmental origins of LH and androgen excess in adulthood.

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

“…Especially studies by Abbott (13,14,15,34,37), in prenatally exposed rhesus monkeys, have strongly encouraged the hypothesis that the intra-uterine exposure to androgens can cause clinical and biochemical features of PCOS in later life, though these androgen concentrations are supraphysiological.…”

Promoter Methylation of <b><i>CYP19A1</i></b> Gene in Chinese Polycystic Ovary Syndrome Patients

“…Whilst the pathogenesis of PCOS remains largely unknown, accumulating data suggest that PCOS is a complex disease which involves both genetic and environmental factors [3,4,5]. PCOS may begin in utero, because female mammals (rhesus monkeys, sheep, mice or rats) exposed to androgen in utero develop masculinized phenotypes similar to PCOS in adulthood [6,7,8]. Obesity in adolescents likely exacerbates the signs of this condition [9,10].…”

Prenatal androgen excess programs metabolic derangements in pubertal female rats

“…Female fetuses exposed to high levels of androgens in the intrauterine environment, including women with virilizing congenital adrenal hyperplasia and congenital adrenal virilizing tumors, have an increased risk of PCOS in adolescence (Xita & Tsatsoulis 2006). In addition, prenatally androgenized (PNA) female nonhuman primates, sheep, rats, and mice manifest most of the reproductive and metabolic derangements observed in women with PCOS (Forsdike et al 2007, Abbott et al 2008a, Roland et al 2010, Tyndall et al 2012. 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).…”