Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring

Abstract

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction.

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

“…It is known that both the embryo development stages and early postnatal life period are crucial to condition adult health life. Thus, currently used PCOS animal models focus on these critical development time windows (Manikkam et al 2006, Demissie et al 2008, Abbott et al 2010, Amalfi et al 2012, Jang et al 2015. Furthermore, the metabolic and endocrine alterations found in the prenatal models lead to several long-term effects, thus highlighting the importance of the in utero environment.…”

“…PCOS etiology remains controversial, and current theories emphasize on genetic and intrauterine origins coupled with environmental factors such as diet and altered lifestyle patterns (Franks 1995). It has been reported that prenatal androgen exposure is able to induce polycystic ovaries in rats (Demissie et al 2008, monkeys (Abbott et al 2010) and sheep (Manikkam et al 2006) and that fetal programming, mediated by prenatal hyperandrogenism, is related to hyperinsulinemia, dyslipidemia, insulin resistance (IR), cardiovascular disease and metabolic syndrome (Demissie et al 2008, Amalfi et al 2012, Heber et al 2013. However, how fetal programming impacts on different tissues is unknown.…”

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

“…These findings suggest a complex relationship between the altered maternal environment and fetal growth in PCOS. The mechanisms leading to the development of PCOS are largely unknown, but the pathogenesis of PCOS is likely to include a combination of genetic and epigenetic factors (51) as well as environmental influences (2).…”

“…These findings indicate that the effects of prenatal androgenization on the placenta, fetus, and female offspring are not caused by changes in maternal metabolism. On the other hand, in monkeys, maternal androgen administration during pregnancy does increase weight gain and alters insulin and glucose responses to glucose and increases conjugated estrogen of the dam, indicating that effects in female offspring may be caused by altered maternal metabolism (2). The placenta normally acts as a barrier that protects the fetus from excessive maternal androgens.…”

Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause

“…Foetuses of animals exposed to androgen excess at the beginning of pregnancy may also exhibit an increased risk of hyperinsulinaemia and visceral obesity in infancy (Escobar-Morreale et al 2014). Although developmental programming by androgen excess might be associated with IUGR in rodents (Sathishkumar et al 2011) and sheep (Beckett et al 2014) and with low birth weight (LBW), these characteristics are not frequently found in that process in non-human primate models for PCOS (Abbott et al 2010). LH, luteinising hormone.…”