including LHCGR, RAB5/SUOX, AMH/AMHR2, and INSR, suggesting convergence of molecular pathogenic mechanisms around the same critical genes. Do similar mechanistic insights emerge from animal models of in utero female hyperandrogenism?
Mechanistic PCOS Insight from Nonhuman Primate Models of in utero Female Hyperandrogenism
To induce fetal male levels of T in fetal female rhesus monkeys, monkey dams require daily SC injections of 10–15 mg T propionate to generate circulating T levels equivalent to nighttime adult male levels of T (∼20 ng/mL). Such high maternal levels are needed to exceed the primate liver’s ability to produce sex hormone-binding globulin, rendering >90% of circulating T non-bioavailable, as well as the primate placenta’s capacity to aromatize, conjugate, and metabolize T, thus delivering a small fraction (1–2%) of dam T concentrations to a female monkey fetus [22], as determined by liquid chromatographytandem mass spectrometry. Why start with such a challenging animal model? When PCOS-like traits are reliably replicated in a nonhuman primate with >90% of its genome shared with humans, and with highly similar neuroendocrine, reproductive, metabolic, developmental, aging, and behavioral attributes to humans [60], translational application is likely.
Table 1. PCOS-like reproductive and metabolic traits exhibited by in utero androgen excess animal models in adulthood, and by naturally occurring hyperandrogenic adult female monkeys
As illustrated in Table 1, T exposure in monkeys during early-to-mid gestation is more effective at inducing reproductive and metabolic PCOS-like signs and symptoms in female offspring than T exposure during late gestation, reinforcing the concept of a particularly vulnerable, mid-gestation developmental window for in utero T reprogramming of females in long gestation species. Mid-gestation excessive maternal weight gain and transient hyperglycemia, accompanied by fetal hyperglycemia, are all T-induced metabolic sequelae contributing potential additional reprogramming to exposed female fetuses [61]. As late gestation T exposure-induced PCOS-like traits demonstrate, however, a degree of fetal female monkey vulnerability to T reprogramming (and its gestational metabolic sequelae) remains beyond mid-gestation (Table 1). Increased incidence of gestational diabetes, as well as increased or diminished birthweight [54], accompanying PCOS gestations, closely emulates metabolic compromise of hyperandrogenic gestation in monkeys. Importantly, metabolically compromised gestation, alone, including obese monkeys and women [62], and women with T2D, is insufficient to cause PCOS. Increased T in utero, however, may reprogram female neurocircuitry controlling energy balance and increase vulnerability to in utero metabolic compromise [62].
Phenotypic manifestation of early-to-mid gestation T reprogramming of female monkeys begins with mid-gestation increase in fetal head size, followed in late gestation by hypolipidemia and fetal LH hypersecretion [22, 61]. LH hypersecretion persists into early infancy, accompanied by modest hyperandrogenism [22], reflecting precocious development of insensitive negative feedback regulation of GnRH/LH in the absence of mature ovarian hormone levels providing homeostatic constraint. While birthweight is normal, accompanying metabolic dysfunctions includes newborn hypoglycemia, accelerated infant weight gain and relative hyperinsulinemia related to defective pancreatic beta cell compensation for insulin sensitivity and excessive beta-to-alpha cell ratio in infant pancreatic islets [61, 63]. Increased fetal growth, neonatal hypoglycemia, and subsequent accelerated postnatal growth are typical of human pregnancies encountering excessive maternal weight gain and hyperglycemia [64], and such gestations greatly increase the risk of developing T2D in adulthood.
During adolescence, menarche is delayed by ∼6 months in both early-to-mid and late gestation T-exposed female monkeys [65], but such pubertal delay is absent when lower amounts of T are administered to monkey dams [66]. Subsequent onset of menstrual cycles in early-to-mid gestation T-exposed monkeys is accompanied by a prolonged succession of luteal insufficiency [65], demonstrating adolescent origins of ovulatory cycle dysfunction, an attribute of adolescent girls presenting with PCOS [54].
By their reproductive years, early-to-mid gestation T-exposed female monkeys become comprehensive counterparts of women with PCOS. Ovarian and adrenal hyperandrogenism co-occur with intermittent and absent menstrual cycles, as well as large, polyfollicular ovaries [9, 22]. Elevated LH levels are omnipresent, driven by increased hypothalamic GnRH pulse frequency and increased pituitary gonadotrope response to GnRH, both likely resulting from diminished sensitivity to E2- and progesterone-mediated negative feedback regulation [67], all neuroendocrine traits found in women with PCOS [68, 69]. Oocyte developmental competence is compromised in these monkeys [70], and may reflect contributions from increased adiposity that accompanies diminished oocyte quality in women with PCOS [71]. Circulating AMH levels in T-exposed monkeys, however, do not exceed those of controls, and exhibit premature, aging-related decline [72]. While the absence of AMH excess is not typical of women with PCOS, PCOS women over 30 years of age demonstrate a steeper decline in circulating AMH levels than their non-PCOS counterparts [73]. Early-to-mid gestation T reprogramming of ovarian follicle granulosa cells may therefore be less pronounced than ovarian theca, stroma, or oocytes, and a maternal source of fetal hyperandrogenism, alone, may be insufficient to reprogram granulosa cell AMH hypersecretion or increased follicle number and proliferation.
Accompanying metabolic dysfunction is just as pronounced in adult T-exposed monkeys as in PCOS women, despite the monkeys’ non-obesogenic diet. Monkey visceral fat accumulation is increased (“metabolic obesity”), likely arising from PCOS-like hyperandrogenic adipogenic constraint, limiting SC adipocyte maturation and safe lipid storage [74]. Such pro-lipotoxic traits may contribute to hyperlipidemia-associated insulin resistance, impaired pancreatic beta cell compensation and compromised islet size [63] enabling increased progression to T2D [12]. Consistent with gestational origins of PCOS-like metabolic dysfunction, increased postnatal weight gain is associated
