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During early-to-mid gestation, ∼40% of fetal girls experience elevated circulating concentrations of unbound, bioavailable, testosterone (T) levels in the fetal male range [21]. This is relevant to PCOS, since comparable circulating T excursions into the fetal male range generate PCOS-like traits in gestational T-exposed female rhesus monkeys [22] and sheep [23], revealing the life-long impact on females of in utero androgen excess. In short-gestation rodents, late gestation, and the immediate postpartum period, provide a comparable developmentally vulnerable period for females [12]. Perhaps not surprisingly, therefore, amniotic fluid from daughters of women with PCOS exhibit male-similar T levels in mid-gestation, exceeding levels in mid-gestation daughters of women without PCOS [24]. As mid-gestation amniotic fluid T originates from the fetus [25], elevated T levels suggest hyperandrogenism in fetal daughters of women with PCOS during a crucial, developmental window when female nonhuman primates and sheep are vulnerable to PCOS-like reprogramming [12, 16]. Approximately 50% of daughters born to PCOS women develop signs and symptoms of PCOS by adolescence [26], indicating the substantial risk for PCOS phenotype accompanying female in utero androgen excess in humans [12].

Fig. 1. Hypothetical maternal and fetal contributions to in utero female androgen excess reprogramming for a hyperandrogenic female offspring.

Pregnant women with PCOS retain hyperandrogenism throughout pregnancy [27], together with elevated AMH levels [28] and reduced placental aromatase expression [29]. Despite population differences [30], ∼40% of PCOS women experience gestational diabetes [31] and other pregnancy complications [32], with maternal diabetes predisposing offspring to metabolic dysfunction in later life through fetal hyperinsulinemia [33]. A recent mouse model suggests that increasing AMH levels in pregnancy (as seen in PCOS women) can promote both LH-mediated T excess and reduced placental aromatization of maternal androgens [28], thereby contributing to fetal hyperandrogenism in their daughters (Fig. 1), although such a mechanism in humans remains to be confirmed.

Post-natal consequences of in utero androgen excess are found as early as the newborn for women with PCOS. Infant daughters not only exhibit transient facial sebum [34], a biomarker of prior T exposure, but also demonstrate an elongated anogenital distance [35], a reliable biomarker for early-to-mid gestation androgen excess [36]. Newborn daughters of women with PCOS also exhibit elevated AMH levels indicative of increased numbers of ovarian antral follicles, a PCOS trait. In adulthood, women with PCOS retain an elongated anogenital distance ([37, 38], typical of in utero, T-exposed, PCOS-like female monkeys [36] and sheep [23]. A diminished or exaggerated 2D:4D finger length ratio is also associated with both in utero androgen excess and PCOS, in women [39], their prepubertal daughters [24] and adult, early-to-mid gestation, T-exposed PCOS-like monkeys [36], since similar T- and E₂-regulated genes control differentiation of gonads, hands, and feet. Prepubertal daughters of women with PCOS also excrete increased concentrations of dihydrotestosterone (DHT) metabolites in their urine compared to prepubertal girls of women without PCOS [40], indicating increased 5-alpha reductase activity, and perhaps amplified target tissue androgen action, well before the onset of PCOS signs and symptoms at puberty.

Mixed umbilical cord blood androgen levels from human female fetuses at term, however, have yielded inconsistent results in support of late gestation fetal hyperandrogenism in daughters of PCOS women, regardless of whether or not “gold standard” liquid chromatography-tandem mass spectrometry assays are employed. Increased T or androstenedione levels are reported in two studies [41, 42], equivalent levels in one [43], and diminished levels in a further two studies [29, 44]. Labor onset and duration, together with increasing term gestational age, however, diminish umbilical cord androgen levels and likely often confound understanding of late gestation female androgenic state from this measure [45]. Moreover, no sex differences remain between circulating T levels in male and female human fetuses by late gestation [21], suggesting term birth is inauspicious for exploration of developmental hyperandrogenism.