PCOS pathogenesis are puzzling and, to date, accounts for <10% of PCOS presentations. Unaccounted heritability notwithstanding, molecular commonality in pathogenic mechanisms is emerging, suggested by co-occurrence at the same gene loci of (1) PCOS genetic variants (PCOS women), (2) epigenetic alterations in DNA methylation (PCOS women), and (3) bioinformatics, gene networks-identified, epigenetic alterations in DNA methylation (female rhesus monkeys exposed to testosterone (T) in utero). In addition, naturally occurring hyperandrogenism in female monkeys singles out individuals with PCOS-like reproductive and metabolic traits accompanied by somatic biomarkers of in utero T exposure. Such phenotypic and molecular convergence between highly related species suggests not only dual genetic and epigenetic contributions to a developmental origin of PCOS but also common molecular pathogenesis extending beyond humans.
© 2019 S. Karger AG, Basel
Introduction
With a staggering 10–20% prevalence among premenopausal women, polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic women’s health disorder [1]. Its diagnosis on the basis of Rotterdam criteria requires at least 2 of the following 3 parameters: high testosterone (T) levels or hirsutism, intermittent or absent menstrual cycles, and ultrasonography-visualized polycystic ovaries, excluding endocrine mimics such as congenital adrenal hyperplasia [1]. Luteinizing hormone (LH) hypersecretion commonly accompanies hyperandrogenism [4] likely due to T-diminished, estradiol (E2) induction of neural progesterone receptors in the mediobasal hypothalamus [2, 3], resulting in diminished E2-progesterone negative feedback regulation of gonadotropin-releasing hormone (GnRH) episodic release from the medial basal hypothalamus. Elevated ovarian granulosa cell anti-Müllerian hormone (AMH) production commonly accompanies polycystic ovary morphology and provides an accurate biomarker for increased numbers of growing follicles [5].
Clinical sequelae for PCOS can include acne, infertility, endometrial hyperplasia and malignancy, obesity, type 2 diabetes (T2D), sleep apnea, cardiovascular disease, mood disorders, and sexual dysfunction [1, 6, 7]. PCOS is thus a uniquely challenging, multifaceted disorder with several phenotypes, in which progressive obesity enhances severity of phenotype, and diminishes the well-being and quality of life [8]. Overt signs and symptoms of PCOS usually manifest at puberty.
While complex, PCOS is highly heritable and familial, and hyperandrogenism is its most heritable trait [1]. Pathogenic mechanisms, however, have remained elusive, hindering progress toward a cure. In this regard, in utero findings of hyperandrogenic origins for PCOS-like traits in nonhuman primates [9, 10], provided a novel, single pathogenic origin for PCOS that mimicked PCOS phenotypic diversity in women (hence PCOS-like traits). Subsequent (androgen-induced) epigenetic mechanisms may provide an amplification mechanism [11], effectively reprogramming diverse genetic backgrounds into PCOS-like individuals [12]. Confirmatory findings soon followed in sheep [13], mice [14], and rats [15], expanding into molecular insight of developmental pathogenesis [16–18]. While acceptance of in utero hyperandrogenic origins for PCOS is not universal [19], accumulating supportive evidence from human studies provides increasing evidence for pathogenic onset for PCOS during fetal life [1, 12, 20]. This brief review focuses on the current understanding emerging from human and animal model studies concerning in utero androgen excess contributing to PCOS and its potential pathogenic mechanisms, with an emphasis on nonhuman primate findings.
In utero Androgen Excess: Human Studies
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],
