Читать книгу Hyperandrogenism in Women - Группа авторов - Страница 11

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.