Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess

Abstract

Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin-releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma-aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions.

The Hidden Link between Polycystic Ovary Syndrome and Kidney Stones: Finding from the Tehran Lipid and Glucose Study (TLGS)

“…The worldwide prevalence of PCOS is estimated to be between 6 and 12% [1,2]. This disorder is primarily caused by the overproduction of androgens by the ovaries and, in some cases, the adrenal glands, leading to a variety of clinical features including menstrual disorders and increased symptoms of male hormones such as hirsutism, acne, oily skin, and androgenic alopecia [3][4][5][6][7]. Hyperandrogenism and/or hyperandrogenemia are the most common diagnostic features of PCOS [5], present in more than 82% of patients [8,9].…”

History of Polycystic Ovary Syndrome, Premature Adrenarche, and Hyperandrogenism in Pediatric Endocrinology

“…Also, a third question considers the role of prenatal androgen and/or AMH exposure on the developing fetus [138, 139]. A fourth question relates to the usefulness of AMH measurements to identify PCOM and applicability to adolescent and emerging adult girls [140]. Additional longitudinal prospective studies are needed to answer these important questions.…”

Investigating GABA Neuron–Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS

“…These preclinical findings align with PCOS patient data indicating elevated cerebrospinal fluid levels of GABA ( 28 , 29 ) and an altered response to positive allosteric modulators of GABA receptors ( 30 ). Although recognized as the major inhibitory neurotransmitter in the brain, GABA actions on GnRH neurons are largely excitatory via GABA A receptors ( 31 ); this aligns with the hyperactive nature of the reproductive axis in PCOS ( 23 ). In mouse models, chronic activation of GABA neurons in the arcuate nucleus is sufficient to drive a PCOS-like phenotype ( 32 ), and the elevated GABAergic innervation and transmission to the GnRH neurons in PCOS-like mice can be reversed with anti-androgen treatment ( 15 , 16 ).…”