Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Centre for Neuroendocrinology, Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Compr Physiol. 2022 Mar 29;12(2):3347-3369. doi: 10.1002/cphy.c210025.
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. © 2022 American Physiological Society. Compr Physiol 12:3347-3369, 2022.
多囊卵巢综合征（PCOS）是一种与雄激素过多强烈相关的主要内分泌紊乱疾病，常导致女性不孕。尽管经典上被认为是一种卵巢疾病，但大脑中促性腺激素释放激素（GnRH）神经元的神经内分泌控制改变和异常促性腺激素分泌可能是 PCOS 表现的基础。PCOS 中 GnRH 脉冲生成的调节缺陷促进了黄体生成素（LH）高脉冲分泌，反过来又过度刺激卵巢雄激素的产生。来自临床前模型的早期和新兴证据表明，母体雄激素过多会导致发育中的神经内分泌回路出现异常，这些异常与 PCOS 病理有关，并且这些异常在青春期后内源性雄激素水平升高时得以维持。本文将讨论来自临床和临床前动物模型的实验证据，这些证据极大地促进了我们对雄激素过多如何影响女性大脑中神经内分泌损伤的组装和维持的理解。在患者和临床前模型中都发现了异常的中枢γ-氨基丁酸（GABA）信号，这可能是雄激素过多和 GnRH/LH 分泌升高之间的联系。增强的 GABA 能神经支配和对 GnRH 神经元的驱动被怀疑是 PCOS 中神经内分泌紊乱的发病机制和早期表现的原因。因此，本文还概述了 GABA 对 GnRH 神经元功能从产前发育到成年的调节，以讨论未来发现研究和治疗干预的可能途径。
