Garg Akanksha, Patel Bijal, Abbara Ali, Dhillo Waljit S
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.
Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, UK.
Clin Endocrinol (Oxf). 2022 Aug;97(2):156-164. doi: 10.1111/cen.14704. Epub 2022 Mar 8.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the leading cause of anovulatory subfertility. Increased gonadotrophin releasing hormone (GnRH) pulsatility in the hypothalamus results in preferential luteinizing hormone (LH) secretion from the pituitary gland, leading to ovarian hyperandrogenism and oligo/anovulation. The resultant hyperandrogenism reduces negative feedback from sex steroids such as oestradiol and progesterone to the hypothalamus, and thus perpetuates the increase in GnRH pulsatility. GnRH neurons do not have receptors for oestrogen, progesterone, or androgens, and thus the disrupted feedback is hypothesized to occur via upstream neurons. Likely candidates for these upstream regulators of GnRH neuronal pulsatility are Kisspeptin, Neurokinin B (NKB), and Dynorphin neurons (termed KNDy neurons). Growing insight into the neuroendocrine dysfunction underpinning the heightened GnRH pulsatility seen in PCOS has led to research on the use of pharmaceutical agents that specifically target the activity of these KNDy neurons to attenuate symptoms of PCOS. This review aims to highlight the neuroendocrine abnormalities that lead to increased GnRH pulsatility in PCOS, and outline data on recent therapeutic advancements that could potentially be used to treat PCOS. Emerging evidence has investigated the use of neurokinin 3 receptor (NK3R) antagonists as a method of reducing GnRH pulsatility and alleviating features of PCOS such as hyperandrogenism. We also consider other potential mechanisms by which increased GnRH pulsatility is controlled, which could form the basis of future avenues of research.
多囊卵巢综合征（PCOS）是育龄女性中最常见的内分泌紊乱疾病，也是无排卵性不孕症的主要原因。下丘脑促性腺激素释放激素（GnRH）脉冲频率增加，导致垂体优先分泌促黄体生成素（LH），进而引起卵巢雄激素过多和少排卵/无排卵。由此产生的雄激素过多会减少雌二醇和孕酮等性类固醇对下丘脑的负反馈，从而使GnRH脉冲频率持续增加。GnRH神经元没有雌激素、孕酮或雄激素的受体，因此推测这种反馈中断是通过上游神经元发生的。这些GnRH神经元脉冲频率上游调节因子的可能候选者是 kisspeptin、神经激肽 B（NKB）和强啡肽神经元（称为 KNDy 神经元）。对 PCOS 中GnRH脉冲频率升高所基于的神经内分泌功能障碍的深入了解，促使人们研究使用专门针对这些KNDy神经元活性的药物来减轻PCOS症状。本综述旨在强调导致PCOS中GnRH脉冲频率增加的神经内分泌异常，并概述有关近期可能用于治疗PCOS的治疗进展的数据。新出现的证据研究了使用神经激肽3受体（NK3R）拮抗剂作为降低GnRH脉冲频率和减轻PCOS特征（如雄激素过多）的一种方法。我们还考虑了控制GnRH脉冲频率增加的其他潜在机制，这可能构成未来研究途径的基础。
