人类的性和生殖发育受下丘脑-垂体-性腺(HPG)轴的调节,其主要由作用于其受体(GnRHR)的促性腺激素释放激素(GnRH)控制。轴的失调导致诸如先天性促性腺激素低性腺功能减退症(CHH)和青春期延迟的状况。GnRHR的病理生理学使其成为几种生殖疾病和先天性肾上腺增生治疗的潜在目标。GnRHR属于G蛋白偶联受体家族及其GnRH配体,绑定时,激活几个复杂的和组织特异性的信号通路。在垂体促性腺激素细胞中,它触发G蛋白亚基解离并引发一系列事件,导致黄体生成素(LH)和卵泡刺激素(FSH)的产生和分泌伴随磷脂酶C,肌醇磷酸生产,和蛋白激酶C激活。药理学上,GnRHR可以通过合成类似物调节。此类类似物包括激动剂,拮抗剂,和药物对照组。激动剂刺激促性腺激素释放并导致长期使用的受体脱敏,而拮抗剂直接阻断GnRHR并迅速减少性激素产生。Pharmacoperones包括最新的GnRHR治疗方法,直接纠正错误折叠的GnRHR,这是由基因突变引起的,对CHH治疗具有重要的前景。了解GnRHR的基因组和蛋白质结构对于最适当地评估突变影响至关重要。GNRHR中的这种突变与正常的低促性腺激素性性腺功能减退症有关,并导致各种临床症状,包括青春期延迟,不孕症,性发育受损。这些突变因其遗传方式而异,可以在纯合子中发现,复合杂合,或处于双基因状态。GnRHR表达延伸到脑垂体,在生殖组织如卵巢中发现,子宫,前列腺和心脏等非生殖组织,肌肉,肝脏和黑色素瘤细胞。这篇综合综述探讨了GnRHR在人类生殖中的多方面作用及其对生殖障碍的临床意义。
Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR\'s genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR\'s multifaceted role in human reproduction and its clinical implications for reproductive disorders.