Kallmann Syndrome and Other Causes of Hypothalamic Hypogonadism and Related Development Disorders
Kallmann Syndrome and Other Causes of Hypothalamic Hypogonadism and Related Development Disorders
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DOI：
10.1016/b978-0-12-375097-6.10027-7
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Bouloux, Pierre M. G.
中科院分区：
文献类型：
--
作者：
Han, Thang S.;Bouloux, Pierre M. G.
低促性腺激素性性腺功能减退症（HH）的特征是继发于黄体生成激素和卵泡刺激激素循环水平缺乏或严重降低的性腺衰竭和青春期性成熟缺乏/延迟或停滞。导致HH的先天性异常可能由GnRH分泌减少引起，单独发生于嗅觉正常（特发性，IHH）或与嗅觉丧失/嗅觉减退（卡尔曼综合征）相关，或作为继发于腺垂体发育障碍的多种垂体激素缺乏症的一部分，也可能作为其他特征不良的中枢神经系统发育障碍的一部分发生。在本章中，首先考虑下丘脑-垂体-性腺轴的神经内分泌组织和调节，然后回顾低促性腺激素性性腺功能减退症的分子发病机制中的当前概念。GnRH神经元的个体发育是复杂的且不完全理解的，这些疾病的发病机制的当前知识来自于几种动物模型和人类观察的证据，这些研究阐明了几个遗传基因座的作用，如果这些基因座被破坏，将导致GnRH神经元迁移或GnRH神经元存活所必需的信号连接异常，或GnRH分泌或作用紊乱，或垂体发育紊乱。在人类中，超过10个不同基因位点的突变，包括FGFR 1、FGF 8、PROK 2和PROKR 2，是卡尔曼综合征和IHH的原因;很明显，这两种疾病之间有相当大的发病重叠，在受影响的家系中，相同的遗传缺陷可能导致任何一种表型。此外，传播并不总是遵循经典的孟德尔遗传模式，越来越多的证据表明，在产生表型的过程中，几个基因（寡基因遗传）之间存在相互作用。最近描述的HH或严重青春期延迟患者kisspeptin/GPR 54系统的遗传病变，以及神经激肽B及其受体在正常性成熟中的关键作用，扩展了我们对GnRH神经元分泌的理解，并可能在人类中具有未来的治疗意义。
Hypogonadotropic hypogonadism (HH) is characterized by gonadal failure and absent/delayed or arrested pubertal sexual maturation secondary to absent or severely reduced circulating levels of luteinizing and follicle-stimulating hormones. Congenital abnormalities leading to HH may result from diminished GnRH secretion, occurring in isolation either with euosmia (idiopathic, IHH) or in association with anosmia/hyposmia (Kallmann syndrome), or as part of multiple pituitary hormone deficiencies secondary to developmental failure of the adenohypophysis, and can also occur as part of other ill-characterized developmental disorders of the central nervous system. In this chapter, the neuroendocrine organization and regulation of the hypothalamic-pituitary-gonadal axis is first considered, followed by a review of current concepts in the molecular pathogenesis of hypogonadotropic hypogonadism.The ontogeny of GnRH neurons is complex and incompletely understood, and current knowledge of the pathogenesis of these disorders draws from evidence from several animal models and human observations, which have elucidated the role of several genetic loci which, if disrupted, lead to abnormalities in GnRH neuronal migration or connections of signals essential for GnRH neuron survival, or perturbation of GnRH secretion or action, or of pituitary development. In the human, mutations in more than 10 separate gene loci, including FGFR1, FGF8, PROK2 and PROKR2, are responsible for both Kallmann syndrome and IHH; it has become evident that there is considerable pathogenetic overlap between these two entities, and that within affected pedigrees the same genetic defect may cause either phenotype. Moreover, transmission does not always follow classical Mendelian inheritance patterns, and there is growing evidence for interplay between several genes (oligogenic inheritance) in producing the phenotype. Recently described genetic lesions in the kisspeptin/GPR54 system in patients with HH or severe pubertal delay, and of the critical role of neurokinin B and its receptor in normal sexual maturation, have extended our understanding of GnRH neuronal secretion, and may have future therapeutic implications in the human.