Perspective: the importance of genetic defects in humans in elucidating the complexities of the hypothalamic-pituitary-gonadal axis.
Perspective: the importance of genetic defects in humans in elucidating the complexities of the hypothalamic-pituitary-gonadal axis.
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DOI：
10.1210/endo.142.6.8261
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发表时间：
2001-06
期刊：
影响因子：
4.8
通讯作者：
S. Seminara;William F. Crowley
中科院分区：
文献类型：
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作者：
S. Seminara;William F. Crowley
人类下丘脑的 GnRH 分泌在整个生命周期中表现出显着的变异性，但受到精细的调节，会引发一系列事件，导致性腺性类固醇分泌、卵泡发生和精子发生。动物研究表明，下丘脑门静脉血中的 GnRH 脉冲与外周血中的 LH 脉冲之间存在显着的一致性 (1)，证实 LH 搏动是 GnRH 先前间歇性放电的反映。脉冲式 GnRH 分泌不仅是维持正常促性腺激素分泌所必需的，而且与脉冲式不同，连续施用 GnRH 实际上会使促性腺激素释放变得不敏感 (2)。在 GnRH 缺乏的动物和人类中，给予脉冲式 GnRH 可重建正常的激素反应，而在先天性低促性腺激素性性腺功能减退症的患者中，脉冲式 GnRH 可以重现正常的青春期发育 (2-5)。尽管 GnRH 分泌的这些原理已经确立了二十多年，但在正常生殖（即月经周期）、生命周期的不同阶段（即青春期促性腺激素扩增）和病理生理状态（即多囊卵巢综合征）中通过性类固醇和非类固醇因子调节 GnRH 分泌是一个复杂且不完全了解的现象。下丘脑-垂体-性腺轴内发生单基因突变的患者为增加我们对生殖神经内分泌学的理解提供了独特的途径。基因工程动物模型通过证实和扩展人类发现、建立物种特异性表型或在不存在人类模型时预测表型，进一步阐明了特定激素在生殖功能中的作用。动物和人类工具的结合已被证明是强大的，揭示了生殖生物学的悖论和物种之间意想不到的差异。例如，20 多年前，一种自然发生的低促性腺激素性性腺功能减退症小鼠模型（hpg 小鼠）被描述为 LH 和 FSH 水平低、性不成熟和不育 (6)。性腺功能减退症是由于编码 GnRH 和 GnRH 相关肽 (GAP) 的基因远端的缺失突变所致 (7)；该突变纯合子小鼠的生殖细胞发育受到抑制，但通过基因治疗可以恢复生殖功能 (8)。然而，尽管 GnRH 明显是人类遗传性性腺功能减退症的一个原因，但在该人群中尚未发现 GnRH 基因内的突变 (9-11)。因此，必须以互补的方式评估人类和动物自发发生的突变以及选定基因的定向破坏。下面讨论其中一些突变的例子、它们的基因型/表型相关性以及它们呈现的生殖悖论。
Demonstrating marked variability across the life cycle, yet exquisitely regulated, the hypothalamic secretion of GnRH in the human triggers a cascade of events leading to gonadal sex steroid secretion, folliculogenesis, and spermatogenesis. Animal studies have demonstrated a remarkable concordance between GnRH pulses in hypothalamic portal blood and LH pulses in the periphery (1), establishing that LH pulsatility is a reflection of antecedent, intermittent discharges of GnRH. Not only is pulsatile GnRH secretion necessary for the maintenance of normal gonadotropin secretion, but continuous, as opposed to pulsatile, administration of GnRH actually desensitizes gonadotropin release (2). In GnRH-deficient animals and humans, administration of pulsatile GnRH reestablishes normal hormone responses, and in patients with congenital hypogonadotropic hypogonadism, pulsatile GnRH can recapitulate normal pubertal development (2–5). Although these principles of GnRH secretion have been established for over two decades, the regulation of GnRH secretion via sex steroid and nonsteroidal factors in normal reproduction (i.e. the menstrual cycle), different stages of the life cycle (i.e. gonadotropin amplification during puberty) and pathophysiologic states (i.e. polycystic ovary syndrome) is a complicated and incompletely understood phenomenon. Patients with single gene mutations within the hypothalamic-pituitary-gonadal axis have provided unique avenues to increase our understanding of reproductive neuroendocrinology. Genetically engineered animal models have further elucidated the roles of specific hormones in reproductive function, by confirming and extending human findings, establishing species-specific phenotypes, or predicting phenotypes when no human model exists. The combination of both animal and human tools has proven to be powerful, revealing paradoxes of reproductive biology and unexpected differences between species. For example, over 20 yr ago, a naturally occurring mouse model of hypogonadotropic hypogonadism (hpg mouse) was described with low levels of LH and FSH, sexual immaturity, and infertility (6). The hypogonadism was due to a deletional mutation encompassing the distal half of the gene encoding GnRH and the GnRH-associated peptide (GAP) (7); mice homozygous for this mutation had arrested germ cell development but reproductive function could be restored with gene therapy (8). However, despite the obvious candidacy of GnRH as a cause of hereditary hypogonadism in the human, no mutations within the GnRH gene have yet been discovered in this population (9–11). Therefore, spontaneously occurring mutations in humans and animals as well as targeted disruption of selected genes must be evaluated in a complementary fashion. Examples of some of these mutations, their genotype/phenotype correlations, and the reproductive paradoxes they present, are discussed below.