Abstract
Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.
Highlights
Fertility and reproduction of sexually reproducing species strictly depend on a functional hypothalamic–pituitary–gonads (HPG) axis, which ensures gonadal development, puberty onset and reproductive capacity.The HPG axis is a neuroendocrine circuit centrally regulated by hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which, in humans, release the GnRH decapeptide in a pulsatile fashion within the pituitary blood portal system to stimulate gonadotrope cells to secrete gonadotropins (i.e., LH and FSH)
This review provides an up-to-date description of all the genes associated with Congenital Hypogonadotropic Hypogonadism (CHH) by focusing on their biological roles in GnRH neuron system development, uncovered by experimental studies through in vitro and in vivo models
GnRH neurons, despite their key role in the control of the HPG axis, consist of a small number of cells, which are dispersed in a bilateral continuum throughout the hypothalamus, with most of their cell bodies concentrated in the medial preoptic area (MPOA) [4]
Summary
Fertility and reproduction of sexually reproducing species strictly depend on a functional hypothalamic–pituitary–gonads (HPG) axis, which ensures gonadal development, puberty onset and reproductive capacity. Because the neurohormone GnRH is the primary driver of the HPG axis, proper development and function of its producing neurons is required. In this context, several factors finely regulate GnRH neuron physiology by acting at different levels, including GnRH neuron development and differentiation, GnRH synthesis, secretion and action. Defects in either GnRH neuron development or function can lead to a pathological condition known as isolated GnRH deficiency or Congenital Hypogonadotropic Hypogonadism (CHH), characterized by incomplete or absent puberty and infertility [2]. This review provides an up-to-date description of all the genes associated with CHH by focusing on their biological roles in GnRH neuron system development, uncovered by experimental studies through in vitro and in vivo models
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