NOVEL INSIGHTS INTO GENETIC AND ENVIRONMENTAL DETERMINANTS SHAPING GNRH NEURON BIOLOGY AND RELATED REPRODUCTIVE DISORDERS
type: CreativeWork
description: The hypothalamic-pituitary-gonadal (HPG) axis is a conserved neuroendocrine system essential for reproductive function in vertebrates. Central to this axis is the secretion of gonadotropin-releasing hormone (GnRH), a neuropeptide that stimulates the release of gonadotropins from the pituitary, driving gametogenesis and sex steroid production. GnRH-secreting neurons originate from the olfactory placode during embryogenesis and migrate into the forebrain to reach the hypothalamus, where they integrate into the reproductive axis. This migratory journey depends on tightly regulated molecular mechanisms involving transcription factors, guidance cues, adhesion molecules, and extracellular matrix components. Disruption of any of these pathways can impair GnRH neuron development and function, leading to isolated GnRH deficiency (IGD), a rare congenital disorder characterized by absent or delayed puberty and infertility. While once considered a monogenic condition, IGD is now recognized as genetically heterogeneous, with oligogenic inheritance frequently observed. Although over 44 genes have been implicated in IGD, only about 50% of cases are genetically explained, highlighting the likely involvement of additional unidentified genetic contributors and environmental factors. A major focus of this thesis is CHARGE syndrome (CS), a multisystem disorder clinically overlapping with IGD and primarily caused by heterozygous loss-of-function variants in the CHD7 gene, encoding a chromatin remodeler essential for neural crest and olfactory system development. CS is characterized by a range of anomalies, including craniofacial malformations, sensory deficits, and hypogonadotropic hypogonadism. Despite CHD7 mutations being the major cause, the broad clinical variability observed among patients suggests the involvement of genetic modifiers. Recent evidence highlights the Semaphorin (SEMA) signalling pathway as a candidate downstream effector of CHD7. To investigate this hypothesis and e…
abstract: The hypothalamic-pituitary-gonadal (HPG) axis is a conserved neuroendocrine system essential for reproductive function in vertebrates. Central to this axis is the secretion of gonadotropin-releasing hormone (GnRH), a neuropeptide that stimulates the release of gonadotropins from the pituitary, driving gametogenesis and sex steroid production. GnRH-secreting neurons originate from the olfactory placode during embryogenesis and migrate into the forebrain to reach the hypothalamus, where they integrate into the reproductive axis. This migratory journey depends on tightly regulated molecular mechanisms involving transcription factors, guidance cues, adhesion molecules, and extracellular matrix components. Disruption of any of these pathways can impair GnRH neuron development and function, leading to isolated GnRH deficiency (IGD), a rare congenital disorder characterized by absent or delayed puberty and infertility. While once considered a monogenic condition, IGD is now recognized as genetically heterogeneous, with oligogenic inheritance frequently observed. Although over 44 genes have been implicated in IGD, only about 50% of cases are genetically explained, highlighting the likely involvement of additional unidentified genetic contributors and environmental factors. A major focus of this thesis is CHARGE syndrome (CS), a multisystem disorder clinically overlapping with IGD and primarily caused by heterozygous loss-of-function variants in the CHD7 gene, encoding a chromatin remodeler essential for neural crest and olfactory system development. CS is characterized by a range of anomalies, including craniofacial malformations, sensory deficits, and hypogonadotropic hypogonadism. Despite CHD7 mutations being the major cause, the broad clinical variability observed among patients suggests the involvement of genetic modifiers. Recent evidence highlights the Semaphorin (SEMA) signalling pathway as a candidate downstream effector of CHD7. To investigate this hypothesis and e…
author: AMORUSO, FEDERICA
language: eng
keywords: GnRH, HPG axis, reproductive disorders, Isolated GnRH deficiency, CHARGE Syndrom, CHD7, Semaphorin, HS6ST, Nanoplastics, Settore BIOS-10/A - Biologia cellulare e applicata
date published: 2025-12-15
date modified: 2026-07-27T20:18:58Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

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property ID: Handle
value: https://hdl.handle.net/2434/1199619