Central Hypogonadotropic Hypogonadism: Genetic Complexity of a Complex Disease

Abstract

Central hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians.

Changes in porcine cauda epididymal fluid proteome by disrupting the HPT axis: Unveiling potential mechanisms of male infertility

“…Our findings clearly demonstrate the impact of anti‐GnRH immunization in CEF proteins involved in the UPS in the swine. Thus, one may consider that man presenting secondary hypogonadism (Basaria, 2014; Giannetta, Gianfrilli, Barbagallo, Isidori, & Lenzi, 2012; Marino, Moriondo, Vighi, Pignatti, & Simoni, 2014) could also present an impairment of these events, leading to poor semen quality and infertility.…”

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

“…This combination of phenotypes is explained by the common embryonic origins and developmental pathways of GnRH and olfactory neurons. More than 20 genes are known to cause CHH [Marino et al, 2014].…”

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…CHH is characterized by inappropriately low serum concentrations of the gonadotropins, LH and FSH, in the presence of low circulating concentrations of sex steroids that lead to the absence of puberty, infertility and consequent reproductive failure [2]. CHH incidence is uncertain and can vary broadly from 1:4000 [38] to 1:30,000 [39] in the male population, with a prevalence of around 4 to 1 compared to the female population [2,40,41]. Most patients are diagnosed late in adolescence or adulthood as they display arrested or absent puberty, clinical evidence of hypogonadism and incomplete sexual maturation [2].…”

“…Clinically, CHH can be solely present with reproductive symptoms (normosmic CHH) or in association with olfaction defects (hyposmia/anosmia), being referred to as Kallmann syndrome (KS) and representing 50% of overall CHH cases [2,38]. KS patients may also exhibit non-reproductive and non-olfactory features, such as bimanual synkinesis, abnormal eye movements, hearing impairment, agenesis of the corpus callosum, unilateral or bilateral renal agenesis, cleft lip or palate, and hypodontia [50].…”