Abstract
Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or “functional” forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH.
Highlights
Isolated hypogonadotropic hypogonadism (IHH) is currently known as a rare congenital disorder which has a male predominance of 3–5 to 1 [1,2,3,4]
Among AO-IHH patients, including patients with milder forms of hypogonadism, we found a higher prevalence of obesity compared to PPO-IHH patients or general population
Step was the comparison of the prevalence of rare variants between patients with severe hormone deficiencies, patients with mild/moderate hormone deficiency and in controls; we compared the prevalence of these mutations in obese HH patients with such prevalence in non-obese hypogonadotropic subjects and controls
Summary
Isolated hypogonadotropic hypogonadism (IHH) is currently known as a rare congenital disorder which has a male predominance of 3–5 to 1 [1,2,3,4]. It consists of an isolated gonadotropin-releasing hormone (GnRH) secretion, regulation, or action defect in the presence of an otherwise normal hypothalamic–pituitary region, which leads to a delayed or absent puberty and infertility [2,5]. It is recognized that a portion of congenital IHH can be explained by an oligogenic origin [8], which can potentially account for the variable penetrance and expressivity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
