Endocrine Abstracts

Introduction: Isolated hypogonadotropic hypogonadism (IHH) often occurs in the pre-pubertal period but it can also manifest in post-puberal age. Recent position statements and guidelines differentiate between a ‘true’ hypogonadotropic hypogonadism, intended as congenital or acquired organic defect (characterized by frankly pathological total Testoterone values, TTe <3.5 nmol/l), and a ‘false’ or functional hypogonadism, associated to older age and comorbidity and characterized by a less severe reduction of TTe levels. However, there is no clear evidence that these two nosological entities are distinct from a pathogenetic point of view. We decided to investigate genetic predisposition in IHH individuals comparing them on the basis of disease onset and degree of hypogonadism.

Patients and methods: We evaluated 115 male patients affected with IHH, both normal and hypo/anosmic. Each patient underwent a genetic investigation, using Next Generation Sequencing (NGS), to search for rare, non intronic, nonsynonymous allelic variants in the candidate genes known for IHH. We performed the same analysis in 79 controls. We compared the prevalence of mutations between patients with severe hormone deficiency (sIHH: TTe ≤3.5 nM), patients with mild/moderate hormone deficiency (mIHH with TTe 3.5–11.0 nM but with low calculated free Te) and in controls with Te >11.0 nM).

Results: The genetic analysis showed a statistically significant difference between the prevalence of mutations in the causal genes of IHH affecting both patients with severe hypotestosteronemia and mild hormone deficiency when compared to controls (P <0.001 and P <0.035 respectively); on the contrary there was no statistically significant difference comparing the two groups of cases. BMI was similar in the groups of IHH patients (sIHH: 27.8 Kg/m² vs mIHH 24.75 Kg/m²). We found no statistically significant difference in the prevalence of oligogenic defects in the two groups of cases (P=0.75).

Conclusions: These data suggest a similar genetic predisposition in both severe and mild phenotypes of IHH, suggesting that IHH of genetic origin is associated with a wide spectrum of GnRH disfunctions.