Endocrine Abstracts

Background: In patients affected by type 2 diabetes mellitus (T2DM) a high prevalence of hypogonadotropic hypogonadism (HH) has been reported, even if there is no consensus on its pathogenic mechanisms. In addition to acquired causes, an individual predisposition has also been suggested. The understanding of

Purpose: The aim of this observational study is to assess: (1) the prevalence of hypogonadism in T2DM using the validated criteria from the EMAS study; (2) the correlations of hypogonadotropic hypogonadism (HH) with specific clinical features and predisposing factors; (3) the enrichment in rare pathogenic or likely pathogenic variants in HH diabetic subjects compared to the general population.

Materials and Methods: We consecutively enrolled 167 male patients affected with T2DM from (aged 18 to 85); patients with other known causes of hypogonadism were excluded. In each patient we studied the gonadal function, classifying them according to the EMAS validated criteria according to calculated free testosterone and LH levels. The age, BMI, smoking habit, the severity of diabetic disease, its treatments, complications, as well as leptin levels and HOMA-IR values were recorded, and used in a multivariate logistic analysis. 33 HH patients with T2DM were analyzed using a Target-Next Generation Sequencing (NGS), to search for rare allelic HH variants (RV). To verify the prediction of pathogenicity, we classyfied the RV according to The American College of Medical Genetics and Genomics (ACMG) guidelines. We conducted the same NGS analysis in 79 controls selected from the general population and compared the prevalences using Fisher Exact Test.

Results: The 51% of patients with T2DM showed some degree of hypogonadism: 30% had HH, and 21% showed primary hypogonadism (PH). To logistic multivariate analysis corrected for confounders, HH was correlated with leptin levels (P=0.039) and smoking (pack-years, P=0.027). No significant enrichment in rare CHH variants was found in T2DM patients with HH, as compared to the general population. However, we found 1 likely pathogenic TBX3 variant according to ACMG criteria among the cases.

Discussion: We confirmed a high prevalence of hypogonadism in diabetes in a large cohort of patients. Genetic predisposition does not appear to be a significant cause of HH in T2DM, although some sporadic cases may occur. The presence of a rare, probably pathogenic genetic variant, and the significant and independent association of HH with leptin levels and smoking habits, seem to suggest that different mechanisms could underlie HH in T2DM