(736) Role of Testosterone Decline in Determining the Symptoms of Functional Hypogonadism Related to Obesity

Introduction Late-onset male hypogonadism (LOH) is a syndrome characterized by reduced testosterone levels associated with physical, psychological, and sexual symptoms. Of particular interest are the forms of functional hypogonadism, which are frequent in obese men and in those with chronic comorbidities. In such cases, it remains unclear whether the reduction in testosterone is the cause of the symptoms or rather an epiphenomenon of an overall compromised health status. Objective To assess whether characterizing subjects with secondary hypogonadism based on FSH values can identify a distinctive phenotype of male hypogonadism.To assess the relative contribution of reduced testosterone levels and obesity to the development of typical LOH symptoms in a population of middle-aged or elderly European men without organic causes of hypogonadism, in whom obesity was a predisposing factor for testosterone reduction. Methods A total of 2,122 subjects from the EMAS study (aged 40–79 years) with baseline and follow-up data on total testosterone (TT), free testosterone (FT), and BMI were included. Sexual, physical, and psychological function was evaluated using validated questionnaires (SFQ, SF-36, BDI, PASE) and objective tests (PPT, DSST, Camden Memory Test). A mediation analysis was performed to assess the role of TT (<10.5 and <8 nmol/L) and FT (<220 and <170 pmol/L) as mediators between obesity and the onset/worsening of symptoms, and vice versa. Results Men with “pure” secondary hypogonadism showed more sexual symptoms, a higher prevalence of metabolic syndrome [B: 2.62 (2.20; 3.12)], and reduced penile blood flow. Obesity was a strong predictor of the onset of hypogonadism and was also associated with the appearance or worsening of physical symptoms (inability to bend, walk >1 km, or perform vigorous activities), reduced mental energy, erectile dysfunction, and decreased morning erections. However, only sexual symptoms were partially mediated by the decline in TT (with OR values between 1.04 and 1.07), whereas physical and psychological symptoms were more directly related to obesity, without significant mediation by androgen deficiency. Only the lower FT threshold (170 pmol/L) was found to mediate erectile dysfunction [OR: 1.05 (1.01–1.09)] and some physical symptoms [inability to bend OR: 1.07 (1.00–1.14); inability to perform vigorous activities OR: 1.04 (1.00–1.07)]. When the model was inverted, it was observed that the effects of TT decline on physical symptoms-particularly the inability to perform vigorous activities (OR: 1.09 for TT <10.5 nmol/L and OR: 1.15 for TT <8 nmol/L)-and of FT decline (for the three physical symptoms, ORs between 1.09 and 1.16) were mediated by obesity. Conversely, sexual symptoms were directly affected by the reduction in testosterone, only partially mediated by obesity. Conclusions Among men with hypogonadism, FSH may help identify a group at higher metabolic and cardiovascular risk, and characterized by greater psychopathological symptoms.Sexual symptoms are confirmed as the most specifically associated with hypogonadism, whereas physical and psychological symptoms appear less distinctive. A TT threshold of 10.5 nmol/L correctly identifies hypogonadism-related symptoms associated with obesity, while for FT, a threshold of 170 pmol/L appears more appropriate. Disclosure No