Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study

Introduction.: Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease. Aim.: To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11 nmol/L or free T at or below 250 pmol/L). Methods.: This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57 ± 8) were randomized (4:1) to receive TU 1,000 mg (every 12 weeks) or placebo (PLB) gel (3-6 g/daily) for 24 months. Main Outcome Measures.: Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP). Results.: At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P <0.001), CIMT (P <0.0001), and hsCRP (P <0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P <0.0001) and 58% (P <0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P <0.0001), visceral fat mass (P <0.0001), and improvement in HOMA-IR without changes in body mass index (BMI). Conclusions.: TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events.