Vitamin D Status Determines Cardiometabolic Effects of Testosterone Replacement Therapy in Men with Late-Onset Hypogonadism

<b><i>Background/Objectives</i>:</b> Low testosterone levels and low vitamin D status are associated with increased cardiometabolic risk. The purpose of this study was to investigate whether vitamin D status determines the cardiometabolic effects of testosterone replacement therapy. <b><i>Methods</i>:</b> The study population consisted of three groups of men with late-onset hypogonadism: vitamin D-naive individuals with 25-hydroxyvitamin D levels between 20 and 30 ng/mL (group I), males with 25-hydroxyvitamin D levels between 30 and 60 ng/mL receiving vitamin D supplementation because of previous low vitamin D status (group II), and vitamin D-naïve subjects with 25-hydroxyvitamin D levels between 30 and 60 ng/mL (group III). Circulating levels of total testosterone, 25-hydroxyvitamin D, glucose, insulin, lipids, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen, and urinary albumin-to-creatinine ratio (UACR) were assessed before and six months after intramuscular testosterone administration (250 mg every three weeks). <b><i>Results</i>:</b> Group I differed from the remaining groups in baseline values of 25-hydroxyvitamin D, hsCRP, homocysteine, fibrinogen, UACR, and the Framingham Risk Score. In all three groups, testosterone injections increased plasma testosterone levels and had a neutral effect on 25-hydroxyvitamin D concentration. In groups II and III, the drug improved insulin sensitivity and reduced LDL cholesterol, uric acid, hsCRP, homocysteine, fibrinogen, and UACR. In group I, the impact of testosterone was limited to a small decrease in HDL cholesterol and hsCRP. Only in groups II and III did testosterone reduce the Framingham Risk Score. There were no differences in the strength of testosterone action between both groups. In groups II and III, the replacement-induced changes in insulin sensitivity, LDL cholesterol, uric acid, hsCRP, homocysteine, fibrinogen, UACR, and the Framingham Risk Score positively correlated with 25-hydroxyvitamin D concentration. <b><i>Conclusions</i>:</b> The study results suggest that the cardiometabolic effects of exogenous testosterone in men with testosterone deficiency may be determined by vitamin D status.