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

Baseline cardiometabolic risk markers differed between men with insufficient versus sufficient vitamin D levels prior to testosterone replacement therapy.

• Group I (25-hydroxyvitamin D 20–30 ng/mL, vitamin D-naive) differed from Groups II and III in baseline values of 25-hydroxyvitamin D, hsCRP, homocysteine, fibrinogen, UACR, and the Framingham Risk Score.
• Group II had 25-hydroxyvitamin D levels between 30 and 60 ng/mL and was receiving vitamin D supplementation due to previous low vitamin D status.
• Group III consisted of vitamin D-naive subjects with 25-hydroxyvitamin D levels between 30 and 60 ng/mL.
• No baseline differences in cardiometabolic markers were found between Groups II and III despite differing vitamin D supplementation history.

Testosterone replacement therapy successfully raised plasma testosterone levels in all three groups but had a neutral effect on 25-hydroxyvitamin D concentrations.

• All groups received intramuscular testosterone at 250 mg every three weeks for six months.
• Plasma testosterone levels increased in all three groups following injections.
• 25-hydroxyvitamin D concentrations were not significantly changed by testosterone administration in any group.
• The neutral effect on vitamin D status was consistent across all three groups regardless of baseline vitamin D level.

In men with sufficient vitamin D levels (Groups II and III), testosterone replacement therapy improved multiple cardiometabolic parameters.

• Testosterone injections improved insulin sensitivity and reduced LDL cholesterol, uric acid, hsCRP, homocysteine, fibrinogen, and UACR in both Groups II and III.
• Only in Groups II and III did testosterone reduce the Framingham Risk Score.
• There were no statistically significant differences in the strength of testosterone's cardiometabolic action between Groups II and III.
• These benefits were observed in both supplemented (Group II) and vitamin D-naive (Group III) men who had 25-hydroxyvitamin D levels between 30 and 60 ng/mL.

In men with insufficient vitamin D levels (Group I), testosterone replacement therapy had limited and partially unfavorable cardiometabolic effects.

• In Group I (25-hydroxyvitamin D 20–30 ng/mL), the impact of testosterone was limited to a small decrease in HDL cholesterol and hsCRP.
• Testosterone did not improve insulin sensitivity, LDL cholesterol, uric acid, homocysteine, fibrinogen, or UACR in Group I.
• Testosterone did not reduce the Framingham Risk Score in Group I.
• A decrease in HDL cholesterol is considered an unfavorable cardiometabolic effect, suggesting a potentially adverse lipid profile change in vitamin D-insufficient men.

In Groups II and III, testosterone-induced changes in cardiometabolic markers positively correlated with baseline 25-hydroxyvitamin D concentration.

• Testosterone 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 in Groups II and III.
• These correlations suggest a dose-response relationship between vitamin D status and the magnitude of cardiometabolic benefit from testosterone therapy.
• No such correlations were reported for Group I.
• The correlations were observed across both supplemented and non-supplemented men with sufficient vitamin D levels.

Low testosterone levels and low vitamin D status are independently associated with increased cardiometabolic risk in men.

• Both low testosterone and low vitamin D status are described as associated with increased cardiometabolic risk in the background of the study.
• Late-onset hypogonadism was the inclusion criterion for all study participants.
• The study was designed to investigate whether vitamin D status determines the cardiometabolic effects of testosterone replacement therapy.
• Previous evidence of low vitamin D status was used as the basis for supplementation in Group II participants.