Vitamin D Adequacy Conditions the Prolactin-Suppressive Effect of Metformin in Men Receiving Prolactin-Elevating Medications

Background/Objectives: Metformin has been proposed as a potential treatment for hyperprolactinemia irrespective of etiology. Previous studies suggest that vitamin D deficiency attenuates the prolactin-lowering effect of metformin in women. This study examined whether vitamin D status modifies the effects of this agent on prolactin and other anterior pituitary hormones in men with iatrogenic hyperprolactinemia. Methods: Seventy-five adult men with antipsychotic-induced hyperprolactinemia and type 2 diabetes or prediabetes were enrolled. Participants were assigned to three equal groups based on vitamin D status and supplementation: vitamin D-naive men with sufficient levels (group 1), vitamin D-naive men with deficiency (group 2), and men with sufficient vitamin D levels receiving oral supplementation for at least six months (group 3). All participants received metformin (3 g/day) for six months. Plasma 25-hydroxyvitamin D, markers of glucose metabolism, total and monomeric prolactin, TSH, gonadotropins, ACTH, testosterone, and IGF-1 were measured at baseline and after treatment. Results: Baseline characteristics were comparable among groups except for 25-hydroxyvitamin D levels. Seventy participants completed the study. Metformin improved glycemic control and insulin sensitivity in all groups, with greater effects in men with sufficient vitamin D status. Reductions in total and monomeric prolactin were observed only in groups 1 and 3 and were associated with baseline prolactin concentrations and pretreatment 25-hydroxyvitamin D levels. These changes were accompanied by modest increases in LH and testosterone, and improvements in sexual functioning. Vitamin D levels and other hormonal parameters remained unchanged. The magnitude of the metformin effect did not differ between groups 1 and 3. Conclusions: Adequate vitamin D status is necessary for metformin to reduce prolactin levels in men with iatrogenic hyperprolactinemia.