The Impact of Exogenous Vitamin D on Pituitary Effects of Metformin in Postmenopausal Women with Subclinical Hypothyroidism and Normal Vitamin D Status: A Pilot Study

<i>Background/Objectives</i>: Low vitamin D status was found to attenuate the impact of metformin on circulating levels of anterior pituitary hormones, but this inhibitory effect was absent in vitamin D-repleted subjects. No previous study investigated the interaction between metformin and exogenous vitamin D at the pituitary levels in individuals with normal vitamin D status. <i>Methods</i>: Our pilot, single-center, prospective, matched-cohort study enrolled 59 postmenopausal women with subclinical hypothyroidism and 25-hydroxyvitamin D levels in the range between 75 and 150 nmol/L. For the following six months, all the participants were treated with either metformin/vitamin D combination therapy (group 1, <i>n</i> = 27) or metformin alone (group 2, <i>n</i> = 32). The outcomes of interest included 25-hydroxyvitamin D, fasting glucose, HOMA-IR, HbA_1c, TSH, FSH, LH, prolactin, ACTH, free thyroid hormones, estradiol and IGF-1. A parallel study investigated the impact of vitamin D monotherapy on the outcome measures in insulin-resistant women meeting the remaining inclusion criteria. <i>Results</i>: No differences in baseline biomarker values were observed between groups 1 and 2. Ninety-three percent of the patients completed the study. The increase in 25-hydroxyvitamin D levels was observed exclusively in group 1. Although glucose homeostasis markers and post-treatment levels of TSH and FSH were lower at the end of the study than at baseline in both groups, the effect of treatment was more pronounced in group 1 than in group 2. Metformin/vitamin D combination therapy, but not metformin alone, reduced LH and prolactin levels. In both groups, the TSH- and gonadotropin-lowering effects of metformin correlated with baseline levels of these pituitary hormones. Levels of ACTH, free thyroxine, free triiodothyronine, estradiol and IGF-1 remained stable throughout the study. The effects of vitamin D monotherapy were confined to an increase in plasma 25-hydroxyvitamin D concentrations and a modest enhancement in insulin sensitivity. <i>Conclusions</i>: Exogenous vitamin D potentiates the pituitary effects of metformin in postmenopausal women with subclinical hypothyroidism.