The Effect of Metformin on Pituitary Function in Postmenopausal Women with Subclinical Hypothyroidism and Macroprolactinemia: A Single-Center Prospective Case–Control Study

<b>Background/Objectives:</b> Metformin inhibits secretory function of overactive thyrotrophs, gonadotrophs, and lactotrophs. The clinical significance of an excess of high-molecular-weight prolactin (macroprolactinemia) remains unclear. The aim of the current study was to investigate for the first time whether macroprolactinemia determines the pituitary effects of this drug. <b>Methods:</b> This single-center prospective case-control study included two groups of postmenopausal women with subclinical hypothyroidism, who were matched for age, insulin sensitivity, and plasma concentrations of gonadotropins and TSH. Group A enrolled women with normal prolactin status, while group B included women with macroprolactinemia. Owing to concomitant type 2 diabetes or prediabetes, all the participants received metformin for six months. The outcomes of interest included glucose homeostasis markers (fasting glucose, glycated hemoglobin, and HOMA-IR), plasma prolactin (total and monomeric), macroprolactin, other pituitary hormones (FSH, LH, TSH, and ACTH), and peripheral hormones (estradiol, free thyroid hormones, and IGF-1). <b>Results:</b> Before metformin treatment, the study groups differed only in concentrations of total prolactin and macroprolactin. Metformin decreased FSH and TSH and tended to decrease LH only in group A, and the strength of this effect showed correlations with the baseline levels of these hormones, the degree of improvement in insulin sensitivity, and the macroprolactin content (only in group B). The decrease in fasting glucose, glycated hemoglobin, and HOMA-IR was more pronounced in group A than group B. There were no differences between the pretreatment and posttreatment values of total prolactin, monomeric prolactin, macroprolactin, ACTH, estradiol, free thyroid hormones, and IGF-1. <b>Conclusions:</b> The obtained results suggest that macroprolactinemia may counteract the pituitary effects of metformin.