Background <p>Subnormal prolactin concentrations were found to be associated with increased risk of metabolic complications. Thus, many patients with prolactin deficiency may be candidates for treatment with insulin-sensitizing drugs. The aim of this pilot prospective cohort study was to investigate metformin action on cardiometabolic risk factors in women with iatrogenic hypoprolactinemia.</p> Methods <p>The study included three groups of reproductive-age women (18–50 years old) with recently diagnosed prediabetes or type 2 diabetes: 18 women with cabergoline-induced hypoprolactinemia (prolactin below 5 ng/mL) [group A], 19 normoprolactinemic women receiving cabergoline treatment because of previous prolactin excess [group B] and 25 cabergoline-naïve women with prolactin levels within the reference range [group C]. The groups were matched for age, fasting glucose and insulin sensitivity. All participants were treated with metformin for the following six months. The outcomes of interest included: glucose homeostasis markers, prolactin, testosterone, plasma lipids, concentrations of uric acid, high-sensitivity C-reactive protein [hsCRP], homocysteine and fibrinogen, and the urinary albumin-to-creatinine ratio [UACR].</p> Results <p>Fifty-eight patients (17 in group A, 18 in group B and 23 in group C) completed the study. There were no statistical differences between groups A and B in cabergoline dose (1.19 ± 0.52 mg vs. 1.05 ± 0.46&#xa0;mg weekly), cabergoline treatment duration (43 ± 12 vs. 47 ± 14 weeks), and long-term glycemic control (HbA_1c in the range between 6.4 ± 0.5% and 6.6 ± 0.5%). At baseline, uric acid, hsCRP, fibrinogen and UACR were higher in group A than in the remaining two groups, while the opposite relationships were found for prolactin and testosterone. Metformin decreased glycated hemoglobin, fasting glucose, HOMA1-IR and hsCRP in all study groups, but this effect was less pronounced in group A than in groups B and C –6 ± 8% vs. –12 ± 8% and − 11 ± 7% [HbA_1c], –13 ± 10% vs. –25 ± 14% and − 23 ± 15% [glucose], –26 ± 20% vs. –52 ± 25% and − 53 ± 30% [HOMA1-IR], –45 ± 30% vs. –47 ± 35% and − 53 ± 30% [HOMA1-IR]). The decrease in triglycerides, uric acid, homocysteine and UACR was observed only in normoprolactinemic women, not differing between groups B (–13 ± 19% –49 ± 31%), and C (–16 ± 23% –58 ± 26%). In neither group did the drug affect levels of prolactin and total testosterone.</p> Conclusion <p>Coexisting hypoprolactinemia may attenuate cardiometabolic effects of metformin in women.</p>