MON-LB60 Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Prospective Study

Introduction: Prolactinomas are the most frequent pituitary-secreting tumors. Medical therapy with cabergoline (CAB), a dopamine agonist (DA), is the first line treatment, but 10% of prolactinomas are resistant to CAB. Recently, in vitro studies have shown anti-tumoral activity of metformin and other biguanids in human prolactinomas(1), which prompted us to investigate that possibility in vivo. Aim: To evaluate the effect of metformin (MET) on Prolactin (PRL) secretion in patients with CAB resistant prolactinomas. Design and Setting: Prospective interventional study in a single referral center. Subjects: Ten patients (7 M; mean age: 44 ± 12y) with CAB resistant (PRL: 148 ± 125ng/ml; range: 38 - 386) prolactinomas (all macroadenomas) and metabolic syndrome on maximally tolerated CAB doses (4.3 ± 1.2 mg/week; range: 2.0-7.0) for ≥ 6 months (45 ± 39mo; range: 6-120). Intervention: Oral extended release metformin (p.o.) was prescribed according to patient’s tolerance (mean dose: 1.3 ± 0.4 g; range: 1.0-2.0). Main Outcome Measurements: Serum PRL (Elecsys, Roche, Indianapolis, USA), body weight (BW), fasting glycemia (FG) and HbA1C were evaluated before and at two time points during metformin treatment (30-60 and 120-180 days). Results: BW, FG, and/or HbA1C reductions were observed in 9/10 patients and mean FG decreased significantly (P=0.04). No significant changes were observed in serum PRL levels during metformin treatment [134 ± 124 ng/ml vs 138 ± 132 ng/ml vs 144 ± 129 ng/ml, before, at 30-60 days and at 120-180 days, respectively (P=0.499, mixed-effects analysis with the Geisser-Greenhouse correction)]. Individually, two patients exhibited a ≥ 50% decrease in PRL levels at a single timepoint (one at 30-60 days, with a further increase at 120-180 days and the other at 120-180 days). Conclusion: Metformin, at usual doses, did not inhibit prolactin secretion in patients with cabergoline-resistant prolactinomas. The discrepancy between our results and in vitro studies is not clear, but may be related to the much higher concentrations of metformin used in vitro(1) as compared to the serum concentrations observed in patients during metformin treatment(2). References: (1)Gao J et al. Metformin inhibits growth and prolactin secretion of pituitary prolactinoma cells and xenografts. J Cell Mol Med. 2018 22:6368-79; (2) Frid A et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 2010 33:1291-3.