Effects of metformin and lutheinizing hormone receptor agonists on steroidogenesis and spermatogenesis in rats with type 2 diabetes with their separate and combined administration

Background: Improving the male reproductive functions in type 2 diabetes mellitus (T2DM) is one of the urgent problems of endocrinology. For this, along with the drugs that enhance testosterone synthesis, such as human chorionic gonadotropin (hCG) and low-molecular-weight allosteric luteinizing hormone receptor (LHR)-agonists, the drugs that normalize glucose homeostasis and insulin sensitivity, such as metformin, can be used. Objective: To study the effectiveness of separate and combined administration of metformin, hCG and allosteric LHR-agonist 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP03) developed by us on steroidogenesis and spermatogenesis in male T2DM rats. Methods: T2DM was induced by high-fat diet (15 weeks) and streptozotocin (25 mg/kg). Metformin treatment (120 mg/kg/day) of diabetic rats was carried out during 4 weeks, while treatment with hCG (20 IU/rat/day) and TP03 (15 mg/kg/day) was performed in the last five days of experiment. Results: In diabetic rats, metformin normalized spermatogenesis and partially restored testicular steroidogenesis. hCG and TP03 significantly increased the testosterone production and partially restored the number of epididymal spermatozoa and their progressive movement. When metformin and LHR-agonists used together, on the first day of treatment with LHR-agonists metformin significantly enhanced their steroidogenic effects, but on the 3-5th day, its potentiating effect disappeared. In metformin-treated rats, LHR-agonists made no additional contribution to improving spermatogenesis, which was fully restored by metformin. Conclusion: In T2DM rats, metformin therapy and LHR-agonists improve steroidogenesis and spermatogenesis, with metformin being more effective in restoring spermatogenesis. Their combined use leads to a significant increase in the steroidogenic effect of LHR-agonists in acute but not chronic administration.