The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.198
• Main Authors: Bakhtyukov, Andrey A, Derkach, Kira V, Sorokoumov, Viktor N, Stepochkina, Anna M, Romanova, Irina V, Morina, Irina Yu, Zakharova, Irina O, Bayunova, Liubov V, Shpakov, Alexander O
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Adenylate Kinase - metabolism; Agonists; allosteric agonist; Allosteric properties; Allosteric Regulation - drug effects; Androgens; Animals; Antidiabetics; Area Under Curve; Aromatase; Blood Glucose - metabolism; Body Weight - drug effects; Chorionic gonadotropin; Cytochrome; Dehydrogenases; Design of experiments; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Disease Models, Animal; Drug Therapy, Combination; Endocrine system; Estradiol - blood; Gene expression; Gene Expression Regulation - drug effects; Glucose; Glycated Hemoglobin - metabolism; Gonadotropins; Insulin - blood; Insulin Resistance; Kinases; Leptin - blood; Lipids; Luteinizing hormone; luteinizing hormone receptor; Male; male reproduction; Metabolism; Metformin; Metformin - pharmacology; Metformin - therapeutic use; Pathology; Phosphorylation - drug effects; Pituitary (anterior); Proteins; Rats; Rats, Wistar; Receptors, LH - agonists; Regulation; Reproductive technologies; Rodents; Seminiferous Tubules - drug effects; Seminiferous Tubules - metabolism; Sex hormones; Sperm; Spermatogenesis; Spermatogenesis - drug effects; Steroidogenesis; Steroids - biosynthesis; Testes; Testosterone; Testosterone - blood; type 2 diabetes mellitus
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010198

In men with type 2 diabetes mellitus (T2DM), steroidogenesis and spermatogenesis are impaired. Metformin and the agonists of luteinizing hormone/human chorionic gonadotropin(hCG)-receptor (LH/hCG-R) (hCG, low-molecular-weight allosteric LH/hCG-R-agonists) can be used to restore them. The aim was to study effectiveness of separate and combined administration of metformin, hCG and 5-amino- -butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3- ]pyrimidine-6-carboxamide (TP3) on steroidogenesis and spermatogenesis in male rats with T2DM. hCG (15 IU/rat/day) and TP3 (15 mg/kg/day) were injected in the last five days of five-week metformin treatment (120 mg/kg/day). Metformin improved testicular steroidogenesis and spermatogenesis and restored LH/hCG-R-expression. Compared to control, in T2DM, hCG stimulated steroidogenesis and StAR-gene expression less effectively and, after five-day administration, reduced LH/hCG-R-expression, while TP3 effects changed weaker. In co-administration of metformin and LH/hCG-R-agonists, on the first day, stimulating effects of LH/hCG-R-agonists on testosterone levels and hCG-stimulated expression of StAR- and CYP17A1-genes were increased, but on the 3-5th day, they disappeared. This was due to reduced LH/hCG-R-gene expression and increased aromatase-catalyzed estradiol production. With co-administration, LH/hCG-R-agonists did not contribute to improving spermatogenesis, induced by metformin. Thus, in T2DM, metformin and LH/hCG-R-agonists restore steroidogenesis and spermatogenesis, with metformin being more effective in restoring spermatogenesis, and their co-administration improves LH/hCG-R-agonist-stimulating testicular steroidogenesis in acute but not chronic administration.