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

Int J Mol Sci. 2021 Dec 24;23(1):198. doi: 10.3390/ijms23010198.

Abstract

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-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]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.

Keywords: allosteric agonist; chorionic gonadotropin; luteinizing hormone receptor; male reproduction; metformin; spermatogenesis; testicular steroidogenesis; type 2 diabetes mellitus.

MeSH terms

  • Adenylate Kinase / metabolism
  • Allosteric Regulation / drug effects
  • Animals
  • Area Under Curve
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Estradiol / blood
  • Gene Expression Regulation / drug effects
  • Glycated Hemoglobin / metabolism
  • Insulin / blood
  • Insulin Resistance
  • Leptin / blood
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, LH / agonists*
  • Seminiferous Tubules / drug effects
  • Seminiferous Tubules / metabolism
  • Spermatogenesis* / drug effects
  • Steroids / biosynthesis*
  • Testosterone / blood

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Insulin
  • Leptin
  • Receptors, LH
  • Steroids
  • Testosterone
  • Estradiol
  • Metformin
  • Adenylate Kinase