The Effect of Metformin Therapy on Luteinizing Hormone Receptor Agonist-Mediated Stimulation of Testosterone Production and Spermatogenesis in Diabetic Rats

A. A. Bakhtyukov, K. V. Derkach, A. M. Stepochkina, V. N. Sorokoumov, L. V. Bayunova, I. A. Lebedev, A. O. Shpakov

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Abstract

The functional restoration of the male reproductive system in type 2 diabetes mellitus (DM2) is one of the urgent global challenges in modern endocrinology. This problem can be solved through the application of both the drugs that improve glucose homeostasis and insulin sensitivity, primarily metformin, and the activators of luteinizing hormone receptor (LHR), such as human chorionic gonadotropin (hCG) and low-molecular-weight allosteric LHR agonists. The aim of the work was to study the effect of metformin therapy (4 weeks, 120 mg/kg/day) on steroidogenesis- and spermatogenesis-stimulating effects induced by the 5-day administration of 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP03), an allosteric LHR agonist (15 mg/kg/day), and hCG (20 IU/rat/day) to male Wistar rats with DM2. The DM2 was induced by a high-fat diet and a low-dose streptozotocin (25 mg/kg). Metformin therapy partially restored testosterone levels and normalized spermatogenesis in DM2 rats. On the first day, metformin treatment enhanced the steroidogenic effects of TP03 and hCG, however, in the following days its potentiating effect was not detected. After five days of treatment of diabetic rats with TP03 and hCG, epididymal sperm count was restored, including the spermatozoa with progressive motility, and the percentage of abnormal sperm was decreased. Spermatogenesis indices when treating with metformin or LHR agonists separately were comparable to those resulted from their co-administration. Thus, metformin therapy enhances TP03- and hCG-induced testosterone production on the first day of treatment with these drugs, however, later on, steroidogenic and spermatogenic effects of LHR agonists in the groups of diabetic rats treated and untreated with metformin did not differ significantly.

Original languageEnglish
Pages (from-to)1382-1393
Number of pages12
JournalJournal of Evolutionary Biochemistry and Physiology
Volume57
Issue number6
DOIs
StatePublished - 1 Nov 2021

Keywords

  • steroidogenesis
  • spermatogenesis
  • type 2 diabetes mellitus
  • metformin
  • chorionic gonadotropin
  • thienopyrimidine
  • testosterone
  • MOLECULAR-WEIGHT AGONIST
  • MALE REPRODUCTIVE FUNCTION
  • LH RECEPTOR
  • STEROIDOGENESIS
  • EXPRESSION
  • MELLITUS
  • STREPTOZOTOCIN
  • IMPAIRMENT
  • LEPTIN

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