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.

Andrey A Bakhtyukov,Liubov V Bayunova,Irina V Romanova,Alexander O Shpakov,Anna M Stepochkina,Irina O Zakharova,Kira V Derkach,Viktor N Sorokoumov,Irina Yu Morina

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.

Highlights

We have shown for the first time that in type 2 diabetes mellitus (T2DM) rats treated with MF, the steroidogenic effects of single-dose orthosteric and allosteric luteinizing hormone (LH)/human chorionic gonadotropin (hCG)-R-agonists, which differ in their mechanisms of receptor activation, are enhanced
We have shown that a five-week administration of MF at a dose of 120 mg/kg/day improves testicular steroidogenesis, restores spermatogenesis, and normalizes seminiferous tubule morphology in male rats with high-fat diet (HFD)/STZ-induced T2DM
The improving effect of MF therapy on the steroidogenic activity of hCG and TP3 can be used in clinical practice to enhance the response of the testes and ovaries to single-dose treatment with the orthosteric and allosteric LH/hCG receptor (LH/hCGR)-agonists

Summary

Introduction

There is numerous evidence that MF improves the functions of the impaired endocrine system, including the restoration of hypothalamic-pituitary-gonadal (HPG) axis, both in men and women [5,6,7,8,9] This is due to both the normalization of hypothalamic regulation of the endocrine system, since the hypothalamus is one of the targets of MF, which penetrates the blood-brain barrier [10,11], and the beneficial effect of MF therapy on metabolism and hormonal regulation at the periphery, including the testes and ovaries [12,13,14,15,16,17]. In male diabetic patients and in animals with experimental models of diabetes, long-term MF therapy improves the spermatogenesis, increasing the fertilizing ability of sperm [7,8,9,18,19]

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