Steroidogenic Effect of Luteinizing Hormone Receptor Agonists and Metformin in Male Rats with Androgenic Deficiency Caused by Diet-Induced Obesity

Abstract

In obese men, along with metabolic disorders and insulin resistance, testosterone levels are decreased and reproductive system functions are impaired. One of the ways to correct them may be the use of agonists of luteinizing hormone receptor (LHR) and antidiabetic drugs, but the mechanisms of their effect on the hypothalamic-pituitary-gonadal axis have not been studied enough. The aim of the work was to study the effects of long-term MF therapy (5 weeks, 120 mg/kg) and five-day treatment with LHR agonists, such as human chorionic gonadotropin (hCG, 20 IU/rat/day, s.c.) and allosteric agonist TP03 (15 mg/kg/day, i.p.), on the blood testosterone levels and the expression of testicular and pituitary genes in male rats with long-term diet-induced obesity (DIO). TP03 moderately stimulated testosterone production in male rats with DIO without having an inhibitory effect on LHR expression in the testes and only weakly reducing the expression of the LH β-subunit gene in the pituitary gland. After a single administration into DIO-rats, the steroidogenic effect of TP03 was comparable to that in the control group, but after a five-day administration, it was significantly inferior to it. In DIO-rats, the steroidogenic effect of hCG after a single administration was lower than that in the control, but comparable to that after a five-day administration of hCG, and significantly exceeded the corresponding effects of TP03. Unlike TP03, hCG significantly reduced LHR expression in the testes and more pronouncedly inhibited LH expression in the pituitary gland. MF treatment restored the androgenic status without significantly affecting the expression of steroidogenesis genes in the testes. There was no increase in the steroidogenic effects of both LHR agonists in the MF-treated groups. The results obtained indicate the prospects for the use of TP03 and hCG to stimulate testicular steroidogenesis and the effectiveness of MF therapy to normalize testosterone production in DIO, which can be used to correct reproductive disorders in obesity. At the same time, in DIO, the combined use of MF and LHR agonists seems to be inappropriate.