A Low-Molecular-Weight Agonist of the Luteinizing Hormone Receptor Stimulatesthe Adenylyl Cyclase in Testicular Membranes and Steroidogenesis in the Testes of Rats with Type 1 Diabetes
A characteristic feature of type 1 diabetes mellitus (DM1) in humans and experimental animals is an androgen deficiency, which is usually compensated by using the gonadotropin preparations with the activity of the agonists of the luteinizing hormone (LH) receptor, including human chorionic gonadotropin (hCG). However, the use of gonadotropins is associated with a number of undesirable effects, and in the conditions of DM1 their steroidogenic effect is weakened. An alternative to gonadotropins can be low-molecular-weight thienopyrimidine-based agonists of the LH/hCG receptor, which bind to an allosteric site located within the transmembrane channel of this receptor. The aim of this work was to study the stimulating effect of hCG and the thienopyrimidine derivative TP03 developed by us earlier on the adenylyl cyclase (AC) in the testicular membranes of male rats with moderate-severe streptozotocin DM1, as well as to investigate the effects of hCG and TP03 on the plasma testosterone levels and the gene expression of steroidogenic proteins in the testes of diabetic rats in the case of a single or five-day administration of these drugs. In DM1, the AC-stimulating effects of hCG, TP03, and guanine nucleotides were decreased in the testicular membranes, and the EC<sub>50</sub> values for the effects of hCG and TP03 were increased; this indicates an impaired sensitivity of the LH/hCG receptors to hCG and TP03 in DM1 and can be associated with a decrease in functional activity of heterotrimeric G-proteins. In diabetic rats with reduced basal testosterone levels, the steroidogenic effects of the single-dose hCG and TP03 were significantly reduced, and the effect of hCG was significantly higher than that of TP03. In the case of a five-day treatment of diabetic rats with hCG and TP03, only the steroidogenic effect of gonadotropin was reduced, while the corresponding effect of TP03 did not change and was comparable to the hCG effect. With a five-day administration, the regulatory effects of TP03 on the expression of steroidogenic proteins in the testes of control and diabetic rats were similar. Compound TP03, in contrast to hCG, in the control and diabetic groups did not reduce the expression of the Lhr gene, which encodes LH/hCG receptor, thus preventing a decrease in the sensitivity of the testes to gonadotropins in DM1. Thus, a low-molecular-weight agonist TP03 is an effective stimulator of testosterone synthesis in severe DM1 with androgen deficiency characteristic of DM1.