ВЛИЯНИЕ НИЗКОМОЛЕКУЛЯРНЫХ АЛЛОСТЕРИЧЕСКИХ АГОНИСТОВ РЕЦЕПТОРА ЛЮТЕИНИЗИРУЮЩЕГО ГОРМОНА НА ЕГО ЭКСПРЕССИЮ В СЕМЕННИКАХ САМЦОВ КРЫС

Abstract

Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) regulate testicular steroidogenesis by interacting with the orthosteric site located in the extracellular domain of the LH receptor (LHR). The use of hCG and LH in medicine is fraught with side effects caused by hyperactivation of LH-dependent cascades and the development of resistance of target cells to endogenous gonadotropins due to a decrease in the activity and expression of LHR. An alternative to gonadotropins is low-molecular-weight compounds which interact with the LHR transmembrane allosteric site. The aim of this work was to study the relationship between the steroidogenic effects of hCG and thieno[2,3-d]pyrimidine derivatives (TPDs) with an activity of LHR agonists and their ability to influence the expression of the LRH-encoding Lhr gene both in vitro, when acting on the primary culture of rat Leydig cells, and in vivo, when administered to male rats. hCG stimulated testosterone production with a high efficiency at an early stage of its effect on Leydig cells (after 30 min) and upon a single administration to male rats (after 3 h), exceeding TPDs in activity by this parameter. After 1–3 h of acting on Leydig cells and long-term administration to male rats, the steroidogenic effect of hCG decreased and became comparable to that of TPDs. In Leydig cells and rat testes, hCG suppressed Lhr gene expression, which was partially restored in vivo on days 7–10 being accompanied by a slight increase in the steroidogenic effect of hCG, though to a significantly smaller extent than on the first day. The treatment with TP03, which was the most active of the TPDs studied, had a little effect on Lhr gene expression in Leydig cells but significantly increased it in rat testes after long-term administration of the drug. The steroidogenic effect of TP03 positively correlated with Lhr gene expression. When TP03 was applied to aging rats, its steroidogenic effect decreased, most likely, due to the absence of its stimulating effect on LHR expression. Thus, after long-term administration, TPDs exert a moderately expressed, stable over time, stimulating effect on testosterone production but do not decrease LHR expression, which prevents testicular resistance to endogenous gonadotropins under conditions of steroidogenesis stimulation.