Search

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG), due to binding to the LH/hCG receptor, activate the adenylyl cyclase (AC) system which regulates testosterone (T) production. Long-term administration of LH and hCG causes desensitization of this system and attenuates the steroidogenic response, thereby necessitating the search for new agonists of the LH/hCG receptor. The aim of the work was to explore, in comparison with hCG, the stimulatory effects of the previously developed thieno[2,3-d]pyrimidines, TP03 and TP04, and a new thieno[2,3-d]pyrimidine derivative, 5-amino-N-(tert-butyl)-4-(3-(4-aminopyrimidine-5-carboxamido)-phenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide (TP37), on AC activity in rat testicular membranes, as well as on T production and gene expression of the LH/hCG receptor and the key testicular steroidogenic proteins under conditions of a single and 3-day administration to male rats. hCG increased AC activity in testicular membranes more efficiently compared to thieno[2,3-d]pyrimidines, and after a single injection (50 and 100 IU/rat) was superior to TP03 and TP04 (15–50 mg/kg) in its steroidogenic effect. After a 3-day administration, the steroidogenic effect of hCG was attenuated compared to that for TP03 and TP04. After 3 days of treatment with gonadotropin, testicular expression of genes encoding the StAR protein and cytochrome P450scc was considerably increased, but expression of the Lhr and Cyp17a1 genes encoding LH/hCG receptor and cytochrome P450-17α was suppressed. TP03 and TP04 slightly increased StAR gene expression but did not affect expression of other genes. TP37, which was active in vitro, after a short stimulation of T production, suppressed the steroidogenic function at a dose of 50 mg/kg, probably due to its degradation and the ability to suppress Cyp17a1 gene expression. Our data indicate significant differences in the mechanisms underlying the effect of gonadotropins and thieno[2,3-d]pyrimidines with an activity of LH/hCG receptor agonists on testicular steroidogenesis. We also demonstrate that long-term administration of thieno[2,3-d]pyrimidines to stimulate T production does not attenuate steroidogenesis and induces no LH resistance. [ABSTRACT FROM AUTHOR]

In clinical practice, luteinizing hormone (LH) and chorionic gonadotropin (CG) are used as activators of the LH receptor, leading to the stimulation of gonadal steroidogenesis. However, high doses of gonadotropin preparations cause a number of side effects. Here we demonstrate that the pretreatment of male rats with TP03, an allosteric agonist of the LH receptor, at doses of 7.5–25 mg/kg significantly increases the testosterone production-stimulating effect of CG administered at a dose of 50 IU/rat, which is twice as low as that inducing a maximum steroidogenic effect. We assume that this is due to additivity of the CG and TP03 effects, as well as the potentiating effect of TP03 on CG signaling pathways. Three hours after CG administration to TP03-pretreated rats, the activation pattern of the genes of steroidogenic enzymes and LH receptor exhibits specific changes which mainly concern 3p-dehydrogenase gene expression. The obtained data indicate a prospectivity of TP03 and CG co-application allowing the effective dose of gonadotropin preparations to be reduced. [ABSTRACT FROM AUTHOR]

Abstract—It was shown that the thienopyrimidine derivative TP03, a low-molecular-weight agonist of the luteinizing hormone receptor (LHR), during the treatment of male rats for 7 days steadily increased the production of testosterone (T), whose elevated level was retained for 7 days, and increased the expression of the gene for LHR, which indicates the maintenance of the sensitivity of Leydig cells to gonadotropins. At the same time, the steroidogenic effect of human chorionic gonadotropin (hCG), which significantly increased the T level on the first day of administration, was further weakened, which was accompanied by a decrease in the expression of the gene for LHR in the testes, indicating the development of resistance of Leydig cells to hCG. Along with this, in the case of hCG administration, a compensatory increase in the expression of genes of the steroidogenic enzymes, such as cytochrome P450scc and dehydrogenase 3β-HSD, was shown in the testes, while in the case of TP03 administration this effect was absent. [ABSTRACT FROM AUTHOR]

Human chorionic gonadotropin that is widely used for improving spermatogenesis. The effect of chorionic gonadotropin is mediated through luteinizing hormone receptor. Treatment with gonadotropin is associated with undesirable effects due to hyperactivation of testosterone production and luteinizing hormone receptor desensitization. A promising alternative could be low-molecular-weight agonists of luteinizing hormone receptors, but their effects on spermatogenesis have not been investigated. Here we analyzed the effect of a thieno[2,3-d]pyrimidines (TP), 4-((3-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno [2,3-d]pyrimidine-4-yl) phenyl)carbamoyl)pyridine 1-oxide (TP22), an allosteric agonist of luteinizing hormone receptors, on the seminiferous tubules and spermatogenic cells in 4- and 18-month-old male rats and in animals with diabetes mellitus. TP22 and gonadotropin were administered in daily doses of 15 mg/kg and 20 U/rat for 5 days. Blood testosterone level, morphology of the seminiferous tubules, and the number of germ cells in them were estimated. Being comparable by the efficiency to gonadotropin, TP22 increased the testosterone level in all the studied groups of rats and restored epithelium thickness in the seminiferous tubules and the number of spermatogonia and pachytenic spermatocytes that are reduced in aging and diabetes, but, unlike gonadotropin, did not suppress the expression of luteinizing hormone receptor. The efficacy of TP22 as a stimulator of testicular spermatogenesis has been demonstrated both under normal conditions and in age-related and diabetes-associated reproductive dysfunctions. [ABSTRACT FROM AUTHOR]