Abstract
To correct androgen deficiency, it is necessary to develop new luteinizing hormone receptor (LHR) agonists and evaluate their steroidogenic effects with different durations and routes of administration in comparison with human chorionic gonadotropin (hCG), the gold standard of steroidogenesis activators. The purpose of the work was to study the effect of the allosteric LHR agonist 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]-pyrimidine-6-carboxamide (TP03) after single-dose five-day intraperitoneal, subcutaneous and oral administration to male rats versus hCG administered intraperitoneally or subcutaneously. Testosterone levels and gene expression of LHR and steroidogenic enzymes were assessed. TP03 and hCG doses were preliminarily determined and subsequently used, causing 65–75% of the maximum steroidogenic effect. TP03 (20 mg/kg) stimulated testosterone production more effectively after one- or five-day intraperitoneal administration than following subcutaneous and oral administration. Five-day intraperitoneal, but not subcutaneous, TP03 administration increased intratesticular gene expression of the LHR and cholesterol-transporting protein StAR, which catalyzes the rate-limiting stage of steroidogenesis. Subcutaneous hCG administration (20 IU/rat) was more effective than intraperitoneal administration and significantly increased the gene expression of 17β-dehydrogenase, which catalyzes the synthesis of androstenedione. Both methods of hCG administration reduced LHR gene expression. Unlike hCG, after five days of administration, the steroidogenic effect of TP03 persisted. The steroidogenic effect of TP03 was concluded to be more pronounced with intraperitoneal, and in the case of hCG, subcutaneous administration, due to the differential effects of these drugs on the expression of steroidogenic enzymes.
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Funding
This work was supported by the Russian Science Foundation (project No. 19-75-20122). The 1H-NMR studies were carried out using the equipment of the St. Petersburg State University Resource Center “Magnetic Resonance Methods of Study”; to obtain high-resolution mass spectra, the equipment of the Resource Center “Methods for Composition Analysis of Matter” was exploited.
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Basic idea and experimental design (A.O.Sh., A.A.B., K.V.D., A.M.S.); data collection (A.A.B., A.M.S., V.N.S., K.V.D.); data processing (A.A.B., A.M.S., K.V.D., A.O.Sh.); writing and editing a manuscript (A.O.Sh., A.M.S., A.A.B., K.V.D.).
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All applicable international, national, and institutional principles of handling and using experimental animals for scientific purposes were observed. All procedures complied with the requirements developed and approved by the Ethics Committee at the Sechenov Institute of Evolutionary Physiology and Biochemistry (St. Petersburg), as well as with rules and regulations formulated in the EU Council Directive 1986 (86/609/EEC) and the Guide for the Care and Use of Laboratory Animals. This study did not involve human subjects as research objects.
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Translated by A. Polyanovsky
Russian Text © The Author(s), 2022, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2022, Vol. 58, No. 1, pp. 51–60https://doi.org/10.31857/S0044452922010077.
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Stepochkina, A.M., Bakhtyukov, A.A., Derkach, K.V. et al. A Comparative Study of the Steroidogenic Effect of 5-Amino-N-tert-butyl-2-(methylthio)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]-pyrimidine-6-carboxamide and Chorionic Gonadotropin with Different Methods of Administration to Male Rats. J Evol Biochem Phys 58, 54–63 (2022). https://doi.org/10.1134/S0022093022010057
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DOI: https://doi.org/10.1134/S0022093022010057