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Development of Approaches to Reducing the Effective Gonadotropin Dose in Treating Androgen Insufficiency in Male Rats with Type 1 Diabetes Mellitus

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Abstract

In type 1 diabetes mellitus (DM1), testicular synthesis of testosterone is impaired, leading to androgen insufficiency and disorders of spermatogenesis. Long-term use of high gonadotropin doses for the correction of these abnormalities leads to a decrease in the sensitivity of luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptors in Leydig cells. The aim of this work was to study the effect of 3-day treatment of DM1 (streptozotocin-induced, 45 mg/kg) male Wistar rats with the allosteric LH/hCG receptor agonist 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP03, 15 mg/kg per day) on the effects of a relatively low hCG dose (10 IU/rat, single dose, s.c.) on blood testosterone levels, expression of steroidogenesis genes, and morphometric parameters of the seminiferous tubules. Pretreatment of rats with TP03 enhanced the stimulating effect of hCG on blood testosterone levels. This effect was produced, on the one hand, by enhanced steroidogenesis due to an increase in the expression of the Cyp11a1 gene, which encodes the mitochondrial cytochrome P450 side-chain cleavage enzyme (P450scc) responsible for the first stage of testosterone synthesis, and, on the other hand, by improved testicular sensitivity to gonadotropins due to an increase in the testicular LH/hCG receptor content in DM1 rats. In addition, pretreatment of DM1 rats with TP03 followed by hCG stimulation resulted in a more pronounced improvement in the morphometric parameters of the seminiferous tubules as compared to the groups that received TP03 or hCG alone. Thus, TP03 enables to increase the effectiveness of the hCG steroidogenic effect and reduce the dose of gonadotropin, which compensates for an androgen deficiency in diabetes.

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Funding

This work was supported by the Russian Science Foundation (project no. 19-75-20122). Biochemical and molecular biological studies were carried out on the basis of the Center for Collective Use of Scientific Equipment for Physiological, Biochemical and Molecular Biological Research at the Sechenov Institute of Evolutionary Physiology and Biochemistry.

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    A. A. Bakhtyukov, I. Yu. Morina, K. V. Derkach, I. V. Romanova, V. N. Sorokoumov & A. O. Shpakov

  2. Institute of Chemistry, Saint Petersburg State University, St. Petersburg, Russia

    V. N. Sorokoumov

Authors
  1. A. A. Bakhtyukov
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  2. I. Yu. Morina
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  3. K. V. Derkach
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  4. I. V. Romanova
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  5. V. N. Sorokoumov
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  6. A. O. Shpakov
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Contributions

Conceptualization and design of the experiment (A.O.S., K.V.D., V.N.S., A.A.B.), data collection (A.A.B., I.V.R., I.Y.M), data processing (A.A.B., I.V.R., K.V.D., I.Y.M.), manuscript writing and editing (A.A.B., I.V.R., K.V.D., A.O.S.).

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Correspondence to A. A. Bakhtyukov.

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The authors declare that they no conflict of interest related to the publication of this article.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 9, pp. 1175–1187https://doi.org/10.31857/S0869813922090023.

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Bakhtyukov, A.A., Morina, I.Y., Derkach, K.V. et al. Development of Approaches to Reducing the Effective Gonadotropin Dose in Treating Androgen Insufficiency in Male Rats with Type 1 Diabetes Mellitus. J Evol Biochem Phys 58, 1503–1513 (2022). https://doi.org/10.1134/S0022093022050209

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