Comparative Study of the Restoring Effect of Metformin, Gonadotropin, and Allosteric Agonist of Luteinizing Hormone Receptor on Spermatogenesis in Male Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus

Derkach, K. V.; Bakhtyukov, A. A.; Morina, I. Yu.; Bayunova, L. V.; Шпаков, А. О.

doi:10.1007/s10517-022-05409-2

Cited by 10 publications

(3 citation statements)

References 15 publications

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“…The most plausible explanation for this disparity of results is the presence of a direct effect of metformin on the testes. Recent studies have shown that metformin treatment of rats with diabetes stimulated testosterone production by improving sensitivity of Leydig cells to LH, by increasing steroidogenic acute regulatory protein expression and probably also by reducing testosterone conversion to estradiol 29,30 . If these effects also occur in some groups of men (including men with early‐onset androgenic alopecia), they may counterbalance the indirect metformin action on gonadotropin production.…”

Section: Discussionmentioning

confidence: 99%

Pituitary Effects of Metformin in Men With Early‐Onset Androgenic Alopecia

Krysiak

Kowalcze

2022

The Journal of Clinical Pharma

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Males with early-onset androgenic alopecia are characterized by elevated androgen levels. The aim of the present study was to investigate whether the presence of this condition modulates the impact of metformin on pituitary hormone production. This study compared 2 groups of young men with prediabetes, matched for age, blood pressure, and insulin sensitivity: 23 subjects with early-onset male-pattern baldness (group 1) and 25 individuals with normal hair growth (group 2). Throughout the study, both groups were treated with metformin for 6 months. Circulating levels of glucose, insulin, glycated hemoglobin, gonadotropins, thyrotropin, prolactin, adrenocorticotropic hormone, insulin-like growth factor-1 and androgens were determined at the beginning of the study and 6 months later. At entry, luteinizing hormone (LH), the LH/follicle-stimulating hormone ratio, total testosterone, bioavailable testosterone, adrenocorticotropic hormone and dehydroepiandrosterone sulfate were higher in group 1 than in group 2. The effect of metformin on fasting glucose, insulin sensitivity, and glycated hemoglobin was more pronounced in group 2 than in group 1. Only in group 1, metformin reduced LH levels and the LH/follicle-stimulating hormone ratio. Metformin did not affect plasma levels of the remaining hormones. In untreated men with androgenic alopecia (group 3, n = 22), glucose homeostasis markers and hormone levels remained similar throughout the study period. The obtained results suggest that the impact of metformin on gonadotroph secretory function is stronger in men with early-onset androgenic alopecia than in men with normal hair growth. Metformin treatment may protect men with early-onset androgenic alopecia against the development of gonadotroph hyperplasia and/or focal testicular changes.

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Section: Discussionmentioning

confidence: 99%

Pituitary Effects of Metformin in Men With Early‐Onset Androgenic Alopecia

Krysiak

Kowalcze

2022

The Journal of Clinical Pharma

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“…As with hCG, TP03 and TP04 improved spermatogenesis in diabetic and aging rats [400,402,406,407]. When TP03 was administered to metformin-treated diabetic rats, a significant increase in its steroidogenic effect was shown upon short-term (but not longterm) TP03 administration [402,406].…”

Section: Luteinizing Hormone Receptormentioning

confidence: 91%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Ao¹

2023

Preprint

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A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].

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“…When co-administered with low doses of gonadotropin, thieno[2,3-d]-pyrimidines potentiated its effect, and potentiation was more pronounced in rats with type 1 diabetes mellitus [ 405 ]. As with hCG, TP03 and TP04 improved spermatogenesis in diabetic and aging rats [ 400 , 402 , 406 , 407 ]. When TP03 was administered to metformin-treated diabetic rats, a significant increase in its steroidogenic effect was shown upon short-term (but not long-term) TP03 administration [ 402 , 406 ].…”

Section: Allosteric Regulators Of Pituitary Glycoprotein Hormone Rece...mentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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Comparative Study of the Restoring Effect of Metformin, Gonadotropin, and Allosteric Agonist of Luteinizing Hormone Receptor on Spermatogenesis in Male Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus

Cited by 10 publications

References 15 publications

Pituitary Effects of Metformin in Men With Early‐Onset Androgenic Alopecia

Pituitary Effects of Metformin in Men With Early‐Onset Androgenic Alopecia

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

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