Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes

Activity in the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes is regulated by hypophyseal hormones – gonadotropins and thyrotropic hormones (thyroid-stimulating hormone, TSH), which are secreted by specialized cells in the adenohypophysis. Luteinizing hormone (LH) and its homolog chorionic gonadotropin (CG) realize their steroidal effects by binding to LH/CG receptors on the surfaces of Leydig cells in the testes and theca cells and granulosa cells in mature follicles in the ovaries. Follicle-stimulating hormone (FSH) binds FSH receptors on Sertoli cells in the testes and granulosa cells in primordial and maturing follicles in the ovaries, controlling the processes of folliculogenesis, spermatogenesis, and steroidogenesis. TSH, via activation of TSH receptors, stimulates the synthesis of thyroid hormones by thyrocytes in the thyroid gland. Gonadotropins (LH, CG, and FSH) and TSH, which bind with high affinity to the extracellular domains of specific G protein-coupled receptors, directly activate various signal cascades operating via different types of G-proteins and β-arrestins. Recombinant gonadotropins and gonadotropins extracted from natural sources and used for the treatment of reproductive dysfunction and as assisted reproduction technologies have a number of drawbacks, which has led to the development of peptide and low molecular weight regulators of LH/CG and FSH receptors which interact with allosteric sites on the transmembrane or cytoplasmic domains of the receptors. Wide perspectives in the regulation of reproductive functions and the control of fertility are opened up by the use of adipokines, peptides of the insulin and relaxin families, and the antidiabetic drug metformin, which not only regulate and modify the responses of the gonads to gonadotropins, but also themselves influence steroidogenesis and gamete maturation. In the case of TSH receptors, the most acute problem is that of reversing increases in their activity in autoimmune and oncological diseases of the thyroid gland and in endocrine ophthalmopathy. The greatest potential in this direction lies in the ongoing development of low molecular weight inverse agonists and neutral antagonists, which interact with an allosteric site located in the transmembrane domain of the TSH receptor. The present review addresses contemporary advances in the development and study of endogenous and synthetic regulators and modulators of gonadotrophic and TSH receptors, along with their influences on the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes.

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References

  1. 1.

    D. Ezcurra, and P. Humaidan, “A review of luteinizing hormone and human chorionic gonadotropin when used in assisted reproductive technology,” Reprod. Biol. Endocrinol., 12, 95 (2014), https://doi.org/10.1186/1477-7827-12-95.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    A. O. Shpakov, Gonadotropins – from Theory to Clinical Practice, Politekh-Press (2018), eLibrary ID: 3642381.

  3. 3.

    K. Szymańska, J. Kałafut, and A. Rivero-Müller, “The gonadotropin system, lessons from animal models and clinical cases,” Minerva Ginecol., 70, No. 5, 561–587 (2018), https://doi.org/10.23736/S0026-4784.18.04307-1.

    Article  PubMed  Google Scholar 

  4. 4.

    B. Lunenfeld, W. Bilger, S. Longobardi, et al., “The development of gonadotropins for clinical use in the treatment of infertility,” Front. Endocrinol. (Lausanne), 10, 429 (2019), https://doi.org/10.3389/fendo.2019.00429.

    Article  Google Scholar 

  5. 5.

    D. Puett, Y. Li, G. DeMars, et al., “A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein,” Mol. Cell. Endocrinol., 260–262: 126–136 (2007), https://doi.org/10.1016/j.mce.2006.05.009.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    D. Puett, K. Angelova, M. R. da Costa, et al., “The luteinizing hormone receptor: insights into structure-function relationships and hormone-receptor-mediated changes in gene expression in ovarian cancer cells,” Mol. Cell. Endocrinol., 329, No. 1–2, 47–55 (2010), https://doi.org/10.1016/j.mce.2010.04.025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    A. Ulloa-Aguirre, J. A. Dias, G. Bousfield, et al., “Trafficking of the follitropin receptor,” Methods Enzymol., 521, 17–45 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    D. Lizneva, A. Rahimova, S. M. Kim, et al., “FSH beyond fertility,” Front. Endocrinol. (Lausanne), 10, 136 (2019), https://doi.org/10.3389/fendo.2019.00136.

  9. 9.

    A. Ulloa-Aguirre, P. Crepieux, A. Poupon, et al., “Novel pathways in gonadotropin receptor signaling and biased agonism,” Rev. Endocr. Metab., Disord., 12, 259–274 (2011).

    CAS  Google Scholar 

  10. 10.

    L. Riccetti, F. De Pascali, L. Gilioli, et al., “Human LH and hCG stimulate differently the early signalling pathways but result in equal testosterone synthesis in mouse Leydig cells in vitro,” Reprod. Biol. Endocrinol., 15, No. 1, 2 (2017), https://doi.org/10.1186/s12958-016-0224-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    L. Riccetti, R. Yvinec, D. Klett, et al., “Human luteinizing hormone and chorionic gonadotropin display biased agonism at the LH and LH/CG receptors,” Sci. Rep., 7, No. 1, 940 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    L. Hollander-Cohen, B. Böhm, K. Hausken, and B. Levavi-Sivan, “Ontogeny of the specifi city of gonadotropin receptors and gene expression in carp,” Endocr. Connect., 8, No. 11, 1433–1446 (2019), https://doi.org/10.1530/EC-19-0389.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    R. C. Anderson, C. L. Newton, and R. P. Millar, “Small molecule follicle-stimulating hormone receptor agonists and antagonists,” Front. Endocrinol. (Lausanne), 9, 757 (2019), https://doi.org/10.3389/fendo.2018.00757.

  14. 14.

    J. Patel, K. Landers, H. Li, et al., “Thyroid hormones and fetal neurological development,” J. Endocrinol., 209, 1–8 (2011).

    CAS  PubMed  Google Scholar 

  15. 15.

    C. Fekete and R. M. Lechan, “Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions,” Endocrine Rev., 35, 159–194 (2014).

    CAS  Google Scholar 

  16. 16.

    A. O. Shpakov, The Thyroid System in Health and Type 1 and Type 2 Diabetes, Polytechnic University Press, St. Petersburg (2016), eLibrary ID: 29744259.

  17. 17.

    G. Kleinau, C. L. Worth, A. Kreuchwig, et al., “Structural-functional features of the thyrotropin receptor: A class A G-protein-coupled receptor at work,” Front. Endocrinol. (Lausanne), 8, 86 (2017), https://doi.org/10.3389/fendo.2017.00086.

  18. 18.

    B. Rapoport and S. M. McLachlan, “The thyrotropin receptor in Graves’ disease,” Thyroid, 17, 911–922 (2007).

    CAS  PubMed  Google Scholar 

  19. 19.

    Y. Hwangbo and Y. J. Park, “Genome-wide association studies of autoimmune thyroid diseases, thyroid function, and thyroid cancer,” Endocrinol. Metab. (Seoul), 33, No. 2, 175–184 (2018), https://doi.org/10.3803/EnM.2018.33.2.175.

    CAS  Article  Google Scholar 

  20. 20.

    G. Krause and P. Marcinkowski, “Intervention strategies into glycoprotein hormone receptors for modulating (mal-)function, with special emphasis on the TSH receptor,” Horm. Metab. Res., 50, No. 12, 894–907 (2018), https://doi.org/10.1055/a-0749-6528.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    T. Fournier, “Human chorionic gonadotropin: Different glycoforms and biological activity depending on its source of production,” Ann. Endocrinol. (Paris), 77, No. 2, 75–81 (2016), https://doi.org/10.1016/j.ando.2016.04.012.

    Article  Google Scholar 

  22. 22.

    G. R. Bousfield and D. J. Harvey, “Follicle-stimulating hormone glycobiology,” Endocrinology, 160, No. 6, 1515–1535 (2019), https://doi.org/10.1210/en.2019-00001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    J. S. Davis, T. R. Kumar, J. V. May, and G. R. Bousfield, “Naturally occurring follicle-stimulating hormone glycosylation variants,” J. Glycomics Lipidomics, 4, No. 1, e117 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    A. O. Shpakov, “Glycosylation of gonadotropins as an important mechanism regulating their activitym,” Ros. Fiziol. Zh., 103, No. 9, 1004–1021 (2017).

    Google Scholar 

  25. 25.

    G. R. Bousfield, J. V. May, J. S. Davis, et al., “In vivo and in vitro impact of carbohydrate variation on human follicle-stimulating hormone function,” Front. Endocrinol. (Lausanne), 9, 216 (2018), https://doi.org/10.3389/fendo.2018.00216.

  26. 26.

    C. Nwabuobi, S. Arlier, F. Schatz, et al., “hCG: biological functions and clinical applications,” Int. J. Mol. Sci., 18, No. 10, pii: E2037 (2017), https://doi.org/10.3390/ijms18102037.

  27. 27.

    L. Casarini, G. Brigante, M. Simoni, and D. Santi, “Clinical applications of gonadotropins in the female: assisted reproduction and beyond,” Prog. Mol. Biol. Transl. Sci., 143, 85–119 (2016), https://doi.org/10.1016/bs.pmbts.2016.08.002.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    H. Wang, J. May, V. Butnev, et al., “Evaluation of in vivo bioactivities of recombinant hypo-(FSH21/18) and fully-(FSH24) glycosylated human FSH glycoforms in Fshb null mice,” Mol. Cell. Endocrinol., 437, 224–236 (2016), https://doi.org/10.1016/j.mce.2016.08.031.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    L. E. Simon, Z. Liu, G. R. Bousfield, et al., “Recombinant FSH glycoforms are bioactive in mouse preantral ovarian follicles,” Reproduction, 158, No. 6, 517–527 (2019), https://doi.org/10.1530/REP-19-0392.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    M. Manfredi-Lozano, J. Roa, F. Ruiz-Pino, et al., “Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty,” Mol. Metab., 5, 844–857 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    O. K. Egan, M. A. Inglis, and G. M. Anderson, “Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice,” J. Neurosci., 37, 3875–3886 (2017), https://doi.org/10.1523/JNEUROSCI.3138-16.2017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    C. M. Kusminski, P. G. McTernan, T. Schraw, et al., “Adiponectin complexes in human cerebrospinal fluid: Distinct complex distribution from serum,” Diabetologia, 50, 634–642 (2007).

    CAS  PubMed  Google Scholar 

  33. 33.

    J. P. Wen, C. Liu, W. K. Bi, et al., “Adiponectin inhibits KISS1 gene transcription through AMPK and specifi city protein-1 in the hypothalamic GT1-7 neurons,” J. Endocrinol., 214, 177–189 (2012).

    CAS  PubMed  Google Scholar 

  34. 34.

    M. Caprio, E. Fabbrini, A. Isidori, et al., “Leptin in reproduction,” Trends Endocrinol. Metab., 12, 65–72 (2001).

    CAS  PubMed  Google Scholar 

  35. 35.

    J. E. Caminos, R. Nogueiras, F. Gaytán, et al., “Novel expression and direct effects of adiponectin in the rat testis,” Endocrinology, 149, 3390–3402 (2008).

    CAS  PubMed  Google Scholar 

  36. 36.

    A. Pfaehler, M. K. Nanjappa, E. S. Coleman, et al., “Regulation of adiponectin secretion by soy isofl avones has implication for endocrine function of the testis,” Toxicol. Lett., 209, 78–85 (2012).

    CAS  PubMed  Google Scholar 

  37. 37.

    A. Kadivar, H. Heidari Khoei, H. Hassanpour, et al., “Correlation of adiponectin mRNA abundance and its receptors with quantitative parameters of sperm motility in rams,” Int. J. Fertil. Steril., 10, 127–135 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    D. A. Landry, F. Sormany, J. Haché, et al., “Steroidogenic genes expressions are repressed by high levels of leptin and the JAK/STAT signaling pathway in MA-10 Leydig cells,” Mol. Cell Biochem., 433, 79–95 (2017).

    CAS  PubMed  Google Scholar 

  39. 39.

    W. A. Banks, R. N. McLay, A. J. Kastin, et al., “Passage of leptin across the blood-testis barrier,” Am. J. Physiol., 276, E1099–E1104 (1999).

    CAS  PubMed  Google Scholar 

  40. 40.

    S. Thomas, D. Kratzsch, M. Schaab, et al., “Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa,” Fertil. Steril., 99, 1256–1263 (2013).

    CAS  PubMed  Google Scholar 

  41. 41.

    J. F. Heinz, S. P. Singh, U. Janowitz, et al., “Characterization of adiponectin concentrations and molecular weight forms in serum, seminal plasma, and ovarian follicular fluid from cattle,” Theriogenology, 83, 326–333 (2015).

    CAS  PubMed  Google Scholar 

  42. 42.

    P. Roumaud and L. Martin, “Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity,” Horm. Mol. Biol. Clin. Invest, 24, 25–45 (2015).

    CAS  Google Scholar 

  43. 43.

    X. Yi, H. Gao, D. Chen, et al., “Effects of obesity and exercise on testicular leptin signal transduction and testosterone biosynthesis in male mice,” Am. J. Physiol. Regul. Integr. Comp. Physiol., 312, R501-R510 (2017), https://doi.org/10.1152/ajpregu.00405.2016.

    Article  PubMed  Google Scholar 

  44. 44.

    N. Attia, S. Caprio, T. W. Jones, et al., “Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes,” J. Clin. Endocrinol. Metab., 84, 2324–2328 (1999).

    CAS  PubMed  Google Scholar 

  45. 45.

    A. M. Isidori, M. Caprio, F. Strollo, et al., “Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels,” J. Clin. Endocrinol. Metab., 84, No. 10, 3673–3680 (1999).

    CAS  PubMed  Google Scholar 

  46. 46.

    V. N. Sorokoumov and A. O. Shpakov, “Protein phosphotyrosine phosphatase 1B: Structure, function, role in the development of metabolic disorders and their correction by the enzyme inhibitors,” J. Evol. Biochem. Physiol., 53, No. 4, 259–270 (2017), https://doi.org/10.1134/S0022093017040020.

    CAS  Article  Google Scholar 

  47. 47.

    D. Landry, A. Paré, S. Jean, and L. J. Martin, “Adiponectin influences progesterone production from MA-10 Leydig cells in a dose-dependent manner,” Endocrine, 48, 957–967 (2015).

    CAS  PubMed  Google Scholar 

  48. 48.

    G. Gurusubramanian and V. K. Roy, “Expression of visfatin in alloxan-induced diabetic rat testis,” Acta Histochem., 116, 1462–1468 (2014).

    CAS  PubMed  Google Scholar 

  49. 49.

    S. Riammer, A. Garten, M. Schaab, et al., “Nicotinamide phosphoribosyltransferase production in human spermatozoa is infl uenced by maturation stage,” Andrology, 4, 1045–1053 (2016).

    CAS  PubMed  Google Scholar 

  50. 50.

    S. Tekin, Y. Erden, S. Sandal, et al., “Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism,” Arch. Physiol. Biochem., 123, 9–15 (2017).

    CAS  PubMed  Google Scholar 

  51. 51.

    Y. Elfassy, J. P. Bastard, C. McAvoy, et al., “Adipokines in semen: Physiopathology and effects on spermatozoas,” Int. J. Endocrinol., 2018, 3906490 (2018), https://doi.org/10.1155/2018/3906490.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    L. J. Spicer and P. Y. Aad, “Insulin-like growth factor (IGF) 2 stimulates steroidogenesis and mitosis of bovine granulosa cells through the IGF1 receptor: role of follicle-stimulating hormone and IGF2 receptor,” Biol. Reprod., 77, No. 1, 18–27 (2007), https://doi.org/10.1095/biolreprod.106.058230.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    M. Reverchon, V. Maillard, P. Froment, et al., “Adiponectin and resistin: a role in the reproductive functions?” Med. Sci., 29, 417–424 (2013), https://doi.org/10.1051/medsci/2013294016.

    Article  Google Scholar 

  54. 54.

    T. Wang, Y. Liu, M. Lv, et al., “miR-323-3p regulates the steroidogenesis and cell apoptosis in polycystic ovary syndrome (PCOS) by targeting IGF-1,” Gene, 683, 87–100 (2019), https://doi.org/10.1016/j.gene.2018.10.006.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    S. G. Kristensen, L. S. Mamsen, J. V. Jeppesen, et al., “Hallmarks of human small antral follicle development: implications for regulation of ovarian steroidogenesis and selection of the dominant follicle,” Front. Endocrinol. (Lausanne), 8, 376 (2018), https://doi.org/10.3389/fendo.2017.00376.

  56. 56.

    A. Sirotkin, R. Alexa, A. Kádasi, et al., “Resveratrol directly affects ovarian cell sirtuin, proliferation, apoptosis, hormone release and response to follicle-stimulating hormone (FSH) and insulin-like growth factor I (IGF-I),” Reprod. Fertil. Dev. (2019), https://doi.org/10.1071/RD18425.

  57. 57.

    J. A. Bøtkjær, S. E. Pors, T. S. Petersen, et al., “Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development,” J. Assist. Reprod. Genet., 36, No. 5, 889–903 (2019), https://doi.org/10.1007/s10815-019-01432-x.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    M. Spitschak and A. Hoeflich, “Potential functions of igfbp-2 for ovarian folliculogenesis and steroidogenesis,” Front. Endocrinol. (Lausanne), 9, 119 (2018), https://doi.org/10.3389/fendo.2018.00119.

  59. 59.

    R. Ivell, K. Heng, and R. Anand-Ivell, “Insulin-like factor 3 and the HPG axis in the male,” Front. Endocrinol. (Lausanne), 5, 6 (2014), https://doi.org/10.3389/fendo.2014.00006.

  60. 60.

    R. Ivell, A. I. Agoulnik, and R. Anand-Ivell, “Relaxin-like peptides in male reproduction – a human perspective,” Br. J. Pharmacol., 174, No. 10, 990–1001 (2017), https://doi.org/10.1111/bph.13689.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    G. Coskun, L. Sencar, A. Tuli, et al., “Effects of osteocalcin on synthesis of testosterone and INSL3 during adult Leydig cell differentiation,” Int. J. Endocrinol., 2019, 1041760 (2019), https://doi.org/10.1155/2019/1041760.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    E. A. Shpakova, K. V. Derkach, and A. O. Shpakov, “Biological activity of lipophilic derivatives of peptide 562–572 of rat luteinizing hormone receptor,” Dokl. Biochem. Biophys., 452, No. 1, 248–250 (2013), https://doi.org/10.1134/S1607672913050116.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    K. V. Derkach, E. A. Shpakova, and A. O. Shpakov, “Palmitoylated peptide 562–572 of luteinizing hormone receptor increases testosterone level in male rats,” Bull. Exp. Biol. Med., 158, No. 2, 209–212 (2014), https://doi.org/10.1007/s10517-014-2724-5.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    N. C. van Straten, G. G. Schoonus-Gerritsma, R. G. van Someren, et al., “The first orally active low molecular weight agonists for the LH receptor: Thienopyr(im)idines with therapeutic potential for ovulation induction,” Chem. Biol. Chem., 3, No. 10, 1023–1026 (2002), https://doi.org/10.1002/1439-7633(20021004)3:10<1023::AIDCBIC1023>3.0.CO;2-9.

    Article  Google Scholar 

  65. 65.

    R. van de Lagemaat, C. M. Timmers, J. Kelder, et al., “Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor,” Hum. Reprod., 24, No. 3, 640–648 (2009), https://doi.org/10.1093/humrep/den412.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    R. van de Lagemaat, B. C. Raafs, C. van Koppen, et al., “Prevention of the onset of ovarian hyperstimulation syndrome (OHSS) in the rat after ovulation induction with a low molecular weight agonist of the LH receptor compared with hCG and rec-LH,” Endocrinology, 152, No. 11, 4350–4357 (2011), https://doi.org/10.1210/en.2011-1077.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    M. Gerrits, B. Mannaerts, H. Kramer, et al., “First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age,” J. Clin. Endocrinol. Metab., 98, No. 4, 1558–1566 (2013), https://doi.org/10.1210/jc.2012-3404.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    K. V. Derkach, D. V. Dar’in, P. S. Lobanov, and A. O. Shpakov, “Intratesticular, intraperitoneal, and oral administration of thienopyrimidine derivatives increases the testosterone level in male rats,” Dokl. Biol. Sci., 459, No. 1, 326–329 (2014), https://doi.org/10.1134/S0012496614060040.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    A. O. Shpakov, D. V. Dar’in, K. V. Derkach, and P. S. Lobanov, “The stimulating influence of thienopyrimidine compounds on the adenylyl cyclase systems in the rat testes,” Dokl. Biochem. Biophys., 456, 104–107 (2014), https://doi.org/10.1134/S1607672914030065.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    K. V. Derkach, D. V. Dar’in, A. A. Bakhtyukov, et al., “In vitro and in vivo studies of functional activity of new low molecular weight agonists of the luteinizing hormone receptor,” Biochemistry (Mosc.) Suppl. Ser A: Membr. Cell Biology, 10, No. 4, 294–300 (2016), https://doi.org/10.1134/S1990747816030132.

    Article  Google Scholar 

  71. 71.

    A. A. Bakhtyukov, K. V. Derkach, D. V. Dar’in, and A. O. Shpakov, “Thienopyrimidine derivatives specifi cally activate testicular steroidogenesis but do not affect thyroid functions,” J. Evol. Biochem. Physiol., 55, No. 1, 30–39 (2019), https://doi.org/10.1134/S0022093019010046.

    CAS  Article  Google Scholar 

  72. 72.

    K. V. Derkach, D. V. Dar’in, and A. O. K. V. Shpakov, “The low-molecular-weight ligands of the luteinizing hormone receptor with antagonistic activity,” Biol Membrany, 37, No. 3, 1–10 (2020), https://doi.org/10.31857/S0233475520030032.

    Article  Google Scholar 

  73. 73.

    A. A. Bakhtyukov, T. V. Sokolova, D. V. Dar’in, et al., “Comparative study of the stimulating effect of a low molecular weight luteinizing hormone and chorionic gonadotropin receptor agonist on steroidogenesis in rat Leydig cells,” Ros. Fiziol. Zh., 103, No. 10, 1181–1192 (2017).

    Google Scholar 

  74. 74.

    A. A. Bakhtyukov, K. V. Derkach, D. V. Dar’in, and A. O. Shpakov, “Conservation of steroidogenic effect of the low-molecular-weight agonist of luteinizing hormone receptor in the course of its long-term administration to male rats,” Dokl. Biochem. Biophys., 484, No. 1, 78–81 (2019); 010216, https://doi.org/10.1134/S1607672919.

  75. 75.

    C. L. Newton, A. M. Whay, C. A. McArdle, et al., “Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist,” Proc. Natl. Acad. Sci. USA, 108, No. 17, 7172–77176 (2011), https://doi.org/10.1073/pnas.1015723108.

    Article  PubMed  Google Scholar 

  76. 76.

    A. A. Bakhtyukov, K. V. Derkach, D. V. Dar’in, et al., “Decrease in the basal and luteinizing hormone receptor agonist-stimulated testosterone production in aging male rats,” Adv. Gerontol., 9, No. 2, 179–185 (2019), https://doi.org/10.1134/S2079057019020036.

    Article  Google Scholar 

  77. 77.

    A. A. Bakhtyukov, K. V. Derkach, D. V. Dar’in, et al., “A low molecular weight agonist of the luteinizing hormone receptor stimulates adenylyl cyclase in the testicular membranes and steroidogenesis in the testes of rats with type 1 diabetes,” Biochemistry (Mosc.) Suppl. Ser. A: Membr. Cell Biology, 13, No. 4, 301–309 (2019), https://doi.org/10.1134/S1990747819040032.

    Article  Google Scholar 

  78. 78.

    J. J. Heidelbaugh, “Endocrinology update: hirsutism,” FP Essent., 451, 17–24 (2016).

    PubMed  Google Scholar 

  79. 79.

    T. Mizushima and H. Miyamoto, “The role of androgen receptor signaling in ovarian cancer,” Cells, 8, No. 2, pii: E176 (2019), https://doi.org/10.3390/cells8020176.

  80. 80.

    N. El Tayer, A. Reddy, and D. N. A. Buckler, Patent US 6,235,755, “FSH mimetics for the treatment of infertility” (2001).

  81. 81.

    S. D. Yanofsky, E. S. Shen, F. Holden, et al., “Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists,” J. Biol. Chem., 281, No. 19, 13226–13233 (2006), https://doi.org/10.1074/jbc.M600601200.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    B. J. Arey, “Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential,” Endocrine, 34, 1–10 (2008), https://doi.org/10.1007/s12020-008-9098-2.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    N. C. van Straten and C. M. Timmers, “Non-peptide ligands for the gonadotropin receptors,” Annu. Rep. Med. Chem., 44, 171–188 (2009), https://doi.org/10.1016/S0065-7743(09)04408-X.

    CAS  Article  Google Scholar 

  84. 84.

    S. G. Nataraja, H. N. Yu, and S. S. Palmer, “Discovery and development of small molecule allosteric modulators of glycoprotein hormone receptors,” Front. Endocrinol. (Lausanne), 6, 142 (2015), https://doi.org/10.3389/fendo.2015.00142.

  85. 85.

    M. Zoenen, E. Urizar, S. Swillens, et al., “Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers,” Nat. Commun., 3, 1007 (2012), https://doi.org/10.1038/ncomms1991.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    V. Sriraman, D. Denis, D. de Matos, et al., “Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: evidence for its ability to support follicular development and ovulation,” Biochem. Pharmacol., 89, No. 2, 266–275 (2014), https://doi.org/10.1016/j.bcp.2014.02.023.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    C. J. van Koppen, P. M. Verbost, R. van de Lagemaat, et al., “Signaling of an allosteric, nanomolar potent, low molecular weight agonist for the follicle-stimulating hormone receptor,” Biochem. Pharmacol., 85, No. 8, 1162–1170 (2013), https://doi.org/10.1016/j.bcp.2013.02.001.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    C. M. Timmers, W. F. Karstens, and P. M. Grima Poveda, Patent US WO2006/117370, “4-Phenyl-5-Oxo-1,4,5,6,7,8-Hexahydroquinoline Derivatives as Medicaments for the Treatment of Infertility” (2006).

  89. 89.

    F. Fares, “The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: development of agonists and antagonists,” Biochim. Biophys. Acta, 1760, 560–567 (2006).

    CAS  PubMed  Google Scholar 

  90. 90.

    L. Persani, “Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity,” Thyroid, 8, 941–946 (1998).

    CAS  PubMed  Google Scholar 

  91. 91.

    H. Tala, R. Robbins, J. A. Fagin, et al., “Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH,” J. Clin. Endocrinol. Metab., 96, No. 7, 2105–2111 (2011), https://doi.org/10.1210/jc.2011-0305.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    D. Rani, S. Kaisar, S. Awasare, et al., “Examining recombinant human TSH primed 131I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol,” Eur. J. Nucl. Med. Mol. Imaging, 41, No. 9, 1767–1780 (2014), https://doi.org/10.1007/s00259-014-2737-3.

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    J. Schaarschmidt, S. Huth, R. Meier, et al., “Influence of the hinge region and its adjacent domains on binding and signaling patterns of the thyrotropin and follitropin receptor,” PLoS One, 9, No. 10 ,e111570 (2014), https://doi.org/10.1371/journal.pone.0111570.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    A. Brüser, A. Schulz, S. Rothemund, et al., “The activation mechanism of glycoprotein hormone receptors with implications in the cause and therapy of endocrine diseases,” J. Biol. Chem., 291, 508–520 (2016).

    PubMed  Google Scholar 

  95. 95.

    C. C. Krieger, J. D. Perry, S. J. Morgan, et al., “TSH/IGF-1 receptor cross-talk rapidly activates extracellular signal-regulated kinases in multiple cell types,” Endocrinology, 158, No. 10, 3676–3683 (2017), https://doi.org/10.1210/en.2017-00528.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    J. S. Paik, S. E. Kim, J. H. Kim, et al., “Insulin-like growth factor-1 enhances the expression of functional TSH receptor in orbital fibroblasts from thyroid-associated ophthalmopathy,” Immunobiology, 25, 151902 (2019), https://doi.org/10.1016/j.imbio.2019.151902.

    CAS  Article  Google Scholar 

  97. 97.

    K. V. Derkach, I. V. Bogush, L. M. Berstein, and A. O. Shpakov, “The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats,” Horm. Metab. Res., 47, No. 12, 916–924 (2015), https://doi.org/10.1055/s-0035-1547236.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    T. J. Smith and J. A. M. J. L. Janssen, “Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy,” Endocr. Rev., 40, No. 1, 236–267 (2019), https://doi.org/10.1210/er.2018-00066.

    Article  PubMed  Google Scholar 

  99. 99.

    K. Nakabayashi, H. Matsumi, A. Bhalla, et al., “Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor,” J. Clin. Invest., 109, 1445–1452 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    F. E. Wondisford, “The thyroid axis just got more complicated,” J. Clin. Invest., 109, 1401–1402 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    M. S. Baquedano, M. Ciaccio, N. Dujovne, et al., “Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening,” J. Clin. Endocrinol. Metab., 95, E98–E103 (2010).

    PubMed  Google Scholar 

  102. 102.

    S. M. McLachlan and B. Rapoport, “Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa,” Thyroid, 23, No. 1, 14–24 (2013), https://doi.org/10.1089/thy.2012.0374.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    R. S. Bahn, “Autoimmunity and Graves’ disease,” Clin. Pharmacol. Ther., 91, 577–579 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    S. Sato, J. Y. Noh, S. Sato, et al., “Comparison of efficacy and adverse effects between methimazole 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves’ disease patients with moderate to severe hyperthyroidism,” Thyroid, 25, 43–50 (2015).

    CAS  PubMed  Google Scholar 

  105. 105.

    S. Moore, H. Jaeschke, G. Kleinau, et al., “Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns,” J. Med. Chem., 49, 3888–3896 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    L. H. Heitman and A. P. Ijzerman, “G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands,” Med. Res. Rev., 28, 975–1011 (2008).

    CAS  PubMed  Google Scholar 

  107. 107.

    S. Neumann and M. C. Gershengorn, “Small molecule TSHR agonists and antagonists,” Ann. Endocrinol. (Paris), 72, 74–76 (2011).

    CAS  Google Scholar 

  108. 108.

    J. R. Lane and A. P. IJzerman, “Allosteric approaches to GPCR drug discovery,” Drug Discov. Today Technol., 10, 219–221 (2013).

    Google Scholar 

  109. 109.

    S. Neumann, E. A. Nir, E. Eliseeva, et al., “A Selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice,” Endocrinology, 155, 310–314 (2014).

    PubMed  Google Scholar 

  110. 110.

    S. Neumann, U. Padia, M. J. Cullen, et al., “An enantiomer of an oral small-molecule TSH receptor agonist exhibits improved pharmaco logic properties,” Front. Endocrinol. (Lausanne), 7, 105 (2016), https://doi.org/10.3389/fendo.2016.00105.

    Article  Google Scholar 

  111. 111.

    A. O. Shpakov, “New advances in the development and study of the mechanisms of action of low molecular weight agonists of thyrotropic and luteinizing hormone receptors,” Tsitologiya, 57, No. 3, 167–176 (2015).

    CAS  Google Scholar 

  112. 112.

    S. Neumann, W. Huang, S. Titus, et al., “Small molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice,” Proc. Natl. Acad. Sci. USA, 106, 12,471–12,476 (2009).

    CAS  Google Scholar 

  113. 113.

    M. D. Allen, S. Neumann, and M. C. Gershengorn, “Small-molecule thyrotropin receptor agonist activates naturally occurring thyrotropin-insensitive mutants and reveals their distinct cyclic adenosine monophosphate signal persistence,” Thyroid, 21, 907–912 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    M. Meyer Zu Horste, K. Pateronis, M. K. Walz, et al., “The effect of early thyroidectomy on the course of active Graves’ Orbitopathy (GO, A retrospective case study,” Horm. Metab. Res., 48, 433–439 (2016).

  115. 115.

    R. S. Bahn, H. S. Burch, D. S. Cooper, et al., “The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration,” Thyroid, 19, 673–674 (2009).

    CAS  PubMed  Google Scholar 

  116. 116.

    S. Neumann, R. F. Place, C. C. Krieger, and M. C. Gershengorn, “Future prospects for the treatment of graves’ hyperthyroidism and eye disease,” Horm. Metab. Res., 47, 789–796 (2015).

    CAS  PubMed  Google Scholar 

  117. 117.

    L. Hegedüs, T. J. Smith, R. S. Douglas, and C. H. Nielsen, “Targeted biological therapies for Graves’ disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab,” Clin. Endocrinol. (Oxford), 74, 1–8 (2011).

    Google Scholar 

  118. 118.

    G. J. Kahaly, O. Shimony, Y. N. Gellman, et al., “Regulatory T-cells in Graves’ orbitopathy: Baseline findings and immunomodulation by anti-lymphocyte globulin,” J. Clin. Endocrinol. Metab., 96, 422–429 (2011).

    CAS  PubMed  Google Scholar 

  119. 119.

    H. Chen, S. J. C. Shan, T. Mester, et al., “TSH-mediated TNFα Production in human fi brocytes is inhibited by teprotumumab, an IGF-1R antagonist,” PLoS One, 10, e0130322 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    T. J. Smith, G. J. Kahaly, D. G. Ezra, et al., “Teprotumumab for thyroid-associated ophthalmopathy,” New Engl. J. Med., 376, 1748–1761 (2017).

    CAS  PubMed  Google Scholar 

  121. 121.

    M. C. Gershengorn and S. Neumann, “Update in TSH receptor agonists and antagonists,” J. Clin. Endocrinol. Metab., 97, 4287–4292 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    S. Neumann, G. Kleinau, S. Costanzi, et al., “A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism,” Endocrinology, 149, 5945–5950 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    S. Neumann, E. Eliseeva, J. G. McCoy, et al., “A new small-molecule antagonist inhibits Graves’ disease antibody activation of the TSH receptor,” J. Clin. Endocrinol. Metab., 96, 548–554 (2011).

    CAS  PubMed  Google Scholar 

  124. 124.

    A. F. Turcu, S. Kumar, S. Neumann, et al., “A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fi broblast functions involved in the pathogenesis of Graves ophthalmopathy,” J. Clin. Endocrinol. Metab., 98, 2153–2159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    P. Marcinkowski, I. Hoyer, E. Specker, et al., “A new highly thyrotropin receptor-selective small-molecule antagonist with potential for the treatment of Graves’ orbitopathy,” Thyroid, 29, No. 1, 111–123 (2019), https://doi.org/10.1089/thy.2018.0349.

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    P. Marcinkowski, A. Kreuchwig, S. Mendieta, et al., “Thyrotropin receptor: allosteric modulators illuminate intramolecular signaling mechanisms at the interface of ecto- and transmembrane domain,” Mol. Pharmacol., 96, No. 4, 452–462 (2019), https://doi.org/10.1124/mol.119.116947.

    CAS  Article  PubMed  Google Scholar 

  127. 127.

    E. A. Shpakova, A. O. Shpakov, O. V. Chistyakova, et al., “Biological activity in vitro and in vivo of peptides corresponding to the third intracellular loop of thyrotropin receptor,” Dokl. Biochem. Biophys., 433, 64–67 (2012), https://doi.org/10.1134/S1607672912020020.

    CAS  Article  Google Scholar 

  128. 128.

    K. V. Derkach, E. A. Shpakova, V. M. Bondareva, and A. O. Shpakov, “Study of the dose dependence of the stimulatory influence of a thyrotropic hormone receptor -derived peptide on the production of thyroid hormones in rats,” Translyats. Med., 1, No. 30, 15–21 (2015).

    Google Scholar 

  129. 129.

    K. V. Derkach, E. A. Shpakova, A. M. Titov, and A. O. Shpakov, “Intranasal and intramuscular administration of lysine-palmitoylated peptide 612–627 of thyroid-stimulating hormone receptor increases the level of thyroid hormones in rats,” Int. J. Pept. Res. Ther., 21, 249–260 (2015).

    CAS  Google Scholar 

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Correspondence to A. O. Shpakov.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 106, No. 6, pp. 696–719, June, 2020.

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Shpakov, A.O. Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes. Neurosci Behav Physi 51, 332–345 (2021). https://doi.org/10.1007/s11055-021-01076-4

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Keywords

  • gonadotropin
  • thyrotropic hormone
  • G-protein-coupled receptors
  • allosteric regulator
  • leptin
  • low molecular weight agonist
  • thyroid gland