ЭНДОГЕННЫЕ И СИНТЕТИЧЕСКИЕ РЕГУЛЯТОРЫ ПЕРИФЕРИЧЕСКИХ ЗВЕНЬЕВ ГИПОТАЛАМО-ГИПОФИЗАРНО-ГОНАДНОЙ- И ТИРЕОИДНОЙ ОСЕЙ
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Ключевые слова

гонадотропин
тиреотропный гормон
G-белок-сопряженный рецептор
аллостерический регулятор
лептин
низкомолекулярный агонист
щитовидная железа

Как цитировать

Шпаков, А. О. (2020). ЭНДОГЕННЫЕ И СИНТЕТИЧЕСКИЕ РЕГУЛЯТОРЫ ПЕРИФЕРИЧЕСКИХ ЗВЕНЬЕВ ГИПОТАЛАМО-ГИПОФИЗАРНО-ГОНАДНОЙ- И ТИРЕОИДНОЙ ОСЕЙ. Российский физиологический журнал им. И. М. Сеченова, 106(6), 696–719. https://doi.org/10.31857/S0869813920060126

Аннотация

Активность периферических звеньев гипоталамо-гипофизарно-гонадной и -тиреоидной осей регулируется гипофизарными гормонами – гонадотропинами и тиреотропным гормоном (ТТГ), которые секретируются специализированными клетками аденогипофиза. Лютеинизирующий гормон (ЛГ) и его гомолог хорионический гонадотропин (ХГ) свои стероидогенные эффекты реализуют посредством связывания с рецепторами ЛГ/ХГ, расположенными на поверхности клеток Лейдига в семенниках и клеток теки и гранулезы зрелого фолликула в яичниках. Фолликулостимулирующий гормон (ФСГ) связывается с рецепторами ФСГ, локализованными на поверхности клеток Сертоли в семенниках и клеток гранулезы примордиальных и созревающих фолликулов в яичниках, контролируя процессы фолликулогенеза, сперматогенеза и стероидогенеза. ТТГ через активацию рецептора ТТГ стимулирует синтез тиреоидных гормонов тироцитами щитовидной железы. Гонадотропины (ЛГ, ХГ, ФСГ) и ТТГ, которые с высоким сродством связываются с внеклеточным доменом специфичных к ним G-белок-сопряженных рецепторов, активируют сразу несколько сигнальных каскадов, реализуемых через различные типы G-белков и β-аррестинов. Применяемые для лечения репродуктивных дисфункций и во вспомогательных репродуктивных технологиях рекомбинантные и выделенные из природных источников гонадотропины имеют ряд недостатков, вследствие чего ведется разработка пептидных и низкомолекулярных регуляторов рецепторов ЛГ/ХГ и ФСГ, взаимодействующих с аллостерическими сайтами, локализованными в трансмембранном или цитоплазматическом доменах рецепторов. Широкие перспективы в регуляции репродуктивных функций и контроле фертильности открывает использование адипокинов, пептидов инсулинового и релаксинового семейств, антидиабетического препарата метформина, которые не только регулируют и модулируют ответ гонад на гонадотропины, но и сами влияют на стероидогенез и созревание гамет. В случае рецепторов ТТГ наиболее остро стоит проблема снижения их повышенной активности при аутоиммунных и онкологических заболеваниях щитовидной железы и при эндокринной офтальмопатии. Наиболее перспективными в этом отношении являются разрабатываемые в настоящее время низкомолекулярные инверсионные агонисты и нейтральные антагонисты, которые взаимодействуют с аллостерическим сайтом, расположенным в трансмембранном домене рецептора ТТГ. Настоящий обзор посвящен современным достижениям в области разработки и изучения эндогенных и синтетических регуляторов и модуляторов рецепторов гонадотропинов и ТТГ, а также их влиянию на периферические компоненты гипоталамо-гипофизарно-гонадной и -тиреоидной осей.

https://doi.org/10.31857/S0869813920060126
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Литература

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

Шпаков А.О. Гонадотропины – от теории к клинической практике. Санкт-Петербург. ПОЛИТЕХ-ПРЕСС. 2018. eLIBRARY ID: 3642381. [Shpakov A.O. Gonadotropins - from theory to clinical practice. St. Petersburg. Polytech-Press. 2018. eLIBRARY ID: 3642381 (In Russ)].

Szymańska K., Kałafut J., Rivero-Müller A. The gonadotropin system, lessons from animal models and clinical cases. Minerva Ginecol. 70(5):561–587. 2018. doi: 10.23736/S0026-4784.18.04307-1

Lunenfeld B., Bilger W., Longobardi S., Alam V., D'Hooghe T., Sunkara S.K. The Development of Gonadotropins for Clinical Use in the Treatment of Infertility. Front. Endocrinol. (Lausanne). 10:429. 2019. doi: 10.3389/fendo.2019.00429

Puett D., Li Y., DeMars G., Angelova K., Fanelli F. A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein. Mol. Cell. Endocrinol. 260–262:126–136. 2007. doi: 10.1016/j.mce.2006.05.009

Puett D., Angelova K., da Costa M.R., Warrenfeltz S.W., Fanelli F. 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(1–2):47–55. 2010. doi: 10.1016/j.mce.2010.04.025

Ulloa-Aguirre A., Dias J.A., Bousfield G., Huhtaniemi I., Reiter E. Trafficking of the follitropin receptor. Methods Enzymol. 521:17–45. 2013.

Lizneva D., Rahimova A., Kim S.M., Atabiekov I., Javaid S., Alamoush B., Taneja C., Khan A., Sun L., Azziz R., Yuen T., Zaidi M. FSH Beyond Fertility. Front. Endocrinol. (Lausanne). 10:136. 2019. doi: 10.3389/fendo.2019.00136

Ulloa-Aguirre A., Crepieux P., Poupon A., Maurel M.C., Reiter E. Novel pathways in gonadotropin receptor signaling and biased agonism. Rev. Endocr. Metab. Disorders. 12:259–274. 2011.

Riccetti L., De Pascali F., Gilioli L., Potì F., Giva L.B., Marino M., Tagliavini S., Trenti T., Fanelli F., Mezzullo M., Pagotto U., Simoni M., Casarini L. 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(1):2. 2017. doi: 10.1186/s12958-016-0224-3

Riccetti L., Yvinec R., Klett D., Gallay N., Combarnous Y., Reiter E., Simoni M., Casarini L., Ayoub M.A. Human luteinizing hormone and chorionic gonadotropin display biased agonism at the LH and LH/CG receptors. Sci. Rep. 7(1):940. 2017.

Hollander-Cohen L., Böhm B., Hausken K., Levavi-Sivan B. Ontogeny of the specificity of gonadotropin receptors and gene expression in carp. Endocr. Connect. 8(11):1433–1446. 2019. doi: 10.1530/EC-19-0389

Anderson R.C., Newton C.L., Millar R.P. Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists. Front. Endocrinol. (Lausanne). 9:757. 2019. doi: 10.3389/fendo.2018.00757

Patel J., Landers K., Li H., Mortimer R.H., Richard K. Thyroid hormones and fetal neurological development. J. Endocrinol. 209:1–8. 2011.

Fekete C., Lechan R.M. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocrin. Rev. 35:159–194. 2014.

Шпаков А.О. Тиреоидная система в норме и при сахарном диабете 1-го и 2-го типов. Санкт-Петербург. Изд-во Политехнического университета. 2016. eLIBRARY ID: 29744259. [Shpakov A.O. The thyroid system is normal and with type 1 and type 2 diabetes. St. Petersburg. Polytechnic Univer. Publ. 2016. eLIBRARY ID: 29744259. (In Russ)].

Kleinau G., Worth C.L., Kreuchwig A., Biebermann H., Marcinkowski P., Scheerer P., Krause G. Structural-functional features of the thyrotropin receptor: A class A G-protein-coupled receptor at work. Front. Endocrinol. (Lausanne). 8:86. 2017. doi: 10.3389/fendo.2017.00086

Rapoport B., McLachlan S.M. The thyrotropin receptor in Graves’ disease. Thyroid. 17:911–922. 2007.

Hwangbo Y., Park Y.J. Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid Cancer. Endocrinol. Metab. (Seoul). 33(2):175–184. 2018. doi: 10.3803/EnM.2018.33.2.175

Krause G., Marcinkowski P. Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal-)function, with Special Emphasis on the TSH Receptor. Horm. Metab. Res. 50(12):894–907. 2018. doi: 10.1055/a-0749-6528

Fournier T. Human chorionic gonadotropin: Different glycoforms and biological activity depending on its source of production. Ann. Endocrinol. (Paris). 77(2):75–81. 2016. doi: 10.1016/j.ando.2016.04.012

Bousfield G.R., Harvey D.J. Follicle-Stimulating Hormone Glycobiology. Endocrinology. 160(6):1515–1535. 2019. doi: 10.1210/en.2019-00001

Davis J.S., Kumar T.R., May J.V., Bousfield G.R. Naturally Occurring Follicle-Stimulating Hormone Glycosylation Variants. J. Glycomics Lipidomics. 4(1):e117. 2014.

Шпаков А.О. Гликозилирование гонадотропинов как важнейший механизм регуляции их активности. Рос. физиол. журн им. И.М. Сеченова. 103(9):1004–1021. 2017. [Shpakov A.O. Glycosylation of gonadotropins as an important mechanism for regulating their activity. Ros. Fiziol. Zh. Im. I.M. Sechenova. 103(9):1004–1021. 2017. (In Russ)].

Bousfield G.R., May J.V., Davis J.S., Dias J.A., Kumar T.R. In Vivo and In Vitro Impact of Carbohydrate Variation on Human Follicle-Stimulating Hormone Function. Front. Endocrinol. (Lausanne). 9:216. 2018. doi: 10.3389/fendo.2018.00216

Nwabuobi C., Arlier S., Schatz F., Guzeloglu-Kayisli O., Lockwood C.J., Kayisli U.A. hCG: Biological Functions and Clinical Applications. Int. J. Mol. Sci. 18(10):pii:E2037. 2017. doi: 10.3390/ijms18102037

Casarini L., Brigante G., Simoni M., Santi D. Clinical Applications of Gonadotropins in the Female: Assisted Reproduction and Beyond. Prog. Mol. Biol. Transl. Sci. 143:85–119. 2016. doi: 10.1016/bs.pmbts.2016.08.002

Wang H., May J., Butnev V., Shuai B., May J.V., Bousfield G.R., Kumar T.R. 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. doi: 10.1016/j.mce.2016.08.031

Simon L.E., Liu Z., Bousfield G.R., Kumar T.R., Duncan F.E. Recombinant FSH glycoforms are bioactive in mouse preantral ovarian follicles. Reproduction. 158(6):517–527. 2019. doi: 10.1530/REP-19-0392

Manfredi-Lozano M., Roa J., Ruiz-Pino F., Piet R., Garcia-Galiano D., Pineda R., Zamora A., Leon S., Sanchez-Garrido M.A., Romero-Ruiz A., Dieguez C., Vazquez M.J., Herbison A.E., Pinilla L., Tena-Sempere M. Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Mol. Metab. 5:844–857. 2016.

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

Kusminski C.M., McTernan P.G., Schraw T., Kos K., O'Hare J.P., Ahima R., Kumar S., Scherer P.E. Adiponectin complexes in human cerebrospinal fluid: Distinct complex distribution from serum. Diabetologia. 50:634–642. 2007.

Wen J.P., Liu C., Bi W.K., Hu Y.T., Chen Q., Huang H., Liang J.X., Li L.T., Lin L.X., Chen G. Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons. J. Endocrinol. 214:177–189. 2012.

Caprio M., Fabbrini E., Isidori A., Aversa A., Fabbri A. Leptin in reproduction. Trends Endocrinol. Metab. 12:65–72. 2001.

Caminos J.E., Nogueiras R., Gaytán F., Pineda R., González C.R., Barreiro M.L., Castaño J.P., Malagón M.M., Pinilla L., Toppari J., Diéguez C., Tena-Sempere M. Novel expression and direct effects of adiponectin in the rat testis. Endocrinology. 149:3390–3402. 2008.

Pfaehler A., Nanjappa M.K., Coleman E.S., Mansour M., Wanders D., Plaisance E.P., Judd R.L., Akingbemi B.T. Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis. Toxicol. Lett. 209:78–85. 2012.

Kadivar A., Heidari Khoei H., Hassanpour H., Golestanfar A., Ghanaei H. Correlation of adiponectin mRNA abundance and its receptors with quantitative parameters of sperm motility in rams. Int. J. Fertil. Steril. 10:127–135. 2016.

Landry D.A., Sormany F., Haché J., Roumaud P., Martin L.J. 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.

Banks W.A., McLay R.N., Kastin A.J., Sarmiento U., Scully S. Passage of leptin across the blood-testis barrier. Am. J. Physiol. 276:E1099–E1104. 1999.

Thomas S., Kratzsch D., Schaab M., Scholz M., Grunewald S., Thiery J., Paasch U., Kratzsch J. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil. Steril. 99:1256–1263. 2013.

Heinz J.F., Singh S.P., Janowitz U., Hoelker M., Tesfaye D., Schellander K., Sauerwein H. Characterization of adiponectin concentrations and molecular weight forms in serum, seminal plasma, and ovarian follicular fluid from cattle. Theriogenology. 83:326–333. 2015.

Roumaud P., Martin L. 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.

Yi X., Gao H., Chen D., Tang D., Huang W., Li T., Ma T., Chang B. 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. doi: 10.1152/ajpregu.00405.2016

Attia N., Caprio S., Jones T.W., Heptulla R., Holcombe J., Silver D., Sherwin R.S., Tamborlane W.V. 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.

Isidori A.M., Caprio M., Strollo F., Moretti C., Frajese G., Isidori A., Fabbri A. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J. Clin. Endocrinol. Metab. 84(10):3673–3680. 1999.

Sorokoumov V.N., Shpakov A.O. 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(4):259–270. 2017. doi: 10.1134/S0022093017040020

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

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

Riammer S., Garten A., Schaab M., Grunewald S., Kiess W., Kratzsch J., Paasch U. Nicotinamide phosphoribosyltransferase production in human spermatozoa is influenced by maturation stage. Andrology. 4:1045–1053. 2016.

Tekin S., Erden Y., Sandal S., Etem Onalan E., Ozyalin F., Ozen H., Yilmaz B. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch. Physiol. Biochem. 123:9–15. 2017.

Elfassy Y., Bastard J.P., McAvoy C., Fellahi S., Dupont J., Levy R. Adipokines in semen: Physiopathology and effects on spermatozoas. Int. J. Endocrinol. 2018:3906490. 2018. doi: 10.1155/2018/3906490

Spicer L.J., Aad P.Y. 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(1):18–27. 2007. doi: 10.1095/biolreprod.106.058230

Wang T., Liu Y., Lv M., Xing Q., Zhang Z., He X., Xu Y., Wei Z., Cao Y. miR-323-3p regulates the steroidogenesis and cell apoptosis in polycystic ovary syndrome (PCOS) by targeting IGF-1. Gene. 683:87–100. 2019. doi: 10.1016/j.gene.2018.10.006

Kristensen S.G., Mamsen L.S., Jeppesen J.V., Bøtkjær J.A., Pors S.E., Borgbo T., Ernst E., Macklon K.T., Andersen C.Y. 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. doi: 10.3389/fendo.2017.00376

Sirotkin A., Alexa R., Kádasi A., Adamcová E., Alwasel S., Harrath A.H. 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. doi: 10.1071/RD18425

Bøtkjær J.A., Pors S.E., Petersen T.S., Kristensen S.G., Jeppesen J.V., Oxvig C., Andersen C.Y. Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development. J. Assist. Reprod. Genet. 36(5):889–903. 2019. doi: 10.1007/s10815-019-01432-x

Spitschak M., Hoeflich A. Potential Functions of IGFBP-2 for Ovarian Folliculogenesis and Steroidogenesis. Front. Endocrinol. (Lausanne). 9:119. 2018. doi: 10.3389/fendo.2018.00119

Ivell R., Heng K., Anand-Ivell R. Insulin-Like Factor 3 and the HPG Axis in the Male. Front. Endocrinol. (Lausanne). 5:6. 2014. doi: 10.3389/fendo.2014.00006

Ivell R., Agoulnik A.I., Anand-Ivell R. Relaxin-like peptides in male reproduction - a human perspective. Br. J. Pharmacol. 174(10):990–1001. 2017. doi: 10.1111/bph.13689.

Coskun G., Sencar L., Tuli A., Saker D., Alparslan M.M., Polat S. Effects of Osteocalcin on Synthesis of Testosterone and INSL3 during Adult Leydig Cell Differentiation. Int. J. Endocrinol. 2019:1041760. 2019. doi: 10.1155/2019/1041760

Shpakova E.A., Derkach K.V., Shpakov A.O. Biological activity of lipophilic derivatives of peptide 562–572 of rat luteinizing hormone receptor. Dokl. Biochem. Biophys. 452(1):248–250. 2013. doi: 10.1134/S1607672913050116

Derkach K.V., Shpakova E.A., Shpakov A.O. Palmitoylated peptide 562–572 of luteinizing hormone receptor increases testosterone level in male rats. Bull. Exp. Biol. Med. 158(2):209–212. 2014. doi: 10.1007/s10517-014-2724-5

van Straten N.C., Schoonus-Gerritsma G.G., van Someren R.G., Draaijer J., Adang A.E., Timmers C.M., Hanssen R.G., van Boeckel C.A. 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(10):1023–1026. 2002. doi: 10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9

van de Lagemaat R., Timmers C.M., Kelder J., van Koppen C., Mosselman S., Hanssen R.G. Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. Hum. Reprod. 24(3):640–648. 2009. doi: 10.1093/humrep/den412

van de Lagemaat R., Raafs B.C., van Koppen C., Timmers C.M., Mulders S.M., Hanssen R.G. 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(11):4350–4357. 2011. doi: 10.1210/en.2011-1077

Gerrits M., Mannaerts B., Kramer H., Addo S., Hanssen R. First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age. J. Clin. Endocrinol. Metab. 98(4):1558–1566. 2013. doi: 10.1210/jc.2012-3404

Derkach K.V., Dar’in D.V., Lobanov P.S., Shpakov A.O. Intratesticular, intraperitoneal, and oral administration of thienopyrimidine derivatives increases the testosterone level in male rats. Dokl. Biol. Sci. 459(1):326–329. 2014. doi: 10.1134/S0012496614060040

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

Derkach K.V., Dar’in D.V., Bakhtyukov A.A., Lobanov P.S., Shpakov A.O. In vitro and in vivo studies of functional activity of new low molecular weight agonists of the luteinizing hormone receptor. Biochemistry (Moscow). Suppl Ser A: Membran. Cell Biology. 10(4):294–300. 2016. doi: 10.1134/S1990747816030132

Bakhtyukov A.A., Derkach K.V., Dar’in D.V., Shpakov A.O. Thienopyrimidine derivatives specifically activate testicular steroidogenesis but do not affect thyroid functions. J. Evol. Biochem. Physiol. 55(1):30–39. 2019. doi: 10.1134/S0022093019010046.

Деркач К.В., Дарьин Д.В., Шпаков А.О. Низкомолекулярные лиганды рецептора лютеинизирующего гормона с активностью антагонистов. Биол. мембраны. 37(3):1–10. 2020. doi: 10.31857/S0233475520030032. [Derkach K.V., Dar’in D.V., Shpakov A.O. The low-molecular-weight ligands of the luteinizing hormone receptor with antagonistic activity. Biol. Membr. 37(3):1–10. 2020. doi: 10.31857/S0233475520030032]

Бахтюков А.А., Соколова Т.В., Дарьин Д.В., Деркач К.В., Шпаков А.О. Сравнительное изучение стимулирующего эффекта низкомолекулярного агониста рецептора лютеинизирующего гормона и хорионического гонадотропина на стероидогенез в клетках Лейдига крысы. Рос. физиол. журн. им. И.М. Сеченова. 103(10):1181–1192. 2017. [Bakhtyukov A.A., Sokolova T.V., Dar’in D.V., Derkach K.V., Shpakov A.O. Comparative study of the stimulating effect of a low molecular weight luteinizing hormone receptor agonist and chorionic gonadotropin on steroidogenesis in the rat Leydig cells. Ros. Fiziol. Zh. im. I.M. Sechenova. 103(10):1181–1192. 2017. (In Russ)].

Bakhtyukov A.A., Derkach K.V., Dar’in D.V., Shpakov A.O. 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(1):78–81. 2019. doi: 10.1134/S1607672919 010216

Newton C.L., Whay A.M., McArdle C.A., Zhang M., van Koppen C.J., van de Lagemaat R., Segaloff D.L., Millar R.P. 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(17):7172–77176. 2011. doi: 10.1073/pnas.1015723108

Bakhtyukov A.A., Derkach K.V., Dar’in D.V., Sharova T.S., Shpakov A.O. Decrease in the basal and luteinizing hormone receptor agonist-stimulated testosterone production in aging male rats. Adv. Gerontol. 9(2):179–185. 2019. https://doi.org/10.1134/S2079057019020036

Bakhtyukov A.A., Derkach K.V., Dar’in D.V., Stepochkina A.M., Shpakov A.O. 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. (Moscow). Suppl Ser A: Membr Cell Biol. 13(4):301–309. 2019. doi: 10.1134/S1990747819040032

Heidelbaugh J.J. Endocrinology Update: Hirsutism. FP Essent. 451:17-24. 2016.

Mizushima T., Miyamoto H. The Role of Androgen Receptor Signaling in Ovarian Cancer. Cells. 8(2):pii: E176. 2019. doi: 10.3390/cells8020176

El Tayer N., Reddy A., Buckler D. Applied Research Systems ARS Holding N.A., assignee FSH Mimetics for the Treatment of Infertility. Unites States patent US 6,235,755. 2001.

Yanofsky S.D., Shen E.S., Holden F., Whitehorn E., Aguilar B., Tate E., Holmes C.P., Scheuerman R., MacLean D., Wu M.M., Frail D.E., López F.J., Winneker R., Arey B.J., Barrett R.W. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. J. Biol. Chem. 281(19):13226–13233. 2006. doi: 10.1074/jbc.M600601200

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

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

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

Zoenen M., Urizar E., Swillens S., Vassart G., Costagliola S. Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers. Nat. Commun. 3:1007. 2012. doi: 10.1038/ncomms1991

Sriraman V., Denis D., de Matos D., Yu H., Palmer S., Nataraja S. 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(2):266–275. 2014. doi: 10.1016/j.bcp.2014.02.023

van Koppen C.J., Verbost P.M., van de Lagemaat R., Karstens W.J., Loozen H.J., van Achterberg T.A., van Amstel M.G., Brands J.H., van Doornmalen E.J., Wat J., Mulder S.J., Raafs B.C., Verkaik S., Hanssen R.G., Timmers C.M. Signaling of an allosteric, nanomolar potent, low molecular weight agonist for the follicle-stimulating hormone receptor. Biochem. Pharmacol. 85(8):1162–1170. 2013. doi: 10.1016/j.bcp.2013.02.001

Timmers C.M., Karstens W.F., Grima Poveda P.M. Inventors; N.V. Organon. Assignee 4-Phenyl-5-Oxo-1,4,5,6,7,8-Hexahydroquinoline Derivatives as Medicaments for the Treatment of Infertility. United States patent US WO2006/117370. 2006.

Fares F. 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.

Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid. 8:941–946. 1998.

Tala H., Robbins R., Fagin J.A., Larson S.M., Tuttle R.M. 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(7):2105–2111. 2011. doi: 10.1210/jc.2011-0305

Rani D., Kaisar S., Awasare S., Kamaldeep, Abhyankar A., Basu S. 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(9):1767–1780. 2014. doi: 10.1007/s00259-014-2737-3

Schaarschmidt J., Huth S., Meier R., Paschke R., Jaeschke H. Influence of the hinge region and its adjacent domains on binding and signaling patterns of the thyrotropin and follitropin receptor. PLoS One. 9(10):e111570. 2014. doi: 10.1371/journal.pone.0111570

Brüser A., Schulz A., Rothemund S., Ricken A., Calebiro D., Kleinau G., Schöneberg T. The activation mechanism of glycoprotein hormone receptors with implications in the cause and therapy of endocrine diseases. J. Biol. Chem. 291:508–520. 2016.

Krieger C.C., Perry J.D., Morgan S.J., Kahaly G.J., Gershengorn M.C. TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types. Endocrinology. 158(10):3676–3683. 2017. doi: 10.1210/en.2017-00528

Paik J.S., Kim S.E., Kim J.H., Lee J.Y., Yang S.W., Lee S.B. Insulin-like growth factor-1 enhances the expression of functional TSH receptor in orbital fibroblasts from thyroid-associated ophthalmopathy. Immunobiology. 25:151902. 2019. doi: 10.1016/j.imbio.2019.151902

Derkach K.V., Bogush I.V., Berstein L.M., Shpakov A.O. The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats. Horm. Metab. Res. 47(12):916–924. 2015. doi: 10.1055/s-0035-1547236

Smith T.J., Janssen J.A.M.J.L. Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy. Endocr. Rev. 40(1):236–267. 2019. doi: 10.1210/er.2018-00066.

Nakabayashi K., Matsumi H., Bhalla A., Bae J., Mosselman S., Hsu S.Y., Hsueh A.J. Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J. Clin. Invest. 109:1445–1452. 2002.

Wondisford F.E. The thyroid axis just got more complicated. J. Clin. Invest. 109:1401–1402. 2002.

Baquedano M.S., Ciaccio M., Dujovne N., Herzovich V., Longueira Y., Warman D.M., Rivarola M.A., Belgorosky A. 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.

McLachlan S.M., Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 23(1):14–24. 2013. doi: 10.1089/thy.2012.0374.

Bahn R.S. Autoimmunity and Graves’ disease. Clin. Pharmacol. Ther. 91:577–579. 2012.

Sato S., Noh J.Y., Sato S., Suzuki M., Yasuda S., Matsumoto M., Kunii Y., Mukasa K., Sugino K., Ito K., Nagataki S., Taniyama M. 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.

Moore S., Jaeschke H., Kleinau G., Neumann S., Costanzi S., Jiang J.K., Childress J., Raaka B.M., Colson A., Paschke R., Krause G., Thomas C.J., Gershengorn M.C. 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.

Heitman L.H., Ijzerman A.P. 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.

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

Lane J.R., IJzerman A.P. Allosteric approaches to GPCR drug discovery. Drug Discov. Today Technol. 10:219–221. 2013.

Neumann S., Nir E.A., Eliseeva E., Huang W., Marugan J., Xiao J., Dulcey A.E., Gershengorn M.C. A Selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology. 155:310–314. 2014.

Neumann S., Padia U., Cullen M.J., Eliseeva E., Nir E.A., Place R.F., Morgan S.J., Gershengorn M.C. An enantiomer of an oral small-molecule TSH receptor agonist exhibits improved pharmacologic properties. Front. Endocrinol. (Lausanne). 7:105. 2016. doi: 10.3389/fendo.2016.00105.

Шпаков А.О. Новые достижения в разработке и изучении механизмов действия низкомолекулярных агонистов рецепторов тиреотропного и лютеинизирующего гормонов. Цитология. 57(3):167–176. 2015. [Shpakov A.O. New advances in the development and study of the mechanisms of action of low molecular weight agonists of thyrotropic and luteinizing hormone receptors. Tsitologiia. 57(3):167–176. 2015.(In Russ)].

Neumann S., Huang W., Titus S., Krause G., Kleinau G., Alberobello A.T., Zheng W., Southall N.T., Inglese J., Austin C.P., Celi F.S., Gavrilova O., Thomas C.J., Raaka B.M., Gershengorn M.C. Small molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc. Natl. Acad. Sci. USA. 106:12471–12476. 2009.

Allen M.D., Neumann S., Gershengorn M.C. 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.

Meyer Zu Horste M., Pateronis K., Walz M.K., Alesina P., Mann K., Schott M., Esser J., Eckstein A.K. The effect of early thyroidectomy on the course of active Graves’ Orbitopathy (GO): A retrospective case study. Horm. Metab. Res. 48:433–439. 2016.

Bahn R.S., Burch H.S., Cooper D.S., Garber J.R., Greenlee C.M., Klein I.L., Laurberg P., McDougall I.R., Rivkees S.A., Ross D., Sosa J.A., Stan M.N. 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.

Neumann S., Place R.F., Krieger C.C., Gershengorn M.C. Future Prospects for the Treatment of Graves’ Hyperthyroidism and Eye Disease. Horm. Metab. Res. 47:789–796. 2015.

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

Kahaly G.J., Shimony O., Gellman Y.N., Lytton S.D., Eshkar-Sebban L., Rosenblum N., Refaeli E., Kassem S., Ilany J., Naor D. Regulatory T-cells in Graves’ orbitopathy: Baseline findings and immunomodulation by anti-lymphocyte globulin. J. Clin. Endocrinol. Metab. 96:422–429. 2011.

Chen H., Shan S.J.C., Mester T., Wei Y.-H., Douglas R.S. TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist. PLoS One. 10:e0130322. 2015.

Smith T.J., Kahaly G.J., Ezra D.G., Fleming J.C., Dailey R.A., Tang R.A., Harris G.J., Antonelli A., Salvi M., Goldberg R.A., Gigantelli J.W., Couch S.M., Shriver E.M., Hayek B.R., Hink E.M., Woodward R.M., Gabriel K., Magni G., Douglas R.S. Teprotumumab for Thyroid-Associated Ophthalmopathy. N. Engl. J. Med. 376:1748–1761. 2017.

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

Neumann S., Kleinau G., Costanzi S., Moore S., Jiang J.K., Raaka B.M., Thomas C.J., Krause G., Gershengorn M.C. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology. 149:5945–5950. 2008.

Neumann S., Eliseeva E., McCoy J.G., Napolitano G., Giuliani C., Monaco F., Huang W., Gershengorn M.C. A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J. Clin. Endocrinol. Metab. 96:548–554. 2011.

Turcu A.F., Kumar S., Neumann S., Coenen M., Iyer S., Chiriboga P., Gershengorn M.C., Bahn R.S. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J. Clin. Endocrinol. Metab. 98:2153–2159. 2013.

Marcinkowski P., Hoyer I., Specker E., Furkert J., Rutz C., Neuenschwander M., Sobottka S., Sun H., Nazare M., Berchner-Pfannschmidt U., von Kries J.P., Eckstein A., Schülein R., Krause G. A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy. Thyroid. 29(1):111-123. 2019. doi: 10.1089/thy.2018.0349

Marcinkowski P., Kreuchwig A., Mendieta S., Hoyer I., Witte F., Furkert J., Rutz C., Lentz D., Krause G., Schülein R. Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain. Mol. Pharmacol. 96(4):452–462. 2019. doi: 10.1124/mol.119.116947.

Shpakova E.A., Shpakov A.O., Chistyakova O.V., Moyseyuk I.V., Derkach K.V. 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. doi: 10.1134/S1607672912020020.

Деркач К.В., Шпакова Е.А., Бондарева В.М., Шпаков А.О. Исследование дозо-зависимости стимулирующего влияния пептида, производного рецептора тиреотропного гормона, на продукцию тиреоидных гормонов у крыс. Трансляционная медицина. 1(30):15–21. 2015. [Derkach K.V., Shpakova E.A., Bondareva V.M., Shpakov A.O. A study of the dose dependence of the stimulating effect of a peptide, a derivative of the thyroid stimulatinцинg hormone receptor, on the production of thyroid hormones in rats. Translational Medicine. 1(30):15–21. 2015. (In Russ)].

Derkach K.V., Shpakova E.A., Titov A.M., Shpakov A.O. 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.