Reviews on Clinical Pharmacology and Drug TherapyReviews on Clinical Pharmacology and Drug TherapyОбзоры по клинической фармакологии и лекарственной терапии1683-41002542-1875Eco-Vector77310.17816/RCF1243-12ArticlesСтатьиKisspeptins in physiology and pathology of sex development - new diagnostic and therapeutic approachesКисспептины в физиологии и патологии полового развития - новые диагностические и терапевтические возможностиNikitinaIrina LeorovnaНикитинаИрина Леоровна

Dr. Med. Sci., Professor, Chief Doctor, Centre of Neonatology

д. м. н., профессор, главный врач Центра неонатологии

BayramovAlekber AzizovichБайрамовАлекбер Азизович

Dr. Med. Sci., Deputy Director, Institute of Endocrinology

д. м. н., зам. директора Института эндокринологии

alekber@mail.ruKhodulevaYuliya NikolaevnaХодулеваЮлия Николаевна

Fellow, Centre of Neonatology

соискатель, Институт эндокринологии

ShabanovPetr DmitriyevichШабановПетр Дмитриевич

Dr. Med. Sci., Professor, Leading Researcher, Institute of Endocrinology

д. м. н., ведущий научный сотрудник Института эндокринологии

pdshabanov@mail.ruAlmazov Federal Medical Recearch CentreФГБУ «Федеральный медицинский исследовательский центр им. В. А. Алмазова» Минздрава РФ15122014124VOL 12, NO4 (2014)ТОМ 12, №4 (2014)31221102015Copyright ©; 2014, Nikitina I.L., Bayramov A.A., Khoduleva Y.N., Shabanov P.D.Copyright ©; 2014, Никитина И.Л., Байрамов А.А., Ходулева Ю.Н., Шабанов П.Д.2014Nikitina I.L., Bayramov A.A., Khoduleva Y.N., Shabanov P.D.Никитина И.Л., Байрамов А.А., Ходулева Ю.Н., Шабанов П.Д.http://creativecommons.org/licenses/by/4.0https://journals.eco-vector.com/RCF/article/view/773

The article is dedicated to mechanisms of the human reproductive system development mechanisms. The evolution of the opinions on that processes was analysed. The review of modern knowledge of molecular and genetic causes of sex development, new mechanisms of gonadal axis regulation and role of kisspeptins in pubertat start and sexual differentiation of the brain are presented. The new actual directions of scientific research as well as the applications of kisspeptin drugs for new therapeutic approaches, treatment of hormone-dependent diseases and abnormalities of sex developmentare are observed.

Публикация посвящена обсуждению механизмов, лежащих в основе функционирования репродуктивной системы человека. Проанализирована эволюция взглядов на данные процессы. Представлен обзор современных представлений о молекулярно-генетических основах половой дифференцировки, механизмах регуляции гонадной оси, роли кисспептинов в старте пубертата и сексуальной дифференцировки мозга. Обозначены актуальные направления научных исследований и возможности применения препаратов кисспептина в новых терапевтических подходах лечения гормонзависимых заболеваний и патологий полового развития.

reproductive systemkisspeptinsdisorder of sex developmentgonadal axiskisspeptin drugsрепродуктивная системакисспептинынарушение формирования полагонадная осьпрепараты кисспептинаБайрамов А. А., Новикова Е. Н., Комяков Б. К., Прошин С. Н. Влияние пренатального стресса на половое поведение в эксперименте // Мед.-биол. и соц.-психол. пробл. безопасности в чрезвыч. ситуациях. - 2008. - № 2. - С. 48-53.Байрамов А. А., Сапронов Н. С. Влияние М- и Н-холинолитиков на пренатальное развитие моноаминергической системы головного мозга // Мед. акад. журнал. - 2007. - Т. 7, № 4. - С. 52-59.Дедов И. И., Семичева Т. В., Петеркова В. А. Половое развитие детей: норма и патология. - М.: Колорит студио, 2002.Никитина И. Л. Старт пубертата - известное и новое // Артер. гипертензия. - 2013. - Т. 19, № 3. - С. 227-236.Altarejos J. Y., Goebel N., Conkright M. D. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility // Nat. Med. - 2008. - Vol. 14. - P. 112-1117.Barker-Gibb M. L., Sahu A., Pohl C. R., Plant T. M. Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta) does not elicit precocious gonadotropin-releasing hormone release, assessed indirectly // J. Clin. Endocrinol. Metab. 2002. - Vol. 87. - P. 4976-4983.Bianco S. D., Kaiser U. B. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism // Nat. Rev. Endocrinol. - 2009. - Vol. 5. - P. 569-576.Brown R. E., Imran S. A., Ur E., Wilkinson M. KiSS-1 mRNA in adipose tissue is regulated by sex hormones and food intake // Mol. Cell Endocrinol. - 2008. - Vol.28. - P. 64-72.Canto P., Munguia P., Söderlund D. et al. Genetic Analysis in Patients With Kallmann Syndrome: Coexistence of Mutations in Prokineticin Receptor 2 and KAL1 // J. Androl. - 2009. - Vol. 30. - P. 41-45.Chan Y. M., Fenoglio-Simeone K. A., Paraschos S. et al. Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1 // Horm. Res. Paediatr. - 2010. - Vol. 73. - P. 312-319.Cota D., Proulx K., Smith K. A. et al. Hypothalamic mTOR signaling regulates food intake // Science. - 2006. - Vol. 312. - P. 927-930.D’Anglemont de Tassigny X., Colledge W. H. The role of kisspeptin signaling in reproduction // Physiology. - 2010. - Vol. 25. - P. 207-217.De Roux N., Genin E., Carel J. C. et al. Hypogonadotropic hypogonadism due to loss of function of the KISS1-derived peptide receptor GPR54 // Proc. Natl. Acad. Sci. USA. - 2003. - Vol. 100. - P. 10972-10976.Dhillo W. S., Chaudhri O. B., Patterson M. et al. Kisspeptin-54 stimulates the hypothalamic-pituitary-gonadal axis in human males // J. Clin. Endocrinol. Metab. - 2005. - Vol. 90. - P. 6609-6615.Dode C., Teixeira L., Levilliers J. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2 // PLoS Genet. - 2006. - Vol. 2. - P.e175.Durnerin C. I., Erb K., Fleming R. et al. Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation // Hum. Reprod. - 2008. - Vol. 23, N 2. - P. 421-426.Ehlers K., Halvorson. L. Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR) // Glob. libr. women’s med. - 2013. (ISSN: 1756-2228); DOI 10.3843/GLOWM.10285Fernandez-Fernandez R., Martini A. C., Navarro V. M. et al. Novel signals for the integration of energy balance and reproduction // Mol. Cell Endoc. - 2006. - Vol. 254-255. - P. 127-132.Funes S., Hedrick J. A., Vassileva G. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system // Biochem. Biophys. Res. Commun. - 2003. - Vol. 312. - P. 1357-1363.Gottsch M. L., Clifton D. K., Steiner R. A. Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis // Mol. Cell Endocrinol. - 2006. - Vol. 254-255. - P. 91-96.Guerriero K. A., Keen K. L., Millar R. P., Terasawa E. Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female rhesus monkeys (Macaca mulatta): implication for the mechanism of puberty // Endocrinology. - 2012. - Vol. 153. - P. 825- 836.Heger S., Partsch C. J., Peter M. et al. Serum leptin levels in patients with progressive central precocious puberty // Pediatr. Res. - 1999. - Vol. 46, N 1. - P.71-75.Herbison A. E. Physiology of the gonadotropin-releasing hormone neuronal network // The Physiology of Reproduction/Ed. by J. D. Neill. - New York: Elsevier. - 2006. - P. 415-1482.Herman-Giddens M. E., Slora E. J., Wasserman R. C. et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network // Pediatrics. - 1997. - Vol. 99. - P. 505-512.Hileman S. M., Pierroz D. D., Flier J. S. Leptin, nutrition, and reproduction: timing is everything // J. Clin. Endocrinol. Metab. - 2000. - Vol. 85. - P. 804-807.Huma T., Ullah F., Hanif F. et al. Peripheral administration of kisspeptin antagonist does not alter basal plasma // Eur. J. Sci. Research. - 2013. - Vol.109, N 4. - P. 668-677.Kalra S. P., Pu S., Horvath T. L., Kalra P. S. Leptin and NPY regulation of GnRH secretion and energy homeostasis // The onset of puberty in perspective/Ed. by J. P. Bourguignon, T. M. Plant. - Amsterdam: Elsevier Science. - 2000. - P. 317-327.Kaplowitz P. B., Oberfield S. E. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment // Pediatrics. - 1999. - Vol. 104. - P. 936 -941.Kaprio J., Rimpela A., Winter T. et. al. Common genetic influences on BMI and age at menarche // Hum Biol. - 1995. - Vol. 67. - P. 739-753.Kobayashi T., Sasaki S., Tomita N. et al. Synthesis and structure-activity relationships of 2-acylamino-4-6-diphenylpyridine derivatives as novel antagonists of GPR54 // Bioorg. Med. Chem. - 2010a. - Vol. 18, N 11. - P. 3841-3859.Kobayashi T., Sasaki S., Tomita N. et al. 2-Acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats // Bioorg. Med. Chem. - 2010b. - Vol. 18, N 14. - P. 5157-5171.Lanfranco F., Gromoll J., von Eckardstein S. et al. Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism // Eur. J. Endocrinol. - 2005. - Vol. 153. - P. 845-852.Lapatto R., Pallais J. C., Zhang D. et al. Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice // Endocrinology. - 2007. - Vol. 148. - P. 4927- 4936.Lee J. H., Miele M. E., Hicks D. J. et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene // J. Natl. Cancer Inst. -1996. - Vol. 88, № 23. - P. 1731-1737.Lee P. A., Guo S. S., Kulin H. E. Age of puberty: data from the United States of America // APMIS. - 2001. - Vol. 109. - P. 81- 88.Lee P. A., Kulin H. E., Shumei S. G. Letter to the editor: age of puberty among girls and the diagnosis of precocious puberty // Pediatrics. - 2001. - Vol. 107. - P. 1493-1494.Leka-Emiri S., Louizou E., Kambouris M. et al. Absence of GPR54 and TACR3 Mutations in Sporadic Cases of Idiopathic Central Precocious Puberty // Horm. Res. Paediatr. - 2014. - Vol. 81, N 3. - P. 177-181.Luan X., Yu H., Wei X. et al. GPR54 polymorphisms in Chinese girls with central precocious puberty // Neuroendocrinology. - 2007. - Vol. 86. - P. 77-83.Marshall W. A., Tanner J. M. Variations in the pattern of pubertal changes in boys // Arch. Dis. Child. - 1970. - Vol. 46. - P. 13-23.Meethal S. V., Liu T., Chan H. W. et al. Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors // J. Neurochemistry. - 2009. - Vol. 110, N 3. - P. 1014-1027.Miraoui H., Dwyer A. A., Sykiotis G. P. et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism // Amer. J. Hum. Genet. - 2013. - Vol. 92. - P. 725-743.Mitchell A. L., Dwyer A., Pitteloud N., Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory // Trends Endocrinol. Metab. - 2011. - Vol. 22. - P. 249-258.Muir A. I., Chamberlain L., Elshourbagy N. A. et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1 // J. Biol. Chem. - 2001. - Vol. 276. - P. 28969-28975.Navarro V. M., Castellano J. M., Fernandez-Fernandez R. et al.Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide // Endocrinology. - 2004. - Vol. 145. - P. 4565-4574.Nimri R., Lebenthal Y., Lazar L. et al. A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family // J. Clin. Endocrinol. Metab. - 2011. - Vol. 96. - P. 536-545.Ohtaki T., Shintani Y., Honda S. et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor // Nature. - 2001. - Vol. 411. - P. 613-617.Ojeda S. R., Lomniczi A., Sandau U., Matagne V. New concepts on the control of the onset of puberty // Endocr. Dev. - 2010. - Vol. 17. - P. 44 -51.Ojeda S. R., Skinner M. K. Puberty in the rat. // The Physiology of Reproduction/Ed. by J. D. Neill. - San Diego: Academic/Elsevier. - 2006. - P. 2061-2126.Palmert M. R., Hayden D. L., Mansfield M. J. et al. The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process // J. Clin. Endocrinol. Metab. - 2001. - Vol. 86. - P. 4536-4542.Palmert M. R., Radovick S., Boepple P. A. Leptin levels in children with central precocious puberty // J. Clin. Endocrinol. Metab. - 1998. - Vol. 83, N 7. - P. 2260-2265.Parent A. S., Teilmann G., Juul A. et al. The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration // Finland Endocrine Rev. - 2003. - Vol. 24, N 5. - P. 668-693.Pfaff D. W., Vasudevan N., Kia H. K. et al. Estrogens, brain and behavior: studies in fundamental neurobiology and observations related to women’s health // Journal Steroid Biochem. Mol. Biol. - 2000. - Vol. 74, N 5. - P. 365-373.Pineda R., Garcia-Galiano D., Roseweir A. et al. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist // Endocrinology. - 2010. - Vol. 151. - P. 722-730.Pitteloud N., Quinton R., Pearce S. et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism // J. Clin. Invest. - 2007. - Vol. 117. - P. 457-463.Plant T. M., Ramaswamy S., Dipietro M. J. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges // Endocrinology. - 2006. - Vol. 147. - P. 1007-1013.Popa S. M., Clifton D. K., Steiner R. A. The role of kisspeptins and GPR54 in the neuroendocrine regulation of reproduction // Annu. Rev. Physiol. - 2008. - Vol. 70. - P. 213-238.Quaynor S. D., Kim H. G., Cappello E. M. et al. The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome // Fertil. Steril. -2011. - Vol. 96. - P. 1424-1430.Rosenfield R. L., Bachrach L. K., Chernausek S. D. et al. Current age of onset of puberty // Pediatrics. - 2000. - Vol. 106. - P. 622- 623.Roseweir A. K. and Millar R. P. Kisspeptin Antagonists // Kisspeptin Signaling in Reproductive Biology. - New York: Springer. - 2013. - P. 159-186.Roseweir A. K., Kauffman A. S., Smith J. T. et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation // J. Neurosci. - 2009. - Vol. 29, N 12. - P. 3920-3929.Sarfati J., Guiochon-Mantel A., Rondard P. et al. A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes // J. Clin. Endocrinol. Metab. - 2010. - Vol. 95. - P. 659-669.Schwartz N. B. Neuroendocrine regulation of reproductive cyclicity // Neuroendocrinology in Physiology and Medicine/Ed. by P. M. Conn, M. E. Freeman. - Totowa, NJ: Humana. - 2000. - P. 135-146.Seminara S. B., Messager S., Chatzidaki E. E. et al. The GPR54 gene as a regulator of puberty // N. Engl. J. Med. - 2003. - Vol. 349. - P. 1614-1627.Shahab M., Mastronardi C., Seminara S. B. et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates // Proc. Natl. Acad. Sci. USA. - 2005. - Vol. 102. - P. 2129-2134.Shepard K. N., Michopoulos V., Toufexis D. J., Wilson M. E. Genetic, epigeneticand environmental impact on sex differences in social behaviour // Physiol. Behav. - 2009. - Vol. 97, N 2. - P. 157-170.Silveira L. G., Noel S. D., Silveira-Neto A. P. et al. Mutations of the KISS1 gene in disorders of puberty // Clin. Endocrinol. Metab. - 2010. - Vol. 95. - P. 2276-2280.Sklar C. A., Kaplan S. L., Grumbach M. M. Evidence for dissociation n between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence // J. Clin. Endocrinol. Metab. - 1980. - Vol. 51. - P. 548 -556.Smith J. T., Li Q., Yap K. S. et al. Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence // Endocrinology. - 2011. - Vol. 152. N 3. - P. 1001-1012.Sorensen K., Mouritsen A., Aksglaede L. et al. Recent secular trends in pubertal timing: implications for evalution and diagnosis of precocious // Horm. Res. Paediatr. - 2012. - Vol. 77. - P.137-145.Sykiotis G., Plummer L., Hughes V. et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency // Proc. Natl. Acad. Sci U. S. A. - 2010. - Vol. 107. - P. 15140-15144.Tanner J. M., Divies P. S. W. Clinical longitudinal standarts for height and height velocity for North American children // J. Pediatr. - 1987. - Vol. 107. - P. 317-329.Tanner J. M., Whitehouse R. H. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty // Arch. Dis. Child. - 1976. - Vol. 51. - P. 170-179.Teles M. G., Bianco S. D., Brito V. N. et al. A GPR54-activating mutation in a patient with central precocious puberty // N. Engl. J. Med. - 2008. - Vol. 358. - P. 709-715.Tena-Sempere M. Kisspeptin signaling in the brain: recent developments and future challenges // Mol. Cell Endocrinol. - 2010. - Vol. 314. - P. 164 -169.Terasawa E., Kurian J. R., Guerriero K. A. et al. Recent discoveries on the control of gonadotrophin-releasing hormone neurones in nonhuman primates // J. Neuroendocrinol. - 2010. - Vol. 22. - P. 630- 638.Topaloglu A. K., Reimann F., Guclu M. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction // Nat. Genet. - 2009. - Vol. 41. - P. 354-358.Topaloglu A. K., Tello J. A., Kotan L. D. et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism // N. Engl. J. Med. - 2012. - Vol. 366. - P. 629-635.Vaaralahti K. Molecular genetics of Kallmann syndrome and constitutional delay of growth and puberty in Finland. - Helsinki, 2014. 104 p.Wahab F., Bano R., Jabeen S. et al. Effect of peripheral kisspeptin administration on adiponectin, leptin, and resistin secretion under fed and fasting conditions in the adult male rhesus monkey (Macaca mulatta) // Horm. Metab. Res. - 2010. - Vol. 42. - P. 570-574.Wahab F., Quinton R., Seminara S. B. The kisspeptin signaling pathway and its role in human isolated GnRH deficiency // Mol. Cell. Endocrinol. - 2011. - Vol. 346. - P. 29-36.