arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2015-21-1-40-47arthyper-172Research ArticleОБЗОРREVIEWРОЛЬ ГЕНЕТИЧЕСКИХ, ГОРМОНАЛЬНЫХ И ВНЕШНЕСРЕДОВЫХ ФАКТОРОВ В ПРОЦЕССАХ ПОЛОВОЙ ДИФФЕРЕНЦИРОВКИ МОЗГАTHE ROLE OF GENETIC, HORMONAL AND ENVIRONMENTAL INFLUENCES ON SEXUAL DIFFERENTIATION OF THE BRAINКудряшоваЕ. К.KudryashovaE. K.aksi-lena@rambler.ruМасельА. С.MaselA. S.aksi-lena@rambler.ruНагорнаяИ. И.NagornayaI. I.aksi-lena@rambler.ruНикитинаИ. Л.NikitinaI. L.

Irina L. Nikitina, MD, PD, DSc, Head, Scientific Laboratory of Pediatric Endocrinology, Federal North-West Medical Research Centre

aksi-lena@rambler.ruСеверо-Западный федеральный медицинский исследовательский центр, Санкт-ПетербургРоссияFederal North-West Medical Research Centre, St PetersburgRussian Federation2015290420152114047Copyright © Кудряшова Е.К., Масель А.С., Нагорная И.И., Никитина И.Л., 20152015Кудряшова Е.К., Масель А.С., Нагорная И.И., Никитина И.Л.Kudryashova E.K., Masel A.S., Nagornaya I.I., Nikitina I.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/172

Влияние различных факторов на половое развитие очень вариабельно и сложно для исследования. Это связано с тем, что при изучении обычно невозможно оценить по отдельности влияние биологических и социальных факторов. В то время как большинство исследований исторически подчеркивают влияние генов и гормонов на половую идентификацию и полоролевые особенности, в последние годы чаще рассматриваются доказательства роли социального фактора и воспитания на половую идентификацию. Публикация посвящена обсуждению механизмов, лежащих в основе нарушений формирования пола и половой дифференцировки мозга. Проанализирована эволюция взглядов на данные процессы. Рассмотрены современные концепции механизмов нарушений формирования пола. Оценен вклад гормональных, молекулярно-генетических, эпигенетических и внешнесредовых факторов, оказывающих влияние на половую дифференцировку мозга. Обозначены актуальные направления и возможные перспективы для дальнейших научных исследований с целью разработки методов коррекции гендерных нарушений. 

Variables influencing gender development in humans are difficult to evaluate because it is usually impossible to tell apart the role of biological and social factors. While most studies of gender development and disorders of sex development have historically emphasized the importance of genes and hormones on gender identity and gender role, recently a significant role of socialization has become more evident. This article considers mechanisms underlying disorders of sexual development and brain sexual differentiation. Advanced concepts of disorders of sex development and sexual differentiation of the brain are discussed. Finally, the paper outlines the possible directions and targets for further investigation aimed at improving existing methods of health care for patients with disorders of sex development.

нарушения формирования полаполовая дифференцировка мозгаполовая идентификацияполоролевое поведениеdisorder of sex developmentsexual differentiation of the braingender identitygender rolegender behaviorReferencesНикитина И. Л. Старт пубертата — известное и новое. Артериальная гипертензия. 2013;19 (3):227–236. [Nikitina IL. The timing of puberty: well-known and new. Arterial’naya Gipertenziya = Arterial Hypertension. 2013;19(3):227–236. In Russian].Никитина И. Л. Старт пубертата — известное и новое. Артериальная гипертензия. 2013;19 (3):227–236. [Nikitina IL. The timing of puberty: well-known and new. Arterial’naya Gipertenziya = Arterial Hypertension. 2013;19(3):227–236. In Russian].Josso N. Professor Alfred Jost: the builder of modern sex differentiation. Sex Dev. 2008; 2(2): 55–63.doi:10.1159/000129690Josso N. Professor Alfred Jost: the builder of modern sex differentiation. Sex Dev. 2008; 2(2): 55–63.doi:10.1159/000129690Savic I, Swaab DF, Garcia-Falgueras A. Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Funct Neurol. 2009;24:17–28. doi: 10.1016/B978–0–444–53630–3.00004-XSavic I, Swaab DF, Garcia-Falgueras A. Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Funct Neurol. 2009;24:17–28. doi: 10.1016/B978–0–444–53630–3.00004-XBlecher SR, Erickson RP. Genetics of sexual development: a new paradigm. Am J Med Genet. 2007;143A(24):3054–3068.Blecher SR, Erickson RP. Genetics of sexual development: a new paradigm. Am J Med Genet. 2007;143A(24):3054–3068.Swain A, Narvaez V, Burgoyne P, Camerino G, LovellBadge R. Dax1 antagonizes Sry action in mammalian sex determination. Nature. 1998;391(6669):761–767.Swain A, Narvaez V, Burgoyne P, Camerino G, LovellBadge R. Dax1 antagonizes Sry action in mammalian sex determination. Nature. 1998;391(6669):761–767.Carani C, Granata AR, Rochira V, Caffagni G, Aranda C, Antunez P et al. Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism. Psychoneuroendocrinology. 2005;30(5):413–417.Carani C, Granata AR, Rochira V, Caffagni G, Aranda C, Antunez P et al. Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism. Psychoneuroendocrinology. 2005;30(5):413–417.Smith EP, Specker B, Bachrach BE, Kimbro KS, Li XJ, Young MF et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J Clin Endocrinol Metab. 2008;93 (8):3088–3096. doi: 10.1210/jc.2007–2397.Smith EP, Specker B, Bachrach BE, Kimbro KS, Li XJ, Young MF et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J Clin Endocrinol Metab. 2008;93 (8):3088–3096. doi: 10.1210/jc.2007–2397.Swaab DF. Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab. 2007;21(3):431–444. doi:10.1016/j.beem.2007.04.003Swaab DF. Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab. 2007;21(3):431–444. doi:10.1016/j.beem.2007.04.003Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A. Androgen insensitivity syndrome: clinical features and molecular defects. Hormones. 2008;7(3):217–229.Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A. Androgen insensitivity syndrome: clinical features and molecular defects. Hormones. 2008;7(3):217–229.WisniewskiAB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, Brown TR et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85(8):2664–2669.WisniewskiAB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, Brown TR et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85(8):2664–2669.Cohen-Bendahan CC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev. 2005;29(2):353–384.Cohen-Bendahan CC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev. 2005;29(2):353–384.Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci. 2006;7(6):477–484.Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci. 2006;7(6):477–484.Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness VS et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex. 2001;11(6):490–497.Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness VS et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex. 2001;11(6):490–497.Luders E, Narr KL, Thompson PM, Rex DE, Woods RP, Deluca H et al. Gender effects on cortical thickness and the influence of scaling. Hum Brain Mapp. 2006;27(4):314–324.Luders E, Narr KL, Thompson PM, Rex DE, Woods RP, Deluca H et al. Gender effects on cortical thickness and the influence of scaling. Hum Brain Mapp. 2006;27(4):314–324.Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62(8):847–855.Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62(8):847–855.Swaab DF, Chung WC, Kruijver FP, Hofman MA, Hestiantoro A. Sex differences in the hypothalamus in the different stages of human life. Neurobiol Aging. 2003;24(1):1–16.Swaab DF, Chung WC, Kruijver FP, Hofman MA, Hestiantoro A. Sex differences in the hypothalamus in the different stages of human life. Neurobiol Aging. 2003;24(1):1–16.Allen LS, Gorski RA. Sex difference in the bed nucleus of the stria terminalis of the human brain. J Comp Neurol. 1990;302 (4):697–706.Allen LS, Gorski RA. Sex difference in the bed nucleus of the stria terminalis of the human brain. J Comp Neurol. 1990;302 (4):697–706.Jazin E, Cahill L. Sex differences in molecular neuroscience: from fruit flies to humans. Nat Rev Neurosci. 2010;11(1):9–17. doi: 10.1038/nrn2754Jazin E, Cahill L. Sex differences in molecular neuroscience: from fruit flies to humans. Nat Rev Neurosci. 2010;11(1):9–17. doi: 10.1038/nrn2754Lippa RA. Gender-related traits in transsexuals and nontranssexuals. Arch Sex Behav. 2001;30(6):603–614.Lippa RA. Gender-related traits in transsexuals and nontranssexuals. Arch Sex Behav. 2001;30(6):603–614.Diamond M, Sigmundson HK. Sex reassignment at birth. Long-term review and clinical implications. Arch Pediatr Adolesc Med. 1997;151(3):298–304.Diamond M, Sigmundson HK. Sex reassignment at birth. Long-term review and clinical implications. Arch Pediatr Adolesc Med. 1997;151(3):298–304.Coolidge FL, Thede LL, Young SE. The heritability of gender identity disorder in a child and adolescent twin sample. Behav Genet. 2002;32(4):251–257.Coolidge FL, Thede LL, Young SE. The heritability of gender identity disorder in a child and adolescent twin sample. Behav Genet. 2002;32(4):251–257.Hare L, Bernard P, Sanchez FJ, Baird PN, Vilain E, Kennedy T et al. Androgen receptor repeat length polymorphism associated with male-to-female transsexualism. Biol Psychiatry. 2009;65(1):93–96. doi10.1016/j.biopsych.2008.08.033Hare L, Bernard P, Sanchez FJ, Baird PN, Vilain E, Kennedy T et al. Androgen receptor repeat length polymorphism associated with male-to-female transsexualism. Biol Psychiatry. 2009;65(1):93–96. doi10.1016/j.biopsych.2008.08.033Hengstschlager M, van Trotsenburg M, Repa C, Marton E, Huber JC, Bernaschek G. Sex chromosome aberrations and transsexualism. Fertil Steril. 2003;79(3):639–640.Hengstschlager M, van Trotsenburg M, Repa C, Marton E, Huber JC, Bernaschek G. Sex chromosome aberrations and transsexualism. Fertil Steril. 2003;79(3):639–640.Henningsson S, Westberg L, Nilsson S, Lundstrom B, Ekselius L, Bodlund O et al. Sex steroid-related genes and maleto-female transsexualism. Psychoneuroendocrinology. 2005;30 (7):657–664.Henningsson S, Westberg L, Nilsson S, Lundstrom B, Ekselius L, Bodlund O et al. Sex steroid-related genes and maleto-female transsexualism. Psychoneuroendocrinology. 2005;30 (7):657–664.Bentz EK, Hefler LA, Kaufmann U, Huber JC, Kolbus A, Tempfer CB. A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not maleto-female transsexualism. Fertil Steril. 2008;90(1):56–59.Bentz EK, Hefler LA, Kaufmann U, Huber JC, Kolbus A, Tempfer CB. A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not maleto-female transsexualism. Fertil Steril. 2008;90(1):56–59.De Vries GJ. Minireview: Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology. 2004;145(3):1063–1068.De Vries GJ. Minireview: Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology. 2004;145(3):1063–1068.Davies W, Wilkinson LS. It is not all hormones: alternative explanations for sexual differentiation of the brain. Brain Res. 2006;1126(1):36–45.Davies W, Wilkinson LS. It is not all hormones: alternative explanations for sexual differentiation of the brain. Brain Res. 2006;1126(1):36–45.Vige A, Gallou-Kabani C, Junien C. Sexual dimorphism in non-Mendelian inheritance. Pediatr Res. 2008;63(4):340–347. doi: 10.1203/PDR.0b013e318165b896Vige A, Gallou-Kabani C, Junien C. Sexual dimorphism in non-Mendelian inheritance. Pediatr Res. 2008;63(4):340–347. doi: 10.1203/PDR.0b013e318165b896Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H. A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet. 2001;17(12):697–701.Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H. A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet. 2001;17(12):697–701.Uematsu A, Yorifuji T, Muroi J, Kawai M, Mamada M, Kaji M et al. Parental origin of normal X chromosomes in Turner syndrome patients with various karyotypes: implications for the mechanism leading to generation of a 45, X karyotype. Am J Med Genet. 2002;111(2):134–139.Uematsu A, Yorifuji T, Muroi J, Kawai M, Mamada M, Kaji M et al. Parental origin of normal X chromosomes in Turner syndrome patients with various karyotypes: implications for the mechanism leading to generation of a 45, X karyotype. Am J Med Genet. 2002;111(2):134–139.Wu JB, Chen K, Li Y, Lau YF, Shih JC. Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. Faseb J. 2009;23(11):4029–4038. doi: 10.1096/fj.09–139097Wu JB, Chen K, Li Y, Lau YF, Shih JC. Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. Faseb J. 2009;23(11):4029–4038. doi: 10.1096/fj.09–139097Ujike H, Otani K, Nakatsuka M, Ishii K, Sasaki A, Oishi T et al. Association study of gender identity disorder and sex hormonerelated genes. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1241–1244. doi: 10.1016/j.pnpbp.2009.07.008.Ujike H, Otani K, Nakatsuka M, Ishii K, Sasaki A, Oishi T et al. Association study of gender identity disorder and sex hormonerelated genes. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1241–1244. doi: 10.1016/j.pnpbp.2009.07.008.

The authors declare that there are no conflicts of interest present.