akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2024.494akusherstvo-2228Research ArticleREVIEW ARTICLESНАУЧНЫЕ ОБЗОРЫThe role of steroidogenesis disorders in developing congenital clitoromegalyРоль нарушений стероидогенеза в формировании врожденной клиторомегалииhttps://orcid.org/0000-0003-4696-9290ИвановН. В.IvanovN. V.

Иванов Никита Владимирович, к.м.н.

191015 Санкт-Петербург, Кирочная ул., д. 41

Scopus Author ID: 57221190481. WoS ResearcherID: JRZ-0207-2023

Nikita V. Ivanov, MD, PhD

Scopus Author ID: 57221190481. WoS ResearcherID: JRZ-0207-2023

baltic.forum@gmail.comhttps://orcid.org/0000-0001-8534-6948СеребряковаИ. П.SerebryakovaI. P.

Серебрякова Инна Павловна, к.м.н. 

191015 Санкт-Петербург, Кирочная ул., д. 41

Scopus Author ID: 58679099300. WoS ResearcherID: JRZ-0285-2023

Inna P. Serebryakova, MD, PhD

41 Kirochnaya Str., Saint Petersburg 191015

Scopus Author ID: 58679099300. WoS ResearcherID: JRZ-0285-2023

https://orcid.org/0009-0001-6111-6862РадугинаЛ. И.RaduginaL. I.

Радугина Любовь Игоревна

191015 Санкт-Петербург, Кирочная ул., д. 41

Lyubov I. Radugina

41 Kirochnaya Str., Saint Petersburg 191015

https://orcid.org/0000-0003-3224-1573РадугинФ. М.RaduginF. M.

Радугин Федор Михайлович

194044 Санкт-Петербург, ул. Чугунная, д. 46

Fyodor M. Radugin, MD

46 Chugunnaya Str., Saint Petersburg 194044

https://orcid.org/0000-0001-5641-9239ЮсуповаШ. К.YusupovaSh. K.

Юсупова Шахноза Кадиржановна, д.м.н.

170127 Андижан, ул. Ю. Отабекова, д. 1

Shakhnoza K. Yusupova, MD, Dr Sci Med

1 Yu. Otabekova Str., Andijan 170127

ФГБОУ ВО «Северо-Западный государственный медицинский университет имени И.И. Мечникова» Министерства здравоохранения Российской ФедерацииРоссияMechnikov North-Western State Medical University, Health Ministry of Russian FederationRussian FederationСПб ГБУЗ «Клиническая больница Святителя Луки»РоссияSaint Luke's Clinical HospitalRussian FederationАндижанский государственный медицинский институтУзбекистанAndijan State Medical InstituteUzbekistan202404112024185679–692Copyright © Ivanov N.V., Serebryakova I.P., Radugina L.I., Radugin F.M., Yusupova S.K., 20242024Иванов Н.В., Серебрякова И.П., Радугина Л.И., Радугин Ф.М., Юсупова Ш.К.Ivanov N.V., Serebryakova I.P., Radugina L.I., Radugin F.M., Yusupova S.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/2228

Clitoromegaly is characterized by enlarged clitoris exceeding normal size typical to healthy women that represents a pressing issue in gynecological endocrinology. It emerges as an idiopathic condition or is formed along with impaired synthesis of sex steroids, accompanied by androgen excess. However, idiopathic clitoromegaly is a rather common diagnosis, since the objective cause of this symptom often remains unidentified. Investigating an alternative pathway for the synthesis of androgens and 11-oxysetroids in women with clitoromegaly is of great interest to practicing endocrinologists and gynecologists due to new opportunities for diagnosing and preventing this condition. This literature review is aimed at assessing current insights into disorders of female androgen steroidogenesis and its role in clitoromegaly pathogenesis.

Клиторомегалия является актуальной проблемой гинекологической эндокринологии и характеризуется увеличением размеров клитора более нормальных значений, характерных для здоровых женщин. Клиторомегалия возникает как идиопатическое состояние или формируется на фоне нарушений синтеза половых стероидов, сопровождающихся избытком андрогенов. Однако идиопатическая клиторомегалия является достаточно частым диагнозом, так как объективная причина этого симптома зачастую остается невыявленной. Изучение альтернативного пути синтеза андрогенов и 11-оксистероидов у женщин с клиторомегалией представляет большой интерес для практикующих эндокринологов и гинекологов ввиду новых возможностей диагностики и профилактики этого состояния. Данный литературный обзор посвящен современным представлениям о нарушениях стероидогенеза андрогенов у женщин и его роли в патогенезе клиторомегалии.

клиторомегалиявирилизацияандрогеныальтернативный путь стероидогенеза андрогенов11-оксигенированные стероидыкетоандрогеныclitoromegalyvirilizationandrogensalternative steroidogenesis11-oxygenated steroidsReferencesИванов Н.В., Серебрякова И.П., Худякова Н.B., Федорова А.И. Клиторомегалия: принципы диагностики и лечения. Акушерство, Гинекология и Репродукция. 2023;17(4):462–75. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.400.Ivanov N.V., Serebryakova I.P., Khudyakova N.V., Fedorova A.I. Clitoromegaly: principles of diagnostics and treatment. [Klitoromegaliya: principy diagnostiki i lecheniya]. Obstetrics, Gynecology and Reproduction. 2023;17(4):462–475. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.400.Андроник Д.И., Башнина Е.Б., Бурцев Е.А. и др. Принцип Лилит. К вопросу формирования пола у человека: практическое руководство для врачей. Под ред. Н.В. Иванова, Е.Б. Башниной. СПб.: ПОЛИТЕХ-ПРЕСС, 2021. 382 с.Andronik D.I., Bashnina E.B., Burtsev E.A. et al. Lilith principle. On the issue of sex formation in humans: a practical guide for doctors. Eds. N.V. Ivanov, E.B. Bashnina. [K voprosu formirovaniya pola u cheloveka: prakticheskoe rukovodstvo dlya vrachej. Pod red. N.V. Ivanova, E.B. Bashninoj]. Saint Petersburg: POLITEH-PRESS, 2021. 382 p. (In Russ.).Speiser P.W., Arlt W., Auchus R.J. et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043–88. https://doi.org/10.1210/jc.2018-01865.Speiser P.W., Arlt W., Auchus R.J. et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043–88. https://doi.org/10.1210/jc.2018-01865.Penning T.M., Burczynski M.E., Jez J.M. et al. Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000;351(Pt1):67–77. https://doi.org/10.1042/0264-6021:3510067.Penning T.M., Burczynski M.E., Jez J.M. et al. Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000;351(Pt1):67–77. https://doi.org/10.1042/0264-6021:3510067.Nakamura Y., Hornsby P.J., Casson P. et al. Type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab. 2009;94(6):2192–8. https://doi.org/10.1210/jc.2008-2374.Nakamura Y., Hornsby P.J., Casson P. et al. Type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab. 2009;94(6):2192–8. https://doi.org/10.1210/jc.2008-2374.Claahsen-van der Grinten H.L., Speiser P.W., Ahmed S.F. Congenital adrenal hyperplasia – current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91–159. https://doi.org/10.1210/endrev/bnab016.Claahsen-van der Grinten H.L., Speiser P.W., Ahmed S.F. Congenital adrenal hyperplasia – current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91–159. https://doi.org/10.1210/endrev/bnab016.Серебрякова И.П., Великанова Л.И., Ворохобина Н.В. и др. Особенности адреналового стероидогенеза у больных с врожденной дисфункцией коры надпочечников вследствие дефекта 21-гидроксилазы. Проблемы эндокринологии. 2005;51(4):22–6. https://doi.org/10.14341/probl200551422-26.Serebryakova I.P., Velikanova L.I., Vorokhobina N.V. et al. The specific features of adrenal steroidogenesis in patients with congenital adrenal cortical dysfunction due to 21-hydroxylase deficiency. [Osobennosti adrenalovogo steroidogeneza u bol'nyh s vrozhdennoj disfunkciej kory nadpochechnikov vsledstvie defekta 21-gidroksilazy]. Problemy endokrinologii. 2005;51(4):22–6. (In Russ.). https://doi.org/10.14341/probl200551422-26.Schiffer L., Barnard L., Baranowski E.S. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. J Steroid Biochem Mol Biol. 2019;194:105439. https://doi.org/10.1016/j.jsbmb.2019.105439.Schiffer L., Barnard L., Baranowski E.S. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. J Steroid Biochem Mol Biol. 2019;194:105439. https://doi.org/10.1016/j.jsbmb.2019.105439.Storbeck K.H., Schiffer L., Baranowski E.S. et al. Steroid metabolome analysis in disorders of adrenal steroid biosynthesis and metabolism. Endocr Rev. 2019;40(6):1605–25. https://doi.org/10.1210/er.2018-00262.Storbeck K.H., Schiffer L., Baranowski E.S. et al. Steroid metabolome analysis in disorders of adrenal steroid biosynthesis and metabolism. Endocr Rev. 2019;40(6):1605–25. https://doi.org/10.1210/er.2018-00262.Miller W.L., Auchus R.J. The "backdoor pathway" of androgen synthesis in human male sexual development. PLoS Biol. 2019;17(4):e3000198. https://doi.org/10.1371/journal.pbio.3000198.Miller W.L., Auchus R.J. The "backdoor pathway" of androgen synthesis in human male sexual development. PLoS Biol. 2019;17(4):e3000198. https://doi.org/10.1371/journal.pbio.3000198.Fukami M., Horikawa R., Nagai T. et al. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. 2005;90(1):414–26. https://doi.org/10.1210/jc.2004-0810.Fukami M., Horikawa R., Nagai T. et al. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. 2005;90(1):414–26. https://doi.org/10.1210/jc.2004-0810.Fukami M., Ogata T. Cytochrome P450 oxidoreductase deficiency: rare congenital disorder leading to skeletal malformations and steroidogenic defects. Pediatr Int. 2014;56(6):805–8. https://doi.org/10.1111/ped.12518.Fukami M., Ogata T. Cytochrome P450 oxidoreductase deficiency: rare congenital disorder leading to skeletal malformations and steroidogenic defects. Pediatr Int. 2014;56(6):805–8. https://doi.org/10.1111/ped.12518.Reisch N., Idkowiak J., Hughes B.A. et al. Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency. J Clin Endocrinol Metab. 2013;98(3):E528–36. https://doi.org/10.1210/jc.2012-3449.Reisch N., Idkowiak J., Hughes B.A. et al. Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency. J Clin Endocrinol Metab. 2013;98(3):E528–36. https://doi.org/10.1210/jc.2012-3449.Reisch N., Auchus R.J., Shackleton C.H.L. et al. Reply to Fluck et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency. Proc Natl Acad Sci U S A. 2020;117(26):14634–5. https://doi.org/10.1073/pnas.2007695117.Reisch N., Auchus R.J., Shackleton C.H.L. et al. Reply to Fluck et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency. Proc Natl Acad Sci U S A. 2020;117(26):14634–5. https://doi.org/10.1073/pnas.2007695117.Gent R., Van Rooyen D., Atkin S.L., Swart A.C. C11-hydroxy and C11-oxo C19 and C21 steroids: pre-receptor regulation and interaction with androgen and progesterone steroid receptors. Int J Mol Sci. 2023;25(1):101. https://doi.org/10.3390/ijms25010101.Gent R., Van Rooyen D., Atkin S.L., Swart A.C. C11-hydroxy and C11-oxo C19 and C21 steroids: pre-receptor regulation and interaction with androgen and progesterone steroid receptors. Int J Mol Sci. 2023;25(1):101. https://doi.org/10.3390/ijms25010101.Turcu A.F., Rege J., Auchus R.J. et al. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol. 2020;16(5):284–96. https://doi.org/10.1038/s41574-020-0336-x.Turcu A.F., Rege J., Auchus R.J. et al. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol. 2020;16(5):284–96. https://doi.org/10.1038/s41574-020-0336-x.Fukami M. 11-Oxyandrogens from the viewpoint of pediatric endocrinology. Clin Pediatr Endocrinol. 2022;31(3):110–5. https://doi.org/10.1297/cpe.2022-0029.Fukami M. 11-Oxyandrogens from the viewpoint of pediatric endocrinology. Clin Pediatr Endocrinol. 2022;31(3):110–5. https://doi.org/10.1297/cpe.2022-0029.Rosenfield R.L. Normal and premature adrenarche. Endocr Rev. 2021;42(6):783–814. https://doi.org/10.1210/endrev/bnab009.Rosenfield R.L. Normal and premature adrenarche. Endocr Rev. 2021;42(6):783–814. https://doi.org/10.1210/endrev/bnab009.Lo J.C., Grumbach M.M. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30(1):207–29. https://doi.org/10.1016/s0889-8529(08)70027-6.Lo J.C., Grumbach M.M. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30(1):207–29. https://doi.org/10.1016/s0889-8529(08)70027-6.Belgorosky A., Guercio G., Pepe C. et al. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009;72(6):321–30. https://doi.org/10.1159/000249159.Belgorosky A., Guercio G., Pepe C. et al. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009;72(6):321–30. https://doi.org/10.1159/000249159.White P.C. Ontogeny of adrenal steroid biosynthesis: why girls will be girls. J Clin Invest. 2006;116(4):872–4. https://doi.org/10.1172/JCI28296.White P.C. Ontogeny of adrenal steroid biosynthesis: why girls will be girls. J Clin Invest. 2006;116(4):872–4. https://doi.org/10.1172/JCI28296.Karahoda R., Kallol S., Groessl M. Revisiting steroidogenic pathways in the human placenta and primary human trophoblast cells. Int J Mol Sci. 2021;22(4):1704. https://doi.org/10.3390/ijms22041704.Karahoda R., Kallol S., Groessl M. Revisiting steroidogenic pathways in the human placenta and primary human trophoblast cells. Int J Mol Sci. 2021;22(4):1704. https://doi.org/10.3390/ijms22041704.Noyola-Martínez N., Halhali A., Barrera D. Steroid hormones and pregnancy. Gynecol Endocrinol. 2019;35(5):376–84. https://doi.org/10.1080/09513590.2018.1564742.Noyola-Martínez N., Halhali A., Barrera D. Steroid hormones and pregnancy. Gynecol Endocrinol. 2019;35(5):376–84. https://doi.org/10.1080/09513590.2018.1564742.Sharpe R.M. Androgens and the masculinization programming window: human-rodent differences. Biochem Soc Trans. 2020;48(4):1725–35. https://doi.org/10.1042/BST20200200.Sharpe R.M. Androgens and the masculinization programming window: human-rodent differences. Biochem Soc Trans. 2020;48(4):1725–35. https://doi.org/10.1042/BST20200200.New M.I., Tong Y.K., Yuen T. et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab. 2014;99:E1022–30. https://doi.org/10.1210/jc.2014-1118.New M.I., Tong Y.K., Yuen T. et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab. 2014;99:E1022–30. https://doi.org/10.1210/jc.2014-1118.Khattab A., Yuen T., Sun L. et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia. Endocr Dev. 2016;30:37–41. https://doi.org/10.1159/000439326.Khattab A., Yuen T., Sun L. et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia. Endocr Dev. 2016;30:37–41. https://doi.org/10.1159/000439326.

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