medalphabetМедицинский алфавитMedical alphabet2078-56312949-2807ООО «Альфмед»10.33667/2078-5631-2026-7-75-90medalphabet-5082Research ArticleСтатьиИсточники вариации и установление референсных интервалов для основных гормонов и онкомаркеров для российской популяцииSources of variation and establishment of Russian reference intervals for major hormones and tumor markershttps://orcid.org/0000-0002-0889-0066РужанскаяА. В.RuzhanskayaA. V.

Ружанская Анна Владиславовна, менеджер по научному маркетингу

Москва

Ruzhanskaya Anna V., scientific marketing managerBeckman Coulter LLC

Moscow

aruzhanskaya@beckman.comИчихараКиёсиIchiharaKiyoshi

Киёси Ичихара, д. м. н., профессор

Убэ

Kiyoshi Ichihara, Dr Med Sci (habil.), professor

Ube

ЕвгинаС. А.EvginaS. A.

Евгина Светлана Александровна, руководитель отдела продуктовой и методической поддержки

Москва

Evgina Svetlana A., head of product and methodological support DeptBeckman Coulter LLC

Moscow

СкибоИ. И.SkiboI. I.

Скибо Ирина Ивановна, директор технологического департамента

Санкт-Петербург

Skibo Irina I., director of Technology Dept

Saint-Petersburg

ВыборноваН. Б.VybornovaN. B.

Выборнова Нина Борисовна

Санкт-Петербург

Vybornova Nina B.

Saint-Petersburg

https://orcid.org/0000-0002-6964-3173ВасильевА. В.VasilieveptA. V.

Васильев Антон Владимирович, врач клинической лабораторной диагностики, руководитель отдела

Санкт-Петербург

Vasiliev Anton V., clinical laboratory diagnostics physician, head of Dept

Saint-Petersburg

АгарковаГ. В.AgarkovaG. A.

Агаркова Галина Александровна, ведущий эксперт по продукции, тренер по иммунохимии

Москва

Agarkova Galina A., leading product expert, immunochemistry trainer

Moscow

https://orcid.org/0000-0002-2079-0439ЭмануэльВ. Л.EmanuelV. L.

Эмануэль Владимир Леонидович, д. м. н., профессор, заведующий кафедрой клинической лабораторной диагностики с курсом молекулярной медицины, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Минздрава России; академик Метрологической академии

Санкт-Петербург

Emanuel Vladimir L., Dr Med Sci (habil.), professor, head of Dept of Clinical Laboratory Diagnostics with a Course in Molecular Medicine, Pavlov First Saint-Petersburg State Medical University (Pavlov University); academician of the Metrology Academy

Saint-Petersburg

vladimirem1@gmail.comООО «Бекмен Культер»РоссияBeckman Coulter LLCRussian FederationФакультет медицинских наук магистратуры по программе «Медицина» университета Ямагути (Yamaguchi University)ЯпонияFaculty of Health Sciences, Yamaguchi University Graduate School of MedicineJapanООО «НПФ «Хеликс»РоссияHelix LaboratoryRussian FederationФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Минздрава РоссииРоссияPavlov First Saint-Petersburg State Medical University (Pavlov University)Russian Federation20260306202607Современная лаборатория (1)7590Copyright © Ружанская А.В., Ичихара К., Евгина С.А., Скибо И.И., Выборнова Н.Б., Васильев А.В., Агаркова Г.В., Эмануэль В.Л., 20262026Ружанская А.В., Ичихара К., Евгина С.А., Скибо И.И., Выборнова Н.Б., Васильев А.В., Агаркова Г.В., Эмануэль В.Л.Ruzhanskaya A.V., Ichihara K., Evgina S.A., Skibo I.I., Vybornova N.B., Vasilievept A.V., Agarkova G.A., Emanuel V.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-alphabet.com/jour/article/view/5082Цели

Цели. С целью изучения источников вариации (ИВ) референсных значений (РЗ) для 22 основных иммунохимических аналитов и определения референсных интервалов (РИ) было организовано многоцентровое исследование российской популяции.

Методы

Методы. В соответствии с протоколом Комитета по референсным интервалам и пороговым значениям (C‑RIDL) Международной федерации клинической химии и лабораторной медицины (IFCC), в исследование, проводившееся в Санкт‑Петербурге, Москве и Екатеринбурге, были включены 758 здоровых добровольцев. С помощью иммунохимического анализатора UniCel DxI 800 компании «Бекмен Культер» в образцах сыворотки крови были проанализированы 5 онкомаркеров и 17 гормонов и сопряженных аналитов. ИВ исследовали методами множественного регрессионного анализа (МРА) и дисперсионного анализа (ANOVA). Основным критерием принятия решения о разделении РИ по полу и возрасту являлся коэффициент стандартного отклонения (SDR), равный 0,4.

Результаты

Результаты. При оценке различий между группами добровольцев, принимавших участие в исследовании в разных городах, SDR составил менее 0,4. Были использованы следующие критерии для вторичного исключения: для женских половых гормонов – применение контрацептивов (8%); для СА19–9 – предположительно отрицательная группа крови системы Lewis (10,5% мужчин и 11,3 % женщин); для инсулина – ИМТ ≥28 кг/м2 (31%); для гормонов щитовидной железы – наличие антител к щитовидной железе (10,3% мужчин и 24,5% женщин); для раково‑эмбрионального антигена(РЭА) – курение (30% мужчин и 16% женщин). Для всех аналитов, за исключением СА19–9, СА15–3, аналитов для оценки функции щитовидной железы, паратиреоидного гормона и инсулина, требовалось разделение РИ по полу. Для альфа‑фетопротеина (АФП), РЭА, всех женских половых гормонов, фолликулостимулирущего гормона (ФСГ) и прогестерона для обоих полов требовалось разделение РИ по возрасту. Как правило, РИ определяли параметрическим методом после трансформации по Гауссу с использованием модифицированной формулы Box‑Cox. Исключение составили гормон роста, эстрадиол у женщин в постменопаузе и прогестерон у женщин в пременопаузе, для которых требовался расчет непараметрическим методом из‑за бимодальности распределения и (или) недостаточного предела обнаружения.

Выводы

Выводы. РИ для основных гормонов и онкомаркеров, специфических для российской популяции, определялись в соответствии с современным международным унифицированным протоколом при тщательном изучении ИВ для каждого аналита.

Objectives

Objectives. To study the sources of variation (SV) in reference values (RV) for 22 key immunoassays and to determine reference intervals (RIs), a multicenter study of the Russian population was conducted.

Methods

Methods. In accordance with the protocol of the Committee on Reference Intervals and Limit Values (C‑RIDL) of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), 758 healthy volunteers were included in the study, conducted in St. Petersburg, Moscow, and Yekaterinburg. Five tumor markers and 17 hormones and related analytes were analyzed in serum samples using the UniCel DxI 800 immunoassay analyzer from Beckman Coulter. SVs were analyzed using multiple regression analysis (MRA) and analysis of variance (ANOVA). The primary criterion for separating the study population by sex and age was a standard deviation ratio (SDR) of 0.4.

Results

Results. When assessing differences between groups of volunteers participating in the study in different cities, the SDR was less than 0.4. The following secondary exclusion criteria were used: for female sex hormones – contraceptive use (8%); for CA19–9—presumably Lewis negative blood type (10.5% of men and 11.3% of women); for insulin – BMI ≥28 kg/m2 (31%); for thyroid hormones – the presence of thyroid antibodies (10.3% of men and 24.5% of women); for carcinoembryonic antigen (CEA)—smoking (30% of men and 16% of women). For all analytes except CA19–9, CA15–3, thyroid function tests, parathyroid hormone, and insulin, RIs had to be separated by sex. For alpha‑fetoprotein (AFP), CEA, all female sex hormones, follicle‑stimulating hormone (FSH), and progesterone, RIs had to be separated by age for both sexes. Typically, RIs were determined parametrically after Gaussian transformation using a modified Box‑Cox formula. Exceptions were growth hormone, estradiol in postmenopausal women, and progesterone in premenopausal women, which required nonparametric calculation due to bimodal distributions and/or insufficient detection limits.

Conclusions

Conclusions. RIs for key hormones and tumor markers specific to the Russian population were determined in accordance with a current international standardized protocol with a thorough examination of the RI for each analyte.

референсные интервалыреференсные значенияисточники вариациииммунохимический анализгормоныонкомаркерыроссийская популяцияIFCC C‑RIDLUniCel DxI 800reference intervalsreference valuessources of variationimmunoassayhormonestumor markersRussian populationIFCC C‑RIDLUniCel DxI 800Поддержка исследования осуществлялась компанией ООО «Бекмен Культер» в виде заработной платы Анны Ружанской, Светланы Евгиной и Галины Агарковой, а также компанией ООО «НПФ «Хеликс» в виде заработной платы Ирины Скибо, Нины Выборновой и Антона Васильева. Конкретные функции этих авторов изложены в разделе «Участие авторов». Компания ООО «Бекмен Культер» оказала поддержку в предоставлении реагентов, а компания ООО «НПФ «Хеликс» – помощь в наборе добровольцев, пробоподготовке и предоставлении материалов для отбора проб. Другие функции в разработке исследования, сборе и анализе данных, принятии решения о публикации или подготовке рукописи спонсоры не выполняли. Авторы выражают искреннюю благодарность компании ООО «Бекмен Культер» (Россия) за предоставление реагентов для проведения исследования. Выражаем благодарность генеральному директору компании ООО «НПФ «Хеликс» Юрию Андрейчуку и его сотрудникам за помощь в привлечении к участию в исследовании добровольцев, сборе проб и за предоставление материалов и оборудования для отбора проб.This study was supported by Beckman Coulter (in the form of salaries for Anna Ruzhanskaya, Svetlana Evgina, and Galina Agarkova), and by Helix Laboratory (in the form of salaries for Irina Skibo, Nina Vybornova, and Anton Vasiliev). The specific roles of these authors are described in the “Author contributions” section. Beckman Coulter provided reagents, and Helix Laboratory assisted with volunteer recruitment, sample preparation, and provision of sample collection materials. The sponsors had no other roles in study design, data collection and analysis, publication decisions, or manuscript preparation. The authors express their sincere gratitude to Beckman Coulter (Russia) for providing reagents for the study. We would like to express our gratitude to Yury Andreychuk, CEO of Helix Laboratory, and his staff for their assistance in recruiting volunteers for the study, collecting samples, and providing materials and equipment for sampling.ReferencesIFCC and CLSI. EP28 A3C Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline, third edition. 2010; vol.28, No.30.IFCC and CLSI. EP28 A3C Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline, third edition. 2010; vol.28, No.30.Ozarda Y, Ichihara K, Barth JH, Klee G. Committee on Reference Intervals and Decision Limits (C RIDL), International Federation for Clinical Chemistry and Laboratory Medicine. Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values. Clin Chem Lab Med. 2013; 51:1027–40. https://doi.org/10.1515/cclm-2013-0249 PMID: 23633469Ozarda Y, Ichihara K, Barth JH, Klee G. Committee on Reference Intervals and Decision Limits (C RIDL), International Federation for Clinical Chemistry and Laboratory Medicine. Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values. Clin Chem Lab Med. 2013; 51:1027–40. https://doi.org/10.1515/cclm-2013-0249 PMID: 23633469Evgina S, Ichihara K, Ruzhanskaya A, Skibo I, Vybornova N, Vasiliev A, et al. Establishing reference intervals for major biochemical analytes for the Russian population: a research conducted as a part of the IFCC global study on reference values. Clin Biochem. 2020; 81:47–58. https://doi.org/10.1016/j.clinbiochem.2020.04.001 PMID: 32278594Evgina S, Ichihara K, Ruzhanskaya A, Skibo I, Vybornova N, Vasiliev A, et al. Establishing reference intervals for major biochemical analytes for the Russian population: a research conducted as a part of the IFCC global study on reference values. Clin Biochem. 2020; 81:47–58. https://doi.org/10.1016/j.clinbiochem.2020.04.001 PMID: 32278594Ichihara K, Ceriotti F, Kazuo M., Huang YY, Shimizu Y, Suzuki H, et al. The Asian project for collaborative derivation of reference intervals: (2) results of non standardized analytes and transference of reference intervals to the participating laboratories on the basis of cross comparison of test results. Clin Chem Lab Med. 2013; 51:1443–57. https://doi.org/10.1515/cclm-2012-0422 PMID: 23435152Ichihara K, Ceriotti F, Kazuo M., Huang YY, Shimizu Y, Suzuki H, et al. The Asian project for collaborative derivation of reference intervals: (2) results of non standardized analytes and transference of reference intervals to the participating laboratories on the basis of cross comparison of test results. Clin Chem Lab Med. 2013; 51:1443–57. https://doi.org/10.1515/cclm-2012-0422 PMID: 23435152Borai A, Ichihara K, Al Masaud A, Tamimi W, Suhad Bahijri S, Armbuster D, et al. Establishment of reference intervals for immunoassay analytes of adult population in Saudi Arabia. Clin Chem Lab Med. 2020; 58:1302–1313. https://doi.org/10.1515/cclm-2019-1049 PMID: 32160154Borai A, Ichihara K, Al Masaud A, Tamimi W, Suhad Bahijri S, Armbuster D, et al. Establishment of reference intervals for immunoassay analytes of adult population in Saudi Arabia. Clin Chem Lab Med. 2020; 58:1302–1313. https://doi.org/10.1515/cclm-2019-1049 PMID: 32160154Woo H Y, Kim YJ, Park H. Establishment of reference intervals of tumor markers in Korean adults. Korean J Lab Med. 2008; 28: 179–84. https://doi.org/10.3343/kjlm.2008.28.3.179 PMID: 18594168Woo H Y, Kim YJ, Park H. Establishment of reference intervals of tumor markers in Korean adults. Korean J Lab Med. 2008; 28: 179–84. https://doi.org/10.3343/kjlm.2008.28.3.179 PMID: 18594168Yang G B. Clinical value of serum cancer antigen 19–9 as a tumor screening marker among healthy individuals. JBUON. 2015; 20: 1612–1616. PMID: 26854460Yang G B. Clinical value of serum cancer antigen 19–9 as a tumor screening marker among healthy individuals. JBUON. 2015; 20: 1612–1616. PMID: 26854460Bakan E, Polat H, Ozarda Y, Ozturk N, Baygutalp NK, Umudum FZ, et al. A reference interval study for common biochemical analytes in Eastern Turkey: a comparison of a reference population with laboratory data mining. Biochem Med. 2016; 26: 210–223. https://doi.org/10.11613/BM.2016.023 PMID: 27346966Bakan E, Polat H, Ozarda Y, Ozturk N, Baygutalp NK, Umudum FZ, et al. A reference interval study for common biochemical analytes in Eastern Turkey: a comparison of a reference population with laboratory data mining. Biochem Med. 2016; 26: 210–223. https://doi.org/10.11613/BM.2016.023 PMID: 27346966Barth JH, Luvai A, Jassam N, Mbagaya W, Kilpatrick ES, Narayanan D, et al. Comparison of method related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review. Ann Clin Biochem. 2018; 55: 107–112. https://doi.org/10.1177/0004563217691549. PMID: 28081637Barth JH, Luvai A, Jassam N, Mbagaya W, Kilpatrick ES, Narayanan D, et al. Comparison of method related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review. Ann Clin Biochem. 2018; 55: 107–112. https://doi.org/10.1177/0004563217691549. PMID: 28081637Yu S, Qiu L, Liu M, Li S, Tao Z, Zhang Q, et al. Establishing reference intervals for sex hormones and SHBG in apparently healthy Chinese adult based on a multicenter study. Clin Chem Lab Med. 2018; 56: 1152–1160. https://doi.org/10.1515/cclm-2017-0749 PMID: 29729137Yu S, Qiu L, Liu M, Li S, Tao Z, Zhang Q, et al. Establishing reference intervals for sex hormones and SHBG in apparently healthy Chinese adult based on a multicenter study. Clin Chem Lab Med. 2018; 56: 1152–1160. https://doi.org/10.1515/cclm-2017-0749 PMID: 29729137Wang D, Yua S, Cheng X, Cao L, Zhang Q, Liu L, et al. Nationwide Chinese study for establishing reference intervals for thyroid hormones and related tests. Clin Chim Acta. 2019; 496: 62–67. https://doi.org/10.1016/j.cca.2019.06.011 PMID: 31238040Wang D, Yua S, Cheng X, Cao L, Zhang Q, Liu L, et al. Nationwide Chinese study for establishing reference intervals for thyroid hormones and related tests. Clin Chim Acta. 2019; 496: 62–67. https://doi.org/10.1016/j.cca.2019.06.011 PMID: 31238040Ichihara K, Boyd JC. An appraisal of statistical procedures used in derivation of reference intervals. Clin Chem Lab Med. 2010; 48:1537–51. https://doi.org/10.1515/CCLM.2010.319 PMID: 21062226Ichihara K, Boyd JC. An appraisal of statistical procedures used in derivation of reference intervals. Clin Chem Lab Med. 2010; 48:1537–51. https://doi.org/10.1515/CCLM.2010.319 PMID: 21062226Ichihara K. Statistical considerations for harmonization of the global multicenter study on reference values. Clin Chim Acta. 2014; 432:108–18. https://doi.org/10.1016/j.cca.2014.01.025 PMID:24518360Ichihara K. Statistical considerations for harmonization of the global multicenter study on reference values. Clin Chim Acta. 2014; 432:108–18. https://doi.org/10.1016/j.cca.2014.01.025 PMID:24518360Ichihara K, Ozarda Y, Barth JH, Klee G, Shimizu Y, Xia L, et al. A global multicenter study on reference values: 2. Exploration of sources of variation across the countries. Clin Chim Acta. 2017; 467: 83–97. https://doi.org/10.1016/j.cca.2016.09.015 PMID: 27666762Ichihara K, Ozarda Y, Barth JH, Klee G, Shimizu Y, Xia L, et al. A global multicenter study on reference values: 2. Exploration of sources of variation across the countries. Clin Chim Acta. 2017; 467: 83–97. https://doi.org/10.1016/j.cca.2016.09.015 PMID: 27666762Cohen J. A power primer. Psychological Bulletin. 1992; 112: 155–9. https://doi.org/10.1037//0033-2909.112.1.155 PMID: 19565683Cohen J. A power primer. Psychological Bulletin. 1992; 112: 155–9. https://doi.org/10.1037//0033-2909.112.1.155 PMID: 19565683Fraser CG. Biological variation: from principles to practice. AACC Press. Copyright 2001; 29–66.Fraser CG. Biological variation: from principles to practice. AACC Press. Copyright 2001; 29–66.Ichihara K, Itoh Y, Lam CWK, Poon PMK, Kim J H, Kyono H, et al. Sources of variation of commonly measured serum analytes among 6 Asian cities and consideration of common reference intervals. Clin. Chem. 2008; 54: 356–65. https://doi.org/10.1373/clinchem.2007.091843 PMID: 18089659Ichihara K, Itoh Y, Lam CWK, Poon PMK, Kim J H, Kyono H, et al. Sources of variation of commonly measured serum analytes among 6 Asian cities and consideration of common reference intervals. Clin. Chem. 2008; 54: 356–65. https://doi.org/10.1373/clinchem.2007.091843 PMID: 18089659Ichihara K, Ozarda Y, Barth JH, Klee G, Qiu L, Erasmus R, et al. A global multicenter study on reference values: 1. Assessment of methods for derivation and comparison of reference intervals. Clin Chim Acta. 2017; 467: 70–82. https://doi.org/10.1016/j.cca.2016.09.016 PMID: 27666761Ichihara K, Ozarda Y, Barth JH, Klee G, Qiu L, Erasmus R, et al. A global multicenter study on reference values: 1. Assessment of methods for derivation and comparison of reference intervals. Clin Chim Acta. 2017; 467: 70–82. https://doi.org/10.1016/j.cca.2016.09.016 PMID: 27666761Li S, Huang S, Mo ZN, Gao Y, Yang X B, Chen X J, et al. Generating a reference interval for fasting serum insulin in healthy nondiabetic adult Chinese men. Singapore Med J. 2012; 53: 821–825. PMID: 23268156Li S, Huang S, Mo ZN, Gao Y, Yang X B, Chen X J, et al. Generating a reference interval for fasting serum insulin in healthy nondiabetic adult Chinese men. Singapore Med J. 2012; 53: 821–825. PMID: 23268156Shen X, Wang R, Yu N, Shi Y, Li H, Xiong C, et al. Reference ranges and association of age and lifestyle characteristics with testosterone, sex hormone binding globulin, and luteinizing hormone among 1166 Western Chinese Men. PLoS One. 2016; 11(10): e0164116. https://doi.org/10.1371/journal.pone.0164116 PMID: 27711240Shen X, Wang R, Yu N, Shi Y, Li H, Xiong C, et al. Reference ranges and association of age and lifestyle characteristics with testosterone, sex hormone binding globulin, and luteinizing hormone among 1166 Western Chinese Men. PLoS One. 2016; 11(10): e0164116. https://doi.org/10.1371/journal.pone.0164116 PMID: 27711240Shi Z, Araujo AB, Martin S, O’Loughlin P, Wittert GA, et al. Longitudinal changes in testosterone over five years in community dwelling men. J Clin Endocrinol Metab. 2013; 98: 3289–97. https://doi.org/10.1210/jc.2012-3842 PMID: 23775354Shi Z, Araujo AB, Martin S, O’Loughlin P, Wittert GA, et al. Longitudinal changes in testosterone over five years in community dwelling men. J Clin Endocrinol Metab. 2013; 98: 3289–97. https://doi.org/10.1210/jc.2012-3842 PMID: 23775354Camacho EM, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM, et al. Age associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Euro J of Endocrinol. 2013; 168: 445–55. https://doi.org/10.1530/EJE-12-0890 PMID: 23425925Camacho EM, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM, et al. Age associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Euro J of Endocrinol. 2013; 168: 445–55. https://doi.org/10.1530/EJE-12-0890 PMID: 23425925Eskes SA, Tomasoa NB, Endert E, Geskus RB, Fliers E, Wiersinga WM. Establishment of reference values for endocrine tests. Part VII: growth hormone deficiency. Neth J Med. 2009; 67: 127–133. PMID: 19581656Eskes SA, Tomasoa NB, Endert E, Geskus RB, Fliers E, Wiersinga WM. Establishment of reference values for endocrine tests. Part VII: growth hormone deficiency. Neth J Med. 2009; 67: 127–133. PMID: 19581656Sajid KM, Chaouachi K, Mahmood R. Hookah smoking and cancer: carcinoembryonic antigen (CEA) levels in exclusive/ever hookah smokers. Harm Reduct J. 2008; 5: 19. https://doi.org/10.1186/1477-7517-5-19 PMID: 18501010Sajid KM, Chaouachi K, Mahmood R. Hookah smoking and cancer: carcinoembryonic antigen (CEA) levels in exclusive/ever hookah smokers. Harm Reduct J. 2008; 5: 19. https://doi.org/10.1186/1477-7517-5-19 PMID: 18501010Vestergaard EM, Hein HO, Meyer H, Grunnet N, Jørgensen J, Wolf H, et al. Values and biological variation for tumor marker CA 19–9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999; 45: 54–61.Vestergaard EM, Hein HO, Meyer H, Grunnet N, Jørgensen J, Wolf H, et al. Values and biological variation for tumor marker CA 19–9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999; 45: 54–61.Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009; 33:197–207. https://doi.org/10.1016/j.jaut.2009.09.008 PMID: 19819109Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009; 33:197–207. https://doi.org/10.1016/j.jaut.2009.09.008 PMID: 19819109Stenman UH, Alfthan H, Hotakainen K. Human chorionic gonadotropin in cancer. Clin Biochem. 2004; 37: 549–61. https://doi.org/10.1016/j.clinbiochem.2004.05.008 PMID: 15234236Stenman UH, Alfthan H, Hotakainen K. Human chorionic gonadotropin in cancer. Clin Biochem. 2004; 37: 549–61. https://doi.org/10.1016/j.clinbiochem.2004.05.008 PMID: 15234236Snyder JA, Haymond S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. ClinChem. 2005; 51: 1830–5. https://doi.org/10.1373/clinchem.2005.053595 PMID: 16099935Snyder JA, Haymond S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. ClinChem. 2005; 51: 1830–5. https://doi.org/10.1373/clinchem.2005.053595 PMID: 16099935Travison TG, Araujo AB, O’Donnell AB, Kupelian V, McKinlay JB. A population level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007; 92: 196–202. https://doi.org/10.1210/jc.2006-1375 PMID: 17062768Travison TG, Araujo AB, O’Donnell AB, Kupelian V, McKinlay JB. A population level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007; 92: 196–202. https://doi.org/10.1210/jc.2006-1375 PMID: 17062768Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WHB. A validated age related normative model for male total testosterone shows increasing variance but no decline after age 40 years. PLoS One. 2014; 9 (10): e109346. https://doi.org/10.1371/journal.pone.0109346 PMID: 25295520Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WHB. A validated age related normative model for male total testosterone shows increasing variance but no decline after age 40 years. PLoS One. 2014; 9 (10): e109346. https://doi.org/10.1371/journal.pone.0109346 PMID: 25295520Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari V, et al. A cross section analysis of FT3 age related changes in a group of old and oldest old subjects, including centenarians’ relatives, shows that a down regulated thyroid function has a familial component and is related to longevity. Age Ageing. 2010; 39: 723–727. https://doi.org/10.1093/ageing/afq116Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari V, et al. A cross section analysis of FT3 age related changes in a group of old and oldest old subjects, including centenarians’ relatives, shows that a down regulated thyroid function has a familial component and is related to longevity. Age Ageing. 2010; 39: 723–727. https://doi.org/10.1093/ageing/afq116Surks MI, Hollowell JG. Age specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92: 4575–82. https://doi.org/10.1210/jc.2007-1499 PMID: 17911171Surks MI, Hollowell JG. Age specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92: 4575–82. https://doi.org/10.1210/jc.2007-1499 PMID: 17911171NICE Clinical Guideline 122. The recognition and initial management of ovarian cancer. 2011. https://www.nice.org.uk/guidance/cg122/chapter/1-Guidance#detection-in-primary-care.NICE Clinical Guideline 122. The recognition and initial management of ovarian cancer. 2011. https://www.nice.org.uk/guidance/cg122/chapter/1-Guidance#detection-in-primary-care.Шестакова И.Г., Ипастова И.Д. Эндометриоз: новый консенсус – новые решения. Информационный бюллетень, ООО «Медиабюро Статус презенс», 2014.Shestakova I.G., Ipastova I.D. Endometriosis: new consensus – new solutions. Information bulletin, OOO Mediabureau Status Present, 2014. (In Russ.).Park HJ, Ahn ST, Moon DG. Evolution of Guidelines for Testosterone Replacement Therapy. Journal of Clinical Medicine. 2019; 8: 410. https://doi.org/10.3390/jcm8030410 PMID: 30934591Park HJ, Ahn ST, Moon DG. Evolution of Guidelines for Testosterone Replacement Therapy. Journal of Clinical Medicine. 2019; 8: 410. https://doi.org/10.3390/jcm8030410 PMID: 30934591Garber J, Cobin R, Gharib H, Hennessey J, Klein I, Mechanick J, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American association of clinical endocrinologists and the American thyroid association. Endocrine Practice. 2012; 18: 988 1028. https://doi.org/10.4158/EP12280.GL PMID: 23246686Garber J, Cobin R, Gharib H, Hennessey J, Klein I, Mechanick J, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American association of clinical endocrinologists and the American thyroid association. Endocrine Practice. 2012; 18: 988 1028. https://doi.org/10.4158/EP12280.GL PMID: 23246686Pearce SHS, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA Guideline: Man agement of Subclinical Hypothyroidism. EurThyroid J. 2013; 2: 215–228. https://doi.org/10.1159/000356507 PMID: 24783053Pearce SHS, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA Guideline: Man agement of Subclinical Hypothyroidism. EurThyroid J. 2013; 2: 215–228. https://doi.org/10.1159/000356507 PMID: 24783053Demers LM, Spencer CA. Laboratory support for the diagnosis and monitoring of thyroid disease. Guideline. Clin Endocrinol (Oxf). 2003; 58: 138–40. https://doi.org/10.1046/j.1365-2265.2003.01681.x PMID: 12580927Demers LM, Spencer CA. Laboratory support for the diagnosis and monitoring of thyroid disease. Guideline. Clin Endocrinol (Oxf). 2003; 58: 138–40. https://doi.org/10.1046/j.1365-2265.2003.01681.x PMID: 12580927Herbomez M, Jarrige V, Darte C. Reference intervals for serum thyrotropin (TSH) and free thyroxine (FT4) in adults using the Access Immunoassay System. Clin Chem Lab Med. 2005; 43: 102–5. https://doi.org/10.1515/CCLM.2005.017 PMID: 15653452Herbomez M, Jarrige V, Darte C. Reference intervals for serum thyrotropin (TSH) and free thyroxine (FT4) in adults using the Access Immunoassay System. Clin Chem Lab Med. 2005; 43: 102–5. https://doi.org/10.1515/CCLM.2005.017 PMID: 15653452Thienpont L, Uytfanghe K, De Grande K, Reynders D, Das B, Faix JD, et al. Harmonization of serum thyroid stimulating hormone measurements paves the way for the adoption of a more uniform reference interval. Clin Chem. 2017; 63: 1248–1260. https://doi.org/10.1373/clinchem.2016.269456 PMID: 28522444Thienpont L, Uytfanghe K, De Grande K, Reynders D, Das B, Faix JD, et al. Harmonization of serum thyroid stimulating hormone measurements paves the way for the adoption of a more uniform reference interval. Clin Chem. 2017; 63: 1248–1260. https://doi.org/10.1373/clinchem.2016.269456 PMID: 28522444

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