vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2022-12-401vedomostiregmed-401Research ArticleТОКСИКОЛОГИЧЕСКИЕ ИССЛЕДОВАНИЯTOXICITY STUDIESЭндокринные нарушения при применении лекарственных средств: подходы к доклинической оценке безопасностиEndocrine Disorders Associated with Medicinal Products: Approaches to Preclinical Safety Assessmenthttps://orcid.org/0000-0003-1451-7716КрышеньК. Л.KryshenK. L.

Крышень Кирилл Леонидович - кандидат биологических наук.

Заводская ул., д. 3, к. 245, г.п. Кузьмоловский, Всеволожский р-н, Ленинградская обл., 188663

Kirill L. Kryshen - Cand. Sci. (Biol).

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

kryshen.kl@doclinika.ruhttps://orcid.org/0000-0002-6866-5741ФаустоваН. М.FaustovaN. M.

Фаустова Наталья Михайловна - кандидат химических наук.

Заводская ул., д. 3, к. 245, г.п. Кузьмоловский, Всеволожский р-н, Ленинградская обл., 188663

Natalia M. Faustova - Cand. Sci. (Chem.).

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

faustova.nm@doclinika.ruhttps://orcid.org/0000-0003-3176-6386МакароваМ. Н.MakarovaM. N.

Макарова Марина Николаевна - доктор медицинских наук.

Заводская ул., д. 3, к. 245, г.п. Кузьмоловский, Всеволожский р-н, Ленинградская обл., 188663

Marina N. Makarova - Dr. Sci (Med.).

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

makarova.mn@doclinika.ruhttps://orcid.org/0000-0002-2447-7888МакаровВ. Г.MakarovV. G.

Макаров Валерий Геннадиевич - доктор медицинских наук.

Заводская ул., д. 3, к. 245, г.п. Кузьмоловский, Всеволожский р-н, Ленинградская обл., 188663

Valery G. Makarov - Dr. Sci. (Med.).

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

makarov.vg@doclinika.ruАкционерное общество «Научно-производственное объединение «ДОМ ФАРМАЦИИ»РоссияJoint Stock Company “Scientific and Production Association HOME OF PHARMACY”Russian Federation2023240320231312741Copyright © Крышень К.Л., Фаустова Н.М., Макарова М.Н., Макаров В.Г., 20232023Крышень К.Л., Фаустова Н.М., Макарова М.Н., Макаров В.Г.Kryshen K.L., Faustova N.M., Makarova M.N., Makarov V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/401

Эндокринная система координирует работу практически всех органов и систем организма позвоночных, в том числе  такие  важные  биологические  функции,  как метаболизм, развитие, размножение и поведение. На сегодняшний день накоплено значительное количество информации об эндокринных нарушениях при использовании химических соединений (эндокринных дизрапторов) в различных отраслях деятельности человека. Цель работы — оценка возможности проведения на стадии доклинических исследований анализа рисков функционального нарушения эндокринной системы при применении новых лекарственных средств. С эндокринными дизрапторами связан широкий спектр нежелательных явлений, включая проблемы развития, возникающие из-за нарушения функционирования эндокринной системы. Особенностями эндокринных нарушений, вызванных дизрапторами, являются длительный латентный период между воздействием и проявлением дисфункции, отсутствие линейной зависимости  «доза–эффект»,  зависимость  степени  нарушений  от  момента  начала  и длительности воздействия. К основным механизмам влияния химических веществ на эндокринную систему относят их взаимодействие с рецепторами клеток, чувствительных к влиянию определенных гормонов, влияние на экспрессию  генов  и   внутриклеточную   передачу   сигналов,   транспорт   гормонов и др. В обзоре обсуждена возможность использования показателей уровней гормонов как индикаторов эндокринной токсичности и приведены  литературные и собственные данные о нормах содержания основных гормонов в крови животных.  Включение  анализа  уровней  основных  гормонов  крови  животных   в программу регистрационных доклинических исследований позволит оценить риски потенциальных угроз ятрогенного происхождения.

The endocrine system coordinates almost all organs and other systems in vertebrates. In particular, it regulates such important biological functions as metabolism, development, reproduction, and behaviour. To date, a significant amount of information has accumulated on endocrine disorders associated with chemical compounds (endocrine disruptors) used in various fields of human activity. The aim of this study was to evaluate the possibility of preclinical risk assessment for the endocrine function disorders attributable to new medicinal products. Endocrine disruptors are associated with a wide range of adverse events, including developmental problems arising from functional abnormalities of the endocrine system. Endocrine disorders caused by endocrine-disrupting chemicals are characterised by a long latency period between exposure and manifestation of a dysfunction; a nonlinear dose–response relationship; and a linear correlation of damage severity to exposure timing and duration. The chemicals influence the endocrine system through multiple mechanisms, the main of which being the interaction with cellular receptors sensitive to certain hormones and the influence on gene expression, intracellular signalling, and hormone transport, etc. This paper discusses the possibility of using hormone levels as indicators of endocrine disruption and presents the literature and authors’ own data on normal levels of relevant hormones in the blood of animals. An analysis of animal blood hormone levels in preclinical programmes will provide an opportunity to evaluate potential iatrogenic risks.

эндокринная системанарушенияэндокринные дизрапторыдоклинические исследованиялекарственные средстваendocrine systemdisordersendocrine disruptorspreclinical studiespharmaceuticalsReferencesLa Merrill MA, Vandenberg LN, Smith MT, Goodson W, Browne P, Patisaul HB, et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol. 2020;16(1):45–57. https://doi.org/10.1038/s41574-019-0273-8La Merrill MA, Vandenberg LN, Smith MT, Goodson W, Browne P, Patisaul HB, et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol. 2020;16(1):45–57. https://doi.org/10.1038/s41574-019-0273-8Lathers CM. Endocrine disruptors: a new scientific role for clinical pharmacologists? Impact on human health, wildlife, and the environment. J Clin Pharm. 2002;42(1):7–23. https://doi.org/10.1177/0091270002042001001Lathers CM. Endocrine disruptors: a new scientific role for clinical pharmacologists? Impact on human health, wildlife, and the environment. J Clin Pharm. 2002;42(1):7–23. https://doi.org/10.1177/0091270002042001001Carson RL. Silent spring. Boston: Houghton Mifflin Co.; 1962.Carson RL. Silent spring. Boston: Houghton Mifflin Co.; 1962.Соловьева ТА. «Безмолвная весна» Рэйчел Карсон и революция в общественном экологическом сознании XX века. В кн.: Человек, экология, культура: Современные практики и проблемы. Сборник научных трудов по материалам Международной молодежной научной конференции. Саратов; 2014. С. 206–11.Solovyeva TA. Rachel Carson’s “Silent spring” and a revolution in public environmental awareness in the 20th century. In: Human, ecology, culture: modern practices and problems. Proceedings of the International Youth Scientific Conference. Saratov; 2014. P. 206–11 (In Russ.)Cohn BA, La Merrill M, Krigbaum NY, Yeh G, Park JS, Zimmermann L, Cirillo PM. DDT exposure in utero and breast cancer. J Clin Endocrinol Metab. 2015;100(8): 2865–72. https://doi.org/10.1210/jc.2015-1841Cohn BA, La Merrill M, Krigbaum NY, Yeh G, Park JS, Zimmermann L, Cirillo PM. DDT exposure in utero and breast cancer. J Clin Endocrinol Metab. 2015;100(8): 2865–72. https://doi.org/10.1210/jc.2015-1841Newbold RR, Padilla-Banks E, Jefferson WN. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology. 2006;147(6 Suppl):11–7. https://doi.org/10.1210/en.2005-1164Newbold RR, Padilla-Banks E, Jefferson WN. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology. 2006;147(6 Suppl):11–7. https://doi.org/10.1210/en.2005-1164McLachlan JA, Newbold RR, Shah HC, Hogan MD, Dixon RL. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982;38(3):364–71. https://doi.org/10.1016/s0015-0282(16)46520-9McLachlan JA, Newbold RR, Shah HC, Hogan MD, Dixon RL. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982;38(3):364–71. https://doi.org/10.1016/s0015-0282(16)46520-9Newbold RR, McLachlan JA. Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res. 1982;42(5):2003–11. PMID: 7066910Newbold RR, McLachlan JA. Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res. 1982;42(5):2003–11. PMID: 7066910Galbiati V, Buoso E, d’Emmanuele R, di Villa Bianca R, Di Paola R, Morroni F, et al. Immune and nervous systems interaction in endocrine disruptors toxicity: the case of atrazine. Front Toxicol. 2021;3:4. https://doi.org/10.3389/ftox.2021.649024Galbiati V, Buoso E, d’Emmanuele R, di Villa Bianca R, Di Paola R, Morroni F, et al. Immune and nervous systems interaction in endocrine disruptors toxicity: the case of atrazine. Front Toxicol. 2021;3:4. https://doi.org/10.3389/ftox.2021.649024Яглова НВ, Яглов ВВ. Эндокринные дизрапторы — новое направление исследований в эндокринологии. Вестник Российской академии медицинских наук. 2012;67(3):56–61.Yaglova NV, Yaglov VV. Endocrine disruptors are a novel direction of endocrinologic scientific investigation. Vestnik Rossiyskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences. 2012;67(3):56–61 (In Russ.)Patisaul HB, Adewale HB. Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior. Front Behav Neurosci. 2009;3:10. https://doi.org/10.3389/neuro.08.010.2009Patisaul HB, Adewale HB. Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior. Front Behav Neurosci. 2009;3:10. https://doi.org/10.3389/neuro.08.010.2009Евтеева АА, Шеремета МС, Пигарова ЕА. Эндокринные дисрапторы в патогенезе таких социально значимых заболеваний, как сахарный диабет, злокачественные новообразования, сердечно-сосудистые заболевания, патология репродуктивной системы. Ожирение и метаболизм. 2021;18(3):327–35. https://doi.org/10.14341/omet12757Evteeva AA, Sheremeta MS, Pigarova EA. Endocrine disruptors in the pathogenesis of socially significant diseases such as diabetes mellitus, malignant neoplasms, cardiovascular diseases, pathology of the reproductive system. Ozhirenie i metabolism = Obesity and Metabolism. 2021;18(3):327–35 (In Russ.) https://doi.org/10.14341/omet12757Lauretta R, Sansone A, Sansone M, Romanelli F, Appetecchia M. Endocrine disrupting chemicals: effects on endocrine glands. Front Endocrinol (Lausanne). 2019;10:178. https://doi.org/10.3389/fendo.2019.00178Lauretta R, Sansone A, Sansone M, Romanelli F, Appetecchia M. Endocrine disrupting chemicals: effects on endocrine glands. Front Endocrinol (Lausanne). 2019;10:178. https://doi.org/10.3389/fendo.2019.00178Andersen ME, Conolly RB, Faustman EM, Kavlock RJ, Portier CJ, Sheehan DM, et al. Quantitative mechanistically based dose-response modeling with endocrine-active compounds. Environ Health Perspect. 1999;107(Suppl 4):631–8. https://doi.org/10.1289/ehp.99107s4631Andersen ME, Conolly RB, Faustman EM, Kavlock RJ, Portier CJ, Sheehan DM, et al. Quantitative mechanistically based dose-response modeling with endocrine-active compounds. Environ Health Perspect. 1999;107(Suppl 4):631–8. https://doi.org/10.1289/ehp.99107s4631Sheehan DM. No-threshold dose–response curves for nongenotoxic chemicals: findings and applications for risk assessment. Environ Res. 2006;100(1):93–9. https://doi.org/10.1016/j.envres.2005.09.002Sheehan DM. No-threshold dose–response curves for nongenotoxic chemicals: findings and applications for risk assessment. Environ Res. 2006;100(1):93–9. https://doi.org/10.1016/j.envres.2005.09.002Vandenberg LN, Wadia PR, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM. The mammary gland response to estradiol: monotonic at the cellular level, non-monotonic at the tissue-level of organization? J Steroid Biochem Mol Biol. 2006;101(4–5):263–74. https://doi.org/10.1016/j.jsbmb.2006.06.028Vandenberg LN, Wadia PR, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM. The mammary gland response to estradiol: monotonic at the cellular level, non-monotonic at the tissue-level of organization? J Steroid Biochem Mol Biol. 2006;101(4–5):263–74. https://doi.org/10.1016/j.jsbmb.2006.06.028Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ Jr, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect. 1996;104(Suppl 4):741–803. https://doi.org/10.1289/ehp.96104s4741Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ Jr, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect. 1996;104(Suppl 4):741–803. https://doi.org/10.1289/ehp.96104s4741Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richard RM, et al. Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project. Am J Obstet Gynecol. 1981;140(5):579–86. https://doi.org/10.1016/0002-9378(81)90236-2Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richard RM, et al. Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project. Am J Obstet Gynecol. 1981;140(5):579–86. https://doi.org/10.1016/0002-9378(81)90236-2Sabir S, Akhtar MF, Saleem A. Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals. Environ Sci Pollut Res Int. 2019;26(2):1277– 86. https://doi.org/10.1007/s11356-018-3774-4Sabir S, Akhtar MF, Saleem A. Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals. Environ Sci Pollut Res Int. 2019;26(2):1277– 86. https://doi.org/10.1007/s11356-018-3774-4Сандаков ДБ, Семененя ИН, Гурин АВ. Изменение содержания некоторых гормонов в крови у крыс при центральном действии ингибиторов протеолиза и белкового синтеза. Проблемы эндокринологии. 1997;43(4):46–7. https://doi.org/10.14341/probl199743446-47Sandakov DB, Semenenya IN, Gurin AV. The change in the content of certain hormones in the blood of rats under the central action of proteolysis inhibitors and protein synthesis. Problemy endokrinologii = Problems of Endocrinology. 1997;43(4):46–7 (In Russ.) https://doi.org/10.14341/probl199743446-47Joseph LJ, Desai KB, Patel MC, Mehta MN, Ganatra RD. Thyroid function and thyrotropin levels in rabbits immunized to produce antibodies against thyroid hormones. Int J Rad Appl Instrum B. 1987;14(5):511–4. https://doi.org/10.1016/0883-2897(87)90119-xJoseph LJ, Desai KB, Patel MC, Mehta MN, Ganatra RD. Thyroid function and thyrotropin levels in rabbits immunized to produce antibodies against thyroid hormones. Int J Rad Appl Instrum B. 1987;14(5):511–4. https://doi.org/10.1016/0883-2897(87)90119-xYeom SC, Cho SY, Park CG, Lee WJ. Analysis of reference interval and age-related changes in serum biochemistry and hematology in the specific pathogen free miniature pig. Lab Anim Res. 2012;28(4):245–53. https://doi.org/10.5625/lar.2012.28.4.245Yeom SC, Cho SY, Park CG, Lee WJ. Analysis of reference interval and age-related changes in serum biochemistry and hematology in the specific pathogen free miniature pig. Lab Anim Res. 2012;28(4):245–53. https://doi.org/10.5625/lar.2012.28.4.245Thorson L. Thyroid diseases in rodent species. Vet Clin North Am Exot Anim Pract. 2014;17(1):51–67. https://doi.org/10.1016/j.cvex.2013.09.002Thorson L. Thyroid diseases in rodent species. Vet Clin North Am Exot Anim Pract. 2014;17(1):51–67. https://doi.org/10.1016/j.cvex.2013.09.002Диатроптов МЕ, Диатроптова МА, Кондашевская МВ. Анализ показателей инфрадианных ритмов стероидных гормонов и процентного содержания нейтрофилов периферической крови у крыс-самцов Вистар. Фундаментальные исследования. 2012;(9-2):273–7.Diatroptov ME, Diatroptova MA, Kondashevskaya MV. Infradian rhythmic of the steroid hormones and peripheral blood’s neutrophiles percentage test in Wistar male rats. Fundamental’nye issledovaniya = Fundamental Research. 2012;(9-2):273–7 (In Russ.)Кассим М, Синдеева ОА, Синдеев СС, Зинченко ЕМ, Уланова МВ, Гекалюк АС и др. Влияние эмоциональных и тяжелых патологических стрессов на уровень артериального давления и продукцию тестостерона у самок и самцов крыс. Известия Саратовского университета. Новая серия. Серия Химия. Биология. Экология. 2015;15(2):46–53.Kassim M, Sindeeva OA, Sindeev SS, Zinchenko EM, Ulanova MV, Gekalyuk AS, et al. The effect of emotional and severe pathological stresses on the level of arterial pressure and the production of testosterone in female and male rats. Izvestiya Saratovskogo universiteta. Novaya seriya. Seriya Khimiya. Biologiya. Ekologiya = Izvestiya of Saratov University. Chemistry. Biology. Ecology. 2015;15(2):46–53 (In Russ.)Косырева АМ, Джалилова ДШ, Макарова ОВ, Сладкопевцев АС. Морфофункциональные изменения тимуса и содержание субпопуляций лимфоцитов в крови у самок крыс Вистар с разной устойчивостью к гипоксии при системном воспалительном ответе. Медицинская иммунология. 2019;21(4):643–52. https://doi.org/10.15789/1563-0625-2019-4-643-652Kosyreva AM, Dzhalilova DSh, Makarova OV, Sladkopevtsev AS. Morpho-functional changes of thymus and contents of blood lymphocyte subpopulations in female Wistar rats with different resistance to hypoxia in systemic inflammatory response. Medical Immunology (Russia). 2019;21(4):643–52 (In Russ.) https://doi.org/10.15789/1563-0625-2019-4-643-652Hilliard J, Pang CN, Penardi R, Sawyer СН. Effect of coitus on serum levels of testosterone and LH in male and female rabbits. Proc Soc Exp Biol Med. 1975;149(4): 1010–4. https://doi.org/10.3181/00379727-149-38945Hilliard J, Pang CN, Penardi R, Sawyer СН. Effect of coitus on serum levels of testosterone and LH in male and female rabbits. Proc Soc Exp Biol Med. 1975;149(4): 1010–4. https://doi.org/10.3181/00379727-149-38945Zaima U, Anas Sarwar Q, Sarmad R, Misbah I, Tanzeela F, Saqib U. Effects of oral administration of black seed (Nigella sativa) oil on histomorphometric dynamics of testes and testosterone profile in rabbits. Pak J Pharm Sci. 2017;30(2):531–6. PMID: 28649080Zaima U, Anas Sarwar Q, Sarmad R, Misbah I, Tanzeela F, Saqib U. Effects of oral administration of black seed (Nigella sativa) oil on histomorphometric dynamics of testes and testosterone profile in rabbits. Pak J Pharm Sci. 2017;30(2):531–6. PMID: 28649080Котлярова АА, Щулькин АВ, Черных ИВ, Якушева ЕН. Особенности кроликов породы Шиншилла как тест-системы для изучения препаратов половых гормонов. Материалы Всероссийской научной конференции молодых ученых, посвященной 95-летию со дня рождения профессора А.А. Никулина. Рязань; 2018. C. 63–4.Kotlyarova AA, Shchul’kin AV, Chernykh IV, Yakusheva EN. Special considerations for Chinchilla rabbits as a test system for studying sex hormone preparations. Proceedings of the All-Russian scientific conference of young scientists dedicated to the 95th anniversary of the birth of Professor A.A. Nikulin. Ryazan; 2018. P. 63–4 (In Russ.)Myren CJ, Einer-Jensen N, Bennett P. The physiology of the testes in the Göttingen mini pig. Z Versuchstierkd. 1989;32(4):183–7. PMID: 2626885Myren CJ, Einer-Jensen N, Bennett P. The physiology of the testes in the Göttingen mini pig. Z Versuchstierkd. 1989;32(4):183–7. PMID: 2626885Faccio LA, Da Silva AS, Tonin AA. Serum levels of LH, FSH, estradiol and progesterone in female rats experimentally infected by Trypanosoma evansi. Experimental Parasitology. 2013;135(1):110-5. https://doi.org/10.1016/j.exppara.2013.06.008Faccio LA, Da Silva AS, Tonin AA. Serum levels of LH, FSH, estradiol and progesterone in female rats experimentally infected by Trypanosoma evansi. Experimental Parasitology. 2013;135(1):110-5. https://doi.org/10.1016/j.exppara.2013.06.008Mukaddam-Daher S, Jankowski M, Wang D, Menaouar A, Gutkowska J. Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum. J Endocrinol. 2002;175(1):211–6. https://doi.org/10.1677/joe.0.1750211Mukaddam-Daher S, Jankowski M, Wang D, Menaouar A, Gutkowska J. Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum. J Endocrinol. 2002;175(1):211–6. https://doi.org/10.1677/joe.0.1750211Røste LS, Taubøll E, Isojarvi JIT, Berner A, Berg KA, Pakarinen AJ, et al. Gonadal morphology and sex hormones in male and female Wistar rats after long-term lamotrigine treatment. Seizure. 2003;12(8):621– 7. https://doi.org/10.1016/s1059-1311(03)00056-6Røste LS, Taubøll E, Isojarvi JIT, Berner A, Berg KA, Pakarinen AJ, et al. Gonadal morphology and sex hormones in male and female Wistar rats after long-term lamotrigine treatment. Seizure. 2003;12(8):621– 7. https://doi.org/10.1016/s1059-1311(03)00056-6Мхитаров ВА. Влияние длительного потребления алкоголя в условиях свободного выбора на уровень половых гормонов. Российский медико-биологический вестник им. академика И.П. Павлова. 2010;18(1):44–8.Mkhitarov VA. Effect of prolonged alcohol consumption in a free elections in the level of sex hormones. Rossiysky mediko-biologicheskiy vestnik im. akademika I. P. Pavlova = I.P. Pavlov Russian Medical Biological Herald. 2010;18(1):44–8 (In Russ.)Peter B, De Rijk EPCT, Zeltner A, Emmen HH. Sexual maturation in the female Göttingen minipig. Toxicol Pathol. 2016;44(3):482–5. https://doi.org/10.1177/0192623315621413Peter B, De Rijk EPCT, Zeltner A, Emmen HH. Sexual maturation in the female Göttingen minipig. Toxicol Pathol. 2016;44(3):482–5. https://doi.org/10.1177/0192623315621413Meijs-Roelofs НМ, de Greef WJ, Uilenbroek JT. Plasma progesterone and its relationship to serum gonadotrophins in immature female rats. J Endocrinol. 1975;64(2):329–36. https://doi.org/10.1677/joe.0.0640329Meijs-Roelofs НМ, de Greef WJ, Uilenbroek JT. Plasma progesterone and its relationship to serum gonadotrophins in immature female rats. J Endocrinol. 1975;64(2):329–36. https://doi.org/10.1677/joe.0.0640329Kriesten К, Murawski U. Concentrations of serum cortisol, progesterone, estradiol-17 beta, cholesterol and cholesterol ester in the doe during the reproductive stadium, in the fetal serum, in the amniotic fluid and in the milk of rabbits, as well as correlations between these parameters. Comp Biochem Physiol A Comp Physiol. 1988;90(3):413–20. https://doi.org/10.1016/0300-9629(88)90211-3Kriesten К, Murawski U. Concentrations of serum cortisol, progesterone, estradiol-17 beta, cholesterol and cholesterol ester in the doe during the reproductive stadium, in the fetal serum, in the amniotic fluid and in the milk of rabbits, as well as correlations between these parameters. Comp Biochem Physiol A Comp Physiol. 1988;90(3):413–20. https://doi.org/10.1016/0300-9629(88)90211-3Noguchi M, Ikedo T, Kawaguchi H, Tanimoto A. Estrus synchronization in microminipig using estradiol dipropionate and prostaglandin F2α. J Reprod Dev. 2016;62(4):373–8. https://doi.org/10.1262/jrd.2015-169Noguchi M, Ikedo T, Kawaguchi H, Tanimoto A. Estrus synchronization in microminipig using estradiol dipropionate and prostaglandin F2α. J Reprod Dev. 2016;62(4):373–8. https://doi.org/10.1262/jrd.2015-169Gharib SD, Wierman ME, Badger TM, Chin WW. Sex steroid hormone regulation of follicle-stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat. J Clin Invest. 1987;80(2):294– 9. https://doi.org/10.1172/JCI113072Gharib SD, Wierman ME, Badger TM, Chin WW. Sex steroid hormone regulation of follicle-stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat. J Clin Invest. 1987;80(2):294– 9. https://doi.org/10.1172/JCI113072Berger M, Jean-Faucher C, de Turckheim M, Veyssiere G, Blanc MR, Poirier JC, Jean C. Testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) in plasma of rabbit from birth to adulthood. Correlation with sexual and behavioural development. Acta Endocrinol (Copenh). 1982;99(3):459–65. https://doi.org/10.1530/acta.0.0990459Berger M, Jean-Faucher C, de Turckheim M, Veyssiere G, Blanc MR, Poirier JC, Jean C. Testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) in plasma of rabbit from birth to adulthood. Correlation with sexual and behavioural development. Acta Endocrinol (Copenh). 1982;99(3):459–65. https://doi.org/10.1530/acta.0.0990459Щулькин АВ, Якушева ЕН, Черных ИВ, Виноградов ИЮ, Попова НМ. Экспрессия гликопротеина P при экспериментальной дисфункции щитовидной железы. Клиническая и экспериментальная тиреоидология. 2015;11(3):11–6. https://doi.org/10.14341/ket2015311-16Shchul’kin AV, Yakusheva EN, Chernykh IV, Vinogradov IYu, Popova NM. P-glycoprotein expression in experimental thyroid dysfunction. Klinicheskaya i eksperimentalnaya tireoidologiya = Clinical and Experimental Thyroidology. 2015;11(3):11–6 (In Russ.) https://doi.org/10.14341/ket2015311-16Noguchi М, Miura N, Ando T, Kubota Ch, Hobo S, Kawaguchi H, Tanimoto A. Profiles of reproductive hormone in the microminipig during the normal estrous cycle. In Vivo. 2015;29(1):17–22.Noguchi М, Miura N, Ando T, Kubota Ch, Hobo S, Kawaguchi H, Tanimoto A. Profiles of reproductive hormone in the microminipig during the normal estrous cycle. In Vivo. 2015;29(1):17–22.Pitt JA, Buckalew AR, House DE, Abbott BD. Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology. 2000;151(1–3):25–35. https://doi.org/10.1016/s0300-483x(00)00257-2Pitt JA, Buckalew AR, House DE, Abbott BD. Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology. 2000;151(1–3):25–35. https://doi.org/10.1016/s0300-483x(00)00257-2Monnier M, Desbals B. Dosage radio-immunologique de l’ACTH chez le lapin: relations stress ACTH-corticostéroïdes et diarrhées. Reprod Nutr Dev. 1985;25(6):1017–28. PMID: 3006192Monnier M, Desbals B. Dosage radio-immunologique de l’ACTH chez le lapin: relations stress ACTH-corticostéroïdes et diarrhées. Reprod Nutr Dev. 1985;25(6):1017–28. PMID: 3006192Tuchscherer M, Kanitz E, Puppe B, Tuchscherer A. Altered immunomodulation by glucocorticoids in neonatal pigs exposed to a psychosocial stressor. Pediatr Res. 2010;68(6):473–8. https://doi.org/10.1203/pdr.0b013e3181f70f08Tuchscherer M, Kanitz E, Puppe B, Tuchscherer A. Altered immunomodulation by glucocorticoids in neonatal pigs exposed to a psychosocial stressor. Pediatr Res. 2010;68(6):473–8. https://doi.org/10.1203/pdr.0b013e3181f70f08Горенко ИН, Киприянова КЕ, Типисова ЕВ. Тиреоидные гормоны и уровень антител у здоровых жителей Архангельской области. Экология человека. 2018;25(9):36–41. https://doi.org/10.33396/1728-0869-2018-9-36-41Gorenko IN, Kipriyanova KE, Tipisova EV. Thyroid hormones and antibody level in healthy residents of the Arkhangelsk region. Ekologiya cheloveka = Human Ecology. 2018;25(9):36–41 (In Russ.) https://doi.org/10.33396/1728-0869-2018-9-36-41Mortoglou A, Candiloros H. The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy. Hormones (Athens). 2004;3(2):120–6. https://doi.org/10.14310/horm.2002.11120Mortoglou A, Candiloros H. The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy. Hormones (Athens). 2004;3(2):120–6. https://doi.org/10.14310/horm.2002.11120Гончаров НП. Значение и роль методов определения гормонов в развитии эндокринологии как общебиологической науки. Вестник Российской академии медицинских наук. 2012;67(3):42–9. https://doi.org/10.15690/vramn.v67i3.184Goncharov NP. Significance and role of hormone detection methods in the development of endocrinology as a biological discipline. Vestnik Rossiyskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences. 2012;67(3):42–9 (In Russ.) https://doi.org/10.15690/vramn.v67i3.184Campanha FVG, Perone D, de Campos DHS, Luvizotto R, De Síbio MT, et al. Thyroxine increases Serca2 and Ryr2 gene expression in heart failure rats with euthyroid sick syndrome. Arch Endocrinol Metab. 2016;60(6): 582–6. https://doi.org/10.1590/2359-3997000000208Campanha FVG, Perone D, de Campos DHS, Luvizotto R, De Síbio MT, et al. Thyroxine increases Serca2 and Ryr2 gene expression in heart failure rats with euthyroid sick syndrome. Arch Endocrinol Metab. 2016;60(6): 582–6. https://doi.org/10.1590/2359-3997000000208Saadia Z. Follicle stimulating hormone (LH: FSH) ratio in polycystic ovary syndrome (PCOS) — obese vs. non-obese women. Med Arch. 2020;74(4):289–93. https://doi.org/10.5455/medarh.2020.74.289-293Saadia Z. Follicle stimulating hormone (LH: FSH) ratio in polycystic ovary syndrome (PCOS) — obese vs. non-obese women. Med Arch. 2020;74(4):289–93. https://doi.org/10.5455/medarh.2020.74.289-293Morshed MS, Banu H, Akhtar N, Sultana T, Begum A, Zamilla M. Luteinizing hormone to follicle-stimulating hormone ratio significantly correlates with androgen level and manifestations are more frequent with hyperandrogenemia in women with polycystic ovary syndrome. J Endocrinol Metab. 2021;11(1):14– 21. https://doi.org/10.14740/jem716Morshed MS, Banu H, Akhtar N, Sultana T, Begum A, Zamilla M. Luteinizing hormone to follicle-stimulating hormone ratio significantly correlates with androgen level and manifestations are more frequent with hyperandrogenemia in women with polycystic ovary syndrome. J Endocrinol Metab. 2021;11(1):14– 21. https://doi.org/10.14740/jem716Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J. The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods. 2010;62(3):196–220. https://doi.org/10.1016/j.vascn.2010.05.009Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J. The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods. 2010;62(3):196–220. https://doi.org/10.1016/j.vascn.2010.05.009Черкасова ОП, Федоров ВИ. Одновременное исследование содержания кортикостерона и 11-дегидрокортикостерона в надпочечниках и плазме крови при остром стрессе. Проблемы эндокринологии. 2001;47(1):37–9. https://doi.org/10.14341/probl11315Cherkasova ОP, Fedorov VI. Simultaneous measurement of corticosterone and 11-dehydrocorticosterone in the adrenals and plasma in acute stress. Problemy endokrinologii = Problems of Endocrinology. 2001;47(1):37–9 (In Russ.) https://doi.org/10.14341/probl11315Кондашевская МВ, Алексанкина ВВ, Артемьева КА, Болтовская МН. Сопоставление адаптивной способности старых и молодых крыс Вистар к стрессорному воздействию и острой гипоксической гипоксии. Бюллетень экспериментальной биологии и медицины. 2021;171(6):783–7. https://doi.org/10.47056/0365-9615-2021-171-6-783-787Kondashevskaya MV, Aleksankina VV, Artemieva KA, Boltovskaya MN. Comparison adaptive capacity of old and young Wistar rats to stress exposure and acute hypoxic hypoxia. Byulleten’ ehksperimental’noi biologii i meditsiny = Bulletin of Experimental Biology and Medicine. 2021;171(6):783–7 (In Russ.) https://doi.org/10.47056/0365-9615-2021-171-6-783-787Меркулов ВМ, Климова НВ, Меркулова ТИ. Внутрисуточный ритм секреции глюкокортикоидов и динамика генного ответа. Вавиловский журнал генетики и селекции. 2015;19(2):214–21.Merkulov VM, Klimova NV, Merkulova TI. The ultradian rhythm of glucocorticoid secretion and the time course of target gene regulation. Vavilovskiy zhurnal genetiki i selektsii = Vavilov Journal of Genetics and Breeding. 2015;19(2):214–21 (In Russ.)Умрюхин ПЕ, Григорчук ОС. Кортикостерон крови и ликвора у крыс с различным поведением в открытом поле при стрессорной нагрузке. Международный журнал прикладных и фундаментальных исследований. 2015;11(3):372–4.Umryukhin PE, Grigorchuk OS. Blood and liquor corticosterone level in the rats with different open field behavior: effects of the stress. Mezhdunarodny zhurnal prikladnykh i fundamental’nykh issledovaniy = International Journal of Applied and Fundamental Research. 2015;11(3):372–4 (In Russ.)Гостюхина АА, Замощина ТА, Зайцев КВ, Гутор СС, Жукова ОБ, Светлик МВ и др. Адаптивные реакции крыс после световых десинхронозов и физического переутомления. Бюллетень сибирской медицины. 2018;17(3):22–34. https://doi.org/10.20538/1682-0363-2018-3-22-34Gostyukhina AA, Zamoshchina TA, Zaitsev KV, Gutor SS, Zhukova OB, Svetlik MV, et al. Adaptive reactions of rats after light desynchronosis and physical overwork. Bulletin of Siberian Medicine. 2018;17(3):22–34 (In Russ.) https://doi.org/10.20538/1682-0363-2018-3-22-34Viau V, Meaney MJ. Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology. 1991;129(5):2503–11. https://doi.org/10.1210/endo-129-5-2503Viau V, Meaney MJ. Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology. 1991;129(5):2503–11. https://doi.org/10.1210/endo-129-5-2503Louch CD, Higginbotham M. The relation between social rank and plasma corticosterone levels in mice. Gen Comp Endocrinol. 1967;8(3):441–4. https://doi.org/10.1016/s0016-6480(67)80006-6Louch CD, Higginbotham M. The relation between social rank and plasma corticosterone levels in mice. Gen Comp Endocrinol. 1967;8(3):441–4. https://doi.org/10.1016/s0016-6480(67)80006-6

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