Андрология и генитальная хирургия. 2015; 16: 13-22
Дегидроэпиандростерон: биосинтез, метаболизм, биологическое действие и клиническое применение (аналитический обзор)
https://doi.org/10.17650/2070-9781-2015-1-13-22Аннотация
Представлена фундаментальная информация относительно метаболизма дегидроэпиандростерона (ДГЭА), его биологической роли и возможности использования для заместительной терапии. Рассмотрены видовые различия в синтезе ДГЭА в коре надпочечников. ДГЭА и ДГЭА-сульфат вырабатывают надпочечники только представителей отряда приматов, т. е. человека, высших и низших обезьян. Их синтез идет по Δ5-пути: холестерин → прегненолон → 17-гидроксипрегненолон → ДГЭА. Надпочечники других видов животных, включая крыс и мышей, не синтезируют ДГЭА. Вместе с тем определенные структуры мозга не только человека и обезьян, но и других животных синтезируют de novo ДГЭА и его предшественники, которые обозначаются как нейростероиды. Показано, что клетки Пуркинье, которые играют важную роль в формировании памяти и в процессе обучения, являются главным местом образования нейростероидов у млекопитающих и других позвоночных. Для выяснения возрастной динамики циркулирующего ДГЭА и других стероидов у человека нами проведено изучение его уровня в различные периоды постнатального развития. Пик образования гормона приходится на возраст 25–30 лет. В промежутке от 20 до 90 лет его уровень у человека падает на 90 %. Уровень кортизола в крови с возрастом не изменяется, что приводит к дисбалансу в соотношении кортизол/ДГЭА. Доказана определяющая роль ДГЭА как источника (предшественника) биологически активных половых стероидов: тестостерона, эстрадиола и эстрона в периферических тканях. Рассмотрены биодоступность и возможные механизмы взаимодействия гормона с физиологическими и патологическими процессами в организме человека и животных. В экспериментах на животных показана более высокая биодоступность ДГЭА при трансдермальном введении по сравнению с его приемом per os, так как в этом случае не происходит быстрая инактивация стероида в печени при первом пассаже. Большинство современных исследований у мужчин и женщин демонстрируют выраженную зависимость биодоступности ДГЭА в организме от способа введения препарата.
Список литературы
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15. Thomas G., Frenoy N., Legrain S. et al. Serum dehydroepiandrosterone sulfate levels as an individual marker. J Clin Endocrinol Metab 1994;79(5):1273–6.
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Andrology and Genital Surgery. 2015; 16: 13-22
Dehydroepiandrosterone biosynthesis, metabolism, biological effects, and clinical use (analytical review)
https://doi.org/10.17650/2070-9781-2015-1-13-22Abstract
The review presents the fundamental information on the metabolism of dehydroepiandrosterone (DHEA), its biological role and possibilities of its use for replacement therapy. There were studied species differences in the synthesis of DHEA in the adrenal cortex. It was found that DHEA and DHEA-sulfate are produced only by the adrenal glands of humans and monkeys, including lower monkeys. Their biosynthesis involves the following steps: cholesterol → pregnenolone → 17-hydroxypregnenolone → DHEA. The adrenal glands of other species, including rats and mice do not synthesize DHEA. At the same time, in certain brain structures not only in man and monkey, but also in other animals DHEA and its precursors are synthesized de novo which are denoted as neurosteroids. It was demonstrated that Purkinje cells which play an important role in memory formation and learning are mainly place neurosteroid formation in mammals and other vertebrates. To establish the relationship of age and the level of DHEA and other steroids we studied the dynamics of their levels at different periods of postnatal development of people. Peak concentration DHEA observed in aged 25–30 years. In the interval from 20 to 90 years in humans the level falls approximately for 90 %. Cortisol levels in blood does not vary with age, leading to an imbalance in the ratio of cortisol/DHEA. Proved a major role of DHEA as a source (precursor) for the synthesis of biologically active sex steroids – testosterone, estradiol and estrone in peripheral tissues. This review presents the bioavailability of DHEA in various physiological and pathological processes in humans and animals. In animal experiments has shown a higher bioavailability of DHEA in transdermal administration as compared with oral administration as in this case there is no steroid rapid inactivation in the liver during its first passage. According to recent studies there is a pronounced dependence of bioavailability of DHEA during replacement therapy from the method of drug administration.
References
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20. Goncharov N.P., Katzya G.V. Adrenal and gonadal steroid levels in long-living males from highland regions of the Southwestern Caucasian Mountains. Aging Male 1998;1:200–5.
21. Bird C.E., Masters V., Clark A.F. Dehydroepiandrosterone sulfate: kinetics of metabolism in normal young men and women. Clin Invest Med 1984;7(2):119–22.
22. Haning R.V. Jr, Chabot M., Flood C.A. et al. Metabolic clearance rate (MCR) of dehydroepiandrosterone sulfate (DS), its metabolism to dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone, and the effect of increased plasma DS concentration on DS MCR in normal women. J Clin Endocrinol Metab 1989;69(5):1047–52.
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24. Horton R., Tait J.F. In vivo conversion of dehydroisoandrosterone to plasma androstenedione and testosterone in man. J Clin Endocrinol Metab 1967;27(1):79–88.
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31. Labrie F., Simard J., Luu-The V. et al. Structure and tissue-specific expression of 3 beta-hydroxysteroid dehydrogenase/ 5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues. J Steroid Biochem Mol Biol 1992;41(3–8):421–35.
32. Luu-The V., Zhang Y., Poirier D., Labrie F. Characteristics of human types 1, 2 and 317 beta-hydroxysteroid dehydrogenase activities: oxidation/reduction and inhibition. J Steroid Biochem Mol Biol 1995;55(5– 6):581–7.
33. Labrie Y., Durocher F., Lachance Y. et al. The human type II 17 beta-hydroxysteroid dehydrogenase gene encodes two alternatively spliced mRNA species. DNA Cell Biol 1995;14(10):849–61.
34. Labrie F., Simard J., Luu-The V. The 3-beta-hydroxysteroid dehydrogenase/ isomerase gene family: lessions from type II 3beta-HSD congenital deficiency. In: V. Hansson, F.O. Levy, K. Tasken (eds.). Signal transduction in testicular cells. Ernst Schering Research Foundation Workshop. Berlin, Heidelberg, New York: SpringerVerlag, 1996. Pp. 185–218.
35. Stahl F., Schnorr D., Pilz C., Dörner G. Dehydroepiandrosterone (DHEA) levels in patients with prostatic cancer, heart diseases and under surgery stress. Exp Clin Endocrinol 1992;99(2):68–70.
36. Zumoff B., Levin J., Rosenfeld R.S. et al. Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer. Cancer Res 1981;41(9 Pt 1):3360–3.
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