cfpdБюллетень физиологии и патологии дыханияBulletin Physiology and Pathology of Respiration1998-5029Дальневосточный научный центр физиологии и патологии дыхания10.12737/article_5936356ad72dd1.30067788cfpd-38Research ArticleСтатьиМЕТАБОЛИЗМ ПРОГЕСТЕРОНА В ПЛАЦЕНТЕ (ОБЗОР ЛИТЕРАТУРЫ)PROGESTERONE METABOLISM IN PLACENTA (REVIEW)ДовжиковаИ. В.DovzhikovaI. V.dov_kova100@rambler.ruЛуценкоМ. Т.LutsenkoM. T.lucenkomt@mail.ruДальневосточный научный центр физиологии и патологии дыханияFar Eastern Scientific Center of Physiology and Pathology of Respiration201718112019064101107Copyright © Довжикова И.В., Луценко М.Т., 20192019Довжикова И.В., Луценко М.Т.Dovzhikova I.V., Lutsenko M.T.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cfpd.elpub.ru/jour/article/view/38

В статье представлены современные данные о метаболизме прогестерона в плаценте. Рассмотрены ферменты, принимающие участие в преобразовании гестагенов: альдокеторедуктазы (AKR1D1, AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2), 3β- и 17β-гидроксистероиддегидрогеназы. Изложены существующие в настоящее время мнения об их существенной роли в поддержании беременности. Представлены основные метаболиты прогестерона в плаценте - 20α-дигидропрогестерон и 5α-дигидропрогестерон. Кроме этого, особое внимание в статье уделено двум другим активно изучаемым в последнее время метаболитам: 5β-дигидропрогестерону и аллопрегненолону. Подчеркнута их центральная роль: 5β-дигидропрогестерон поддерживает тонус миометрия в состоянии покоя, аллопрегненолон является ключевым нейроактивным стероидом в период жизни плода. Сделан вывод о необходимости дальнейшего исследования метаболизма прогестерона в плаценте.

Current data on progesterone metabolism in placenta are presented in the article. Enzymes involved in the conversion of gestogens: aldo-keto reductases (AKR1D1, AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2), 3β- and 17β-hydroxysteroid dehydrogenases were studied. Existing opinions on their essential role in the maintenance of pregnancy were presented. The main metabolites of progesterone in placenta, namely 20α-dihydroprogesterone and 5α-dihydroprogesterone were presented. In addition, special attention was paid to other two metabolites actively studied at present: 5β-dihydroprogesterone and allopregnenolone. Their central role was emphasized: 5β-dihydroprogesterone maintains myometrium tonus at quiescent interval, and allopregnenolon is a key neuroactive steroid during the fetal life. It was concluded that further research is needed to study progesterone metabolism in placenta.

прогестеронплацентаферменты метаболизма прогестеронаprogesteroneplacentaenzymes of progesterone metabolismReferencesBardin C.W., Milgrom E., Mauvais-Jarvis P. Progesterone and progestins. Raven Press: New York, 1983. 448 р.Bardin C.W., Milgrom E., Mauvais-Jarvis P. Progesterone and progestins. Raven Press: New York, 1983. 448 р.Bienvenu T., Pons G., Rey E., Thiroux G., Olive G. Effect of pregnandiol on caffeine metabolism in female rats // Eur. J. Drug Metab. Pharmacokinet. 1993. Vol.18, Iss.2. P.181-185.Bienvenu T., Pons G., Rey E., Thiroux G., Olive G. Effect of pregnandiol on caffeine metabolism in female rats // Eur. J. Drug Metab. Pharmacokinet. 1993. Vol.18, Iss.2. P.181-185.Blackmore P.F. Progesterone metabolites rapidly stimulate calcium influx in human platelets by a src-dependent pathway // Steroids. 2008. Vol.73, №7. Р.738-750.Blackmore P.F. Progesterone metabolites rapidly stimulate calcium influx in human platelets by a src-dependent pathway // Steroids. 2008. Vol.73, №7. Р.738-750.Burger K., Fahrenholz F., Gimpl G. Non-genomic effects of progesterone on the signaling function of G protein-coupled receptors // FEBS Lett. 1999. Vol.464, №1-2. Р.25-29.Burger K., Fahrenholz F., Gimpl G. Non-genomic effects of progesterone on the signaling function of G protein-coupled receptors // FEBS Lett. 1999. Vol.464, №1-2. Р.25-29.Burton A., Lockhart F., Bosnjak S., Yong S. Stimulation by 17 alpha-hydroxyprogesterone of glycoprotein and glycosaminoglycan synthesis in human placenta in vitro // Biol. Neonate. 1989. Vol.55, №3. Р.151-155.Burton A., Lockhart F., Bosnjak S., Yong S. Stimulation by 17 alpha-hydroxyprogesterone of glycoprotein and glycosaminoglycan synthesis in human placenta in vitro // Biol. Neonate. 1989. Vol.55, №3. Р.151-155.Byrns M.C. Role of aldo-keto reductase enzymes in mediating the timing of parturition // Front. Pharmacol. 2011. Vol.2. P.92. URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253584/Byrns M.C. Role of aldo-keto reductase enzymes in mediating the timing of parturition // Front. Pharmacol. 2011. Vol.2. P.92. URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253584/Chen M., Drury J. E., Penning T. M. Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1) // Steroids. 2011. Vol.76, №5. P.484-490.Chen M., Drury J. E., Penning T. M. Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1) // Steroids. 2011. Vol.76, №5. P.484-490.Cooke D., Wiqvist N., Diczfalusy E. Metabolism of pregnanediol in the human foeto-placental unit at midpregnancy // Acta Endocrinol. 1967. Vol.56, №1. P.43-55.Cooke D., Wiqvist N., Diczfalusy E. Metabolism of pregnanediol in the human foeto-placental unit at midpregnancy // Acta Endocrinol. 1967. Vol.56, №1. P.43-55.Dombroski R.A., Casey M.L., MacDonald P.C. 5-Alpha-dihydroprogesterone formation in human placenta from 5alpha-pregnan-3beta/alpha-ol-20-ones and 5-pregnan-3beta-yl-20-one sulfate // J. Steroid Biochem. Mol. Biol. 1997. Vol.63, №1-3. Р.155-163.Dombroski R.A., Casey M.L., MacDonald P.C. 5-Alpha-dihydroprogesterone formation in human placenta from 5alpha-pregnan-3beta/alpha-ol-20-ones and 5-pregnan-3beta-yl-20-one sulfate // J. Steroid Biochem. Mol. Biol. 1997. Vol.63, №1-3. Р.155-163.Francis F.E., Kinsella R.A.Jr. Enteric Excretion of Metabolites of Steroid Hormones in the Human Subject. IV. Isolation of 5β-Pregnane-3α,20α-diol from Meconium // J. Clin. Endocrinol. Metab. 1966. Vol.26, №2. Р.128-132.Francis F.E., Kinsella R.A.Jr. Enteric Excretion of Metabolites of Steroid Hormones in the Human Subject. IV. Isolation of 5β-Pregnane-3α,20α-diol from Meconium // J. Clin. Endocrinol. Metab. 1966. Vol.26, №2. Р.128-132.Grazzini E., Guillon G., Mouillac B., Zingg H.H. Inhibition of oxytocin receptor function by direct binding of progesterone // Nature. 1998. Vol.392, № 6675. P.509-512.Grazzini E., Guillon G., Mouillac B., Zingg H.H. Inhibition of oxytocin receptor function by direct binding of progesterone // Nature. 1998. Vol.392, № 6675. P.509-512.Hill M., Pařízek A., Kancheva R., Jirásek J. E. Reduced progesterone metabolites in human late pregnancy // Physiol. Res. 2011. Vol.60, №2. Р.225-241.Hill M., Pařízek A., Kancheva R., Jirásek J. E. Reduced progesterone metabolites in human late pregnancy // Physiol. Res. 2011. Vol.60, №2. Р.225-241.Hirst J.J., Kelleher M.A., Walker D.W., Palliser H.K. Neuroactive steroids in pregnancy: Key regulatory and protective roles in the foetal brain // J. Steroid Biochem. Mol. Biol. 2013. URL: http://www.ncbi.nlm.nih.gov/pubmed/23669456Hirst J.J., Kelleher M.A., Walker D.W., Palliser H.K. Neuroactive steroids in pregnancy: Key regulatory and protective roles in the foetal brain // J. Steroid Biochem. Mol. Biol. 2013. URL: http://www.ncbi.nlm.nih.gov/pubmed/23669456Jaffe R.B., Ledger W.J. In vivo steroid biogenesis and metabolism in the human term placenta. 1. In situ placental perfusion with isotopic pregnenolone // Steroids. 1966. Vol.8, Iss.5. P.695-710.Jaffe R.B., Ledger W.J. In vivo steroid biogenesis and metabolism in the human term placenta. 1. In situ placental perfusion with isotopic pregnenolone // Steroids. 1966. Vol.8, Iss.5. P.695-710.Jayasekara W.S.N., Yonezawa T., Ishida M., Yamanouchi K, Nishihara M. Expression and possible role of 20α-hydroxysteroid dehydrogenase in the placenta of the goat // J. Reprod. Dev. 2005. Vol.51, №2. P.265-272.Jayasekara W.S.N., Yonezawa T., Ishida M., Yamanouchi K, Nishihara M. Expression and possible role of 20α-hydroxysteroid dehydrogenase in the placenta of the goat // J. Reprod. Dev. 2005. Vol.51, №2. P.265-272.Jin Y. Mesaros A.C., Blair I.A., Penning T.M. Stereospecific reduction of 5β-reduced steroids by human ketosteroid reductases of the AKR (aldo-keto reductase) superfamily: role of AKR1C1-AKR1C4 in the metabolism of testosterone and progesterone via the 5β-reductase pathway // Biochem. J. 2011. Vol.437, №1. Р.53-61.Jin Y. Mesaros A.C., Blair I.A., Penning T.M. Stereospecific reduction of 5β-reduced steroids by human ketosteroid reductases of the AKR (aldo-keto reductase) superfamily: role of AKR1C1-AKR1C4 in the metabolism of testosterone and progesterone via the 5β-reductase pathway // Biochem. J. 2011. Vol.437, №1. Р.53-61.Junkermann H., Runnebaum B., Lisboa B.P. New progesterone metabolites in human myometrium // Steroids. 1977. Vol.30, №1. Р.1-14.Junkermann H., Runnebaum B., Lisboa B.P. New progesterone metabolites in human myometrium // Steroids. 1977. Vol.30, №1. Р.1-14.Kochakian C.D. Conversion of testosterone and androstenedione to 5 beta-androstanes by adult male hamster liver cytosol // J. Steroid Biochem. 1983. Vol.19, №4. Р.1521-1526.Kochakian C.D. Conversion of testosterone and androstenedione to 5 beta-androstanes by adult male hamster liver cytosol // J. Steroid Biochem. 1983. Vol.19, №4. Р.1521-1526.Kubli-Garfias C., Medrano-Conde L., Beyer C., Bondani A. In vitro inhibition of rat uterine contractility induced by 5 alpha and 5 beta progestins // Steroids. 1979. Vol.34, №6. P.609-617.Kubli-Garfias C., Medrano-Conde L., Beyer C., Bondani A. In vitro inhibition of rat uterine contractility induced by 5 alpha and 5 beta progestins // Steroids. 1979. Vol.34, №6. P.609-617.Lacy L.R., Knudson M.M., Williams J.J., Richards J.S., Midgley A.R. Jr. Progesterone Metabolism by the Ovary of the Pregnant Rat: Discrepancies in the Catabolic Regulation Model // Endocrinology. 1976. Vol.99, №4. P.929-934.Lacy L.R., Knudson M.M., Williams J.J., Richards J.S., Midgley A.R. Jr. Progesterone Metabolism by the Ovary of the Pregnant Rat: Discrepancies in the Catabolic Regulation Model // Endocrinology. 1976. Vol.99, №4. P.929-934.Li Y., Isomaa V., Pulkka A., Herva R., Peltoketo H., Vihko P.Expression of 3beta-hydroxysteroid dehydrogenase type 1, P450 aromatase, and 17beta-hydroxysteroid dehydrogenase types 1, 2, 5 and 7 mRNAs in human early and mid-gestation placentas // Placenta. 2005. Vol.26, №5. Р.387-392.Li Y., Isomaa V., Pulkka A., Herva R., Peltoketo H., Vihko P.Expression of 3beta-hydroxysteroid dehydrogenase type 1, P450 aromatase, and 17beta-hydroxysteroid dehydrogenase types 1, 2, 5 and 7 mRNAs in human early and mid-gestation placentas // Placenta. 2005. Vol.26, №5. Р.387-392.Lin S.X., Shi R., Qiu W., Azzi A., Zhu D.W., Dabbagh H.A., Zhou M.Structural basis of the multispecificity demonstrated by 17beta-hydroxysteroid dehydrogenase types 1 and 5 // Mol. Cell. Endocrinol. 2006. Vol.248, №1-2. Р.38-46.Lin S.X., Shi R., Qiu W., Azzi A., Zhu D.W., Dabbagh H.A., Zhou M.Structural basis of the multispecificity demonstrated by 17beta-hydroxysteroid dehydrogenase types 1 and 5 // Mol. Cell. Endocrinol. 2006. Vol.248, №1-2. Р.38-46.Little B., Dimartinis J., Nyholm B. The conversion of progesterone to delta 4 pregnene-20 alpha-ol, 3-one by human placenta in vitro // Acta Endocrinol. (Copenh). 1959. Vol.30, №4. Р.530-538.Little B., Dimartinis J., Nyholm B. The conversion of progesterone to delta 4 pregnene-20 alpha-ol, 3-one by human placenta in vitro // Acta Endocrinol. (Copenh). 1959. Vol.30, №4. Р.530-538.Matsuura K., Shiraishi H., Hara A., Sato K., Deyashiki Y., Ninomiya M., Sakai S. Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity // J. Biochem. 1998. Vol.124, №5. Р.940-946.Matsuura K., Shiraishi H., Hara A., Sato K., Deyashiki Y., Ninomiya M., Sakai S. Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity // J. Biochem. 1998. Vol.124, №5. Р.940-946.Meis P.J. 17 hydroxyprogesterone for the prevention of preterm delivery // Obstet. Gynecol. 2005. Vol.105, №5(Pt1). Р.1128-1135.Meis P.J. 17 hydroxyprogesterone for the prevention of preterm delivery // Obstet. Gynecol. 2005. Vol.105, №5(Pt1). Р.1128-1135.Merlob P., Stahl B., Klinger G. 17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth // Reprod. Toxicol. 2012. Vol.33, №1. Р.15-19.Merlob P., Stahl B., Klinger G. 17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth // Reprod. Toxicol. 2012. Vol.33, №1. Р.15-19.Mickan H. Saturated metabolites of progesterone in human myometrium during pregnancy // Steroids. 1976. Vol.27, №1. Р.65-77.Mickan H. Saturated metabolites of progesterone in human myometrium during pregnancy // Steroids. 1976. Vol.27, №1. Р.65-77.Milewich L., Gant N.F., Schwarz B.E., Prough R.A., Chen G.T., Athey B., MacDonald P.C. Initiation of human parturition. VI. Identification and quantification of progesterone metabolites produced by the components of human fetal membranes // J. Clin. Endocrinol. Metab. 1977. Vol.45, №3. P.400-411.Milewich L., Gant N.F., Schwarz B.E., Prough R.A., Chen G.T., Athey B., MacDonald P.C. Initiation of human parturition. VI. Identification and quantification of progesterone metabolites produced by the components of human fetal membranes // J. Clin. Endocrinol. Metab. 1977. Vol.45, №3. P.400-411.Milewich L., Gant N.F., Schwarz B.E., Chen G.T., Macdonald P.C. Initiation of human parturition. IX. Progesterone metabolism by placentas of early and late human gestation // Obstet. Gynecol. 1978. Vol.51, №3. Р.278-280.Milewich L., Gant N.F., Schwarz B.E., Chen G.T., Macdonald P.C. Initiation of human parturition. IX. Progesterone metabolism by placentas of early and late human gestation // Obstet. Gynecol. 1978. Vol.51, №3. Р.278-280.Milewich L., Gant N.F., Schwarz B.E., Chen G.T., Mac Donald P.C. 5 alpha-reductase activity in human placenta // Am. J. Obstet. Gynecol. 1979. Vol.133, №6. Р.611-617.Milewich L., Gant N.F., Schwarz B.E., Chen G.T., Mac Donald P.C. 5 alpha-reductase activity in human placenta // Am. J. Obstet. Gynecol. 1979. Vol.133, №6. Р.611-617.Mitchell B.F., Mitchell J.M., Chowdhury J., Tougas M., Engelen S.M., Senff N., Heijnen I., Moore J.T., Goodwin B., Wong S., Davidge S.T. Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy? // Am. J. Obstet. Gynecol. 2005. Vol.192, №4. Р.1304-1313.Mitchell B.F., Mitchell J.M., Chowdhury J., Tougas M., Engelen S.M., Senff N., Heijnen I., Moore J.T., Goodwin B., Wong S., Davidge S.T. Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy? // Am. J. Obstet. Gynecol. 2005. Vol.192, №4. Р.1304-1313.Okuda A., Okuda K. Purification and characterization of delta 4-3-ketosteroid 5 beta-reductase // J. Biol. Chem. 1984. Vol.259, №12. Р.7519-7524.Okuda A., Okuda K. Purification and characterization of delta 4-3-ketosteroid 5 beta-reductase // J. Biol. Chem. 1984. Vol.259, №12. Р.7519-7524.Pasqualini J.R. Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments // J. Steroid Biochem. Mol. Biol. 2005. Vol.97, №5. Р.401-415.Pasqualini J.R. Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments // J. Steroid Biochem. Mol. Biol. 2005. Vol.97, №5. Р.401-415.Payne A.H., Hales D.B. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones // Endocr. Rev. 2004. Vol.25, №6. P.947-970.Payne A.H., Hales D.B. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones // Endocr. Rev. 2004. Vol.25, №6. P.947-970.Pearson Murphy B.E., Steinberg S.I., Hu F.Y., Allison C.M. Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: elevated levels of 5 alpha-dihydroprogesterone in depressed patients during the latter half of pregnancy // J. Clin. Endocrinol. Metab. 2001. Vol.86, №12. Р.5981-5987.Pearson Murphy B.E., Steinberg S.I., Hu F.Y., Allison C.M. Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: elevated levels of 5 alpha-dihydroprogesterone in depressed patients during the latter half of pregnancy // J. Clin. Endocrinol. Metab. 2001. Vol.86, №12. Р.5981-5987.Peltoketo H., Nokelainen P., Piao Y.S., Vihko R., Vihko P.Two 17beta-hydroxysteroid dehydrogenases (17HSDs) of estradiol biosynthesis: 17HSD type 1 and type 7 // J. Steroid Biochem. Mol. Biol. 1999. Vol.69, №1-6. Р.431-439.Peltoketo H., Nokelainen P., Piao Y.S., Vihko R., Vihko P.Two 17beta-hydroxysteroid dehydrogenases (17HSDs) of estradiol biosynthesis: 17HSD type 1 and type 7 // J. Steroid Biochem. Mol. Biol. 1999. Vol.69, №1-6. Р.431-439.Penning T.M., Burczynski M.E., Jez J.M., Lin H.K., Ma H., Moore M., Ratnam K., Palackal N.Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) // Mol. Cell Endocrinol. 2001. Vol.171, №1-2. Р.137-149.Penning T.M., Burczynski M.E., Jez J.M., Lin H.K., Ma H., Moore M., Ratnam K., Palackal N.Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) // Mol. Cell Endocrinol. 2001. Vol.171, №1-2. Р.137-149.Penning T.M., Steckelbroeck S., Bauman D.R., Miller M.W., Jin Y., Peehl D.M., Fung K.M., Lin H.K. Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors // Mol. Cell. Endocrinol. 2006. Vol.248, №1-2. Р.182-191.Penning T.M., Steckelbroeck S., Bauman D.R., Miller M.W., Jin Y., Peehl D.M., Fung K.M., Lin H.K. Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors // Mol. Cell. Endocrinol. 2006. Vol.248, №1-2. Р.182-191.Reddy D.S. Neurosteroids: endogenous role in the human brain and therapeutic potentials // Prog. Brain Res. 2010. Vol.186. P.113-137.Reddy D.S. Neurosteroids: endogenous role in the human brain and therapeutic potentials // Prog. Brain Res. 2010. Vol.186. P.113-137.Riley S.C., Dupont E., Walton J.C., Luu-The V., Labrie F., Pelletier G., Challis J.R. Immunohistochemical localization of 3 beta-hydroxy-5-ene-steroid dehydrogenase/delta 5->delta 4 isomerase in human placenta and fetal membranes throughout gestation // J. Clin. Endocrinol. Metab. 1992. Vol.75, №3. Р.956-961.Riley S.C., Dupont E., Walton J.C., Luu-The V., Labrie F., Pelletier G., Challis J.R. Immunohistochemical localization of 3 beta-hydroxy-5-ene-steroid dehydrogenase/delta 5->delta 4 isomerase in human placenta and fetal membranes throughout gestation // J. Clin. Endocrinol. Metab. 1992. Vol.75, №3. Р.956-961.Roberson A.E., Hyatt K., Kenkel C., Hanson K., Myers D.A. Interleukin 1β Regulates Progesterone Metabolism in Human Cervical Fibroblasts // Reprod. Sci. 2012. Vol.19, №3. Р.271-281.Roberson A.E., Hyatt K., Kenkel C., Hanson K., Myers D.A. Interleukin 1β Regulates Progesterone Metabolism in Human Cervical Fibroblasts // Reprod. Sci. 2012. Vol.19, №3. Р.271-281.Sakurai N., Miki Y., Suzuki T., Watanabe K., Narita T., Ando K., Yung T.M., Aoki D., Sasano H., Handa H. Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12 // J. Steroid Biochem. Mol. Biol. 2006. Vol.99, №4-5. Р.174-181.Sakurai N., Miki Y., Suzuki T., Watanabe K., Narita T., Ando K., Yung T.M., Aoki D., Sasano H., Handa H. Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12 // J. Steroid Biochem. Mol. Biol. 2006. Vol.99, №4-5. Р.174-181.Saloniemi T., Jokela H., Strauss L., Pakarinen P., Poutanen M.The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models // J. Endocrinol. 2012. Vol.212, №1. Р.27-40.Saloniemi T., Jokela H., Strauss L., Pakarinen P., Poutanen M.The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models // J. Endocrinol. 2012. Vol.212, №1. Р.27-40.Schatz F., Morrill G.A. 5β-reductive pathway of progesterone metabolism in the amphibian ovarian cytosol // Biol. Reprod. 1975. Vol.13, №4. P.408-414.Schatz F., Morrill G.A. 5β-reductive pathway of progesterone metabolism in the amphibian ovarian cytosol // Biol. Reprod. 1975. Vol.13, №4. P.408-414.Sheehan P. M. A possible role for progesterone metabolites in human parturition // Aust. N. Z. J. Obstet. Gynaecol. 2006. Vol.46, №2. Р.159-163.Sheehan P. M. A possible role for progesterone metabolites in human parturition // Aust. N. Z. J. Obstet. Gynaecol. 2006. Vol.46, №2. Р.159-163.Sheldrick E.L., Ricketts A.P., Flint A.P. Placental production of 5 beta-pregnane-3 alpha,20 alpha-diol in goats // J. Endocrinol. 1981. Vol.90, №2. Р.151-158.Sheldrick E.L., Ricketts A.P., Flint A.P. Placental production of 5 beta-pregnane-3 alpha,20 alpha-diol in goats // J. Endocrinol. 1981. Vol.90, №2. Р.151-158.Steckelbroeck S., Jin Y., Gopishetty S., Oyesanmi B., Penning T.M. Human cytosolic 3alphahydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3betahydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action // J. Biol. Chem. 2004. Vol.279, №11. Р.10784-10795.Steckelbroeck S., Jin Y., Gopishetty S., Oyesanmi B., Penning T.M. Human cytosolic 3alphahydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3betahydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action // J. Biol. Chem. 2004. Vol.279, №11. Р.10784-10795.Thornton S., Terzidou V., Clark A., Blanks A. Progesterone metabolite and spontaneous myometrial contractions in vitro // Lancet. 1999. Vol.353, №9161. P.1327-1329.Thornton S., Terzidou V., Clark A., Blanks A. Progesterone metabolite and spontaneous myometrial contractions in vitro // Lancet. 1999. Vol.353, №9161. P.1327-1329.Vu T.T., Hirst J.J., Stark M., Wright I.M., Palliser H.K., Hodyl N., Clifton V.L. Changes in human placental 5alpha-reductase isoenzyme expression with advancing gestation: effects of fetal sex and glucocorticoid exposure // Reprod. Fertil. Dev. 2009. Vol.21, №4. Р.599-607.Vu T.T., Hirst J.J., Stark M., Wright I.M., Palliser H.K., Hodyl N., Clifton V.L. Changes in human placental 5alpha-reductase isoenzyme expression with advancing gestation: effects of fetal sex and glucocorticoid exposure // Reprod. Fertil. Dev. 2009. Vol.21, №4. Р.599-607.Wiebe J.P. Progesterone metabolites in breast cancer // Endocr. Relat. Cancer. 2006. Vol.13, №3. Р.717-738.Wiebe J.P. Progesterone metabolites in breast cancer // Endocr. Relat. Cancer. 2006. Vol.13, №3. Р.717-738.

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