Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review)

This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered.

1. Casado-Espada N.M., de Alarcón R., de la Iglesia-Larrad J.I., Bote-Bonaechea B., Montejo Á.L. Hormonal contraceptives, female sexual dysfunction, and managing strategies: a review. J Clin Med 2019; 8(6): 908, https://doi.org/10.3390/jcm8060908.
2. Piette P. The history of natural progesterone, the never-ending story. Climacteric 2018; 21(4), https://doi.org/10.1080/13697137.2018.1462792.
3. Carp H.J.A. Progestogens in luteal support. Horm Mol Biol Clin Investig 2020; 21(4): 380–384, https://doi.org/10.1515/hmbci-2019-0067.
4. Garcia J.M., Shamliyan T.A. Off-label megestrol in patients with anorexia-cachexia syndrome associated with malignancy and its treatments. Am J Med 2018; 131(6): 623–629.e1, https://doi.org/10.1016/j.amjmed.2017.12.028.
5. Kareva E.N., Bulgakova V.A., Gutorova D.S., Oleinikova O.M., Kononova I.N., Gorbunov A.A., Breusenko V.G., Fisenko V.P. Progesterone membrane receptor PGRMC1: potential drug target. Eksperimentalnaya i klinicheskaya farmakologiya 2020; 83(6): 19–29, https://doi.org/10.30906/0869-2092-2020-83-6-19-29.
6. Pedroza D.A., Subramani R., Lakshmanaswamy R. Classical and non-classical progesterone signaling in breast cancers. Cancers (Basel) 2020; 12(9): 2440, https://doi.org/10.3390/cancers12092440.
7. Petersen S.L., Intlekofer K.A., Moura-Conlon P.J., Brewer D.N., Del Pino Sans J., Lopez J.A. Novel progesterone receptors: neural localization and possible functions. Front Neurosci 2013; 7: 164, https://doi.org/10.3389/fnins.2013.00164.
8. Pang Y., Dong J., Thomas P. Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and ε (mPRδ and mPRε) and mPRδ involvement in neurosteroid inhibition of apoptosis. Endocrinology 2013; 154(1): 283–295, https://doi.org/10.1210/en.2012-1772.
9. Ryu C.S., Klein K., Zanger U.M. Membrane associated progesterone receptors: promiscuous proteins with pleiotropic functions — focus on interactions with cytochromes P450. Front Pharmacol 2017; 8: 159, https://doi.org/10.3389/fphar.2017.00159.
10. Thejer B.M., Adhikary P.P., Kaur A., Teakel S.L., Van Oosterum A., Seth I., Pajic M., Hannan K.M., Pavy M., Poh P., Jazayeri J.A., Zaw T., Pascovici D., Ludescher M., Pawlak M., Cassano J.C., Turnbull L., Jazayeri M., James A.C., Coorey C.P., Roberts T.L., Kinder S.J., Hannan R.D., Patrick E., Molloy M.P., New E.J., Fehm T.N., Neubauer H., Goldys E.M., Weston L.A., Cahill M.A. PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth. BMC Mol and Cell Biol 2020; 21(1): 24, https://doi.org/10.1186/s12860-020-00256-3.
11. Idkowiak J., Randell T., Dhir V., Patel P., Shackleton C.H., Taylor N.F., Krone N., Arlt W. A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency. J Clin Endocrinol Metab 2012; 97(3): E465–E475, https://doi.org/10.1210/jc.2011-2413.
12. Price T., Dai Q. The role of a mitochondrial progesterone receptor (PR-M) in progesterone action. Semin Reprod Med 2015; 33(3): 185–194, https://doi.org/10.1055/s-0035-1552583.
13. Ren J., Chung-Davidson Y.W., Jia L., Li W. Genomic sequence analyses of classical and non-classical lamprey progesterone receptor genes and the inference of homologous gene evolution in metazoans. BMC Evol Biol 2019; 19(1): 136, https://doi.org/10.1186/s12862-019-1463-7.
14. Africander D., Verhoog N., Hapgood J.P. Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76(7): 636–652, https://doi.org/10.1016/j.steroids.2011.03.001.
15. Smetnik A.A. Contraception with drospirenone: effect on the body weight and some lipid metabolism indicators. Meditsinskiy sovet 2016; 12: 95–97, https://doi.org/10.21518/2079-701x-2016-12-95-97.
16. Fedotcheva T.A., Shimanovskiy N.L. Gestagens in the treatment of endometriosis. Problemy endokrinologii 2018; 64(1): 54–61, https://doi.org/10.14341/probl201864154-61.
17. Stepanova E.S., Makarenkova L.M., Chistyakov V.V., Fedotcheva T.A., Parshin V.A., Shimanovsky N.L. Metabolism of gestobutanoil, a novel drug of progestin group. Sovremennye tehnologii v medicine 2019; 11(3): 48–54, https://doi.org/10.17691/stm2019.11.3.06.
18. Trojano G., Olivieri C., Tinelli R., Damiani G.R., Pellegrino A., Cicinelli E. Conservative treatment in early stage endometrial cancer: a review. Acta Biomed 2019; 90(4): 405–410, https://doi.org/10.23750/abm.v90i4.7800.
19. Mitsuhashi A., Kawasaki Y., Hori M., Fujiwara T., Hanaoka H., Shozu M. Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial). BMJ Open 2020; 10(2): e035416, https://doi.org/10.1136/bmjopen-2019-035416.
20. Mitsuhashi A., Habu Y., Kobayashi T., Kawarai Y., Ishikawa H., Usui H., Shozu M. Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients. J Gynecol Oncol 2019; 30(6): e90, https://doi.org/10.3802/jgo.2019.30.e90.
21. Stepan J.J., Hruskova H., Kverka M. Update on menopausal hormone therapy for fracture prevention. Curr Osteoporos Rep 2019; 17(6): 465–473, https://doi.org/10.1007/s11914-019-00549-3.
22. Ruiz-García V., López-Briz E., Carbonell-Sanchis R., Bort-Martí S., Gonzálvez-Perales J.L. Megestrol acetate for cachexia-anorexia syndrome. A systematic review. J Cachexia Sarcopenia Muscle 2018; 9(3): 444–452, https://doi.org/10.1002/jcsm.12292.
23. Tuca A., Jimenez-Fonseca P., Gascón P. Clinical evaluation and optimal management of cancer cachexia. Crit Rev Oncol Hematol 2013; 88(3): 625–636, https://doi.org/10.1016/j.critrevonc.2013.07.015.
24. Yang H.C., Liu J.C., Liu F.S. Fertility-preserving treatment of stage IA, well-differentiated endometrial carcinoma in young women with hysteroscopic resection and high-dose progesterone therapy. Taiwan J Obstet Gynecol 2019; 58(1): 90–93, https://doi.org/10.1016/j.tjog.2018.11.017.
25. Di Renzo G.C., Giardina I., Clerici G., Brillo E., Gerli S. Progesterone in normal and pathological pregnancy. Horm Mol Biol Clin Investig 2016; 27(1): 35–48, https://doi.org/10.1515/hmbci-2016-0038.
26. Wang X., Luo Q., Bai W. Efficacy of progesterone on threatened miscarriage: difference in drug types. J Obstet Gynaecol Res 2019; 45(4): 794–802, https://doi.org/10.1111/jog.13909.
27. Abdelhakim A.M., Abd-ElGawad M., Hussein R.S., Abbas A.M. Vaginal versus intramuscular progesterone for luteal phase support in assisted reproductive techniques: a systematic review and meta-analysis of randomized controlled trials. Gynecol Endocrinol 2020; 36(5): 389–397, https://doi.org/10.1080/09513590.2020.1727879.
28. Coomarasamy A., Devall A.J., Brosens J.J., Quenby S., Stephenson M.D., Sierra S., Christiansen O.B., Small R., Brewin J., Roberts T.E., Dhillon-Smith R., Harb H., Noordali H., Papadopoulou A., Eapen A., Prior M., Di Renzo G.C., Hinshaw K., Mol B.W., Lumsden M.A., Khalaf Y., Shennan A., Goddijn M., van Wely M., Al-Memar M., Bennett P., Bourne T., Rai R., Regan L., Gallos I.D. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol 2020; 223(2): 167–176, https://doi.org/10.1016/j.ajog.2019.12.006.
29. Lee H.J., Park T.C., Kim J.H., Norwitz E., Lee B. The influence of oral dydrogesterone and vaginal progesterone on threatened abortion: a systematic review and meta-analysis. Biomed Res Int 2017; 2017: 3616875, https://doi.org/10.1155/2017/3616875.
30. Coomarasamy A., Devall A.J., Cheed V., Harb H., Middleton L.J., Gallos I.D., Williams H., Eapen A.K., Roberts T., Ogwulu C.C., Goranitis I., Daniels J.P., Ahmed A., Bender-Atik R., Bhatia K., Bottomley C., Brewin J., Choudhary M., Crosfill F., Deb S., Duncan W.C., Ewer A., Hinshaw K., Holland T., Izzat F., Johns J., Kriedt K., Lumsden M.A., Manda P., Norman J.E., Nunes N., Overton C.E., Quenby S., Rao S., Ross J., Shahid A., Underwood M., Vaithilingam N., Watkins L., Wykes C., Horne A., Jurkovic D. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med 2019; 380(19): 1815–1824, https://doi.org/10.1056/nejmoa1813730.
31. Egarter C. Progestogen-only pills: which progestogen would be ideal. Horm Mol Biol Clin Investig 2020, https://doi.org/10.1515/hmbci-2019-0042.
32. Shimanovskiy N.L., Svistunov A.A., Napolov Yu.K. Novye dostizheniya v gormonal’noy kontratseptsii [New achievements in hormonal contraception]. Moscow; 2013.
33. Chen M.J., Hsia J.K., Creinin M.D. Etonogestrel implant use in women primarily choosing a combined oral contraceptive pill: a proof-of-concept trial. Contraception 2018; 97(6): 533–537, https://doi.org/10.1016/j.contraception.2018.02.009.
34. Floyd J.L., Beasley A.D., Swaim L.S., Turrentine M.A., Nijjar J.B. Association of immediate postpartum etonogestrel implant insertion and venous thromboembolism. Obstet Gynecol 2020; 135(6): 1275–1280, https://doi.org/10.1097/aog.0000000000003760.
35. Louw-du Toit R., Hapgood J.P., Africander D. A direct comparison of the transcriptional activities of progestins used in contraception and menopausal hormone therapy via the mineralocorticoid receptor. Biochem Biophys Res Commun 2020; 526(2): 466–471, https://doi.org/10.1016/j.bbrc.2020.03.100.
36. Secura G.M., Allsworth J.E., Madden T., Mullersman J.L., Peipert J.F. The Contraceptive CHOICE Project: reducing barriers to long-acting reversible contraception. Am J Obstet Gynecol 2010; 203(2): 115.e1–115.e1157, https://doi.org/10.1016/j.ajog.2010.04.017.
37. Bahar Y.Z., Gold M.A. Providing long-acting reversible contraception to adolescents: a review. Clin Obstet Gynecol 2020; 63(3): 561–573, https://doi.org/10.1097/grf.0000000000000541.
38. Festin M.P.R. Overview of modern contraception. Best Pract Res Clin Obstet Gynaecol 2020; 66: 4–14, https://doi.org/10.1016/j.bpobgyn.2020.03.004.
39. Savilova A.M., Yushina M.N., Rudimova Y.V., Khabas G.N., Chuprynin V.D., Sukhikh G.T. Characteristics of multipotent mesenchymal stromal cells isolated from human endometrium and endometriosis lesions. Bull Exp Biol Med 2016; 161(4): 610–615, https://doi.org/10.1007/s10517-016-3469-0.
40. Guo H., Li J., Shen X., Cong Y., Wang Y., Wu L., Li B., Gao H., Ma M., Zhang W., Mao X., Fu Y., Lyu Q., Chai W., Kuang Y. Efficacy of different progestins in women with advanced endometriosis undergoing controlled ovarian hyperstimulation for in vitro fertilization — a single-center non-inferiority randomized controlled trial. Front Endocrinol (Lausanne) 2020; 11: 129, https://doi.org/10.3389/fendo.2020.00129.
41. Dianat S., Fox E., Ahrens K.A., Upadhyay U.D., Zlidar V.M., Gallo M.F., Stidd R.L., Moskosky S., Dehlendorf C. Side effects and health benefits of depot medroxyprogesterone acetate: a systematic review. Obstet Gynecol 2019; 133(2): 332–341, https://doi.org/10.1097/aog.0000000000003089.
42. Shimanovskiy N.L., Fedotcheva T.A., Semeykin A.V., Parshin V.A., Sheina N.I., Skryabina E.G. Oral form of gestagen-containing composition for treating women with conditions of gestagen insufficiency and method for preparing it. Patent RU 2684917. 2019.
43. Sheina N.I., Parshin V.A., Fedotcheva T.A., Shimanovsky N.L. Effect of the new steroid drug gestobutanoil for hormone replacement therapy of gestagenous insufficiency on the development of fetus and offspring in experiments on rats. Toksikologiceskij vestnik 2019; 2: 28–36, https://doi.org/10.36946/0869-7922-2019-2-28-36.
44. Sheina N.I., Parshin V.A., Kolesnikova V.V., Myalina L.I., Sazonova L.P., Fedotcheva T.A., Shimanovskiy N.L. Estimation of the generative function of female rats upon intra-gastric administration of tablets of new steroid drug gestobutanoil. Khimiko-farmatsevticheskii zhurnal 2020; 54(5): 11–15, https://doi.org/10.30906/0023-1134-2020-54-5-11-15.
45. Sheina N.I., Parshin V.A., Rybakov Yu.L., Gukasov V.M., Kostyaeva M.G., Semeykin A.V., Samoylikov R.V., Fedotcheva T.A., Shimanovskiy N.L. Evaluation of the toxicity of new progestogen gestobutanoil in experiments on rats and mice. Eksperimentalnaya i klinicheskaya farmakologiya 2018; 81(11): 18–25, https://doi.org/10.30906/0869-2092-2018-81-11-18-25.
46. Petrosyan M.A., Balashova N.N., Polyanskikh L.S., Baziyan E.V., Tral’ T.G., Fasakhutdinova L.Kh., Razygraev A.V., Sapronov N.S. Effect of progesterone analogs on endometrioid heterotopias in an experimental model of endometriosis. Eksperimentalnaya i klinicheskaya farmakologiya 2018; 81(7): 14–19, https://doi.org/10.30906/0869-2092-2018-81-7-14-19.
47. Lee S.Y., Kim M.K., Park H., Yoon B.S., Seong S.J., Kang J.H., Jun H.S., Park C.T. The effectiveness of levonorgestrel releasing intrauterine system in the treatment of endometrial hyperplasia in Korean women. J Gynecol Oncol 2010; 21(2): 102–105, https://doi.org/10.3802/jgo.2010.21.2.102.
48. Lai Y.J., Chou Y.C., Lin Y.J., Yu M.H., Ou Y.C., Chu P.W., Wu C.C., Wang Y.C., Chao T.K. Pyruvate kinase M2 expression: a potential metabolic biomarker to differentiate endometrial precancer and cancer that is associated with poor outcomes in endometrial carcinoma. Int J Environ Res Public Health 2019; 16(23): 4589, https://doi.org/10.3390/ijerph16234589.
49. Travaglino A., Raffone A., Saccone G., Mascolo M., D’Alessandro P., Arduino B., Mollo A., Insabato L., Zullo F. Nuclear expression of β-catenin in endometrial hyperplasia as marker of premalignancy. APMIS 2019; 127(11): 699–709, https://doi.org/10.1111/apm.12988.
50. Zaino R.J. Unusual patterns of endometrial carcinoma including MELF and its relation to epithelial mesenchymal transition. Int J Gynecol Pathol 2014; 33(4): 357–364, https://doi.org/10.1097/pgp.0000000000000137.
51. Gallos I.D., Alazzam M., Clark T. Endometrial hyperplasia, management of (green-top guideline No. 67). Royal College of Obstetricians and Gynaecologists; 2016; URL: https://www.rcog.org.uk/en/guidelines- research-services/guidelines/gtg67/.
52. Landersoe S.K., Forman J.L., Birch Petersen K., Larsen E.C., Nøhr B., Hvidman H.W., Nielsen H.S., Nyboe Andersen A. Ovarian reserve markers in women using various hormonal contraceptives. Eur J Contracept Reprod Health Care 2020; 25(1): 65–71, https://doi.org/10.1080/13625187.2019.1702158.
53. Korennaya V.V., Mass E.E., Koloda Yu.A., Poletova T.N. Hyperplastic endometrial processes: the new approach to the problem. Effektivnaa farmakoterapia 2018; 3: 34–39.
54. Morice P., Leary A., Creutzberg C., Abu-Rustum N., Darai E. Endometrial cancer. Lancet 2016; 387(10023): 1094–1108, https://doi.org/10.1016/s0140-6736(15)00130-0.
55. Gompel A. Progesterone, progestins and the endometrium in perimenopause and in menopausal hormone therapy. Climacteric 2018; 21(4): 321–325, https://doi.org/10.1080/13697137.2018.1446932.
56. Nechushkina V.M., Den’gina N.V., Kolomiets L.A., Kravets O.A., Morkhov K.Yu., Novikova E.G., Tyulyandina A.S., Ul’rikh E.A., Fedenko A.A., Khokhlova S.V. Practical recommendations for drug treatment of uterine body cancer and uterine sarcomas. Zlokachestvennye opukholi 2017; 7(3-S2): 168–180.
57. Tamauchi S., Kajiyama H., Utsumi F., Suzuki S., Niimi K., Sakata J., Mizuno M., Shibata K., Kikkawa F. Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer. J Obstet Gynaecol Res 2018; 44(1): 151–156, https://doi.org/10.1111/jog.13473.
58. Yamagami W., Susumu N., Makabe T., Sakai K., Nomura H., Kataoka F., Hirasawa A., Banno K., Aoki D. Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility? J Gynecol Oncol 2018; 29(2): e21, https://doi.org/10.3802/jgo.2018.29.e21.
59. Kim J.J., Kurita T., Bulun S.E. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 2013; 34(1): 130–162, https://doi.org/10.1210/er.2012-1043.
60. Cao W., Gao W., Zheng P., Sun X., Wang L. Medroxyprogesterone acetate causes the alterations of endoplasmic reticulum related mRNAs and lncRNAs in endometrial cancer cells. BMC Med Genomics 2019; 12(1): 163, https://doi.org/10.1186/s12920-019-0601-9.
61. Urmancheeva A.F. Endometrial cancer drug therapy. Prakticeskaa onkologia 2004; 5(1): 41–51.
62. Badwe R., Hawaldar R., Parmar V., Nadkarni M., Shet T., Desai S., Gupta S., Jalali R., Vanmali V., Dikshit R., Mittra I. Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. J Clin Oncol 2011; 29(21): 2845–2851, https://doi.org/10.1200/jco.2010.33.0738.
63. Khokhlova S.V., Den’gina N.V., Kolomiets L.A., Kravets O.A., Morkhov K.Yu., Nechushkina V.M., Novikova E.G., Tyulyandina A.S., Urmancheeva A.F. Practical guidelines for drug treatment of cervical cancer. Zlokachestvennye opukholi 2017; 7(3-S2): 158–167.
64. Ulrikh E.A., Berlev I.V., Urmancheeva A.F., Verbitskaya E.A., Mikaya N.A., Mikhailov A.V., Iliin A.B., Gamzatova Z.N., Yankevich Yu.V., Artemieva A.S., Korolkova E.N. Personalization in treatment for cervical cancer during pregnancy. Voprosy onkologii 2015; 61(3): 486–493.
65. Liu Y., Tian L.B., Yang H.Y., Zhang H.P. Effects of estradiol and progesterone on the growth of HeLa cervical cancer cells. Eur Rev Med Pharmacol Sci 2017; 21(17): 3959–3965.
66. Numata T., Sato-Numata K., Okada Y. TRPM7 is involved in acid-induced necrotic cell death in a manner sensitive to progesterone in human cervical cancer cells. Physiol Rep 2019; 7(13): e14157, https://doi.org/10.14814/phy2.14157.
67. Fedotcheva T.A., Sveshnikova E.D., Sheina N.I., Sokolov M.N., Kudryavtsev K.V., Fedotcheva N.I., Shimanovskiy N.L. Synthesis and cytostatic activity of new derivatives of mepregenol 17-acetate with respect to HeLa cancer cells. Khimiko-farmatsevticheskii zhurnal 2020; 54(2): 17–23, https://doi.org/10.30906/0023-1134-2020-54-2-17-23.
68. Semeikin A.V., Fedotcheva T.A., Tikhonov D.A., Kareva E.N., Shimanovskii N.L., Levina I.S., Kulikova L.E., Zavarzin I.V. Synthesis and cytostatic activity of some pregna-d’-pentaranes on Hela cell culture. Khimiko-farmatsevticheskii zhurnal 2014; 48(6): 9–13.
69. Yang B.Y., Gulinazi Y., Du Y., Ning C.C., Cheng Y.L., Shan W.W., Luo X.Z., Zhang H.W., Zhu Q., Ma F.H., Liu J., Sun L., Yu M., Guan J., Chen X.J. Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial. BJOG 2020; 127(7): 848–857, https://doi.org/10.1111/1471-0528.16108.
70. Petchsila K., Prueksaritanond N., Insin P., Yanaranop M., Chotikawichean N. Effect of metformin for decreasing proliferative marker in women with endometrial cancer: a randomized double-blind placebo-controlled trial. Asian Pac J Cancer Prev 2020; 21(3): 733–741, https://doi.org/10.31557/APJCP.2020.21.3.733.
71. Zhao Y., Sun H., Feng M., Zhao J., Zhao X., Wan Q., Cai D. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol 2018; 34(5): 428–432, https://doi.org/10.1080/09513590.2017.1409714.
72. Lheureux S., Oza A.M. Endometrial cancer-targeted therapies myth or reality? Review of current targeted treatments. Eur J Cancer 2016; 59: 99–108, https://doi.org/10.1016/j.ejca.2016.02.016.
73. Lee D.Y., Lee T.S. Associations between metabolic syndrome and gynecologic cancer. Obstet Gynecol Sci 2020; 63(3): 215–224, https://doi.org/10.5468/ogs.2020.63.3.215.
74. Horwitz K.B., Sartorius C.A. 90 years of progesterone: progesterone and progesterone receptors in breast cancer: past, present, future. J Mol Endocrinol 2020; 65(1): T49–T63, https://doi.org/10.1530/jme-20-0104.
75. Prior J.C. Progesterone for treatment of symptomatic menopausal women. Climacteric 2018; 21(4): 358–365, https://doi.org/10.1080/13697137.2018.1472567.
76. Prior J.C. Progesterone is important for transgender women’s therapy-applying evidence for the benefits of progesterone in ciswomen. J Clin Endocrinol Metab 2019; 104(4): 1181–1186, https://doi.org/10.1210/jc.2018-01777.
77. Warren M.P., Biller B.M., Shangold M.M. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999; 180(1): 42–48, https://doi.org/10.1016/s0002-9378(99)70147-x.
78. Farquhar C., Rombauts L., Kremer J.A., Lethaby A., Ayeleke R.O. Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2017; 5(5): CD006109, https://doi.org/10.1002/14651858.cd006109.pub3.
79. Zolton J.R., Lindner P.G., Terry N., DeCherney A.H., Hill M.J. Gonadotropins versus oral ovarian stimulation agents for unexplained infertility: a systematic review and meta-analysis. Fertil Steril 2020; 113(2): 417–425.e1, https://doi.org/10.1016/j.fertnstert.2019.09.042.
80. Syrkasheva A.G., Petrosyan Y.A., Dolgushina N.V. Gestagens in assisted reproductive technology programs. Ginekologia 2019; 21(2): 76–79, https://doi.org/10.26442/20795696.2019.2.190238.
81. Bulgakova V.P., Borovikov I.O. Use of micronized natural progesterone as preparation for assisted reproductive technologies in patients with uterine infertility factor. Problemy reprodukcii 2018; 24(6): 67–75, https://doi.org/10.17116/repro20182406167.
82. Khramtsova A.Yu., Bashmakova N.V. Global view on the problem of “thin” endometrium: solutions to the problem in assisted reproductive technology (literature review). Problemy reprodukcii 2019; 25(4): 69–76, https://doi.org/10.17116/repro20192504169.
83. Metodicheskie rekomendatsii po opredeleniyu spetsificheskoy farmakologicheskoy aktivnosti steroidnykh gormonov i ikh antagonistov. V kn.: Rukovodstvo po provedeniyu doklinicheskikh issledovaniy lekarstvennykh sredstv [Guidelines for determining the specific pharmacological activity of steroid hormones and their antagonists. In: Guidelines for conducting preclinical studies of drugs]. Pod red. Mironova A.N. [Mironov A.N. (editor)]. Moscow: Grif i K; 2012; p. 702–711.
84. Arab H., Alharbi A.J., Oraif A., Sagr E., Al Madani H., Abduljabbar H., Bajouh O.S., Faden Y., Sabr Y. The role of progestogens in threatened and idiopathic recurrent miscarriage. Int J Womens Health 2019; 11: 589–596, https://doi.org/10.2147/ijwh.s224159.
85. Goddard L.M., Ton A.N., Org T., Mikkola H.K.A., Iruela-Arispe M.L. Selective suppression of endothelial cytokine production by progesterone receptor. Vascul Pharmacol 2013; 59(1–2): 36–43, https://doi.org/10.1016/j.vph.2013.06.001.
86. VanLandingham J.W., Cekic M., Cutler S., Hoffman S.W., Stein D.G. Neurosteroids reduce inflammation after TBI through CD55 induction. Neurosci Lett 2007; 425(2): 94–98, https://doi.org/10.1016/j.neulet.2007.08.045.
87. Qin Y.Y., Zhou Y.H., Lu Y.Q., Sun F., Yang S., Harypursat V., Chen Y.K. Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial. Chin Med J (Engl) 2020; 133(9): 1080–1086, https://doi.org/10.1097/CM9.0000000000000791.
88. Erickson T.B., Chai P.R., Boyer E.W. Chloroquine, hydroxychloroquine and COVID-19. Toxicol Commun 2020; 4(1): 40–42, https://doi.org/10.1080/24734306.2020.1757967.
89. Zhao W., Cong Y., Li H.M., Li S., Shen Y., Qi Q., Zhang Y., Li Y.Z., Tang Y.J. Challenges and potential for improving the druggability of podophyllotoxin-derived drugs in cancer chemotherapy. Nat Prod Rep 2020, https://doi.org/10.1039/d0np00041h.
90. Ogurtsov S.I., Dukhanin A.S., Levina I.S., Shimanovskiy N.L. Effect of synthetic progestogens from the group of nitrogen-containing pentarans on the activity of rat liver tyrosine aminotransferase. Eksperimentalnaya i klinicheskaya farmakologiya 2015; 78(5): 47–48.
91. Fedotcheva T.A., Kruglov A.G., Teplova V.V., Fedotcheva N.I., Rzheznikov V.M., Shimanovskii N.L. Effect of steroid hormones on production of reactive oxygen species in mitochondria. Biophysics 2012; 57(6): 792–795, https://doi.org/10.1134/s0006350912060061.
92. Liga A.B., Ukhina T.V., Shimanovski N.L. Activity lysosomal enzymes in rat skin fibroblasts after treatment with progesterone and new gestagen ABMP. Bull Exp Biol Med 2008; 145(1): 44–46, https://doi.org/10.1007/s10517-008-0013-x.
93. Shchelkunova T.A., Morozov I.A. Molecular basis and tissue specificity of the progestin effect. Molekularnaa biologia 2015; 49(5): 728, https://doi.org/10.7868/s0026898415050158.
94. Porokhin A.P., Kudrin V.S., Klodt P.M., Narkevich V.B., Matyushin A.I., Rogovsky V.S., Rzheznikov V.M., Shimanovsky N.L. Synthetic gestagen buterol influence on monoamine metabolism in rats brain. Vestnik RGMU 2011; 2: 72–74.
95. Fedotcheva T.A., Teplova V.V., Fedotcheva N.I. Activation of the calcium-dependent cyclosporin-sensitive mitochondrial pore by doxorubicin in combination with iron ions. Biologicheskie membrany: zhurnal membrannoy i kletochnoy biologii 2018; 35(1): 79–84, https://doi.org/10.7868/s0233475518010097.
96. Sergeyev P.V., Atroshkin K.A., Semeikin A.V., Shimanovsky N.L. Fedotcheva T.A., Sekirina M.A. Gestagen regulation of target cell proliferation activity. Vestnik Rossijskogo onkologiceskogo naucnogo centra imeni N.N. Blohina RAMN 2008; 19(1): 22–28.
97. Fedotcheva N.I., Teplova V.V., Fedotcheva T.A., Rzheznikov V.M., Shimanovskii N.L. Effect of progesterone and its synthetic analogues on the activity of mitochondrial permeability transition pore in isolated rat liver mitochondria. Biochem Pharmacol 2009; 78(8): 1060–1068, https://doi.org/10.1016/j.bcp.2009.05.028.
98. Fedotcheva T.A., Odintsova E.V., Shimanovsky N.L. Molecular mechanisms of cytostatic and chemosensitizing action of gestagens. Vestnik Rossiiskoi akademii meditsinskikh nauk 2010; 9: 42–50.
99. Chiu H.C., Li C.J., Yiang G.T., Tsai A.P., Wu M.Y. Epithelial to mesenchymal transition and cell biology of molecular regulation in endometrial carcinogenesis. J Clin Med 2019; 8(4): 439, https://doi.org/10.3390/jcm8040439.
100. van der Horst P.H., Wang Y., Vandenput I., Kühne L.C., Ewing P.C., van Ijcken W.F., van der Zee M., Amant F., Burger C.W., Blok L.J. Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer. PLoS One 2012; 7(1): e30840, https://doi.org/10.1371/journal.pone.0030840.
101. Huang X., Zhong R., He X., Deng Q., Peng X., Li J., Luo X. Investigations on the mechanism of progesterone in inhibiting endometrial cancer cell cycle and viability via regulation of long noncoding RNA NEAT1/microRNA-146b-5p mediated Wnt/β-catenin signaling. IUBMB Life 2019; 71(2): 223–234, https://doi.org/10.1002/iub.1959.
102. Fedotcheva T.A., Odintsova E.V., Banin V.V., Shimanovskiy N.L. Pharmacological significance of the conjugate regulation of the multiple drug resistance system and the mitochondrial pore by gestagens. Vestnik Rossijskogo onkologiceskogo naucnogo centra imeni N.N. Blohina RAMN 2011; 22(4): 12–16.
103. Dong J., Qin Z., Zhang W.D., Cheng G., Yehuda A.G., Ashby C.R. Jr., Chen Z.S., Cheng X.D., Qin J.J. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: an update. Drug Resist Updat 2020; 49: 100681, https://doi.org/10.1016/j.drup.2020.100681.
104. Bukowski K., Kciuk M., Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020; 21(9): 3233, https://doi.org/10.3390/ijms21093233.
105. Brayboy L.M., Knapik L.O., Long S., Westrick M., Wessel G.M. Ovarian hormones modulate multidrug resistance transporters in the ovary. Contracept Reprod Med 2018; 3: 26, https://doi.org/10.1186/s40834-018-0076-7.
106. Wu X., Zhang X., Sun L., Zhang H., Li L., Wang X., Li W., Su P., Hu J., Gao P., Zhou G. Progesterone negatively regulates BCRP in progesterone receptor-positive human breast cancer cells. Cell Physiol Biochem 2013; 32(2): 344–354, https://doi.org/10.1159/000354442.
107. Yuan S., Tao F., Zhang X., Zhang Y., Sun X., Wu D. Role of Wnt/β-catenin signaling in the chemoresistance modulation of colorectal cancer. Biomed Res Int 2020; 2020: 9390878, https://doi.org/10.1155/2020/9390878.
108. Mehdinejadiani S., Amidi F., Mehdizadeh M., Barati M., Pazhohan A., Alyasin A., Mehdinejadiani K., Sobhani A. Effects of letrozole and clomiphene citrate on Wnt signaling pathway in endometrium of polycystic ovarian syndrome and healthy women. Biol Reprod 2019; 100(3): 641–648, https://doi.org/10.1093/biolre/ioy187.
109. Medina M.A., Oza G., Sharma A., Arriaga L.G., Hernández Hernández J.M., Rotello V.M., Ramirez J.T. Triple-negative breast cancer: a review of conventional and advanced therapeutic strategies. Int J Environ Res Public Health 2020; 17(6): 2078, https://doi.org/10.3390/ijerph17062078.

Fedotcheva T.A. Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review). Sovremennye tehnologii v medicine 2021; 13(1): 93, https://doi.org/10.17691/stm2021.13.1.11