MOLECULAR MECHANISMS OF ACTION OF PROGESTERONE IN THE ENDOMETRIUM

DOI: https://doi.org/None

E.N. Kareva (1), A.A. Solomatina (1), L.H. Bekhbudova (1), N.A. Kotsyubinskaya (1), O.S. Gorenkova (2), D.A. Tikhonov (1), T.N. Ivanovskaya (1), L.S. Bulatova (1) 1 -Pirogov Russian National Research Medical University, Ostrovitianov str. 1, Moscow, 117997, Russian Federation; 2 -Moscow Regional Research Institute of Obstetrics and Gynecology, Pokrovka str., 22a, Moscow, 101000, Russian Federation

The problem of the treatment of hyperplastic diseases of endometrium currently remains to be a matter of interest. Existing methods of hormone therapy fail to differ in high efficacy. Authors tried to find out reasons for the lack of success of hormonal management of endometrial hyperplastic processes. Investigations are based on our own and published data on molecular mechanisms of the action of progesterone receptor ligand. The hypothesis – «indivisible estrogen-progestin control of proliferation in female reproductive tract's cells» is proposed. The main proliferation role in this hypothesis is referred to gestagen component, whereas estradiol has «resolution» function. On the one hand this hypothesis allows to clear up previously unexplained effects of hormone therapy and, on the other hand, to develop a clever personal strategy of hormone therapy in patients with endometrium hyperplastic processes.
Keywords: 
endometrial hyperplasia, progesterone receptors, oestradiolreceptors, progestins, hypothesis

Список литературы: 
  1. Sergeev P.V. Receptory fiziologicheski aktivnyh veshhestv. M.-Volgograd, 1999. [Sergeev P.V. Receptors of physiologically active substances, M.-Volgograd, 1999 (in Russian)]
  2. Kim J.J., Kurita T., Bulun S.E. Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer Endocr Rev. 2013; 34 (1): 130–62.
  3. Berek and Hacker’s. Gynecologic Oncology, 5th Edition, Lippincott Williams & Wilkins, 2010.
  4. Ferenczy A. Anatomy and histology of the uterine corpus. 3rd ed New York: Springer–Verlag. 1987.
  5. Shimanovskiy N.L., Kareva E.N., Semeykin A.V. Metodicheskie rekomendacii po opredeleniyu specificheskoy farmakologicheskoy aktivnosti steroidnyh gormonov i ih antagonistov (v knige «Rukovodstvo po provedeniyu doklinicheskih issledovaniy lekarstvennyh sredstv» chast` 1, gl. 43, izd-vo FBGU «NCE`MSP» Roszdravsocrazvitiya, 2012,), s. 702–11. [Szymanowski N.L., Kareva E.N., Semeykin A.V. Guidelines to determine the specific pharmacological activity of steroid hormones and their antagonists (in the book «Guidelines for preclinical studies of drugs» Part 1, Chap. 43, M., 2012, sect. 2): 702–11 (in Russian)]
  6. Richer J.K., Jacobsen B.M., Manning N.G., Abel M.G., Wolf D.M., Horwitz K.B. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J. Biol. Chem. 2002; 277: 5209–18.
  7. Takano M., Lu Z., Goto T., Fusi L., Higham J., Francis J., Withey A., Hardt J., Cloke B., Stavropoulou A.V., Ishihara O., Lam E.W., Unterman T.G., Brosens J.J., Kim J.J. Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Mol. Endocrinol. 2007; 21: 2334–49.
  8. Migliaccio A., Piccolo D., Castoria G., Di Domenico M., Bilancio A., Lombardi M., Gong W., Beato M., Auricchio F. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J. 1998; 17: 2008–18.
  9. Mulac-Jericevic B., Mullinax R.A., DeMayo F.J., Lydon J.P., Conneely O.M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science. 2000; 289: 1751–4.
  10. Condon J.C., Hardy D.B., Kovaric K., Mendelson C.R. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-κB may contribute to the onset of labor through inhibition of PR function. Mol. Endocrinol. 2006; 20: 764–75.
  11. Kareva E.N., Shimanovskiy N.L. Molekulyarnye mehanizmy deystviya gestagenov. Zh. E`ksp. i klinicheskaya farmakologiya. 2011; 74 (4): 36–42.[Kareva E.N., Szymanowski N.L. Molecular mechanisms of action of progestogens. J. Exp. and Clinical Pharmacology, 2011; 74 (4): 36–42 (in Russian)]
  12. Kareva E.N., Gankovskaya L.V., Shimanovskiy N.L. Polovye steroidy i immunitet. Rossiyskiy immunologicheskiy zhurnal, 2012, 6 (15), №1: 3–13.[Kareva E.N., Gankovskaya L.V., Szymanowski N.L. Sex steroids and immunity. Russian J. of immunological. 2012; 6 (15), №1: 3–13 (in Russian)]
  13. Thomas P., Pang Y., Dong J. Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinol. 2007; 148: 705–18.
  14. Peluso J.J. Multiplicity of progesterone’s actions and receptors in the mammalian ovary. Biol. Reprod. 2006; 75: 2–8.
  15. Engmann L., Losel R., Wehling M. Progesterone regulation of human granulosa/luteal cell viability by an RU486-independent mechanism. J. Clin. Endocrinol. 2006; 91: 4962–8.
  16. Kao L.C., Tulac S., Lobo S., Imani B., Yang J. P., Germeyer A. Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002; 143: 2119–2138 10.1210/en.143.6.2119.
  17. Pru J.K. and Clark N.C. PGRMC1 and PGRMC2 in uterine physiology and disease. Front Neurosci. 2013; 7: 168.
  18. Keator C.S., Mah K., Slayden O. D. Alterations in progesterone receptor membrane component 2 (PGRMC2) in the endometrium of macaques afflicted with advanced endometriosis. Mol. Hum. Reprod. 2012; 18: 308–19 10.1093/molehr/gas006
  19. Spitz I.M. Progesterone antagonists and progesterone receptor modulators: an overview. Steroids. 2003; 68: 981–93.
  20. Chabbert-Buffet N., Meduri G., Bouchard P., Spitz I.M. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod. Update. 2005; 11: 293–307.
  21. Kurita T., Young P., Brody J.R., Lydon J.P., O’Malley B.W., Cunha G.R. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology. 1998; 139: 4708–13.
  22. Franco H.L., Rubel C.A., Large M.J., Wetendorf M., Fernandez-Valdivia R., Jeong J.W., Spencer T.E., Behringer R.R., Lydon J.P., Demayo FJ. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J. 2012; 26: 1218–27.
  23. Savel`eva G.M., V.G. Breusenko. Ginekologiya. M.: GE`OTAR-Media, 2007. [Savelieva G.M., V.G. Breusenko. Gynecology. M.: GEOTAR Media, 2007 (in Russian)]
  24. Kurman R.J., Kaminski P.F., Norris H.J. The behavior of endometrial hyperplasia: a long-term study of «untreated» hyperplasia in 170 patients. Cancer. 1985; 56: 403–12.
  25. Ferenczy A., Gelfand M.M., Tzipris F. The cytodynamics of endometrial hyperplasia and carcinoma: a review. Ann. Pathol. 1983; 3: 189–201.
  26. Bershteyn L.M., E`pidemiologiya, patogenez i puti profilaktiki raka e`ndometriya: stabil`nost` ili e`volyuciya? Prakticheskaya onkologiya. 2004; 5 (1): 1–8.[Berstein L.M. Epidemiology, pathogenesis, and ways of preventing endometrial cancer: stability or evolution? Practical. Oncol. 2004; 5 (1): 1–8 (in Russian)]
  27. Strizhova N.V., Sergeev P.V., Lysenko O.N., Kareva E.N., Nesterova O.A. Rol` polovyh gormonov i ih receptornogo apparata pri vybore metodov lecheniya u pacientok s giperplasticheskimi processami e`ndometriya v sochetanii s miomoy matki. Zh. Akusherstvo i ginekologiya. 1998; 3: 30–3. [Strizhova N.V., Sergeev P.V., Lysenko O.N., Kareva E.N., Nesterova O.A. The role of sex hormones and their receptor system in selecting therapies in patients with endometrial hyperplastic processes in combination with uterine myoma. J. Obstetrics and Gynecology. 1998; 3: 30–3 (in Russian)]
  28. Lippi U.G., Analysis of estrogen- and progesterone-receptor expression in endometrial polyps. J. Minim. Invasive Gynecol. 2007; 14 (3): 300–3.
  29. Zaino R.J., Kauderer J., Trimble C.L., Silverberg S.G., Curtin J.P., Lim P.C. Reproducibility of the diagnosis of atypical hyperplasia. A GOG study. Cancer 2006; 106: 804–11.
  30. Kuz`mina I.Yu., Pasieshvili N.M., Pashhenko O.N. Differencirovannye podhody k vyboru lechebnoy taktiki u bol`nyh s giperplasticheskimi processami e`ndometriya. Mezhdunarodnyy medicinskiy zhurnal. 2011; 4: 61–4. [Kuzmina I.Y., Pasieshvili L.M. Pascenco O.N. Differentiated approach to the choice of treatment tactics in patients with endometrial hyperplasia. International Medical J. 2011; 4: 61–4 (in Russian)]
  31. Pieczysska B., Wojtylak S., Zawrocki A. Analysis of PTEN, estrogen receptor b and progesterone receptor expression in endometrial hyperplasia using tissue microarray. Pol. J. Pathol. 2011; 62 (3): 133–8.
  32. Samarnthai N., Hall K., Yeh I.T. Molecular Profiling of Endometrial Malignancies. Obstet Gynecol Int. 2010; http://www.hindawi.com/journals/ogi/2010/162363/
  33. Darvishian F., Hummer A.J., Thaler H.T., Bhargava R., Linkov I., Asher M., Soslow R.A. Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases. Am. J. Surg. Pathol. 2004; 28: 1568–78.
  34. Lin B.C., Suzawa M., Blind R.D., Tobias S.C., Bulun S.E., Scanlan T.S., Ingraham H.A. Stimulating the GPR30 Estrogen Receptor with a Novel Tamoxifen Analogue Activates SF-1 and Promotes Endometrial Cell Proliferation. Cancer Res. 2009; 69 (13): 5415–23.
  35. Susini T., Amunni G., Molino C., Carriero C., Rapi S., Branconi F. Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma. Cancer 2007; 109: 882–90.
  36. Mylonas I., Jeschke U., Shabani N. Normal and malignant human endometrium express immunohistochemically estrogen receptor alpha (ER-alpha), estrogen receptor beta (ER-beta) and progesterone receptor (PR). Anticancer. Res. 2005; 25 (3A); 1679–86.
  37. Smuc T., Rizner T.L. Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. Mol. Cell. Endocrinol. 2009; 301 (1–2): 74–82.
  38. Jazaeri A.A., Nunes K.J., Dalton M.S. Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression. Oncogene. 2001; 20 (47): 6965–9.
  39. Kudela M., Pilka R., Lubusky M. Prognostic importance of selected molecular immunohistochemical markers and DNA ploidy in endometrial cancer. Eur. J. Gynaecol. Oncol. 2012; 33 (2): 159–63.
  40. Jongen V., Briet J., De Jong R. Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer. Gynecol. Oncol. 2009; 112 (3): 537–42.
  41. Jeon Y.T., Park I.A., Kim Y.B. Steroid receptor expressions in endometrial cancer: clinical significance and epidemiological implication. Cancer. Lett. 2006; 239 (2): 198–204.
  42. Vandenput I., Trovik J., Leunen K. Evolution in endometrial cancer: evidence from an immunohistochemical study. Int. J. Gynecol. Cancer. 2011; 21 (2): 316–22.
  43. Smith H.O., Leslie K.K., Singh M. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am. J. Obstet. Gynecol. 2007; 196 (4): 386.e1-9.
  44. Clement P.B., Young R.H. Endometrioid carcinoma of the uterine corpus: a review of its pathology with emphasis on recent advances and problematic aspects. Adv. Anat. Pathol. 2002; 9:145–84.
  45. Arnold J.T., Lessey B.A., Seppälä M., Kaufman D.G. Effect of normal endometrial stroma on growth and differentiation in Ishikawa endometrial adenocarcinoma cells. Cancer Res. 2002; 62: 79–88.
  46. Krasnopol`skiy V.I., Gasparyan N.D., Logutova L.S., Kareva E.N., Gorenkova O.S., Tihonov D.A. Novaya tehnologiya protivorecidivnoy gormonal`noy terapii giperplasticheskih processov e`ndometriya u zhenshhin pozdnego reproduktivnogo vozrasta. Zh. Lechashhiy Vrach. 2012; 11: 12–6. [Krasnopolskiy V.I., Gasparian N.D., Logutova L.S., Kareva E.N., Gorenkova O.S., Tihonov D.A. The new technology of anti-hormonal therapy of endometrial hyperplastic processes in women of late reproductive age. J. The attending physician. 2012; 11: 12–6 (in Russian)]
  47. Kokka F., Brockbank E., Oram D., Gallagher C., Bryant A. Hormonal therapy in advanced or recurrent endometrial cancer. Cochrane Database Syst Rev. 2010; 12: CD007926.
  48. Thigpen J.T., Brady M.F., Alvarez R.D., Adelson M.D., Homesley H.D., Manetta A. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J. Clin. Oncol. 1999; 17: 1736–44.
  49. Vergote I., Kjorstad K., Abeler V., Kolstad P. A randomized trial of adjuvant protestogen in early endometrial cancer. Cancer. 1989; 64: 1011–6.
  50. Kareva E.N., Gasparian N.D., Gorenkova O.S., Krasnopolski V.I., Logutova L.S., Sergeev P.V. Praparat zur Behandlung von hyperplastischen Vorgangen in der Gebarmutterschleimhaut. Urkunde uber die Eintragung des Gebrauchsmasters №20 2007 018 859.5. IPC A61K 31/57 (2006.01). – 27.08.2009.