Blagoveschensk, Blagoveshchensk, Russian Federation
Blagoveschensk, Blagoveshchensk, Russian Federation
Progesterone is a natural steroid hormone that has many functions in the organism, regulating the work of non-reproductive and reproductive tissues. The article describes the mechanism of hormone effects. The data about genomic and nongenomic effects of progesterone through intracellular and plasma membrane´s receptors are presented. Specific effects of progesterone in various tissues depend on the ratio of receptors and their coregulators. Progesterone is the main hormone of pregnancy; therefore a large section is devoted to its action in that period. The hormone functions include participation in the ovulation and implantation processes, decidual transformation of endometrial tissue, inhibition of uterine contractility, suppression of the mother immune system, the accumulation of nutrients for fetal growth, development of the mammary glands, co-operation in the development of the embryo tissues. Several mechanisms of preventing myometrial contractility and transition mechanism of maternal immune system to function in conditions of pregnancy are considered in detail. Besides the hormone role during pregnancy, the regulation of other important functions of the human body is described.
progesterone, mechanism of action, pregnancy
1. Karachentsev A.N., Sergeev P.V., Matyushin A.I. Gestagens and heart. Problemy endokrinologii 1996; 42(2):42–45 (in Russian).
2. Lutsenko M.T., Samsonov V.P. Main research directions and development prospects at the Institute of Physiology and Pathology of Respiration. Bûlleten´ fiziologii i patologii dyhaniâ 1999; 2:1–9 (in Russian).
3. Lutsenko M.T., Andrievskaya I.A. The State of Fetoplacental Barrier at Herpes Viral Infection in Pregnant Women. Sibirskiy nauchniy meditsinskiy zhurnal 2008; 28(5):142–147 (in Russian).
4. Pustotina O.A. Placental insufficiency and treat of pregnancy loss-arguments for use of progesterone drugs. Rossiyskiy vestnik akushera-ginekologa 2006; 2:51–54 (in Russian).
5. Aktas G., Kayton R. Ultrastructural immunolocalization of basic fibroblast growth factor in fibroblasts and extracellular matrix. Histochem. Cell Biol. 2000; 113(3):227–233.
6. Alkhalaf M., El-Mowafy A., Karam S. Growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with cell differentiation and phosphorylation of Akt protein. Eur. J. Cancer Prev. 2002; 11(5):481–488.
7. Bardin C.W., Milgrom E., Mauvais-Jarvis P. Progesterone and progestins. New York: Raven Press; 1983.
8. Barrera D., Avila E., Díaz L. Immunological role of progesterone in the maintenance of pregnancy. Rev. Invest. Clin. 2007; 59(2):139–145.
9. Boomsma D., Paoletti J. A Review of current research on the effects of progesterone. Int. J. Pharm. Compd. 2002; 6(4):245–250.
10. Boonyaratnakonkit V., McGowan E., Sherman L., Mancini M.A., Cheskis B.J., Edwards D.P. The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and cell cycle. Mol. Endocrinol. 2007; 21(2):359–375.
11. Challis J.R.G., Matthews S.G., Gibb W., Lye S.J. Endocrine and paracrine regulation of birth at term and preterm. Endocr. Rev. 2000; 21(5):514–550.
12. Chao T.C., Van Alten P.J., Walter R.J. Steroid sex hormones and macrophage function: modulation of reactive oxygen intermediates and nitrite release. Am. J. Reprod. Immunol. 1994; 32(1):43–52.
13. Conneely O.M., Mulac-Jericevic B., Lydon J.P. Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids 2003; 68(10-13):771–778
14. Das S.K., Tsukamura H., Paria B.C., Andrews G.K., Dey S.K. Differential expression of epidermal growth factor receptor (EGF-R) gene and regulation of EGF-R bioactivity by progesterone and estrogen in the adult mouse uterus. Endocrinology 1994; 134(2):971–981.
15. Djebaili M., Guo Q., Pettus E.H., Hoffman S.W., Stein D.G. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J. Neurotrauma 2005; 22(1):106–118.
16. Dosiou C., Hamilton A.E., Pang Y., Overgaard M.T., Tulac S., Dong J., Thomas P., Giudice L.C. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J. Endocrinol. 2008; 196(1):67–77.
17. Druckmann R., Druckmann M.A. Progesterone and the immunology of pregnancy J. Steroid Biochem. Mol. Biol. 2005; 97(5):389–396.
18. Engmann L., Losel R., Wehling M., Peluso J.J. Progesterone regulation of human granulosa/luteal cell viability by an RU486-independent mechanism. J. Clin. Endocrinol. Metab. 2006; 91(12):4962–4968.
19. Ferguson J.E., Gorman J.V., Bruns D.E., Weir E.C., Burtis W.J., Martin T.J., Bruns M.E. Abundant expression of parathyroid hormone-related protein in human amnion and its association with labor. PNAS 1992; 89(17):8384-8388.
20. Flake G.P., Andersen J., Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ. Health Perspect. 2003; 111(8):1037–1054.
21. Flötotto T., Niederacher D., Hohmann D., Heimerzheim T., Dall P., Djahansouzi S., Bender H.G., Hanstein B. Molecular mechanism of estrogen receptor (ER)alpha-specific, estradiol-dependent expression of the progesterone receptor (PR) B-isoform. J. Steroid Biochem. Mol. Biol. 2004; 88(2):131–142.
22. Graham J.D., Clarke C.L. Physiological action of progesterone in target tissues. Endocrine Reviews 1997; 18(4):502–519.
23. Irwin R.W., Yao J., Hamilton R., Cadenas E., Brinton R.D., Nilsen J. Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria. Endocrinology 2008; 149(6):3167–3175.
24. Kapur S., Tamada H., Dey S.K., Andrews G.K. Expression of insulin-like growth factor-I (IGF-I) and its receptor in the peri-implantation mouse uterus, and cell-specific regulation of IGF-I gene expression by estradiol and progesterone. Biol. Reprod. 1992; 46(2):208–219.
25. Karteris E., Zervou S., Pang Y., Dong J., Hillhouse E.W., Randeva H.S., Thomas P. Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol. Endocrinol. 2006; 20(7):1519–1534.
26. King, R.J.B., Whitehead M.I. Application of steroid receptor analyses to clinical and biological investigations of the postmenopausal endometrium. In: Bresciani F., editor. Perspectives in Steroid Receptor Research. New York: Raven Press; 1980:259–271.
27. Ko L., Cardona G.R., Henrion-Caude A., Chin W.W. Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. Mol. Cell Biol. 2002; 22(1):357–369.
28. Lee W.S., Harder J.A., Yoshizumi M., Lee M.E., Haber E. Progesterone inhibits arterial smooth muscle cell proliferation. Nat. Med. 1997; 3(9):1005–1008.
29. Leonhardt S.A., Boonyaratanakornkit V., Edwards D.P. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 2003; 68(10-13):761–770.
30. Li X., O´Malley B.W. Unfolding the Action of Progesterone Receptors J. Biol. Chem. 2003; 278(41):39261–39264.
31. Lockwood C.J., Krikun G., Schatz F. Decidual cell-expressed tissue factor maintains hemostasis in human endometrium. Ann. NY Acad. Sci. 2001; 943:77–88.
32. Madsen G., Zakar T., Ku C.Y., Sanborn B.M., Smith R., Mesiano S. Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: evidence for prostaglandin-induced functional progesterone withdrawal. J. Clin. Endocrinol. Metab. 2004; 89(2):1010–1013.
33. Mani S.K., Oyola M.G. Progesterone signaling mechanisms in brain and behavior. Front. Endocrinol. (Lausanne). 2012; 3:7.
34. Mellon S.H., Gong W., Schonemann M.D. Endogenous and synthetic neurosteroids in treatment of Niemann Pick Type C Disease. Brain Res. Rev. 2008; 57(2):410–420.
35. Molinary C., Battaglia A., Grossini E., Mary D.A., Stoker J.B., Surico N., Vacca G. The effect of progesterone on coronary blood flow in anaesthesized pigs. Exp. Physiol. 2001; 86(1):101–118.
36. Mulac-Jericevic B., Conneely O.M. Reproductive tissue selective actions of progesterone receptors. Reproduction 2004; 128(2):139–146.
37. Obermann W.M., Sondermann H., Russo A.A., Pavletich N.P., Hartl F.U. In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J. Cell Biol. 1998; 143(4):901–910.
38. Orshal J.M., Khalil R.A. Gender, sex hormones, and vascular tone. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004; 286(2):R233–249.
39. Peluso J.J. Multiplicity of progesterone´s actions and receptors in the mammalian ovary. Biol. Reprod. 2006; 75(1):2–8.
40. Peluso J.J., Liu X., Gawkowska A., Lodde V., Wu C.A. Progesterone inhibits apoptosis in part by PGRMC1-regulated gene expression. Mol. Cell. Endocrinol. 2010; 320(1-2):153–161.
41. Pepe G.J., Albrecht E.D. Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Endocr. Rev. 1995; 16(5):608–648.
42. Petz L.N., Ziegler Y.S., Schultz J.R., Kim H., Kemper J.K., Nardulli A.M. Differential regulation of the human progesterone receptor gene through an estrogen response element half site and Sp1 sites. J. Steroid Biochem. Mol. Biol. 2004; 88(2):113–122.
43. Piccinni M.P., Scaletti C., Maggi E., Romagnani S. Role of hormone-controlled Th1- and Th2-type cytokines in successful pregnancy. J. Neuroimmunol. 2000; 109(1):30–33.
44. Pollard J.W., Bartocci A., Arceci R., Orlofsky A., Ladner M.B., Stanley E.R. Apparent role of the macrophage growth factor, CSF-I, in placental development. Nature. 1987; 330(6147):484–486.
45. Potvin W., Varma D.R. Down-regulation of myometrial atrial natriuretic factor receptors by progesterone and pregnancy and up-regulation by oestrogen in rats. J. Endocrinol. 1991; 131(2):259–266.
46. Robertson C.L., Puskar A., Hoffman G.E., Murphy A.Z., Saraswati M., Fiskum G. Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats. Exp. Neurol. 2006; 197(1):235–243.
47. Roof R.L., Hoffman S.W., Stein D.G. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol. Chem. Neuropathol. 1997; 31(1):1–11.
48. Rothchild I. Role of progesterone in initiating and maintaining pregnancy. In: Bardin C.W., Milgrom E., Mauvais-Jarvis P., editors. Progesterone and Progestins. New York: Raven Press; 1983: 219–229.
49. Tarachand U., Eapen J. Influence of estrogen, progesterone and estrous cycle on gamma-glutamyltranspeptidase of rat endometrium. FEBS Lett. 1982; 141(2):210–212.
50. Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front. Neuroendocrinol. 2008; 29(2):292–312.
51. Thomas P., Pang Y., Dong J., Groenen P., Kelder J., de Vlieg J., Zhu Y., Tubbs C. Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology. 2007; 148(2):705–718.
52. Scarpin K.M., Graham J.D., Mote P.A., Clarke C.L. Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl. Recept. Signal. 2009; 7:е009.
53. Schirar A., Capponi A., Catt K.J. Regulation of uterine angiotensin II receptors by estrogen and progesterone. Endocrinology 1980; 106(1):5–12.
54. Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine 2001; 14(3):407–415.
55. Subramanian M., Pusphendran C.K., Tarachand U. Devasagayam T.P. Gestation confers temporary resistance to peroxidation in the maternal rat brain. Neurosci. Lett. 1993; 155(2):151–154.
56. Stjernholm Y.V. Progesterone in Human Pregnancy and Parturition. In: Dubey R., editor. Sex Hormones; 2012: available at: http://www.intechopen.com/books/sex-hormones/progesterone-in-pregnancy-and-parturition.
57. Szekeres-Bartho J., Halasz M., Palkovics T. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways. J. Reprod. Immunol. 2009; 83(1-2):60–64.
58. Szekeres-Bartho J., Poigar B. PIBF: the double edged sword. Pregnancy and tumor. Am. J. Reprod. Immunol. 2010; 64(2):77–86.
59. Xu Q., Ohara N., Chen W., Liu J., Sasaki H., Morikawa A., Sitruk-Ware R., Johansson E.D., Maruo T. Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells. Hum. Reprod. 2006; 21(9):2408–2416.
60. VanLandingham J.W., Cutler S.M., Virmani S., Hoffman S.W., Covey D.F., Krishnan K., Hammes S.R., Jamnongjit M., Stein D.G. The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury. Neuropharmacology 2006; 51(6):1078–1085.
61. Vivat V., Cohen-Tannoudji J., Revelli J.-P., Muzzin P., Giacobino J.-P., Maltier J.-P., Legrand C. Progesterone transcriptionally regulates the β2-adrenergic receptor gene in pregnant rat myometrium. J. Biol. Chem. 1992; 267(12):7975–7978.
62. Wagner C.K., Nakayama A.Y., De Vries G.J. Potential role of maternal progesterone in the sexual differentiation of the brain. Endocrinology 1998; 139(8):3658–3661.
63. Wei L.L., Hawkins P., Baker C., Norris B., Sheridan P. L., Quinn P.G. An amino-terminal truncated progesterone receptor isoform, PRc, enhances progestin-induced transcriptional activity. Mol. Endocrinol. 1996; 10(11):1379–1387.
64. Wulff C., Wilson H., Dickson S.E., Wiegand S.J., Fraser H.M. Hemochorial placentation in the primate: expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy. Biol. Reprod. 2002; 66(3):802–812.
65. Yki-Jarvinen H., Wahlstrom T., Seppala M. Human endometrium contains relaxin that is progesterone-dependent. Acta Obstet. Gynecol. Scand. 1985; 64(8):663–665.
66. Zhu L.J., Cullinan-Bove K., Polihronis M., Bagchi M.K., Bagchi I.C. Calcitonin is a progesterone-regulated marker that forecasts the receptive state of endometrium during implantation. Endocrinology 1998; 139(9):3923–3934.
