Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy

Raj Raghupathy, Julia Szekeres-Bartho, Raj Raghupathy, Julia Szekeres-Bartho

Abstract

Progesterone is well known for its numerous endocrinologic roles in pregnancy but is also endowed with fascinating immunomodulatory capabilities. It can downregulate the induction of inflammatory reactions, the activation of immune cells and the production of cytokines, which are critical mediators of immune responses. These features appear to be critical to the success of pregnancy, given the ability of maternal immune reactivity to interfere with pregnancy and to contribute to several pregnancy complications. This review summarizes the contribution of maternal immune effectors in general, and cytokines in particular, to pregnancy complications such as recurrent miscarriage, pre-eclampsia and preterm labor; it describes the promise offered by supplementation with progesterone and the oral progestogen dydrogesterone, as well as the progesterone-induced blocking factor in the prevention and/or treatment of these serious complications.

Keywords: cytokines; dydrogesterone; immunomodulation; pregnancy; pregnancy complications; progesterone; progestogens.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunomodulatory effects of progestogens on cytokine production patterns.

References

    1. Siiteri P.K., Febres F., Clemens L.E., Chang R.J., Gondos B., Stites D. Progesterone and maintenance of pregnancy: Is progesterone nature’s immunosuppressant? Ann. N. Y. Acad. Sci. 1977;286:384–397. doi: 10.1111/j.1749-6632.1977.tb29431.x.
    1. Watnick A.S., Russo R.A. Survival of skin homografts in uteri of pregnant and progesterone-estrogen treated rats. Proc. Soc. Exp. Biol. Med. 1968;128:1–4. doi: 10.3181/00379727-128-32928.
    1. Hansen P.J., Bazer F.W., Segerson E.C. Skin graft survival in the uterine lumen of ewes treated with progesterone. Am. J. Reprod. Immunol. Microbiol. 1986;12:48–54. doi: 10.1111/j.1600-0897.1986.tb00062.x.
    1. Black W.G., Simon J., McNutt S.H., Casida L.E. Investigations on the physiological basis for the differential response of estrous and pseudopregnant rabbit uteri to induced infection. Am. J. Vet. Res. 1953;14:318–323.
    1. Rowson L.E.A., Lamming G.E., Fry R.M. The relationship between ovarian hormones and uterine infection. Vet. Rec. 1953;65:335–340.
    1. Hansen P.J. Regulation of uterine immune function by progesterone—Lessons from the sheep. J. Reprod. Immunol. 1998;40:63–79. doi: 10.1016/S0165-0378(98)00035-7.
    1. Jones L.A., Kreem S., Shweash M., Paul A., Alexander J., Roberts C.W. Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J. Immunol. 2010;185:4525–4534. doi: 10.4049/jimmunol.0901155.
    1. Menzies F.M., Henriquez F.L., Alexander J., Roberts C.W. Selective inhibition and augmentation of alternative macrophage activation by progesterone. Immunology. 2011;134:281–291. doi: 10.1111/j.1365-2567.2011.03488.x.
    1. Schumacher A., Costa S.D., Zenclussen A.C. Endocrine factors modulating immune responses in pregnancy. Front Immunol. 2014;5:196. doi: 10.3389/fimmu.2014.00196.
    1. Butts C.L., Shukair S.A., Duncan K.M., Bowers E., Horn C., Belyavskaya E., Tonelli L., Sternberg E.M. Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int. Immunol. 2007 19:287–296. doi: 10.1093/intimm/dxl145.
    1. Jones L.A., Anthony J.P., Henriquez F.L., Lyons R.E., Nickdel M.B., Carter K.C., Alexander J., Roberts C.W. Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology. 2008;125:59–69. doi: 10.1111/j.1365-2567.2008.02820.x.
    1. Su L., Sun Y., Ma F., Lü P., Huang H., Zhou J. Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. Immunol. Lett. 2009;125:151–1555. doi: 10.1016/j.imlet.2009.07.003.
    1. Vassiliadou N., Tucker L., Anderson D.J. Progesterone-induced inhibition of chemokine receptor expression on peripheral blood mononuclear cells correlates with reduced HIV-1 infectability in vitro. J. Immunol. 1999;162:7510–7518.
    1. Thiele K., Hierweger A.M., Riquelme J.I.A., Solano M.E., Lydon J.P., Arck P.C. Impaired progesterone-responsiveness of CD11c(+) dendritic cells affects the generation of CD4(+) regulatory T cells and is associated with intrauterine growth restriction in mice. Front. Endocrinol. 2019;10:96–102. doi: 10.3389/fendo.2019.00096.
    1. Csabai T., Pallinger E., Kovacs A.F., Miko E., Bognar Z., Szekeres-Bartho J. Altered immune response and implantation failure in progesterone-induced blocking factor-deficient mice. Front. Immunol. 2020;11:349–356. doi: 10.3389/fimmu.2020.00349.
    1. Shah N.M., Lai P.F., Imami N., Johnson M.R. Progesterone-related immune modulation of pregnancy and labor. Front. Endocrinol. 2019;10:198–210. doi: 10.3389/fendo.2019.00198.
    1. Li X., O’Malley B.W. Unfolding the action of progesterone receptors. J. Biol. Chem. 2003;278:39261–39264. doi: 10.1074/jbc.R300024200.
    1. 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;289:1751–1754. doi: 10.1126/science.289.5485.1751.
    1. Chien E.J., Liao C.F., Chang C.P., Pu H.F., Lu L.M., Shie M.C., Hsieh D.J., Hsu M.T. The non-genomic effects on Na(+)/H(+)-exchange 1 by progesterone and 20alpha-hydroxyprogesterone in human T cells. J. Cell Physiol. 2007;211:544–550. doi: 10.1002/jcp.20962.
    1. Szekeres-Bartho J., Barakonyi A., Miko E., Polgar B., Palkovics T. The role of γ/δ T cells in the feto-maternal relationship. Semin. Immunol. 2000;13:229–233. doi: 10.1006/smim.2000.0318.
    1. Arruvito L., Giulianelli S., Flores A.C., Paladino N., Barboza M., Lanari C., Fainboim L. NK cells expressing a progesterone receptor are susceptible to progesterone-induced apoptosis. J. Immunol. 2008;180:5746–5753. doi: 10.4049/jimmunol.180.8.5746.
    1. Henderson T.A., Saunders P.T., Moffet-King A., Grrome N.O., Critchley H.O. Steroid receptor expression in uterine natural killer cells. J. Clin. Endocrinol. Metabol. 2003;88:440–449. doi: 10.1210/jc.2002-021174.
    1. Chien H., Guo W., Li P., Zhao G., Fan H., Hu Y., Hou Y. Glucocorticoid receptor mediates the effect of progesterone on uterine natural killer cells. Am. J. Reprod. Immunol. 2012;67:463–473.
    1. Gellersen B., Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: A decidualizing affair. J. Endocrinol. 2003;178:357–372. doi: 10.1677/joe.0.1780357.
    1. Florio P., Rossi M., Viganò P., Luisi S., Torricelli M., Torres P.B., Di Blasio A.M., Petraglia F. Interleukin 1beta and progesterone stimulate activin a expression and secretion from cultured human endometrial stromal cells. Reprod. Sci. 2007;14:29–36. doi: 10.1177/1933719106298191.
    1. Hantak A.M., Bagchi I.C., Bagchi M.K. Role of uterine stromal-epithelial crosstalk in embryo implantation. Int. J. Dev. Biol. 2014;58:139–146. doi: 10.1387/ijdb.130348mb.
    1. Vota D., Aguero M., Grasso E., Hauk V., Gallino L., Soczewski E., Pérez Leirós C., Ramhorst R. Progesterone and VIP cross-talk enhances phagocytosis and anti-inflammatory profile in trophoblast-derived cells. Mol. Cell. Endocrinol. 2017;443:146–154. doi: 10.1016/j.mce.2017.01.022.
    1. Fujiwara H. Immune cells contribute to systemic cross-talk between the embryo and mother during early pregnancy in cooperation with the endocrine system. Reprod. Med. Biol. 2006;5:19–29. doi: 10.1111/j.1447-0578.2006.00119.x.
    1. Verma P., Verma R., Nair R.R., Budhwar S., Khanna A., Agrawal N.R., Sinha R., Birendra R., Rajender S., Singh K. Altered crosstalk of estradiol and progesterone with myeloid-derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal-fetal tolerance. Am. J. Reprod. Immunol. 2019;81:e13081. doi: 10.1111/aji.13081.
    1. Ren J., Hou H., Zhao W., Wang J., Peng Q. Administration of exogenous progesterone protects against Brucella abortus infection-induced inflammation in pregnant mice. J. Infect. Dis. 2021;224:532–543. doi: 10.1093/infdis/jiaa722.
    1. Kirshenbaum M., Orvieto R. Premature ovarian insufficiency (POI) and autoimmunity-an update appraisal. J. Assist. Reprod. Genet. 2019;36:2207–2215. doi: 10.1007/s10815-019-01572-0.
    1. Vickram A.S., Dhama K., Chakraborty S., Samad H.A., Latheef S.K., Sharun K., Khurana S.K., Tiwari R., Bhatt P.K.V., Chaicumpa W. Role of antisperm antibodies in infertility, pregnancy, and potential for contraceptive and antifertility vaccine designs: Research progress and pioneering vision. Vaccines. 2019;7:116.
    1. Dinarello C.A. Historical insights into cytokines. Eur. J. Immunol. 2007;37:S34–S45. doi: 10.1002/eji.200737772.
    1. Moudgil K.D., Choubey D. Cytokines in autoimmunity: Role in induction, regulation, and treatment. J. Interferon Cytokine Res. 2011;10:695–703. doi: 10.1089/jir.2011.0065.
    1. Lambrecht B.N., Hammad H., Fahy J.V. The cytokines of asthma. Immunity. 2019;50:975–991. doi: 10.1016/j.immuni.2019.03.018.
    1. Kany S., Vollrath J.T., Relja B. Cytokines in inflammatory disease. Int. J. Mol. Sci. 2019;20:6008. doi: 10.3390/ijms20236008.
    1. Zhu X., Zhu J. CD4 T helper cell subsets and related human immunological disorders. Int. J. Mol. Sci. 2020;21:8011. doi: 10.3390/ijms21218011.
    1. Romagnani S. T cell subpopulations. Chem. Immunol. Allergy. 2014;100:155–164.
    1. Mosmann T.R., Kobie J.J., Lee F.E., Quataert S.A. T helper cytokine patterns: Defined subsets, random expression, and external modulation. Immunol. Res. 2009;45:173–184. doi: 10.1007/s12026-009-8098-5.
    1. Kim C.J., Romero R., Chaemsaithong P., Kim J.S. Chronic inflammation of the placenta: Definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. Gynecol. 2015;213:S53–S69. doi: 10.1016/j.ajog.2015.08.041.
    1. Tan H.X., Yang S.L., Li M.Q., Wang H.Y. Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion. Cell Commun. Signal. 2020;18:73–80. doi: 10.1186/s12964-020-00579-w.
    1. Chaouat G., Menu E., Clark D.A., Dy M., Minkowski M., Wegmann T.G. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy. J. Reprod. Fertil. 1990;89:447–458. doi: 10.1530/jrf.0.0890447.
    1. Haimovici F., Hill J.A., Anderson D.J. The effects of soluble products of activated lymphocytes and macrophages on blastocyst implantation events in vitro. Biol. Reprod. 1991;44:69–75. doi: 10.1095/biolreprod44.1.69.
    1. Pijnenborg. R., Luyten C., Vercruysse L., Keith J.C., Jr., Van Assche F.A. Cytotoxic effects of tumour necrosis factor (TNF)-α and interferon -γ on cultured human trophoblast are modulated by fibronectin. Mol. Hum. Reprod. 2000;6:635–641. doi: 10.1093/molehr/6.7.635.
    1. Kwak-Kim J., Bao S., Lee S.K., Kim J.W., Gilman-Sachs A. Immunological modes of pregnancy loss: Inflammation, immune effectors, and stress. Am. J. Reprod. Immunol. 2014;72:129–140. doi: 10.1111/aji.12234.
    1. Hill J.A., Polgar K., Anderson D.J. T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. JAMA. 1995;273:1933–1936. doi: 10.1001/jama.1995.03520480053039.
    1. Raghupathy R., Makhseed M., Azizieh F., Omu A., Gupta M., Farhat R. Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum. Reprod. 2000;15:713–718. doi: 10.1093/humrep/15.3.713.
    1. Makhseed M., Raghupathy R., Azizieh F., Al-Azemi M.M., Hassan N.A., Bandar A. Mitogen-induced cytokine responses of maternal peripheral blood lymphocytes indicate a differential Th-type bias in normal pregnancy and pregnancy failure. Am. J. Reprod. Immunol. 1999;42:273–281. doi: 10.1111/j.1600-0897.1999.tb00101.x.
    1. Raghupathy R., Makhseed M., Azizieh F., Hassan N., Al-Azemi M., Al-Shamali E. Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol. 1999;196:122–130. doi: 10.1006/cimm.1999.1532.
    1. Makhseed M., Raghupathy R., Azizieh F., Omu A., Al-Shamali E., Ashkanani L. Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum. Reprod. 2001;16:2219–2226. doi: 10.1093/humrep/16.10.2219.
    1. Marzi M., Vigano A., Trabattoni D., Villa M.L., Salvaggio A., Clerici E., Clerici M. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin. Exp. Immunol. 1996;106:127–133. doi: 10.1046/j.1365-2249.1996.d01-809.x.
    1. Piccinni M.P., Lombardelli L., Logiodice F., Kullolli O., Romagnani S., Le Bouteiller P. T helper cell mediated-tolerance towards fetal allograft in successful pregnancy. Clin. Mol. Allergy. 2015;13:9–18. doi: 10.1186/s12948-015-0015-y.
    1. Banerjee P., Ghosh S., Dutta M., Subramani E., Khalpada J., Roychoudhury S., Chakravarty B., Chaudhury K. Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage. PLoS ONE. 2013;8:e80940. doi: 10.1371/journal.pone.0080940.
    1. Malik R., Kumar V. Hypertension in pregnancy. Adv. Exp. Med. Biol. 2017;956:375–393.
    1. Mol B.W.J., Roberts C.T., Thangaratinam S., Magee L.A., de Groot C.J.M., Hofmeyr G.J. Pre-eclampsia. Lancet. 2016;387:999–1011. doi: 10.1016/S0140-6736(15)00070-7.
    1. Robertson W.B., Brosens I., Dixon H.G. The pathological response of the vessels of the placental bed to hypertensive pregnancy. J. Pathol. Bacteriol. 1967;93:581–592. doi: 10.1002/path.1700930219.
    1. Burton G.J., Woods A.W., Jauniaux E., Kingdom J.C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30:473–482. doi: 10.1016/j.placenta.2009.02.009.
    1. Phipps E.A., Thadhani R., Benzing T., Karumanchi S.A. Pre-eclampsia: Pathogenesis, novel diagnostics and therapies. Nat. Rev. Nephrol. 2019;15:275–289. doi: 10.1038/s41581-019-0119-6.
    1. Aggarwal R., Jain A.K., Mittal P., Kohli M., Jawanjal P., Rath G. Association of pro- and anti-inflammatory cytokines in preeclampsia. J. Clin. Lab. Anal. 2019;33:e22834. doi: 10.1002/jcla.22834.
    1. Equils O., Kellogg C., McGregor J., Gravett M., Neal-Perry G., Gabay C. The role of the IL-1 system in pregnancy and the use of IL-1 system markers to identify women at risk for pregnancy complications. Biol. Reprod. 2020;103:684–694. doi: 10.1093/biolre/ioaa102.
    1. Tranquilli A.L., Corradetti A., Giannubilo S.R. Placental cytokines in the pathogenesis of preeclampsia and HELLP syndrome. Curr. Womens Health Rev. 2008;4:280–285. doi: 10.2174/157340408786848241.
    1. Weel I.C., Romão-Veiga M., Matias M.L., Fioratti E.G., Peraçoli J.C., Borges V.T., Araujo J.P., Jr., Peraçoli M.T. Increased expression of NLRP3 inflammasome in placentas from pregnant women with severe preeclampsia. J. Reprod. Immunol. 2017;123:40–47. doi: 10.1016/j.jri.2017.09.002.
    1. Sakai M., Tsuda H., Tanebe K., Sasaki Y., Saito S. Interleukin-12 secretion by peripheral blood mononuclear cells is decreased in normal pregnant subjects and increased in preeclamptic patients. Am. J. Reprod. Immunol. 2002;47:91–97. doi: 10.1034/j.1600-0897.2002.1o020.x.
    1. Sheibak N., Mahmoudzadeh-Sagheb H., Moudi B., Heidari Z. Elevated immunoexpression of interferon-gamma in placenta tissue samples from pregnancies complicated with preeclampsia compared to the placenta previa. Pregnancy Hypertens. 2020;22:175–180. doi: 10.1016/j.preghy.2020.08.003.
    1. Xu J., Gu Y., Sun J., Zhu H., Lewis D.F., Wang Y. Reduced CD200 expression is associated with altered Th1/Th2 cytokine production in placental trophoblasts from preeclampsia. Am. J. Reprod. Immunol. 2018;79:e12763. doi: 10.1111/aji.12763.
    1. Szarka A., Rigó J., Jr., Lázár L., Beko G., Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 2010;11:59–66. doi: 10.1186/1471-2172-11-59.
    1. Saito S., Umekage H., Sakamoto Y., Sakai M., Tanebe K., Sasaki Y., Morikawa H. Increased T-helper-1-type immunity and decreased T-helper-2-type immunity in patients with preeclampsia. Am. J. Reprod. Immunol. 1999;41:297–306. doi: 10.1111/j.1600-0897.1999.tb00442.x.
    1. Darmochwal-Kolarz D., Rolinski J., Leszczynska-Goarzelak B., Oleszczuk J. The expressions of intracellular cytokines in the lymphocytes of preeclamptic patients. Am. J. Reprod. Immunol. 2002;48:381–386. doi: 10.1034/j.1600-0897.2002.01089.x.
    1. Rein D.T., Schondorf T., Gohring U.J., Kurbacher C.M., Pinto I., Breidenbach M., Mallmann P., Kolhagen H., Engel H. Cytokine expression in peripheral blood lymphocytes indicates a switch to T(HELPER) cells in patients with preeclampsia. J. Reprod. Immunol. 2002;54:133–142. doi: 10.1016/S0165-0378(01)00128-0.
    1. Luppi P., Deloia J.A. Monocytes of preeclamptic women spontaneously synthesize pro-inflammatory cytokines. Clin. Immunol. 2006;118:268–275. doi: 10.1016/j.clim.2005.11.001.
    1. Boij R., Svensson J., Nilsson-Ekdahl K., Sandholm K., Lindahl T.L., Palonek E., Garle M., Berg G., Ernerudh J., Jenmalm M., et al. Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am. J. Reprod. Immunol. 2012;68:258–270. doi: 10.1111/j.1600-0897.2012.01158.x.
    1. Orange S., Horvath J., Hennessy A. Preeclampsia is associated with a reduced interleukin-10 production from peripheral blood mononuclear cells. Hypertens Pregnancy. 2003;22:1–8. doi: 10.1081/PRG-120016788.
    1. Azizieh F.Y., Raghupathy R. IL-10 and pregnancy complications. Clin. Exp. Obstet. Gynecol. 2017;44:252–258.
    1. Jonsson Y., Rubèr M., Matthiesen L., Berg G., Nieminen K., Sharma S., Ernerudh J., Ekerfelt C. Cytokine mapping of sera from women with preeclampsia and normal pregnancies. J. Reprod. Immunol. 2006;70:83–91. doi: 10.1016/j.jri.2005.10.007.
    1. Azizieh F., Raghupathy R., Makhseed M. Maternal cytokine production patterns in women with pre-eclampsia. Am. J. Reprod. Immunol. 2005;54:30–37. doi: 10.1111/j.1600-0897.2005.00278.x.
    1. Raghupathy R. Cytokines as key players in the pathophysiology of preeclampsia. Med. Princ. Pract. 2013;22((Suppl. 1)):8–19. doi: 10.1159/000354200.
    1. Da Fonseca E.B., Damião R., Moreira D.A. Preterm birth prevention. Best Pract. Res. Clin. Obstet. Gynaecol. 2020;69:40–49. doi: 10.1016/j.bpobgyn.2020.09.003.
    1. Lien Y.C., Zhang Z., Barila G., Green-Brown A., Elovitz M.A., Simmons R.A. Intrauterine inflammation alters the transcriptome and metabolome in placenta. Front. Physiol. 2020;11:592689. doi: 10.3389/fphys.2020.592689.
    1. Makhseed M., Raghupathy R., El-Shazly S., Azizieh F., Al-Harmi J.A., Al-Azemi M.M. Pro-inflammatory maternal cytokine profile in preterm delivery. Am. J. Reprod. Immunol. 2003;49:308–318. doi: 10.1034/j.1600-0897.2003.00038.x.
    1. Ashford K., Chavan N.R., Wiggins A.T., Sayre M.M., McCubbin A., Critchfield A.S., O’Brien J. Comparison of serum and cervical cytokine levels throughout pregnancy between preterm and term births. AJP Rep. 2018;8:e113–e120. doi: 10.1055/s-0038-1656534.
    1. Park H., Park K.H., Kim Y.M., Kook S.Y., Jeon S.J., Yoo H.N. Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: A retrospective study. BMC Pregnancy Childbirth. 2018;18:146–155. doi: 10.1186/s12884-018-1780-7.
    1. Denney J.M., Nelson E., Wadhwa P., Waters T., Mathew L., Goldenberg R.L., Culhane J.F. Cytokine profiling: Variation in immune modulation with preterm birth vs. uncomplicated term birth identifies pivotal signals in pathogenesis of preterm birth. J. Perinat. Med. 2020;49:299–309. doi: 10.1515/jpm-2020-0025.
    1. Christiaens I., Zaragoza D.B., Guilbert L., Robertson S.A., Mitchell B.F., Olson D.M. Inflammatory processes in preterm and term parturition. J. Reprod. Immunol. 2008;79:50–57. doi: 10.1016/j.jri.2008.04.002.
    1. Jung E.Y., Park J.W., Ryu A., Lee S.Y., Cho S.H., Park K.H. Prediction of impending preterm delivery based on sonographic cervical length and different cytokine levels in cervicovaginal fluid in preterm labor. J. Obstet. Gynaecol. Res. 2016;42:158–165. doi: 10.1111/jog.12882.
    1. El-Shazly S., Makhseed M., Azizieh F., Raghupathy R. Increased expression of pro-inflammatory cytokines in placentas of women undergoing spontaneous preterm delivery or premature rupture of membranes. Am. J. Reprod. Immunol. 2004;52:45–52. doi: 10.1111/j.1600-0897.2004.00181.x.
    1. Yockey L.J., Iwasaki A. Interferons and proinflammatory cytokines in pregnancy and fetal development. Immunity. 2018;49:397–412. doi: 10.1016/j.immuni.2018.07.017.
    1. Romero R., Dey S.K., Fisher S.J. Preterm labor: One syndrome, many causes. Science. 2014;345:760–765. doi: 10.1126/science.1251816.
    1. Dudley D.J. Immunoendocrinology of preterm labor: The link between corticotropin-releasing hormone and inflammation. Am. J. Obstet. Gynecol. 1999;180 Pt 3:S251–S256. doi: 10.1016/S0002-9378(99)70711-8.
    1. Choi B.C., Polgar K., Xiao L., Hill J.A. Progesterone inhibits in-vitro embryotoxic Th1 cytokine production to trophoblast in women with recurrent pregnancy loss. Hum. Reprod. 2000;15:46–59. doi: 10.1093/humrep/15.suppl_1.46.
    1. Piccinni M.P., Raghupathy R., Saito S., Szekeres-Bartho J. Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front. Immunol. 2021;12:717808. doi: 10.3389/fimmu.2021.717808.
    1. Schindler A.E. Progestogens for treatment and prevention of pregnancy disorders. Horm. Mol. Biol. Clin. Investig. 2010;3:453–460. doi: 10.1515/hmbci.2010.069.
    1. Oates-Whitehead R.M., Haas D.M., Carrier J.A. Progestogen for preventing miscarriage. Cochrane Database Syst. Rev. 2003;4:CD003511.
    1. Haas D.M., Ramsey P.S. Progestogen for preventing miscarriage. Cochrane Database Syst. Rev. 2008;16:CD003511.
    1. 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., et al. Micronized vaginal progesterone to prevent miscarriage: A critical evaluation of randomized evidence. Am. J. Obstet. Gynecol. 2020;223:167–176. doi: 10.1016/j.ajog.2019.12.006.
    1. Haas D.M., Hathaway T.J., Ramsey P.S. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst. Rev. 2019;2019:CD003511. doi: 10.1002/14651858.CD003511.pub5.
    1. Carp H.J.A. Progestogens and pregnancy loss. Climacteric. 2018;21:380–384. doi: 10.1080/13697137.2018.1436166.
    1. Coomarasamy A., Williams H., Truchanowicz E., Seed P.T., Small R., Quenby S., Gupta P., Dawood F., Koot Y.E., Atik R.B., et al. PROMISE: First-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages—A randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol. Assess. 2016;20:1–92. doi: 10.3310/hta20410.
    1. Carp H. Immunotherapy for recurrent pregnancy loss. Best Pract. Res. Clin. Obstet. Gynaecol. 2019;60:77–86. doi: 10.1016/j.bpobgyn.2019.07.005.
    1. Schmouder V.M., Prescott G.M., Franco A., Fan-Havard P. The rebirth of progesterone in the prevention of preterm labor. Ann. Pharmacother. 2013;47:527–536. doi: 10.1345/aph.1R281.
    1. Dodd J.M., Crowther C.A., Cincotta R., Flenady V., Robinson J.S. Progesterone supplementation for preventing preterm birth: A systematic review and meta-analysis. Acta Obstet. Gynecol. Scand. 2005;84:526–533. doi: 10.1111/j.0001-6349.2005.00835.x.
    1. Matei A., Saccone G., Vogel J.P., Armson A.B. Primary and secondary prevention of preterm birth: A review of systematic reviews and ongoing randomized controlled trials. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;236:224–239. doi: 10.1016/j.ejogrb.2018.12.022.
    1. Wiegratz I., Kuhl H. Metabolic and clinical effects of progestogens. Eur. J. Contracept. Reprod. Health Care. 2006 11:153–161. doi: 10.1080/13625180600772741.
    1. Schindler A.E. Progestogen effects on various organs and their functions. Gynecol. Endocrinol. 2007;23:1. doi: 10.1080/09513590701584816.
    1. Schindler A.E., Campagnoli C., Druckmann R., Huber J., Pasqualini J.R., Schweppe K.W., Thijssen J.H. Classification and pharmacology of progestins. Maturitas. 2003;46:S7–S16. doi: 10.1016/j.maturitas.2003.09.014.
    1. Raghupathy R., Al Mutawa E., Makhseed M., Azizieh F., Szekeres-Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. BJOG. 2005;112:1096–1101. doi: 10.1111/j.1471-0528.2005.00633.x.
    1. AbdulHussain G., Azizieh F., Makhseed M., Raghupathy R. Effects of progesterone, dydrogesterone and estrogen on the production of Th1/Th2/Th17 cytokines by lymphocytes from women with recurrent spontaneous miscarriage. J. Reprod. Immunol. 2020;140:103132. doi: 10.1016/j.jri.2020.103132.
    1. Xu W.M., Xiao Z.N., Wang X.B., Huang Y. IL-17 induces fetal loss in a CBA/J×BALB/c mouse model, and an anti-IL-17 antibody prevents fetal loss in a CBA/J×DBA/2 mouse model. Am. J. Reprod. Immunol. 2016;75:51–58. doi: 10.1111/aji.12437.
    1. Wang W.J., Hao C.F., Yi-Lin, Yin G.J., Bao S.H., Qiu L.H., Lin Q.D. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J. Reprod. Immunol. 2010;84:164–170. doi: 10.1016/j.jri.2009.12.003.
    1. Qian J., Zhang N., Lin J., Wang C., Pan X., Chen L., Li D., Wang L. Distinct pattern of Th17/Treg cells in pregnant women with a history of unexplained recurrent spontaneous abortion. Biosci. Trends. 2018;12:157–167. doi: 10.5582/bst.2018.01012.
    1. Raghupathy R., Szekeres-Bartho J. Dydrogesterone and the immunology of pregnancy. Horm. Mol. Biol. Clin. Investig. 2016;27:63–71. doi: 10.1515/hmbci-2015-0062.
    1. El-Zibdeh M.Y. Dydrogesterone in the reduction of recurrent spontaneous abortion. J. Steroid. Biochem. Mol. Biol. 2005;97:431–434. doi: 10.1016/j.jsbmb.2005.08.007.
    1. Pandian R.U. Dydrogesterone in threatened miscarriage: A Malaysian experience. Maturitas. 2009;65:S47–S50. doi: 10.1016/j.maturitas.2009.11.016.
    1. Kumar A., Begum N., Prasad S., Aggarwal S., Sharma S. Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: A double-blind, randomized, parallel, placebo-controlled trial. Fertil. Steril. 2014;102:1357–1363.e3. doi: 10.1016/j.fertnstert.2014.07.1251.
    1. Carp H. A systematic review of dydrogesterone for the treatment of recurrent miscarriage. Gynecol. Endocrinol. 2015;31:422–430. doi: 10.3109/09513590.2015.1006618.
    1. Guo H., Lu Q. Efficacy of dydrogesterone on treating recurrent miscarriage and its influence on immune factors: A systematic review and meta-analysis. Ann. Palliat. Med. 2021;10:10971–10985. doi: 10.21037/apm-21-2605.
    1. Saccone G., Schoen C., Franasiak J.M., Scott R.T., Jr., Berghella V. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: A systematic review and meta-analysis of randomized, controlled trials. Fertil. Steril. 2017;107:430–438.e3. doi: 10.1016/j.fertnstert.2016.10.031.
    1. Schindler A.E. Present and future aspects of dydrogesterone in prevention or treatment of pregnancy disorders: An outlook. Horm. Mol. Biol. Clin. Investig. 2016;27:49–53. doi: 10.1515/hmbci-2016-0028.
    1. Schindler A.E. New data about preeclampsia: Some possibilities of prevention. Gynecol. Endocrinol. 2018;34:636–637. doi: 10.1080/09513590.2018.1441401.
    1. Hudic I., Schindler A.E., Szekeres-Bartho J., Stray-Pedersen B. Dydrogesterone and pre-term birth. Horm. Mol. Biol. Clin. Investig. 2016;27:81–83. doi: 10.1515/hmbci-2015-0064.
    1. Mohamad Razi Z.R., Schindler A.E. Review on role of progestogen (dydrogesterone) in the prevention of gestational hypertension. Horm. Mol. Biol. Clin. Investig. 2016;27:73–76. doi: 10.1515/hmbci-2015-0070.
    1. Tskhay V., Schindler A., Shestakova M., Klimova O., Narkevich A. The role of progestogen supplementation (dydrogesterone) in the prevention of preeclampsia. Gynecol. Endocrinol. 2020;36:698–701. doi: 10.1080/09513590.2019.1706085.
    1. Ali A.B., Ahmad M.F., Kwang N.B., Shan L.P., Shafie N.M., Omar M.H. Dydrogesterone support following assisted reproductive technique (ART) reduces the risk of pre-eclampsia. Horm. Mol. Biol. Clin. Investig. 2016;27:93–96. doi: 10.1515/hmbci-2015-0063.
    1. Stute P. Dydrogesterone indications beyond menopausal hormone therapy: An evidence review and woman’s journey. Gynecol. Endocrinol. 2021;37:683–688. doi: 10.1080/09513590.2021.1908252.
    1. Mirza F.G., Patki A., Pexman-Fieth C. Dydrogesterone use in early pregnancy. Gynecol. Endocrinol. 2016;32:97–106. doi: 10.3109/09513590.2015.1121982.
    1. Stanczyk F.Z. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev. Endocr. Metab. Disord. 2002;3:211–224. doi: 10.1023/A:1020072325818.
    1. Maxson W.S., Hargrove J.T. Bioavailability of oral micronized progesterone. Fertil. Steril. 1985;44:622–626. doi: 10.1016/S0015-0282(16)48977-6.
    1. Raghupathy R., Al-Azemi M. Modulation of cytokine production by the dydrogesterone metabolite dihydrodydrogesterone. Am. J. Reprod. Immunol. 2015;74:419–426. doi: 10.1111/aji.12418.
    1. Szekeres-Bartho J., Kilaŕ F., Falkay G., Csernus V., Török A., Pacsa A.S. The mechanism of the inhibitory effect of progesterone on lymphocyte cytotoxicity: I. Progesterone-treated lymphocytes release a substance inhibiting cytotoxicity and prostaglandin synthesis. Am. J. Reprod. Immunol. Microbiol. 1985;9:15–18. doi: 10.1111/j.1600-0897.1985.tb00334.x.
    1. Kozma N., Halasz M., Polgar B., Poehlmann T.G., Markert U.R., Palkovics T., Keszei M., Par G., Kiss K., Szeberenyi J., et al. Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor. J. Immunol. 2006;176:819–826. doi: 10.4049/jimmunol.176.2.819.
    1. Szekeres-Bartho J., Wegmann T.G. A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J. Reprod. Immunol. 1996;31:81–95. doi: 10.1016/0165-0378(96)00964-3.
    1. Raghupathy R., Al-Mutawa E., Al-Azemi M., Makhseed M., Azizieh F., Szekeres-Bartho J. Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J. Reprod. Immunol. 2009;80:91–99. doi: 10.1016/j.jri.2009.01.004.
    1. Arck P., Hansen P.J., Mulac Jericevic B., Piccinni M.P., Szekeres-Bartho J. Progesterone during pregnancy: Endocrine-immune cross talk in mammalian species and the role of stress. Am. J. Reprod. Immunol. 2007;58:268–279. doi: 10.1111/j.1600-0897.2007.00512.x.
    1. Cottrell J.N., Witcher A.C., Comley K., Cunningham M.W., Jr., Ibrahim T., Cornelius D.C., LaMarca B., Amaral L.M. Progesterone-induced blocking factor improves blood pressure, inflammation, and pup weight in response to reduced uterine perfusion pressure (RUPP) Am. J. Physiol. Regul. Integr. Comp. Physiol. 2021;320:R719–R727. doi: 10.1152/ajpregu.00152.2020.
    1. Lim M.K., Ku C.W., Tan T.C., Lee Y.H.J., Allen J.C., Tan N.S. Characterisation of serum progesterone and progesterone-induced blocking factor (PIBF) levels across trimesters in healthy pregnant women. Sci. Rep. 2020;10:3840. doi: 10.1038/s41598-020-59452-y.
    1. Check J.H., Levin E., Bollendorf A., Locuniak J. Miscarriage in the first trimester according to the presence or absence of the progesterone-induced blocking factor at three to five weeks from conception in progesterone supplemented women. Clin. Exp. Obstet. Gynecol. 2005;32:13–14.
    1. Liang Q., Tong L., Xiang L., Shen S., Pan C., Liu C., Zhang H. Correlations of the expression of γδ T cells and their co-stimulatory molecules TIGIT, PD-1, ICOS and BTLA with PR and PIBF in the peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion. Clin. Exp. Immunol. 2021;203:55–65. doi: 10.1111/cei.13534.
    1. Kalinka J., Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am. J. Reprod. Immunol. 2005;53:166–171. doi: 10.1111/j.1600-0897.2005.00261.x.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner