Progesterone and Treatment for Preterm Birth: Past, Present and Future

Article ID: e190822207731 Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality in the United States and worldwide. Efforts to predict and delay preterm birth have been largely unsuccessful thus far. This paper seeks to illuminate the history and relevant discoveries regarding the role of progesterone in the prevention of PTB, which includes maintaining quiescence of the myometrium and counteracting cervical ripening. We will review the outcomes and methodologies of recent clinical trials, which have led to debate over the efficacy of progesterone in delaying PTB among at-risk women. The aim of this paper is to explore the historical and scientific basis for progestin treatments in the prevention of PTB, briefly discuss the results of recent clinical trials, and suggest direction for future research.

Keywords: preterm birth, labor, progesterone, progestin, trimegestone, uterine myometrium, cervix

[1]
Martin, J.A.; Hamilton, B.E.; Osterman, M.J.K.; Driscoll, A.K. Births: Final data for 2018. Natl. Vital Stat. Rep., 2019, 68(13), 1-47.
[PMID: 32501202]
[2]
Blencowe, H.; Cousens, S.; Oestergaard, M.Z.; Chou, D.; Moller, A.B.; Narwal, R.; Adler, A.; Vera Garcia, C.; Rohde, S.; Say, L.; Lawn, J.E. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: A systematic analysis and implications. Lancet, 2012, 379(9832), 2162-2172.
[http://dx.doi.org/10.1016/S0140-6736(12)60820-4] [PMID: 22682464]
[3]
WHO. March of dimes, partnership for maternal, newborn & child health, save the children. Born too soon: The global action report on preterm birth. WHO , 2012; pp. 24-30. Available from: www.who.int/maternal_child_adolescent/docu- ments/born_too_soon/en/
[4]
Mitchell, B.F.; Aguilar, H.N.; Mosher, A.; Wood, S.; Slater, D.M. The uterine myocyte as a target for prevention of preterm birth. Facts Views Vis. ObGyn, 2013, 5(1), 72-81.
[PMID: 24753931]
[5]
ACOG. Practice bulletin no 171: Management of preterm labor. 2016, 128(4), 155-164.
[6]
Csapo, A.I.; Corner, G.W. The antagonistic effects of estrogen and progesterone on the staircase phenomenon in uterine muscle. Endocrinology, 1952, 51(5), 378-385.
[http://dx.doi.org/10.1210/endo-51-5-378] [PMID: 13010191]
[7]
Hajdu, S.; Szent-Gyorgyi, A. Action of digitalis glucosides on isolated frog heart. Am. J. Physiol., 1952, 168(1), 171-175.
[http://dx.doi.org/10.1152/ajplegacy.1951.168.1.171] [PMID: 14903125]
[8]
Goto, M.; Csapo, A. The effect of the ovarian steroids on the membrane potential of uterine muscle. J. Gen. Physiol., 1959, 43(2), 455-466.
[http://dx.doi.org/10.1085/jgp.43.2.455] [PMID: 13851418]
[9]
Matthews, S.G.; Gibb, W.; Lye, S.J.; Lye, S.J. Endocrine and paracrine regulation of birth at term and preterm. Endocr. Rev., 2000, 21(5), 514-550.
[http://dx.doi.org/10.1210/er.21.5.514] [PMID: 11041447]
[10]
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.
[http://dx.doi.org/10.1210/me.2005-0243] [PMID: 16484338]
[11]
Garfield, R.E.; Sims, S.; Daniel, E.E. Gap junctions: Their presence and necessity in myometrium during parturition. Science, 1977, 198(4320), 958-960.
[http://dx.doi.org/10.1126/science.929182] [PMID: 929182]
[12]
Garfield, R.E.; Hayashi, R.H.; Harper, M.J.K. In vitro studies on the control of human myometrial gap junctions. Int. J. Gynecol. Obstet., 1987, 241-248.
[13]
Mahendroo, M. Cervical remodeling in term and preterm birth: Insights from an animal model. Reproduction, 2012, 143(4), 429-438.
[http://dx.doi.org/10.1530/REP-11-0466] [PMID: 22344465]
[14]
Ekman-Ordeberg, G.; Dubicke, A. Preterm cervical ripening in humans. Facts Views Vis. ObGyn, 2012, 4(4), 245-253.
[PMID: 24753916]
[15]
Sennström, M.B.; Ekman, G.; Westergren-Thorsson, G.; Malmström, A.; Byström, B.; Endrésen, U.; Mlambo, N.; Norman, M.; Ståbi, B.; Brauner, A. Human cervical ripening, an inflammatory process mediated by cytokines. Mol. Hum. Reprod., 2000, 6(4), 375-381.
[http://dx.doi.org/10.1093/molehr/6.4.375] [PMID: 10729321]
[16]
Anbe, H.; Okawa, T.; Sugawara, N.; Takahashi, H.; Sato, A.; Vedernikov, Y.P.; Saade, G.R.; Garfield, R.E. Influence of progesterone on myometrial contractility in pregnant mice treated with lipopolysaccharide. J. Obstet. Gynaecol. Res., 2007, 33(6), 765-771.
[http://dx.doi.org/10.1111/j.1447-0756.2007.00653.x] [PMID: 18001439]
[17]
Attardi, B.J.; Zeleznik, A.; Simhan, H.; Chiao, J.P.; Mattison, D.R.; Caritis, S.N. Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins. Am. J. Obstet. Gynecol., 2007, 197(6), 599.e1-599.e7.
[http://dx.doi.org/10.1016/j.ajog.2007.05.024] [PMID: 18060946]
[18]
Meis, P.J.M.D.; Klebanoff, M.M.D.; Thom, E.P.D.; Dombrowski, M.P.M.D.; Sibai, B.M.D.; Moawad, A.H.M.D.; Spong, C.Y.M.D.; Hauth, J.C.M.D.; Miodovnik, M.M.D.; Varner, M.W.M.D.; Leveno, K.J.M.D.; Caritis, S.N.M.D.; Iams, J.D.M.D.; Wapner, R.J.M.D.; Conway, D.M.D.; O’Sullivan, M.J.M.D.; Carpenter, M.M.D.; Mercer, B.M.D.; Ramin, S.M.M.D. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N. Engl. J. Med., 2003, 348(24), 2379-2385.
[http://dx.doi.org/10.1056/NEJMoa035140] [PMID: 12802023]
[19]
Grobman, W.A.; Thom, E.A.; Spong, C.Y.; Iams, J.D.; Saade, G.R.; Mercer, B.M.; Tita, A.T.N.; Rouse, D.J.; Sorokin, Y.; Wapner, R.J.; Leveno, K.J.; Blackwell, S.; Esplin, M.S.; Tolosa, J.E.; Thorp, J.M., Jr; Caritis, S.N.; Van Dorsten, J.P. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am. J. Obstet. Gynecol., 2012, 207(5), 390.e1-390.e8.
[http://dx.doi.org/10.1016/j.ajog.2012.09.013] [PMID: 23010094]
[20]
Martinez de Tejada, B.; Karolinski, A.; Ocampo, M.C.; Laterra, C.; Hösli, I.; Fernández, D.; Surbek, D.; Huespe, M.; Drack, G.; Bunader, A.; Rouillier, S.; López de Degani, G.; Seidenstein, E.; Prentl, E.; Antón, J.; Krähenmann, F.; Nowacki, D.; Poncelas, M.; Nassif, J.C.; Papera, R.; Tuma, C.; Espoile, R.; Tiberio, O.; Breccia, G.; Messina, A.; Peker, B.; Schinner, E.; Mol, B.W.; Kanterewicz, L.; Wainer, V.; Boulvain, M.; Othenin-Girard, V.; Bertolino, M.V.; Irion, O. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): Randomised double-blind placebo-controlled trial. BJOG, 2015, 122(1), 80-91.
[http://dx.doi.org/10.1111/1471-0528.13061] [PMID: 25209926]
[21]
Norman, J.E.; Marlow, N.; Messow, C.M.; Shennan, A.; Bennett, P.R.; Thornton, S.; Robson, S.C.; McConnachie, A.; Petrou, S.; Sebire, N.J.; Lavender, T.; Whyte, S.; Norrie, J. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): A multicentre, randomised, double-blind trial. Lancet, 2016, 387(10033), 2106-2116.
[http://dx.doi.org/10.1016/S0140-6736(16)00350-0] [PMID: 26921136]
[22]
Romero, R.; Nicolaides, K.H.; Conde-Agudelo, A.; O’Brien, J.M.; Cetingoz, E.; Da Fonseca, E.; Creasy, G.W.; Hassan, S.S. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: An updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet. Gynecol., 2016, 48(3), 308-317.
[http://dx.doi.org/10.1002/uog.15953] [PMID: 27444208]
[23]
Blackwell, S.C.; Gyamfi-Bannerman, C.; Biggio, J.R., Jr; Chauhan, S.P.; Hughes, B.L.; Louis, J.M.; Manuck, T.A.; Miller, H.S.; Das, A.F.; Saade, G.R.; Nielsen, P.; Baker, J.; Yuzko, O.M.; Reznichenko, G.I.; Reznichenko, N.Y.; Pekarev, O.; Tatarova, N.; Gudeman, J.; Birch, R.; Jozwiakowski, M.J.; Duncan, M.; Williams, L.; Krop, J. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG Study): A multicenter, international, randomized double-blind trial. Am. J. Perinatol., 2020, 37(2), 127-136.
[http://dx.doi.org/10.1055/s-0039-3400227] [PMID: 31652479]
[24]
Kuon, R.J.; Shi, S.Q.; Maul, H.; Sohn, C.; Balducci, J.; Maner, W.L.; Garfield, R.E. Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle. Am. J. Obstet. Gynecol., 2010, 202(5), 455.e1-455.e9.
[http://dx.doi.org/10.1016/j.ajog.2010.03.025] [PMID: 20452487]
[25]
Boelig, R.C.; Zuppa, A.F.; Kraft, W.K.; Caritis, S. Pharmacokinetics of vaginal progesterone in pregnancy. Am. J. Obstet. Gynecol., 2019, 221(3), 263.e1-263.e7.
[http://dx.doi.org/10.1016/j.ajog.2019.06.019] [PMID: 31211965]
[26]
Garfield, R.E.; Shi, L.; Shi, S-Q. Use of progesterone and progestin analogs for inhibition of preterm birth and other uterine contractility disorders. Facts Views Vis. ObGyn, 2012, 4(4), 237-244.
[PMID: 24753915]
[27]
Fang, D.; Moreno, M.; Garfield, R.E.; Kuon, R.; Xia, H. Optimal routes of administration, vehicles and timing of progesterone treatment for inhibition of delivery during pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol., 2017, 216, 164-168.
[http://dx.doi.org/10.1016/j.ejogrb.2017.06.004] [PMID: 28777967]
[28]
Ruddock, N.K.; Shi, S.Q.; Jain, S.; Moore, G.; Hankins, G.D.V.; Romero, R.; Garfield, R.E. Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions. Am. J. Obstet. Gynecol., 2008, 199(4), 391.e1-391.e7.
[http://dx.doi.org/10.1016/j.ajog.2008.06.085] [PMID: 18928984]
[29]
Sexton, D.J.; O’Reilly, M.W.; Friel, A.M.; Morrison, J.J. Functional effects of 17alpha-hydroxyprogesterone caproate (17P) on human myometrial contractility in vitro. Reprod. Biol. Endocrinol., 2004, 2(1), 80.
[http://dx.doi.org/10.1186/1477-7827-2-80] [PMID: 15585068]
[30]
Norwitz, E.R.; Robinson, J.N.; Challis, J.R. The control of labor. N. Engl. J. Med., 1999, 341(9), 660-666.
[http://dx.doi.org/10.1056/NEJM199908263410906] [PMID: 10460818]
[31]
Lucovnik, M.; Novak-Antolic, Z.; Garfield, R.E. Use of non-invasive uterine electromyography in the diagnosis of preterm labour. Facts Views Vis. ObGyn, 2012, 4(1), 66-72.
[PMID: 24753891]
[32]
Garfield, Robert E Diagnosis and effective management of preterm labor. MGM J. Med. Sci., 2014, 1(1), 22-37.
[http://dx.doi.org/10.5005/jp-journals-10036-1005]
[33]
Lucovnik, M.; Trojner Bregar, A.; Bombac, L.; Gersak, K.; Garfield, R.E. Effects of vaginal progesterone for maintenance tocolysis on uterine electrical activity. J. Obstet. Gynaecol. Res., 2018, 44(3), 408-416.
[http://dx.doi.org/10.1111/jog.13545] [PMID: 29297950]
[34]
Shynlova, O.; Nadeem, L.; Zhang, J.; Dunk, C.; Lye, S. Myometrial activation: Novel concepts underlying labor. Placenta, 2020, 92, 28-36.
[http://dx.doi.org/10.1016/j.placenta.2020.02.005]
[35]
Vegeto, E.; Shahbaz, M.M.; Wen, D.X.; Goldman, M.E.; O’Malley, B.W.; McDonnell, D.P. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol. Endocrinol., 1993, 7(10), 1244-1255.
[http://dx.doi.org/10.1210/mend.7.10.8264658] [PMID: 8264658]
[36]
Pieber, D.; Allport, V.C.; Hills, F.; Johnson, M.; Bennett, P.R. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol. Hum. Reprod., 2001, 7(9), 875-879.
[http://dx.doi.org/10.1093/molehr/7.9.875] [PMID: 11517295]
[37]
Mesiano, S.; Chan, E.C.; Fitter, J.T.; Kwek, K.; Yeo, G.; Smith, R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J. Clin. Endocrinol. Metab., 2002, 87(6), 2924-2930.
[http://dx.doi.org/10.1210/jcem.87.6.8609] [PMID: 12050275]
[38]
Mansour, D. Use of the new progestogens in contraception and gynaecology. Obstet. Gynaecol., 2006, 8(4), 229-234.
[http://dx.doi.org/10.1576/toag.8.4.229.27272]
[39]
Bouchoux, F.; Cerede, E.; Philibert, D. Measurement of the relative binding affinity of RU27987 to recombinant human steroid receptors: Progestogen, glucocorticoid, androgen and estrogen. Determination of the binding parameters of RU27987 and progesterone for the recombinant human progesterone receptor. 93/5353/PH. Data on file at Roussel-Uclaf; Romainville: France, 1995.
[40]
Kuhl, H. Pharmacology of estrogens and progestogens: Influence of different routes of administration. Climacteric, 2005, 8(1), 3-63.
[http://dx.doi.org/10.1080/13697130500148875] [PMID: 16112947]
[41]
Winneker, R.C.; Bitran, D.; Zhang, Z. The preclinical biology of a new potent and selective progestin. Trimegestone. Steroids, 2003, 68(10-13), 915-920.
[http://dx.doi.org/10.1016/S0039-128X(03)00142-9] [PMID: 14667983]
[42]
Zhang, Z.; Lundeen, S.G.; Zhu, Y.; Carver, J.M.; Winneker, R.C. In vitro characterization of trimegestone: A new potent and selective progestin. Steroids, 2000, 65(10-11), 637-643.
[http://dx.doi.org/10.1016/S0039-128X(00)00120-3] [PMID: 11108870]
[43]
Doherty, M.A. Annual Reports in Medicinal Chemistry; Amsterdam, Netherlands: Elsevier, 2002, p. 273.
[44]
Grubb, G.; Spielmann, D.; Pickar, J.; Constantine, G. Clinical experience with trimegestone as a new progestin in HRT. Steroids, 2003, 68(10-13), 921-926.
[http://dx.doi.org/10.1016/j.steroids.2003.09.001] [PMID: 14667984]
[45]
Duijkers, I.J.M.; Klipping, C.; Draeger, C.; Schug, B.S.; Dax, A.; Friedrich, M.; Nickisch, K. Ovulation inhibition with a new vaginal ring containing trimegestone. Contraception, 2020, 102(4), 237-242.
[http://dx.doi.org/10.1016/j.contraception.2020.06.006] [PMID: 32569678]
[46]
Sitruk-Ware, R.; Bossemeyer, R.; Bouchard, P. Preclinical and clinical properties of trimegestone: A potent and selective progestin. Gynecol. Endocrinol., 2007, 23(6), 310-319.
[http://dx.doi.org/10.1080/09513590701267727] [PMID: 17616854]
[47]
Nelson, D.B.; McIntire, D.D.; McDonald, J.; Gard, J.; Turrichi, P.; Leveno, K.J. 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am. J. Obstet. Gynecol., 2017, 216(6), 600.e1-600.e9.
[http://dx.doi.org/10.1016/j.ajog.2017.02.025] [PMID: 28223163]
[48]
Facchinetti, F.; Paganelli, S.; Comitini, G.; Dante, G.; Volpe, A. Cervical length changes during preterm cervical ripening: Effects of 17-α-hydroxyprogesterone caproate. Am. J. Obstet. Gynecol., 2007, 196(5), 453.e1-453.e4.
[http://dx.doi.org/10.1016/j.ajog.2006.09.009] [PMID: 17466698]
[49]
Facchinetti, F.; Vergani, P.; Di Tommaso, M.; Marozio, L.; Acaia, B.; Vicini, R.; Pignatti, L.; Locatelli, A.; Spitaleri, M.; Benedetto, C.; Zaina, B.; DʼAmico, R. Progestogens for maintenance tocolysis in women with a short cervix. Obstet. Gynecol., 2017, 130(1), 64-70.
[http://dx.doi.org/10.1097/AOG.0000000000002065] [PMID: 28594783]
[50]
Da Fonseca, E.B.; Bittar, R.E.; Carvalho, M.H.B.; Zugaib, M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study. Am. J. Obstet. Gynecol., 2003, 188(2), 419-424.
[http://dx.doi.org/10.1067/mob.2003.41]
[51]
Fonseca, E.B.; Celik, E.; Parra, M.; Singh, M.; Nicolaides, K.H. Progesterone and the risk of preterm birth among women with a short cervix. N. Engl. J. Med., 2007, 357(5), 462-469.
[http://dx.doi.org/10.1056/NEJMoa067815] [PMID: 17671254]
[52]
O’Brien, J.M.; Adair, C.D.; Lewis, D.F.; Hall, D.R.; Defranco, E.A.; Fusey, S.; Soma-Pillay, P.; Porter, K.; How, H.; Schackis, R.; Eller, D.; Trivedi, Y.; Vanburen, G.; Khandelwal, M.; Trofatter, K.; Vidyadhari, D.; Vijayaraghavan, J.; Weeks, J.; Dattel, B.; Newton, E.; Chazotte, C.; Valenzuela, G.; Calda, P.; Bsharat, M.; Creasy, G.W. Progesterone vaginal gel for the reduction of recurrent preterm birth: Primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet. Gynecol., 2007, 30(5), 687-696.
[http://dx.doi.org/10.1002/uog.5158] [PMID: 17899572]
[53]
Hassan, S.S.; Romero, R.; Vidyadhari, D.; Fusey, S.; Baxter, J.K.; Khandelwal, M.; Vijayaraghavan, J.; Trivedi, Y.; Soma-Pillay, P.; Sambarey, P.; Dayal, A.; Potapov, V.; O’Brien, J.; Astakhov, V.; Yuzko, O.; Kinzler, W.; Dattel, B.; Sehdev, H.; Mazheika, L.; Manchulenko, D.; Gervasi, M.T.; Sullivan, L.; Conde-Agudelo, A.; Phillips, J.A.; Creasy, G.W. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: A multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet. Gynecol., 2011, 38(1), 18-31.
[http://dx.doi.org/10.1002/uog.9017] [PMID: 21472815]