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Myometrial Progesterone Responsiveness and the Control of Human Parturition

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Abstract

Objective

The goal of this review is to assess the body of literature addressing the mechanism of progesterone withdrawal in the control of human parturition and in particular the recent advances in testing the hypothesis that human parturition is initiated by decreased myometrial responsiveness to progesterone, ie, functional progesterone withdrawal.

Methods

Published studies of progesterone responsiveness of the pregnant human myometrium in the context of parturition control were reviewed.

Results

Advances in understanding the molecular basis for progesterone receptor (PR)-mediated control of progesterone responsiveness has led to the hypothesis that functional progesterone withdrawal in human parturition is mediated by specific changes in myometrial PR expression, function, or both. The human PR exists as two major subtypes, PR-A and PR-B. As PR-A represses progesterone actions mediated by PR-B, the extent of progesterone responsiveness is inversely related to the PR-A/PR-B expression ratio. In women, the onset of term labor is associated with a significant increase in the myometrial PR-A/PR-B expression ratio that may facilitate functional progesterone withdrawal. Interestingly, expression of the estrogen receptor-α (ERα) increases concor-dantly with the PR-A/PR-B expression ratio in nonlaboring myometrium. This finding indicates that functional estrogen activation and functional progesterone withdrawal are linked.

Conclusion

Functional progesterone withdrawal in human parturition is likely mediated by an increase in the myometrial PR-A/PR-B expression ratio and possibly by modulation of coactivator and corepressor proteins. Functional progesterone withdrawal appears to induce functional estrogen activation. Thus, for most of pregnancy, progesterone may decrease myometrial estrogen responsiveness by inhibiting ERα expression. Such an interaction would explain why the human myometrium is refractory to the high levels of circulating estrogens for most of pregnancy. At term, functional progesterone withdrawal removes the suppression of ERa expression leading to an increase in ERα and a concomitant increase in myometrial estrogen responsiveness. Estrogen can then act to transform the myometrium to a contractile phenotype. This model explains why disruption of progesterone action alone triggers the full parturition cascade. The link between functional progesterone withdrawal and functional estrogen activation may be a critical mechanism for the endocrine control of human parturition.

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References

  1. Csapo A. Progesterone “block.” Am J Anat 1956;98:273–92.

    Article  CAS  PubMed  Google Scholar 

  2. Young IR. The comparative physiology of parturition in mammals. Front Horm Res 2001;27:10–30.

    Article  CAS  PubMed  Google Scholar 

  3. Liggins GC. Endocrinology of parturition. In: Novy MJ, Resko JA, eds. Fetal endocrinology. New York: Academic Press, Inc, 1981:211–37.

    Chapter  Google Scholar 

  4. Liggins GC, Fairclough RJ, Grieves SA, Kendall JZ, Knox BS. The mechanism of initiation of parturition in the ewe. Recent Prog Horm Res 1973;29:111–59.

    CAS  PubMed  Google Scholar 

  5. Challis JRG, Lye SJ. Parturition. In: Knobil E, Neil JD, eds. The physiology of reproduction. New York: Raven Press, 1994:985–1031.

    Google Scholar 

  6. Tulchinsky D, Hobel CJ, Yeager E, Marshall JR. Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. Am J Obstet Gynecol 1972;112:1095–100.

    Article  CAS  PubMed  Google Scholar 

  7. Walsh SW, Stanczyk FZ, Novy MJ. Daily hormonal changes in the maternal, fetal, and amniotic fluid compartments before parturition in a primate species. J Clin Endocrinol Metab 1984;58:629–39.

    Article  CAS  PubMed  Google Scholar 

  8. Boroditsky RS, Reyes FI, Winter JS, Faiman C. Maternal serum estrogen and progesterone concentrations preceding normal labor. Obstet Gynecol 1978;51:686–91.

    CAS  PubMed  Google Scholar 

  9. Haluska GJ, Cook MJ, Novy MJ. Inhibition and augmentation of progesterone production during pregnancy: Effect on parturition in rhesus monkeys. Am J Obstet Gynecol 1997;176:682–91.

    Article  CAS  PubMed  Google Scholar 

  10. Selinger M, MacKenzie IZ, Gillmer MD, Phipps SL, Ferguson J. Progesterone inhibition in mid-trimester termination of pregnancy: Physiological and clinical effects. Br J Obstet Gynaecol 1987;94:1218–22.

    Article  CAS  PubMed  Google Scholar 

  11. Evans JJ, Sin IL, White FJ. Progesterone-binding globulin and progesterone in guinea-pigs after ovariectomy, abortion and parturition. J Steroid Biochem 1982;16:171–3.

    Article  CAS  PubMed  Google Scholar 

  12. Lea OA, Bessesen A, Stoa KF. Progesterone-binding globulin and testosterone-binding activity in guinea pig serum during pregnancy: Relationship to progesterone and oestrogens. Acta Endocrinol (Copenh) 1976;81:367–78.

    Article  CAS  Google Scholar 

  13. Westphal U, Stroupe SD, Kute T, Cheng SL. Steroid interactions with progesterone-binding globulin. J Steroid Biochem 1977;8:367–74.

    Article  CAS  PubMed  Google Scholar 

  14. Benassayag C, Souski I, Mignot TM, et al. Corticosteroid-binding globulin status at the fetomaternal interface during human term pregnancy. Biol Reprod 2001;64:812–21.

    Article  CAS  PubMed  Google Scholar 

  15. Wuu J, Hellerstein S, Lipworth L, et al. Correlates of pregnancy oestrogen, progesterone and sex hormone-binding globulin in the USA and China. Eur J Cancer Prev 2002;11:283–93.

    Article  CAS  PubMed  Google Scholar 

  16. Evans JJ, Sin IL, Duff GB, Frampton CM. Estrogen-induced transcortin increase and progesterone and Cortisol interactions: Implications from pregnancy studies. Ann Clin Lab Sci 1987;17:101–5.

    CAS  PubMed  Google Scholar 

  17. Mitchell BF, Wong S. Changes in 17 beta,20 alpha-hydroxy-steroid dehydrogenase activity supporting an increase in the estrogen/progesterone ratio of human fetal membranes at parturition. Am J Obstet Gynecol 1993;168:1377–85.

    CAS  PubMed  Google Scholar 

  18. Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol 1999;13:981–92.

    CAS  PubMed  Google Scholar 

  19. Mahendroo MS, Cala KM, Russell DW. 5 Alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol 1996;10:380–92.

    CAS  PubMed  Google Scholar 

  20. Robinson BG, Emanuel RL, Frim DM, Majzoub JA. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA 1988;85:5244–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Karalis K, Majzoub JA. Regulation of placental corticotropin-releasing hormone by steroids. Possible implications in labor initiation. Ann N Y Acad Sci 1995;771:551–5.

    Article  CAS  PubMed  Google Scholar 

  22. Karalis K, Goodwin G, Majzoub JA. Cortisol blockade of progesterone: A possible molecular mechanism involved in the initiation of human labor. Nat Med 1996;2:556–60.

    Article  CAS  PubMed  Google Scholar 

  23. Cheng YH, Nicholson RC, King B, Chan EC, Fitter JT, Smith R. Glucocorticoid stimulation of corticotropin-releasing hormone gene expression requires a cyclic adenosine 3′,5′ monophosphate regulatory element in human primary placental cytotrophoblast cells. J Clin Endocrinol Metab 2000;85:1937–45.

    CAS  PubMed  Google Scholar 

  24. King BR, Smith R, Nicholson RC. Novel glucocorticoid and cAMP interactions on the CRH gene promoter. Mol Cell Endocrinol 2002;194:19–28.

    Article  CAS  PubMed  Google Scholar 

  25. Henderson D, Wilson T. Reduced binding of progesterone receptor to its nuclear response element after human labor onset. Am J Obstet Gynecol 2001;185:579–85.

    Article  CAS  PubMed  Google Scholar 

  26. Condon JC, Jeyasuria P, Faust JM, Wilson JW, Mendelson CR. A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc Natl Acad Sci U S A 2003;100:9518–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bernard A, Duffek L, Torok I, Kosa Z. Progesterone and oestradiol levels and cytoplasmic receptor concentrations in the human myometrium at term, before labour and during labour. Acta Physiol Hung 1988;71:507–10.

    CAS  PubMed  Google Scholar 

  28. Giannopoulos G, Tulchinsky D. Cytoplasmic and nuclear progestin receptors in human myometrium during the menstrual cycle and in pregnancy at term. J Clin Endocrinol Metab 1979;49:100–6.

    Article  CAS  PubMed  Google Scholar 

  29. How H, Huang ZH, Zuo J, Lei ZM, Spinnato JA, Rao CV. Myometrial estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet Gynecol 1995;86:936–40.

    Article  CAS  PubMed  Google Scholar 

  30. Khan-Dawood FS, Dawood MY. Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy. Am J Obstet Gynecol 1984;150:501–5.

    CAS  PubMed  Google Scholar 

  31. Mesiano S, Chan EC, Fitter JT, 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;87:2924–30.

    Article  CAS  PubMed  Google Scholar 

  32. Padayachi T, Pegoraro RJ, Rom L, Joubert SM. Enzyme immunoassay of oestrogen and progesterone receptors in uterine and intrauterine tissue during human pregnancy and labour. J Steroid Biochem Mol Biol 1990;37:509–11.

    Article  CAS  PubMed  Google Scholar 

  33. Pieber D, Allport VC, Hills F, Johnson M, Bennett PR. Interaction between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod 2001;7:875–9.

    Article  CAS  PubMed  Google Scholar 

  34. Winkler M, Kemp B, Classen-Linke I, et al. Estrogen receptor alpha and progesterone receptor A and B concentration and localization in the lower uterine segment in term parturition. J Soc Gynecol Investig 2002;9:226–32.

    CAS  PubMed  Google Scholar 

  35. Rezapour M, Backstrom T, Lindblom B, Ulmsten U. Sex steroid receptors and human parturition. Obstet Gynecol 1997;89:918–24.

    Article  CAS  PubMed  Google Scholar 

  36. Haluska GJ, Wells TR, Hirst JJ, Brenner RM, Sadowsky DW, Novy MJ. Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: Evidence for functional progesterone withdrawal at parturition. J Soc Gynecol Investig 2002;9:125–36.

    CAS  PubMed  Google Scholar 

  37. Roh CR, Lee BL, Oh WJ, et al. Induction of c-Jun mRNA without changes of estrogen and progesterone receptor expression in myometrium during human labor. J Korean Med Sci 1999;14:552–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Evans R. The steroid and thyroid receptor superfamily. Science 1988;240:889–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bouchard P. Progesterone and the progesterone receptor. J Reprod Med 1999;44:153–7.

    CAS  PubMed  Google Scholar 

  40. Chauchereau A, Savouret JF, Milgrom E. Control of biosynthesis and post-transcriptional modification of the progesterone receptor. Biol Reprod 1992;46:174–7.

    Article  CAS  PubMed  Google Scholar 

  41. Giangrande PH, McDonnell DP. The A and B isoforms of the human progesterone receptor: Two functionally different transcription factors encoded by a single gene. Recent Prog Horm Res 1999;54:291–313.

    CAS  PubMed  Google Scholar 

  42. Conneely OM, Lydon JP. Progesterone receptors in reproduction: Functional impact of the A and B isoforms. Steroids 2000;65:571–7.

    Article  CAS  PubMed  Google Scholar 

  43. Horwitz KB, Alexander PS. In situ photolinked nuclear progesterone receptor of human breast cancer cells: Subunit molecular weights after transformation and translocation. Endocrinology 1983;113:2195–201.

    Article  CAS  PubMed  Google Scholar 

  44. Krett NL, Wei LL, Francis MD, et al. Human progesterone A-receptors can be synthesized intracellularly and are biologically functional. Biochem Biophys Res Commun 1988;157:278–85.

    Article  CAS  PubMed  Google Scholar 

  45. Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990;9:1603–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hisatomi H, Kohno N, Wakita K, et al. Novel alternatively spliced variant with a deletion of 52 BP in exon 6 of the progesterone receptor gene is observed frequently in breast cancer tissues. Int J Cancer 2003;105:182–5.

    Article  CAS  PubMed  Google Scholar 

  47. Hirata S, Shoda T, Kato J, Hoshi K. The novel isoform of the progesterone receptor cDNA in the human testis and detection of its mRNA in the human uterine endometrium. Oncology 2000; 59(Suppl 1):39–44.

    Article  CAS  PubMed  Google Scholar 

  48. Hirata S, Shoda T, Kato J, Hoshi K. The novel exon, exon T, of the human progesterone receptor gene and the genomic organization of the gene. J Steroid Biochem Mol Biol 2002;80:365–7.

    Article  CAS  PubMed  Google Scholar 

  49. Yamanaka T, Hirata S, Shoda T, Hoshi K. Progesterone receptor mRNA variant containing novel exon insertions between exon 4 and exon 5 in human uterine endometrium. Endocr J 2002;49:473–82.

    Article  CAS  PubMed  Google Scholar 

  50. Saner KJ, Welter BH, Zhang F, et al. Cloning and expression of a novel, truncated, progesterone receptor. Mol Cell Endocrinol 2003;200:155–63.

    Article  CAS  PubMed  Google Scholar 

  51. Wei LL, Gonzalez-Aller C, Wood WM, Miller LA, Horwitz KB. 5′-Heterogeneity in human progesterone receptor transcripts predicts a new amino-terminal truncated “C”-receptor and unique A-receptor messages. Mol Endocrinol 1990;4:1833–40.

    Article  CAS  PubMed  Google Scholar 

  52. Zhu Y, Rice CD, Pang Y, Pace M, Thomas P. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci U S A 2003;100:2231–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sartorius CA, Melville MY, Hovland AR, Tung L, Takimoto GS, Horwitz KB. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol 1994;8:1347–60.

    CAS  PubMed  Google Scholar 

  54. Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, Horwitz KB. Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors. Mol Endocrinol 1993;7:1256–65.

    CAS  PubMed  Google Scholar 

  55. Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 2000;20:3102–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O’Malley BW, McDonnell DP. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 1993;7:1244–55.

    CAS  PubMed  Google Scholar 

  57. Cermik D, Karaca M, Taylor HS. HOXA10 expression is repressed by progesterone in the myometrium: Differential tissue-specific regulation of HOX gene expression in the reproductive tract. J Clin Endocrinol Metab 2001;86:3387–92.

    CAS  PubMed  Google Scholar 

  58. Leavitt WW, Cobb AD, Takeda A. Progesterone modulation of estrogen action: Rapid downregulation of nuclear receptor sites for the estrogen receptor. In: Leavitt W, ed. Advances in experimental medicine and biology. New York: Plenum, 1987:49–78.

    Google Scholar 

  59. Kalkhoven E, Wissink S, van der Saag PT, van der Burg B. Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J Biol Chem 1996;271:6217–24.

    Article  CAS  PubMed  Google Scholar 

  60. Allport VC, Pieber D, Slater DM, Newton R, White JO, Bennett PR. Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the ‘functional progesterone withdrawal’. Mol Hum Reprod 2001;7:581–6.

    Article  CAS  PubMed  Google Scholar 

  61. Madsen G, Zakar T, Ku CY, Sanborn BM, 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;80:1010–3.

    Article  CAS  Google Scholar 

  62. Embrey M. PGE compounds for induction of labor and abortion. Annals N Y Acad Sci 1971;180:518–23.

    Article  CAS  Google Scholar 

  63. Thiery J. Induction of labor with prostaglandins. In: Keirse M, Anderson A, Benebroek-Gravenhorst J, eds. Human parturition. The Hague: Martinus Nijhoff, 1979:155–64.

    Chapter  Google Scholar 

  64. Sugimoto Y, Yamasaki A, Segi E, et al. Failure of parturition in mice lacking the prostaglandin F receptor. Science 1997;277:681–3.

    Article  CAS  PubMed  Google Scholar 

  65. Elger W, Hasan SH, Friedreich E. “Uterine” and “luteal” effects of prostaglandins (PG) in rats and guinea pigs as potential abor-tifacient mechanisms. Acta Endocrinol (Copenh) 1973; 173(Suppl):46.

    Article  CAS  Google Scholar 

  66. Elger W, Hasan SG. Studies on the mechanism of action of antifertile PG in animal models. Acta Physiol Hung 1985;65:415–32.

    CAS  PubMed  Google Scholar 

  67. Challis JR, Lye SJ, Gibb W. Prostaglandins and parturition. Ann N Y Acad Sci 1997;828:254–67.

    Article  CAS  PubMed  Google Scholar 

  68. Patel FA, Challis JR. Prostaglandins and uterine activity. Front Horm Res 2001;27:31–56.

    Article  CAS  PubMed  Google Scholar 

  69. Robins J, Mann LI. Midtrimester pregnancy termination by intramuscular injection of a 15-methyl analogue of prostaglandin F2 alpha. Am J Obstet Gynecol 1975;123:625–31.

    Article  CAS  PubMed  Google Scholar 

  70. Jain JK, Mishell DR Jr. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290–3.

    Article  CAS  PubMed  Google Scholar 

  71. Monga M, Ku CY, Dodge K, Sanborn BM. Oxytocin-stimu-lated responses in a pregnant human immortalized myometrial cell line. Biol Reprod 1996;55:427–32.

    Article  CAS  PubMed  Google Scholar 

  72. Flint APP, Anderson ABM, Steele PA, Turnbull AC. The mechanism by which foetal Cortisol controls the onset of parturition in the sheep. Biochem Soc Trans 1975;3:1189–94.

    Article  CAS  Google Scholar 

  73. Tsai MJ, Clark JH, Schrader WT, O’Malley BW. Mechanisms of action of hormones that act as transcription-regulatory factors. In: Wilson J, Foster D, Kronenberg H, Larsen P, eds. Williams textbook of endocrinology. Philadelphia: WB Saunders Company, 1998:55–94.

    Google Scholar 

  74. Katzenellenbogen BS. Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J Soc Gynecol Investig 2000;7:S33–7.

    Article  CAS  PubMed  Google Scholar 

  75. Katzenellenbogen BS, Nardulli AM, Read LD. Estrogen regulation of proliferation and hormonal modulation of estrogen and progesterone receptor biosynthesis and degradation in target cells. Prog Clin Biol Res 1990;322:201–11.

    CAS  PubMed  Google Scholar 

  76. Haluska GJ, West NB, Novy MJ, Brenner RM. Uterine estrogen receptors are increased by RU486 in late pregnant rhesus macaques but not after spontaneous labor. J Clin Endocrinol Metab 1990;70:181–6.

    Article  CAS  PubMed  Google Scholar 

  77. Price HV, Cone BR, Keogh M. Length of gestation in congenital adrenal hyperplasia. J Obstet Gynecol Br Commonw 1971;78:430–4.

    Article  CAS  Google Scholar 

  78. da Fonseca EB, Bittar RE, Carvalho MH, 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;188:419–24.

    Article  PubMed  CAS  Google Scholar 

  79. Meis PJ, Klebanoff M, Thorn E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–85.

    Article  CAS  PubMed  Google Scholar 

  80. Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci U S A 2003;100:2237–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Grazzini E, Guillon G, Mouillac B, Zingg HH. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998;392:509–12.

    Article  CAS  PubMed  Google Scholar 

  82. Astle S, Khan RN, Thornton S. The effects of a progesterone metabolite, 5 beta-dihydroprogesterone, on oxytocin receptor binding in human myometrial membranes. Br J Obstet Gynecol 2003;110:589–92.

    CAS  Google Scholar 

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  1. Mothers and Babies Research Centre, University of Newcastle and John Hunter Hospital, Locked Bag 1 HRMC, Newcastle, New South Wales, 2310, Australia

    Sam Mesiano PhD

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  1. Sam Mesiano PhD
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Correspondence to Sam Mesiano PhD.

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This work was supported by the National Health and Medical Research Council of Australia, The University of Newcastle, and the Hunter Medical Research Institute.

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Mesiano, S. Myometrial Progesterone Responsiveness and the Control of Human Parturition. Reprod. Sci. 11, 193–202 (2004). https://doi.org/10.1016/j.jsgi.2003.12.004

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