Cortisol blockade of progesterone: A possible molecular mechanism involved in the initiation of human labor

Abstract

In most mammals, labor is heralded by progesterone withdrawal, which is believed to be related to the activation of multiple pathways leading to parturition. In humans, despite no decrease in placental progesterone production, activation of similar pathways preceding labor suggests the presence of an endogenous antiprogestin, which we reasoned might be cortisol, whose secretion from the fetal adrenal rises markedly at the end of human gestation. We report that in primary cultures of human placenta, cortisol is able to compete with the action of progesterone in the regulation of the corticotropinreleasing hormone (CRH) gene. CRH is a peptide highly expressed in human placenta at the end of gestation, which has been suggested to be involved in regulating the timing of parturition. These findings provide a model for functional progesterone withdrawal at the end of human pregnancy, which may be involved in the initiation of labor.

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References

  1. 1

    Csapo, A.I. The “see-saw” theory of parturition. Ciba Found. Symp. 47, 159–210 (1977).

    CAS  Google Scholar 

  2. 2

    Liggins, G.C. Mechanisms of the onset of labor: The New Zealand perspective. Aust. N. Z. J. Obstet. Gynaecol. 34, 338–342 (1994).

    CAS  Article  Google Scholar 

  3. 3

    Casey, M.L. & MacDonald, P.C. Biomolecular processes in the initiation of parturition: Decidual activation. Clin. Obstet. Gynecol. 31, 533–552 (1988).

    CAS  Article  Google Scholar 

  4. 4

    Tulchinsky, D., Hobel, C.J., Yeager, E. & Marshall, J.R. Plasma estrone, estradiol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. Am. J. Obstet. Gynecol. 112, 1095–1100 (1972).

    CAS  Article  Google Scholar 

  5. 5

    Baulieu, E.E. Contragestion and other clinical applications of RU 486, an anti-progesterone at the receptor. Science 245, 1351–1357 (1989).

    CAS  Article  Google Scholar 

  6. 6

    Lelaidier, C. et al. Mifepristone for labour induction after previous caesarean section. Br. J. Obstet. Gynaecol. 101, 501–503 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Westphal, U., Stroupe, S.D. & Cheng, S.L. Progesterone binding to serum proteins. Ann. NY Acad. Sci. 286, 10–28 (1977).

    CAS  Article  Google Scholar 

  8. 8

    Casey, M.L. & MacDonald, P.C. Human parturition: Distinction between the initiation of parturition and the onset of labor. Semin. Reprod. Endocrinol. 11, 272–284 (1993).

    Article  Google Scholar 

  9. 9

    Khan-Dawood, F.S. & Dawood, M.Y. Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy. Am. J. Obstet. Gynecol. 150, 501–505 (1984).

    CAS  Article  Google Scholar 

  10. 10

    Anderson, A.B., Flint, A.P. & Turnbull, A.C. Mechanism of action of glucocorticoids in induction of ovine parturition: Effect on placental steroid metabolism. J. Endocrinol. 66, 61–70 (1975).

    CAS  Article  Google Scholar 

  11. 11

    Fencl, M.D., Stillman, R.J., Cohen, J. & Tulchinsky, D. Direct evidence of sudden rise in fetal corticoids late in human gestation. Nature 287, 225–226 (1980).

    CAS  Article  Google Scholar 

  12. 12

    Siiteri, P.K. & MacDonald, P.C. The utilization of circulating dehydroisoandrosterone sulfate for estrogen synthesis during human pregnancy. Steroids 2, 713–730 (1963).

    CAS  Article  Google Scholar 

  13. 13

    Ryan, K.J. Maintenance of pregnancy and the initiation of labor. in Maternal-Fetal Endocrinology (eds. Tulchinsky, D. & Ryan, K. J.) 297–309 (Saunders, Philadelphia, 1980).

    Google Scholar 

  14. 14

    Jahn, G.A., Houbedine, L.-M. & Djiane, J. Antiprogesterone and antiglucocorticoid actions of RU 486 on rabbit mammary explant cultures: Evidence for a persistent inhibitory action of residual progesterone upon the mammary tissue. J. Steroid Biochem. 28, 371–377 (1987).

    CAS  Article  Google Scholar 

  15. 15

    Nordeen, S.K., Kuhnel, B., Lawler-Heavner, J., Barber, D.A. & Edwards, D.P. A quantitative comparison of dual control of a hormone response element by progestins and glucocorticoids in the same cell line. Mol. Endocrinol. 3, 1270–1278 (1989).

    CAS  Article  Google Scholar 

  16. 16

    Vale, W., Spiess, J. & Rivier, C., Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotrophin and beta-endorphin. Science 213, 1394–1397 (1981).

    CAS  Article  Google Scholar 

  17. 17

    Frim, D., Emanuel, R., Robinson, B. & Majzoub, J.A. Characterization and gestational regulation of corticotrophin releasing hormone messenger RNA in human placenta. J. Clin. Invest. 82, 287–292 (1988).

    CAS  Article  Google Scholar 

  18. 18

    Goland, R.S., Wardlaw, S.L., Blum, M., Tropper, P.J. & Stark, R.I. Biologically active corticotropin-releasing hormone in maternal and fetal plasma during pregnancy. Am. J. Obstet. Gynecol. 159, 884–890 (1988).

    CAS  Article  Google Scholar 

  19. 19

    Robinson, B., Emanuel, R., Frim, D. & Majzoub, J.A. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc. Natl. Acad. Sci. USA 88, 5244–5248 (1988).

    Article  Google Scholar 

  20. 20

    Jones, S.A., Brooks, A.N. & Challis, J.R. Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta. J. Clin. Endocrinol. Metab. 68, 825–830 (1989).

    CAS  Article  Google Scholar 

  21. 21

    Sawchenko, P.E. Adrenalectomy-induced enhancement of CRF and vasopressin immunoreactivity in parvocellular neurosecretory neurons: Anatomic, peptide, and steroid specificity. J. Neurosci. 7, 1093–1106 (1987).

    CAS  Article  Google Scholar 

  22. 22

    Speeg, K.V. & Harrison, R.W. The ontogeny of human placental glucocorticoid receptor and inducibility of heat-stable alkaline phosphatase. Endocrinology 104, 1364–1370 (1979).

    CAS  Article  Google Scholar 

  23. 23

    Kliman, H.J., Nestler, J.E., Sermasi, E., Sanger, J.M. & Strauss, J., Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 118, 1567–1582 (1986).

    CAS  Article  Google Scholar 

  24. 24

    Bloch, K. The biological conversion of cholesterol to pregnanediol. J. Biol. Chem. 157, 661–666 (1945).

    CAS  Google Scholar 

  25. 25

    Okamoto, E. et al. Immunoreactive corticotropin-releasing hormone, adreno-corticotropin and cortisol in human plasma during pregnancy and delivery and postpartum. Horm. Metab. Res. 21, 566–572 (1989).

    CAS  Article  Google Scholar 

  26. 26

    von der Ahe, D. et al. Glucocorticoid and progesterone receptors bind to the same sites in two hormonally regulated promoters. Nature 313, 706–709 (1985).

    CAS  Article  Google Scholar 

  27. 27

    Strahle, U., Boshart, M., Klock, G., Stewart, F. & Schutz, G. Glucocorticoid-and progesterone-specific effects are determined by differential expression of the respective hormone receptors. Nature 339, 629–632 (1989).

    CAS  Article  Google Scholar 

  28. 28

    Philibert, C.G. et al. From RU 38486 towards dissociated anti-glucocorticoid and antiprogesterone. Front. Horm. Res. 19, 1–17 (1991).

    CAS  Article  Google Scholar 

  29. 29

    Ojasoo, T., Dore, J.C., Gilbert, J. & Raynaud, J-P., Binding of steroids to the progestin and glucocorticoid receptors analyzed by correspondence analysis. J. Med. Chem. 31, 1160–1169 (1989).

    Article  Google Scholar 

  30. 30

    Slater, E.P., Cato, A.C., Karin, M., Baxter, J.D. & Beato, M. Progesterone induction of metallothionein-IIA Gene expression. Mol. Endocrinol. 2, 485–491 (1988).

    CAS  Article  Google Scholar 

  31. 31

    Lippman, M., Huff, K. & Bolan, G. Progesterone and glucocorticoid interactions with receptor in breast cancer cells in long-term tissue culture. Ann. NY Acad. Sci. 286, 101–115 (1977).

    CAS  Article  Google Scholar 

  32. 32

    Gasparoni, A. et al. Neutrophil chemotaxis in infants delivered by caesarean section. Eur. J. Pediatr. 150, 481–482 (1991).

    CAS  Article  Google Scholar 

  33. 33

    Liggins, G.C. Endocrinology of parturition. in Fetal Endocrinology (eds. Novy, M.J. & Resko, J.A.) 211–237 (Academic Press, New York, 1981).

    Google Scholar 

  34. 34

    Schwarz, B.E. et al. Progesterone binding and metabolism in human fetal membranes. Ann. NY Acad. Sci. 286, 304–312 (1977).

    CAS  Article  Google Scholar 

  35. 35

    Robinson, E.G., Arbiser, J.L., Emanuel, R. & Majzoub, J.A. Species-specific placental corticotropin-releasing hormone messenger RNA and peptide expression. Mol. Cell. Endocrinol. 62, 337–341 (1989).

    CAS  Article  Google Scholar 

  36. 36

    Stalla, G.K. et al. Human corticotropin-releasing hormone during pregnancy. Gynecol. Endocrinol. 3, 1–10 (1989).

    CAS  Article  Google Scholar 

  37. 37

    Berghorn, K.A., Albrecht, E.D. & Pepe, G.J. Responsivity of the baboon fetal pituitary to corticotropin-releasing hormone in utero at midgestation. J. Clin. Endocrinol. Metab. 129, 1424–1428 (1991).

    CAS  Google Scholar 

  38. 38

    Siiteri, P.K. & Seron-Ferre, M. Some new thoughts on the feto-placental unit and parturition in primates. in Fetal Endocrinology, (eds. M.J. Novy, M.J. & Resko, J.A.) 1–34 (Academic Press, New York, 1981).

    Google Scholar 

  39. 39

    Emanuel, R.L. et al. Corticotropin releasing hormone levels in human plasma and amniotic fluid during gestation. Clin. Endocrinol. 40, 257–262 (1994).

    CAS  Article  Google Scholar 

  40. 40

    McLean, M. et al. A placental clock controlling the length of human pregnancy. Nature Med. 1, 460–463 (1995).

    CAS  Article  Google Scholar 

  41. 41

    Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & Rutter, W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18, 5294–5299 (1979).

    CAS  Article  Google Scholar 

  42. 42

    Cidlowski, J.A., Bellingham, D.L., Powell-Oliver, F.E., Lubahn, D.B. & Sar, M. Novel antipeptide antibodies to the human glucocorticoid receptor: Recognition of multiple receptor forms in vitro and distinct localization of cytoplasmic and nuclear receptors. Mol. Endocrinol. 4, 1427–1437 (1990).

    CAS  Article  Google Scholar 

  43. 43

    Press, M.F., Udove, J.A. & Greene, G.L. Progesterone receptor distribution in the human endometrium. Am. J. Pathol. 131, 112–124 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Majzoub, J.A. & Adler, G. Assays for Corticotropin releasing hormone and vasopressin messenger RNAs. Methods Neurosci. 52, 1160–1167 (1988).

    Google Scholar 

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Karalis, K., Goodwin, G. & Majzoub, J. Cortisol blockade of progesterone: A possible molecular mechanism involved in the initiation of human labor. Nat Med 2, 556–560 (1996). https://doi.org/10.1038/nm0596-556

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