The Role of Corticotropin-releasing Hormone in Blastocyst Implantation and Early Fetal Immunotolerance[*]

Abstract

During blastocyst implantation, the maternal endometrial response to the invading semi-allograft has characteristics of an acute, aseptic inflammatory response. However, once implanted, the embryo suppresses this response and prevents rejection. Simultaneously, the mother's immune system prevents a graft vs. host reaction deriving from the fetal immune system. We have shown that embryonic trophoblast and maternal decidua cells, i.e., cells located in the interface between the fetal placenta and the maternal endometrium, produce corticotropin-releasing hormone (CRH) and express Fas ligand. CRH may play a crucial role in the implantation and the anti-rejection process that protects the fetus from the maternal immune system, primarily by killing activated T cells through the Fas-FasL interaction. In experimental animals, type 1 CRH receptor (CRH-R1) blockade by antalarmin, a specific type 1 CRH receptor antagonist, decreased implantation sites by approximately 70%. CRH is also involved in controlled trophoblast invasion, by downregulating the synthesis of the carcinoembryonic antigen-related cell adhesion molecule 1 by extravillous trophoblast cells. In vitro findings showed that CRH-R1 blockade by antalarmin increased trophoblast invasion by approximately 60%. Defective uterine CRH/CRH-R1 system during early pregnancy may be implicated in the pathophysiology of recurrent miscarriage, placenta accreta, and preeclampsia.

Endometrial corticotropin-releasing hormone - placental corticotropin-releasing hormone - implantation - maternal tolerance

References

• 1 Gill TJ. Immunological and genetic factors influencing pregnancy and development.  Am J Reprod Immunol Microbiol. 1986;  10 116-120
• 2 Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications.  Ann Intern Med. 1998;  129 229-240
• 3 Mastorakos G, Scopa CD, Kao LC, Vryonidou A, Friedman TC, Kattis D, Phenekos C, Rabin D, Chrousos GP. Presence of immunoreactive corticotropin releasing hormone in human endometrium.  J Clin Endocrinol Metab. 1996;  81 1046-1050
• 4 Makrigiannakis A, Zoumakis E, Margioris AN, Theodoropoulos P, Stournaras C, Gravanis A. The corticotropin-releasing hormone in normal and tumoral epithelial cells of human endometrium.  J Clin Endocrinol Metab. 1995;  80 185-193
• 5 Grino M, Chrousos GP, Margioris AN. The corticotropin releasing hormone gene is expressed in human placenta.  Biochem Biophys Res Commun. 1987;  148 1208-1214
• 6 Clifton VL, Telfer JF, Thompson AJ, Cameron IT, Teoh TG, Lye SJ, Challis JR. Corticotropin-releasing hormone and proopiomelanocortin-derived peptides are present in human myometrium.  J Clin Endocrinol Metab. 1998;  83 3716-3721
• 7 Frim DM, Emanuel RL, Robinson BG, Smas CM, Adler GK, Majzoub JA. Characterization and gestational regulation of corticotropin-releasing hormone messenger RNA in human placenta.  J Clin Invest. 1988;  82 287-292
• 8 Petraglia F, Tabanelli S, Galassi MC, Garuti GC, Mancini AC, Genazzani AR, Gurpide E. Human decidua and in vitro decidualized endometrial stromal cells at term contain immunoreactive corticotropin-releasing factor (CRF) and CRF-messenger ribonucleic acid.  J Clin Endocrinol Metab. 1992;  74 1427-1431
• 9 Jones SA, Brooks AN, Challis JR. Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta.  J Clin Endocrinol Metab. 1989;  68 825-830
• 10 Makrigiannakis A, Zoumakis E, Kalantaridou S, Coutifaris C, Margioris AN, Coukos G, Rice KC, Gravanis A, Chrousos GP. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance.  Nat Immunol. 2001;  2 1018-1024
• 11 Runic R, Lockwood CJ, Ma Y, Dipasquale B, Guller S. Expression of Fas ligand by human cytotrophoblasts: implication in placentation and fetal survival.  J Clin Endocrinol Metab. 1996;  81 3119-3122
• 12 Makrigiannakis A, Margioris AN, Le Goascogne C, Zoumakis E, Nikas G, Stournaras C, Psychoyos A, Gravanis A. Corticotropin-releasing hormone (CRH) is expressed at the implantation sites of early pregnant rat uterus.  Life Sci. 1995;  57 1869-1875
• 13 Ferrari A, Petraglia F, Gurpide E. Corticotropin-releasing factor decidualizes human endometrial stromal cells in vitro. Interaction with progestin.  J Steroid Biochem Mol Biol. 1995;  54 251-255
• 14 Di Blasio AM, Giraldi FP, Vigano P, Petraglia F, Vignali M, Cavagnini F. Expression of corticotropin-releasing hormone and its R1 receptor in human endometrial stromal cells.  J Clin Endocrinol Metab. 1997;  82 1594-1597
• 15 Hillhouse EW, Grammatopoulos D, Milton NG, Quartero HW. The identification of a human myometrial corticotropin-releasing hormone receptor that increases in affinity during pregnancy.  J Clin Endocrinol Metab. 1993;  76 736-741
• 16 Makrigiannakis A, Zoumakis E, Margioris AN, Stournaras C, Chrousos GP, Gravanis A. Regulation of the promoter of the human corticotropin-releasing hormone gene in transfected human endometrial cells.  Neuroendocrinology. 1996;  64 85-93
• 17 Makrigiannakis A, Margioris AN, Zoumakis E, Stournaras Gravanis A. The transcription of corticotropin-releasing hormone in human endometrial cells is regulated by cytokines.  Neuroendocrinology. 1999;  70 451-459
• 18 Zoumakis E, Chatzaki E, Charalampopoulos I, Margioris AN, Angelakis E, Koumantakis E, Gravanis A. Cycle and age-related changes in corticotropin-releasing hormone levels in human endometrium and ovaries.  Gynecol Endocrinol. 2001;  15 98-102
• 19 Zoumakis E, Margioris A, Stournaras C, Dermitzaki E, Angelakis E, Makrigiannakis A, Koumantakis E, Gravanis A. Corticotropin-releasing hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects decidualization of human endometrial stroma.  Mol Hum Reprod. 2000;  6 344-351
• 20 Makrigiannakis A, Margioris A, Chatzaki E, Zoumakis E, Chrousos GP, Gravanis A. The decidualizing effect of progesterone may involve direct transcriptional activation of corticotropin-releasing hormone (CRH) from human endometrial stroma cells.  Mol Hum Reprod. 1999;  5 788-796
• 21 Frank GR, Brar AK, Jikihara H, Cedars MI, Handwerger S. Interleukin-1 beta and the endometrium: an inhibitor of stromal cell differentiation and possible autoregulator of decidualization in humans.  Biol Reprod. 1995;  52 184-191
• 22 Karalis K, Sano H, Redwine J, Listwak S, Wilder RL, Chrousos GP. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo.  Science. 1991;  254 421-423
• 23 Sheth KV, Roca GL, Al-Sedairy S, Parhar RS, Hamilton CJ, al-Abdul Jabbar F. Prediction of successful embryo implantation by measuring interleukin-1-alpha and immunosuppressive factor(s) in preimplantation.  Fertil Steril. 1991;  55 952-958
• 24 Lass A, Weiser W, Munafo A, Loumaye E. Leukimia inhibitory factor in human reproduction.  Fertil Steril. 2001;  76 1091-1096
• 25 Athanassakis I, Farmakiotis V, Aifantis I, Gravanis A, Vassiliadis S. Expression of corticotropin-releasing hormone in the mouse uterus: participation in embryo implantation.  J Endocrinol. 1999;  163 221-227
• 26 Psychoyos A. Uterine receptivity for nidation.  Ann N Y Acad Sci. 1986;  476 36-42
• 27 Muglia L, Jacobson L, Dikkes P, Majzoub JA. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need.  Nature. 1995;  373 427-432
• 28 Turnbull AV, Smith GW, Lee S, Vale WW, Lee KF, Rivier C. CRF type I receptor-deficient mice exhibit a pronounced pituitary-adrenal response to local inflammation.  Endocrinology. 1999;  140 1013-1017
• 29 Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.  Cell. 1991;  66 233-243
• 30 Yamashita H, Otsuki Y, Matsumoto K, Ueki K, Ueki M. Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle.  Mol Hum Reprod. 1999;  5 358-364
• 31 Bamberger AM, Minas V, Kalantaridou SN, Radde J, Sadeghian H, Loning T, Charalampopoulos I, Brummer J, Wagener C, Bamberger CM, Schulte HM, Chrousos GP, Makrigiannakis A. Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation.  Am J Pathol. 2006;  168 141-150
• 32 Brosens IA. Morphological changes in the utero-placental bed in pregnancy hypertension.  Clin Obstet Gynaecol. 1977;  4 573-593
• 33 Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, Van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.  Br J Obstet Gynaecol. 1994;  101 669-674
• 34 Perkins AV, Linton EA, Eben F, Simpson J, Wolfe CD, Redman CW. Corticotropin-releasing hormone and corticotropin-releasing hormone binding protein in normal and pre-eclamptic human pregnancies.  Br J Obstet Gynaecol. 1995;  102 118-122
• 35 Karteris E, Vatish M, Hillhouse EW, Grammatopoulos DK. Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by corticotropin-releasing hormone (CRH) and CRH-related peptides.  J Clin Endocrinol Metab. 2005;  90 3680-3687
• 36 Grammatopoulos D, Chrousos GP. Structural and signaling diversity of corticotropin-releasing hormone (CRH) and related peptides and their receptors: potential clinical applications of CRH receptor antagonists.  Trends Endocrinol Metab. 2002;  13 436-444

1 This review is dedicated to the late Alexander Psychoyos, a pioneer in the field of implantation, and a good mentor and friend to many of the authors.

Correspondence