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.

Corticotropin-releasing hormone stimulates expression of leptin, 11beta-HSD2 and syncytin-1 in primary human trophoblasts

“…Thus, we cannot exclude possible minor fractions of extravillous trophoblasts (EVT) in our cell culture. EVT express CRHR1 [51] and show Syn1 expression [20,52]. Therefore, we cannot completely rule out that the Syn1 induction measured is derived from EVT.…”

Stress and reproductive failure: past notions, present insights and future directions

“…CRH produced in the endometrium may participate in decidualization, implantation, and early maternal tolerance to the semiallograft embryo possibly by killing activated T cells through the Fas-FasL interaction [54]; ovarian CRH is involved in follicular maturation, ovulation, and luteolysis; placental CRH has been proposed to directly modulate the endocrine function of placental trophoblasts, including the production of estrogen, ACTH, and prostaglandin, and is involved in the timing of parturition [55][56][57]. Remarkably the trajectory of CRH increase during pregnancy has been described to differ by ethnicity and also upon statistical adjusting for sociodemographic and biomedical factors.…”

Mechanisms of Maternal Immune Tolerance During Pregnancy

“…However CRH produced at peripheral inflammatory sites has been shown to possess potent proinflammatory properties that can influence both innate and acquired immune responses (Kalantaridou et al, 2007). In the reproductive system, intrauterine and ovarian CRH can have proinflammatory properties.…”

“…For intrauterine CRH, various studies have shown that it may participate in the acute aseptic inflammatory response that is characteristic of embryo implantation (Makrigiannakis et al, www.intechopen.com 2001). Ovarian CRH can also participate in the inflammatory processes of ovulation and luteolysis (Kalantaridou et al, 2007). However, following implantation, the embryo suppresses the inflammatory response and prevents immune rejection.…”