Endometrial and placental CRH as regulators of human embryo implantation.
Epithelial cells of the human endometrium and differentiated endometrial stromal cells express the corticotropin-releasing hormone (CRH) gene. CRH is also produced by human placental cytotrophoblast. Endometrial and placental CRH are under the endocrine control of gonadal steroids as well as under autocrine/paracrine regulation by prostanoids and interleukins. Human endometrium, myometrium and placenta express the relevant receptors. Human trophoblast and decidualized endometrial cells also express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intra-uterine CRH may participate in local inflammatory phenomena associated with blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1 (CRH-R1)-specific antagonist decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto-paracrine fashion. Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T lymphocytes, an effect potentiated by CRH and inhibited by the CRH antagonist. Female rats treated with the CRH antagonist in the first 6 days of gestation had a dose-dependent decrease of endometrial implantation sites and live embryos as well as markedly diminished endometrial FasL expression. However, embryos of mothers lacking T cells (nude rats) and embryos of syngeneic matings were not rejected when mothers were treated with antalarmin, suggesting that the effect of antalarmin on embryonic implantation is not due to a nonspecific toxicity of this compound but a specific effect on T cells. Our data suggest important physiological roles of endometrial and placental CRH in the regulation of blastocyst implantation and early maternal tolerance.
Department of Obstetrics & Gynocology, Medical School, University of Crete, Heraklion 71110, Greece. makrigia@med.uoc.gr
A
A
Makrigiannakis
E
E
Zoumakis
S
S
Kalantaridou
G
G
Chrousos
D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*; D010064:Embryo Implantation; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy
D003346:Corticotropin-Releasing Hormone