PubMed · 11266035
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J R Challis. 2001. Understanding pre-term birth.. https://pubmed.ncbi.nlm.nih.gov/11266035/
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The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.
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.
Data on biological effects and localization of corticotropin-releasing factor (CRF), a neuropeptide structurally and biologically related to urocortins, have triggered the study on expression of urocortins and their function in human reproductive tissues. Ovary, endometrium, placenta and fetal membranes (amnion and chorion), myometrium, and prostate are sources of urocortin 1 and, they also express urocortin binding sites (receptors and CRF-binding protein), thus suggesting that these tissues are also targets of urocortin 1. The current concept thus is that urocortin 1 may affect the physiology of human reproduction through paracrine/autocrine actions. In particular, in vitro data have shown that urocortin 1 plays a major role in human placenta: it stimulates the secretion of ACTH, prostaglandins and activin A from cultured human placental cells, and regulates placental vessel resistance to blood flow. Furthermore, when incubated in myometrial strips, urocortins stimulate uterine contractility, by activating specific intracellular pathways. Taken together, these findings do suggest an important role of urocortins in the physiology of pregnancy and parturition.