Expression of corticotrophin-releasing hormone in the mouse uterus: Participation in embryo implantation

Abstract

The detection of corticotropin-releasing hormone (CRH) in the pregnant and non-pregnant uterus has driven research to determine the role of this 41 amino acid neuropeptide in the female reproductive system. As concentrations of CRH mRNA and its peptide product are greater in the implantation sites of the early pregnant uterus compared with the regions between implantation sites, CRH has been hypothesised to participate in blastocyst implantation. Using the mouse system as an experimental model, we studied the distribution of CRH in the uterus during the oestrus cycle and early gestational period, and now provide evidence for its involvement in embryo implantation using cell culture techniques. The percentage of CRH-positive uterine cells and the amount of CRH released during anoestrus, pro-oestrus and oestrus were determined by immunofluorescence and ELISA experiments respectively. The highest number of intracellularly CRH-positive cells was obtained during pro-oestrus, whereas the highest CRH concentration in uterine cell culture supernatants was detected during anoestrus. At early stages of gestation, CRH was detected in the endometrium on days 2, 3 and 4 of pregnancy and in the myometrium on days 3 and 4, whereas it was undetectable on day 5. The functional role of CRH during early gestation was evaluated by administering anti-CRH antibody to mice from day 3 to day 8 of pregnancy. This treatment resulted in implantation failure in 60% of the cases, in which implantation sites, although clearly present in the uterus, had failed to host an embryo. These results provide direct evidence about the involvement of CRH in murine embryo implantation and are in agreement with hypotheses postulated in humans.