Regulation of the Oxytocin Receptor in Bovine Reproductive Tissues and the Role of Steroids

Contents The oxytocin receptor (OTR) plays a central role in the functioning of the reproductive tract in the female ruminant. During the oestrous cycle endometrial OTR is suppressed through most of the cycle, probably in a progesterone-dependent manner, to be massively up-regulated during the few days before and after oestrus. At this time, luteal OT triggers a positive feedback loop, the endometrial OTR mediating the release of luteolytic PGF2α which feeds back to the corpus luteum to cause the secretion of more OT and to induce luteolysis. This feedback is only interrupted if a newly formed blastocyst is present. Ruminant blastocysts secrete the cytokine interferon-τ, which interacts directly with the endometrial epithelial cells, preventing the up-regulation of OTR in late luteal phase. During early pregnancy the levels of OTR in endometrium remain very low whereas myometrial OTR are less affected. OTR in endometrium are up-regulated around day 50 and then progressively increase to reach a maximum at the onset of labour; those in the myometrium are upregulated somewhat later in gestation, around day 100. The OTR in the cervix are differently regulated: their concentrations are very low through most of the cycle and gestation and do not increase until pro-oestrus and at parturition when they abruptly rise to high values. Ligand binding to the mucosal and endometrial OTR causes specific release of prostaglandins, which in turn activate paracrine pathways in the surrounding tissues to induce softening of the connective tissue of the uterine wall during pregnancy, and of the cervix at term. Additionally, local uterine contractions induced by OT and potentiated by prostaglandins may serve a physiological function during pregnancy by improving uterine blood flow. Due to the appearance of gap junctions in myometrium at term the OT-induced contractions become synchronized and well propagated and because of concomitant cervical softening the contractions become expulsive. Although OTR-dependent physiology correlates well with the levels of circulating gonadal steroids, there is no evidence for any direct effect of steroids either on the OTR gene or OTR protein. Instead, progesterone appears to exert an indirect inhibitory effect on the OTR gene, probably mediated via other cell types. This is in contrast to the inhibition by interferon-τ which appears to activate a pathway which directly suppresses the OTR gene expression. The important role of OTR in female uterine physiology, and its value as an indicator molecule, make it imperative to understand the complex molecular mechanisms underlying its regulation. These are likely to be of fundamental importance for many aspects of uterine function both in ruminants and in other species, including the human.