Regulation of the oxytocin receptor in bovine reproductive tissues and therole of steroids

The oxytocin receptor (OTR) plays a central role in the functioning of the reproductive tract in the female ruminant. During the oestrous cycle endome trial OTR is suppressed through most of the cycle, probably in a progestero ne-dependent manner, to be massively up-regulated during the few days befor e and after oestrus. At this time, luteal OT triggers a positive feedback l oop, the endometrial OTR mediating the release of luteolytic PGF(2 alpha) w hich 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 b lastocyst is present. Ruminant blastocysts secrete the cytokine interferon- tau, which interacts directly with the endometrial epithelial cells, preven ting 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. Liga nd binding to the mucosal and endometrial OTR causes specific release of pr ostaglandins, which in turn activate paracrine pathways in the surrounding tissues to induce softening of the connective tissue of the uterine wall du ring pregnancy, and of the cervix at term. Additionally, local uterine cont ractions induced by OT and potentiated by prostaglandins may serve a physio logical function during pregnancy by improving uterine blood flow. Due to t he appearance of gap junctions in myometrium at term the OT-induced contrac tions become synchronized and well propagated and because of concomitant ce rvical 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 g ene or OTR protein. Instead, progesterone appears to exert an indirect inhi bitory effect on the OTR gene, probably mediated via other cell types. This is in contrast to the inhibition by interferon-tau which appears to activa te a pathway which directly suppresses the OTR gene expression. The importa nt 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 importanc e for many aspects of uterine function both in ruminants and in other speci es, including the human.