Control of synthesis and secretion of ovarian oxytocin in ruminants.

Increased expression of the oxytocin gene of ruminants is associated with the process of luteinization both in vivo and in vitro. Cell culture studies and measurements of mRNA in luteal extracts have confirmed that the gene is switched on in the preovulatory follicle about 24 h before ovulation, at the time of the gonadotrophin surge. It is downregulated again equally rapidly after ovulation, so that by day 2 of the cycle the capacity of the luteal cells to make oxytocin has already been greatly reduced. A number of factors can increase oxytocin production by luteinizing granulosa cells. They include oestradiol and compounds such as gonadotrophins and catecholamines which are known to act by increasing intracellular concentrations of adenylyl cyclase. However, all of these factors are ineffective if the follicle is collected too early, suggesting that an initial maturation step is necessary to develop responsiveness. Analysis of the promoter region of the bovine oxytocin gene has indicated that neither oestradiol nor cAMP can directly initiate activation; instead regulation appears to occur via a COUP factor binding site. Additional transacting nuclear proteins may therefore be required to act as intermediaries. The same factors that initially stimulate oxytocin production switch to inhibiting production shortly after ovulation, leading to downregulation of the gene. After translation of oxytocin mRNA during the luteal phase, oxytocin precursor is packaged into secretory granules in the large luteal cells. Processing involves a series of enzymatic steps, culminating in amidation to produce oxytocin. Cultured cells may secrete intermediate forms of partially processed peptide, but it is not known if this also occurs in vivo. Oxytocin release from the cell involves granule exocytosis which is probably triggered by an increase in intracellular calcium. During luteolysis this is regulated by the release of prostaglandin F2 alpha (PGF2 alpha) from the uterus, although additional factors may also contribute. Neither PGF2 alpha nor catecholamines appear to be prime regulators of luteal oxytocin release during the early and mid-luteal phases of the cycle and it remains to be determined how secretion is controlled at this time.