The central oxytocin pulse generator: a pacemaker for luteolysis

Oxytocin (OT) is released from the neurohypophysis into the jugular vein of sheep in small 1-2 min pulses (ca. 10 pg/ml) in both cyclic and ovariectomized sheep. In intact cycling sheep, additional hour long bursts of OT (up to 200 pg/ml) occur in peripheral blood during luteolysis at intervals of 6 to 9 hrs which appear to regulate large luteolytic pulses of uterine prostaglandin F2a (PGF2a). Since the ovine corpus luteum (CL) also synthesizes OT, experiments were performed to distinguish between the relative contributions of the neurohypophysis and the CL to the large bursts of OT secreted during luteolysis. Two models were used. First, ovariectomized sheep were given exogenous E and/or P by constant infusion to simulate levels during the estrous cycle. Second, in tact cycling sheep, the CL was surgically excised during the luteal phase to exclude the CL as a source of OT and, at the same time, subject the animals to the withdrawal of P. Pulses of OT in jugular vein plasma were determined by RIA or biometry of the uterus. The findings are summarized as follows: In ovariectomized sheep, maintained on low E (0.05 g/hr) to preserve the OT pulse generator, infusion of E (1 microgram, 2 micrograms or 4 micrograms/hr) for 12 to 36 hr, caused a series (4 to 6) of rapid increases in OT pulse frequency each lasting 1 to 2 hrs at intervals of 3 hrs. The time of onset of high frequency pulses was dose-dependent. Withdrawal of 10 day infusions of P (500 micrograms/hr) superimposed on low E (0.05 microgram/hr) also evoked a series of high frequency episodes of OT pulses beginning 24 hrs after P withdrawal. In intact sheep, surgical removal of the CL resulted in a series of high frequency pulses similar in duration and frequency to those following the withdrawal of P in the ovariectomized animal. We conclude that: (1) an increase in E or returning E action causes the OT pulse generator to alter its frequency intermittently thus producing a series of 4 to 6 episodes of high frequency pulses of OT. (2) Similar changes can be evoked by withdrawal of P either by terminating an infusion of P in the presence of E in the ovariectomized sheep or by surgically removing the CL from the ovary in the intact sheep. (3) At the end of the reproductive cycle, the central OT pulse generator appears to act as a pacemaker which, acting on the endometrial OT receptors, triggers a series of pulses of PGF2a from the uterus and hence causes regression of the CL. In the sheep and other ruminants, an intermittent supplemental secretion of OT from the CL, triggered via the central OT pulse generator, may also be required to amplify the luteolytic pulses of PGF2a from the uterus. (4) In addition to the well established interaction of ovarian steroid hormones, and the hypothalamic pituitary system for the initiation of the reproductive cycle via the gonadotrophins, there is now good evidence for an interaction of ovarian steroids and the posterior pituitary for terminating the reproductive cycle.