Luteolysis: a neuroendocrine-mediated event.

In many nonprimate mammalian species, cyclical regression of the corpus luteum (luteolysis) is caused by the episodic pulsatile secretion of uterine PGF2alpha, which acts either locally on the corpus luteum by a countercurrent mechanism or, in some species, via the systemic circulation. Hysterectomy in these nonprimate species causes maintenance of the corpora lutea, whereas in primates, removal of the uterus does not influence the cyclical regression of the corpus luteum. In several nonprimate species, the episodic pattern of uterine PGF2alpha secretion appears to be controlled indirectly by the ovarian steroid hormones estradiol-17beta and progesterone. It is proposed that, toward the end of the luteal phase, loss of progesterone action occurs both centrally in the hypothalamus and in the uterus due to the catalytic reduction (downregulation) of progesterone receptors by progesterone. Loss of progesterone action may permit the return of estrogen action, both centrally in the hypothalamus and peripherally in the uterus. Return of central estrogen action appears to cause the hypothalamic oxytocin pulse generator to alter its frequency and produce a series of intermittent episodes of oxytocin secretion. In the uterus, returning estrogen action concomitantly upregulates endometrial oxytocin receptors. The interaction of neurohypophysial oxytocin with oxytocin receptors in the endometrium evokes the secretion of luteolytic pulses of uterine PGF2alpha. Thus the uterus can be regarded as a transducer that converts intermittent neural signals from the hypothalamus, in the form of episodic oxytocin secretion, into luteolytic pulses of uterine PGF2alpha. In ruminants, portions of a finite store of luteal oxytocin are released synchronously by uterine PGF2alpha pulses. Luteal oxytocin in ruminants may thus serve to amplify neural oxytocin signals that are transduced by the uterus into pulses of PGF2alpha. Whether such amplification of episodic PGF2alpha pulses by luteal oxytocin is a necessary requirement for luteolysis in ruminants remains to be determined. Recently, oxytocin has been reported to be produced by the endometrium and myometrium of the sow, mare, and rat. It is possible that uterine production of oxytocin may act as a supplemental source of oxytocin during luteolysis in these species. In primates, oxytocin and its receptor and PGF2alpha and its receptor have been identified in the corpus luteum and/or ovary. Therefore, it is possible that oxytocin signals of ovarian and/or neural origin may be transduced locally at the ovarian level, thus explaining why luteolysis and ovarian cyclicity can proceed in the absence of the uterus in primates. However, it remains to be established whether the intraovarian process of luteolysis is mediated by arachidonic acid and/or its metabolite PGF2alpha and whether the central oxytocin pulse generator identified in nonprimate species plays a mediatory role during luteolysis in primates. Regardless of the mechanism, intraovarian luteolysis in primates (progesterone withdrawal) appears to be the primary stimulus for the subsequent production of endometrial prostaglandins associated with menstruation. In contrast, luteolysis in nonprimate species appears to depend on the prior production of endometrial prostaglandins. In primates, uterine prostaglandin production may reflect a vestigial mechanism that has been retained during evolution from an earlier dependence on uterine prostaglandin production for luteolysis.

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.