Luteolysis: A Neuroendocrine-Mediated Event

Abstract

In many nonprimate mammalian species, cyclical regression of the corpus luteum (luteolysis) is caused by the episodic pulsatile secretion of uterine PGF2α, 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 PGF2α secretion appears to be controlled indirectly by the ovarian steroid hormones estradiol-17β 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 PGF2α. 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 PGF2α. In ruminants, portions of a finite store of luteal oxytocin are released synchronously by uterine PGF2α pulses. Luteal oxytocin in ruminants may thus serve to amplify neural oxytocin signals that are transduced by the uterus into pulses of PGF2α. Whether such amplification of episodic PGF2α 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 PGF2α 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 PGF2α 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.