the hormones prolactin (PRL) and oxytocin (OT) are functionally linked to regulate processes in and beyond reproduction. Both hormones are released into the circulation in response to orgasm, mating, nursing, stress, and osmotic stimulation to regulate reproductive behavior, pregnancy, lactation, stress-related responses, and fluid and electrolyte homeostasis (3, 4, 7, 9, 10, 13). Notably, PRL and OT stimulate the release of each other. Elevating PRL (20) or OT (6) in the brain or in the circulation leads to the systemic increase of OT or PRL, respectively. This reciprocal interaction raises important questions concerning the functional relevance of the interplay between OT and PRL and the nature of the mechanisms involved.
The mating-induced PRL rhythm in female rats is a challenging system in which to study OT and PRL interplay. It is in this paradigm that Helena et al. (11) have identified a novel mechanism for systemic OT to influence PRL secretion. In rats, the first half of pregnancy is characterized by daily nocturnal and diurnal surges of PRL in the circulation. These surges are initiated by cervical stimulation at mating and are responsible for corpus luteum maintenance in early pregnancy. Because cervical stimulation induces the transient release of OT into the circulation (15) and OT acts on anterior pituitary cells to stimulate PRL secretion (5), OT may be the stimulus that triggers the PRL rhythm in pregnancy. This possibility has been a main focus of research in the Freeman laboratory for more than 20 years (1). Their recent findings have shown that a bolus injection of OT initiates rhythmic PRL surges comparable to those seen in cervically stimulated rats (6) and that an OT antagonist abolishes PRL surges induced by cervical stimulation (14). The fact that PRL rhythm continued after the clearance of exogenous OT indicates that transient elevation of systemic OT triggers a memory mechanism similar to that of cervical stimulation and that this mechanism may depend on OT actions at the level of the brain or the pituitary gland. In this regard, OT-induced release of anterior pituitary PRL may be relevant, since the central or systemic administration of PRL initiates a PRL secretory rhythm similar to that triggered by exogenous OT or cervical stimulation (12). Mating-induced pseudopregnancy also requires activation of OT receptors in the ventromedial hypothalamus (16).
The mechanisms mediating the action of OT in mating-induced PRL surges are still, however, largely elusive. In this issue, Helena et al. (11) from Freeman's group, build upon their own previous work to show that peripheral and not central actions initiate the circadian release of PRL induced by exogenous OT. The PRL rhythm occurred after the systemic, but not after the intracerebroventricular administration, of OT. Furthermore, an OT antagonist that does not cross the blood-brain barrier eliminated the PRL rhythm. They also showed that exogenous OT does not act through anterior pituitary lactotrophs to initiate PRL rhythm. Mimicking OT-induced acute release of PRL by treatment with thyrotropin-releasing hormone (a known stimulator of anterior pituitary PRL secretion) did not induce the rhythm. In search of a peripheral target, the authors demonstrated that sectioning the pelvic nerve blocks OT-induced PRL circadian release.
Altogether, the work by Helena et al. (11) raises interesting possibilities for the physiological setting. They propose that OT released by cervical stimulation at mating would cause contractions of the reproductive tract (uterine cervix and vagina), which would signal the central nervous system through the pelvic nerve to initiate PRL rhythm. This proposal implies that systemic OT triggers PRL rhythm by acting through peripheral innervation and not by directly stimulating pituitary lactotrophs. Notably, the pelvic nerve input may stimulate the release of brain OT, which could initiate and maintain PRL surges. Indeed, mating activates OT neurons in the hypothalamic paraventricular nucleus (8) to release OT onto the ventromedial hypothalamus, the median eminence, and the pituitary gland (17–19). Therefore, both systemic and brain OT would determine postmating PRL surges.
Extrapolating these findings to the physiological condition and to other species may not be entirely straightforward. The authors noted discrepancies between the PRL surges induced by OT injection and those initiated by cervical stimulation, suggesting that additional sensory pathways and receptor systems likely operate in the physiological state. These additional mechanisms explain the observation that oxytocin-null mice undergo a normal pregnancy (22). It should be noted, however, that there are species-related differences in the control of mating-induced pseudopregnancy. Unlike the rat, mice require a more complex mating stimulation, which activates somewhat different brain areas and results in only a single diurnal PRL surge (21). A very different situation occurs in humans, where there is no evidence for a PRL luteotropic effect, PRL levels are low, and no PRL rhythm develops in early pregnancy (2).
Although disparities occur among the various species, the study of OT-induced PRL rhythm in pregnant rats illustrates the complex mechanisms mediating the interaction of OT and PRL in the regulation of common functions. The finding that OT induces the mechanosensitive activation of the pelvic nerve triggering neuroendocrine responses is novel and should be explored in other physiological conditions in which peripheral nerves influence the release and function of OT and PRL, such as lactation. The results undoubtedly will stimulate many discussions and speculations leading to testable new hypotheses.
No conflicts of interest, financial or otherwise, are declared by the authors.
The authors thank Fernando Lopez-Barrera for technical assistance and Dorothy D. Pless for critically editing the manuscript.
- Copyright © 2011 the American Physiological Society