OXYTOCIN IN REPRODUCTIVE BIOLOGY:
NEWLY DISCOVERED SITES OF PRODUCTION AND OF ACTION
Department of Physiology, University Medical Centre, 1211 Geneva 4, Switzerland
At the turn of the century, within little more than a decade, the main actions of posterior pituitary extract were described: on blood pressure, on urine output and, as far as oxytocin is concerned, the contraction of uterine muscle in late pregnancy and the stimulation of milk ejection during lactation. Although oxytocin is a strong uterotonic agent and is therefore widely used to induce or augment labour, the physiological role of oxytocin in normal human parturition has remained controversial. In this short review I summarize recent evidence that oxytocin that is produced within the uterus itself may play a major role in the initiation of parturition. The uterine synthesis of oxytocin had escaped notice until recently because the gene is expressed only for a short time during the later stages of pregnancy (8).
The view that oxytocin might, in addition to its endocrine effects, exert neurotransmitter-like actions within the central nervous system and that oxytocin acting centrally is involved in the expression of behaviours related to reproduction has been much investigated during the last decade, including in the author’s laboratory. Some of these studies will also be reviewed. Taken together, the data suggest that oxytocin participates at various levels in an integrated process aimed at insuring the birth and the survival of the new-born mammal.
In utero production of oxytocin
There is no consensus in the literature as to whether or not a rise in circulating oxytocin precedes the onset of parturition. Electrophysiological studies in rats indicate that activation of hypothalamic oxytocin neurones occurs seemingly as a consequence of labour, but not before its onset (14). Human labour can proceed normally in cases of severe maternal posterior pituitary dysfunction as well as in the absence of fetal oxytocin. Moreover, administration of oxytocin antiserum to rats was shown to suppress lactation, but not to prevent parturition.
The solution of this long-standing paradox may be found in the recent demonstration of oxytocin synthesis in the uterus, in the rat as well as in the human. Lefebvre et al. (8) dissected whole uteri from non-pregnant control rats and from rats at 14, 18 and 21 days of gestation and at 1, 2 and 9 days of lactation. RNA was extracted and analyzed by Northern blot with an oligonucleotide probe complementary of oxytocin messenger RNA. The amount of OT mRNA, which was low in the uterus of non-pregnant rats, increased more than a 100-fold during the last three days of pregnancy; this was followed by a precipitous fall during the first days of lactation. By comparison, hypothalamic OT mRNA increased only threefold during pregnancy and remained elevated during lactation. The increase in uterine OT mRNA precedes in time the similarly short-lived and marked increase in uterine oxytocin binding sites, which is known to occur before parturition in response to rising estrogen and declining progesterone levels in maternal plasma (6,13).
Radioimmunoassay allowed to ascertain that oxytocin was synthesized in rat uterine tissue: concomitant with the rise in uterine OT mRNA, there was a 35-fold increase in uterine oxytocin-like immunoreactivity. By immunocytochemistry and in situ hybridization, it was shown that the main site of uterine oxytocin gene expression in the rat is the luminal epithelium of the endometrium. No signal was emitted from the underlying stroma (8).
The demonstration that the rat uterus is a major site of oxytocin gene expression during the late stages of pregnancy resolves the apparent paradox between the powerful actions of exogenously administered oxytocin and the lack of unequivocal evidence for a role of circulating oxytocin. These findings suggest that, with respect to parturition, oxytocin may act locally rather than as a circulating hormone. The identification in the endometrial epithelium of oxytocin receptors that are linked to prostaglandin production supports an autocrine action of oxytocin on epithelial prostaglandin synthesis. Moreover, oxytocin produced in the endometrium may also reach the myometrium via stromal veins and bind to the myometrial oxytocin receptors. Thus, it appears that the uterus contains an intrinsic oxytocin system in which both ligand and receptor are subject to co-regulation. The rise in uterine oxytocin gene expression, in concert with the rise in uterine oxytocin receptors, may represent the trigger for parturition. Circulating oxytocin may however still have a role in maintaining labour.
Recently Chibbar et al. (1) demonstrated synthesis of OT mRNA in human amnion, chorion, and decidua using probes directed against the OT gene and Northern blot analysis as well as in situ hybridization. Levels were highest in decidua with considerably less in chorion and amnion. OT gene expression in chorio-decidual tissues increased three- to fourfold around the time of onset of labour. Estradiol stimulated synthesis of OT mRNA during in vitro incubation. These results support the hypothesis of a paracrine system involving oxytocin and sex steroids also within human intrauterine tissues, wherein significant changes could occur without being reflected in the maternal circulation.
Central effects of oxytocin
In recent years, the presence of oxytocin and of sites which bind this peptide with high affinity has been reported in various areas of the brain and spinal cord, suggesting that oxytocin may exert some of its effects centrally (9,15). Indeed, oxytocin has a broad spectrum of behavioural effects, amongst which several are related to reproductive biology: female sexual receptivity, penile erection, male mounting behaviour, parental behaviour, to name only some (11). It is noteworthy that, in certain areas of the brain, oxytocin and its receptors are regulated by circulating estrogen, as they are in the uterus (16).
New-born mammals are incapable of independent life and their survival requires nursing and maternal care. Thus, an adequate supply of milk is required to provide the young with the nutrients needed for growth. During nursing, maternal oxytocin released in response to suckling stimulates the contraction of myoepithelial cells of the mammary gland and milk is ejected. In lactating rats, in which it is possible to measure the rise in intrammamary pressure at milk ejection, an abrupt rise in pressure is seen every few minutes during suckling. The pressure wave occurs simultaneously in recordings taken from different teats and is similar in amplitude from one milk ejection to the next. Each pulse of oxytocin released during nursing is preceded by an explosive, short-lived burst in firing in all, or nearly all, oxytocin-secreting hypothalamo-neurohypophysial neurons (2).
It is not yet known how the essentially persistent suckling stimulus is transformed into a sequence of intermittent bursts of action potentials generated by the oxytocin-producing neurons which project to the neural loge. Nor is it known where in the central nervous system of the nursing mother the sensory information elicited by the sucklings is integrated and then either " gated " during the interval between two milk ejections or, if sufficient time has elapsed since the previous ejection, conveyed to the oxytocin-secreting neurons.
There is however strong evidence that oxytocin itself, by a central action, determines the interval between each milk ejection: intracerebroventricular or intracerebral injection of oxytocin evokes a striking acceleration of the reflex (5). Within minutes, the frequency of the bursts of action potentials increases, as does the number of action potentials in each burst. These changes are mirrored by the pulses of oxytocin released from the neural lobe, which occur more frequently and are of greater amplitude. Conversely, intracerebroventricular administration of an oxytocin antagonist temporarily slows the milk ejections, suggesting that endogenous oxytocin is normally involved in their timing (5).
Rats are born immature and helpless. Their mother keeps them in a nest which she builds prior to parturition. When in the nest, she crouches over her young and by so doing exposes her mammary region, thereby allowing suckling. If a pup is displaced, the mother quickly carries it back to the nest.
Evidence is available which supports a role for endogenous oxytocin in stimulating the onset of maternal behaviour. Indeed, intracerebroventricular injection of oxytocin can induce, after a short latent period, all aspects of maternal hehaviour in virgin female rats, provided their estrogen levels are high (10). In addition, it is possible to retard spontaneous maternal behaviour following natural parturition in rats by injecting an oxytocin antagonist into the ventricular spaces. After delivery, the pups were removed from the doe for a period and thereafter, pups and nesting material were presented to her in a test cage. Saline-injected mothers started gathering the pups immediately and displayed full maternal behaviour within minutes. Antagonist-treated mothers showed a marked delay in these behaviours (17).
These studies indicate that oxytocin—including endogenous oxytocin—exerts some of its effects within the central nervous system. From the late 1970s, the existence of vasopressin- and oxytocin-containing pathways and synapses in several areas of the central nervous system had been established (12). Moreover, in our laboratory, we have accumulated during the last years much evidence compatible with a neuronal action of oxytocin. These studies have been reviewed elsewhere (3,4). Further rapid progress can be expected following the recent successful molecular cloning of the human oxytocin receptor (7).
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