Anna-Riitta Fuchs

Oxytocin receptors in the human uterus during pregnancy and parturition

We have determined the concentration and distribution of oxytocin receptors in myometrial and decidual tissues obtained at cesarean section or hysterectomy during pregnancy. Myometrial receptor concentration was low at 13 to 17 weeks but had risen about twelvefold by 37 to 41 weeks. After the onset of labor, either preterm or term, the receptor levels were maximal and significantly higher than before the onset of labor. In cases of failed induction of labor with oxytocin and in postterm pregnancies (43 to 46 weeks), the receptor concentration was significantly lower than in spontaneous labor. Myometrial receptor concentrations in the fundus and the corpus were similar and significantly higher than in the lower part of the uterine segment, and the cervix had the lowest concentration. The parietal decidua had oxytocin receptor concentrations of the same magnitude as the myometrium. These results are consistent with a functional role of endogenous oxytocin in the activation of the human uterus during pregnancy and parturition.

Endocrinology of human parturition: a review

Summary. The existing data on the hormonal factors involved in human parturition indicate that the steroid hormones, progesterone and the oestrogens, play only a facilitatory role in the initiation of labour. A definite role for fetal adrenal steroids in this process has yet to be established, and they too may serve only a facilitating function. The stimulation of the uterine muscle during labour results from an interaction of oxytocin and prostaglandin (PG) F2α. Recent evidence suggests that oxytocin is most important for the initial phase of labour, whereas increased synthesis of PGF2α is essential for the progression of labour. The role of PGE2 remains unclear, but this PG may play an important role in the ripening of the cervix which in turn is essential for successful parturition. The finding of maximal oxytocin receptor concentrations in the myometrium in labour adds strong support to the notion that oxytocin is the trigger for uterine contractions. The factors which control oxytocin receptor formation are therefore important; this may be one of the processes where the steroids play a crucial role. Oxytocin is also one of the stimuli that increase uterine PG synthesis; the coupling of oxytocin receptor occupancy and PG synthetase activity in uterine tissues may be another crucial factor in the mechanism of labour. The formation of gap junctions between the myometrial cells also seems essential for the synchronization and progression of myometrial activity. We propose, therefore, that the co‐ordinating of oxytocin receptor formation, PG synthesis and gap junction formation is a key to the initiation and maintenance of human labour. The fetus may fulfil such a co‐ordinating role through its influence on placental oestrogen production, through mechanical distention of the uterus, and through its secretion of neurohypophysial hormones and other stimulators of PG synthesis.

Effect of alcohol on threatened premature labor

Abstract Evidence has been accumulating that oxytocin plays a role in the initiation and maintenance of labor in the human and other species. It has been demonstrated that ethyl alcohol inhibits the release of oxytocin during parturition and lactation in the rabbit and during lactation in the human. If oxytocin is essential for human parturition, alcohol should have an effect on uterine activity in labor. Alcohol was given to 68 patients in threatened premature labor, including 52 with intact and 16 with ruptured membranes. The alcohol was given intravenously as a 9.5 per cent solution in dextrose/water. A loading dose was given during the first one or 2 hours, followed by a maintenance dose of one tenth of the loading dose per hour. Of the 52 patients with intact membranes, in 35 delivery was postponed for 3 days or more, 30 of them carrying their pregnancy to 37 weeks or more. In 10 patients, labor was arrested initially but recurred and was allowed to progress, and in 7 patients labor could not be arrested. In all 16 patients with ruptured membranes, the treatment with alcohol failed to postpone delivery significantly. However, an inhibitory effect on the uterine contractions was observed in all 68 cases, as well as in 10 cases of labor at term and in 3 cases of threatened premature labor in connection with a Shirodkar procedure. It is concluded that alcohol can inhibit the uterine activity during labor and that this presumably is due to an inhibition of the release of oxytocin from the neurohypophysis.

Oxytocin and the initiation of human parturition

Abstract Concentrations of plasma prostaglandins E and F and the 15-keto-13, 14-dihydrometabolite of PGF2ɑ (PGFM) were determined by radioimmunoassay in 15 women whO underwent induction of labor with oxytocin. Plasma PGFM rose significantly during the oxytocin infusion in nine women who went on to deliver vaginally but did not change in six women in whom induction of labor failed. Plasma PGE and PGF levels also rose during the infusion in the nine women with successful induction of labor but the changes were not statistically significant. In comparison to the six women in whom induction failed, however, plasma PGE in the nine women with succesfull induction reached significantly higher levels. Oxytocin infusions elicited uterine contractions similar frequency in both groups of women, but the cervix failed to dilate in the six women in whom induction failed. The oxytocin-induced rise in plasma PGFM is, therefore, not simply a consequence of uterine contractions, We suggest that oxytocin stimulates PGF production in the pregnant uterus when it is appropriately sensitized to oxytocin, causing a potention of the oxytocin-induced contractions which is necessary for the contractions to become efficient in dilating the cervix. We further suggest that the stimulation of PGF production by oxytocin is mediated by oxytocin receptors, probably in the decidua. (Am. J. Obstet. Gynecol. 141:688, 1981.)

Oxytocin and the initiation of human parturition. II. Stimulation of prostaglandin production in human decidua by oxytocin.

In the present study we have investigated the effect of oxytocin on the production of prostaglandins E and F (PGE and PGF) by human decidua, amnion, and myometrium in vitro. We found that oxytocin causes a significant increase in the production of both PGE and PGF in the decidua and in the production of PGE in the amnion. In the myometrium the stimulatory effect of oxytocin on PGF production was small and not statistically significant, and PGE production was not affected at all. On the basis of these results, we propose that oxytocin provides the stimulus for the accelerated prostaglandin production in decidua and fetal membranes at the onset of labor. Since oxytocin levels rise in the fetal circulation at this time, the oxytocin stimulus may be of fetal origin as well as of maternal origin.

Oxytocin and the initiation of human parturition: III. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2α in spontaneous and oxytocin-induced labor at term

The plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were measured in serial samples collected during the first stage of spontaneous and oxytocin-induced labor in 17 and 15 women, respectively. Four women in late pregnancy served as control subjects, with serial samples collected at similar intervals as during labor. During spontaneous labor, mean plasma oxytocin levels were consistently raised over the levels observed 1 to 2 weeks before the onset of labor and were higher than the levels in the control patients (mean, 19.9 +/- 3.1 pg/ml) and the initial levels in the oxytocin-induced group of women (mean, 17.4 +/- 4.8 pg/ml). The mean plasma oxytocin levels during spontaneous labor (45 +/- 3.9 pg/ml) were similar to those observed during infusion of 4 to 6 mU/min of synthetic oxytocin (49.1 +/- 10.9 pg/ml). Plasma oxytocin levels increased progressively with stepwise increments of the infusion. Plasma PGFM levels also rose during labor, but, in contrast to the oxytocin levels which increased in early labor, plasma PGFM levels did not increase significantly until relatively late in labor, provided the membranes were intact. The state of the membranes had a marked influence on plasma PGFM; patients with spontaneous rupture of membranes had significantly increased PGFM levels when admitted early in labor or when membranes ruptured during labor. This increase in prostaglandin F2 alpha (PGF2 alpha) production does not by itself suffice to initiate labor, as evidenced by the failure of premature rupture of the membranes to initiate labor in a number of patients with elevated PGFM levels in whom labor was then induced with oxytocin. Conversely, oxytocin induction was successful only when PGFM levels increased during the infusion of oxytocin; in the absence of a rise in plasma PGFM, oxytocin induction failed. These data add support to the view that both oxytocin and PGF2 alpha are required for adequate stimulation of the human uterus during labor. In addition, the data suggest that oxytocin rather than PGF2 alpha may be the major stimulus that initiates labor, whereas PGF2 alpha appears responsible for the progress of labor.

Plasma membrane receptors regulating myometrial contractility and their hormonal modulation

Virtually all hormones, neurohormones, neurotransmitters, neuropeptides, drugs, and other ligands initiate their biological effects by binding to specific receptors. Myometrial function is regulated by intracellular steroid receptors that exert long-term responses at the genomic level and plasma membrane receptors that elicit rapid responses. At the organ level, functional complexity derives from the existence of paracrine routes of regulation by substances generated in adjacent tissues. Myometrial cells can be influenced in this way by compounds having receptors on endometrial/deci dual cells, endothelial cells, mast cells, or resident macrophages.

Vasopressin receptors in human pregnant myometrium and decidua: Interactions with oxytocin and vasopressin agonists and antagonists

Saturation analysis and competition experiments were performed to identify and characterize [3H]arginine vasopressin binding to human myometrium and decidua in late pregnancy. [3H]Arginine vasopressin bound with affinity similar to that of [3H]oxytocin to both tissues (dissociation constant 1 to 2 nmol/L). The concentration of [3H]arginine vasopressin binding sites was high, particularly in decidua, but in all instances was about 50% to 60% of [3H]oxytocin binding. Analogs with selective oxytocic potency (4-threonine oxytocin, isotocin) had high affinity to both [3H]arginine vasopressin and [3H]oxytocin binding sites, as did analogs with both oxytocic and vasopressor activity (vasotocin). Analogs with selective antidiuretic activity (1-deamino-8-D-arginine vasopressin) showed drastically reduced affinity to [3H]oxytocin binding sites and relatively low but significantly higher affinity to [3H]arginine vasopressin binding sites. A new oxytocin antagonist (RW22164 or [1-deamino-2D-tyrosine-(O-ethyl)-4-threonine-8-ornithine]oxytocin) competitively bound to both binding sites. Its affinity to [3H]oxytocin binding sites was greater than to [3H]arginine vasopressin binding sites whereas the relative affinities of a predominantly vasopressor antagonist [Manning compound) were reversed, suggesting the presence of distinct receptors for oxytocin and arginine vasopressin in pregnant human myometrium and decidua.

Plasma levels of oxytocin and 13,14-dihydro-15-keto prostaglandin F2α in preterm labor and the effect of ethanol and ritodrine☆

We have measured the concentrations of circulating oxytocin and the 13, 14-dihydro, 15-keto-metabolite of prostaglandin F2 alpha (PGFM) in women during preterm labor. Twelve women were given intravenous ethanol and 11 women received intravenous ritodrine for the prevention of preterm birth. Blood samples were obtained before and 1/2, 1, 2, 4, 12, and/or 24 hours after treatment began. On admission, the plasma concentrations of both oxytocin and PGFM were raised over levels observed in women with normal pregnancies of similar gestational age, 25 to 36 weeks. The initial oxytocin level was 58.5 +/- 8.2 pg/ml (mean +/- SE, n = 23) and the mean initial PGFM level was 264 +/ 33.1 pg/ml (n = 15); both values were significantly higher than in 10 control subjects (17.4 +/- 4.8 and 156 +/- 21.8 pg/ml, respectively). During infusion of ethanol, the plasma oxytocin level fell rapidly, the levels at 1/2 and 1 hour after infusion being significantly lower than before the infusion (29.0 +/- 5.5 and 27.8 +/- 3.5 pg/ml, respectively). The plasma oxytocin level remained low in women in whom the treatment arrested labor and prevented preterm birth (n = 8) but rose 2 to 4 hours after the infusion began in women in whom the treatment failed to arrest labor (n = 4). Ritodrine, on the other hand, had no significant effect on circulating oxytocin levels. The plasma PGFM level decreased significantly during ritodrine treatment only in the successfully treated patients. Ethanol had no consistent effect on plasma PGFM levels in the four patients in whom PGFM levels were measured. In the ritodrine-treated patients, the plasma PGFM level was positively correlated with the frequency of uterine contractions whereas in the ethanol-treated patients a correlation of plasma oxytocin to the frequency of contractions was observed. Thus, oxytocin secretion is increased during preterm labor, and the release of prostaglandin F is also increased. While it is not possible to determine whether any or both of these oxytocic agents actually trigger preterm labor, both seem to play a role in its mechanism.

Prostaglandin F2alpha and oxytocin interactions in ovarian and uterine function

The oxytocin-neurophysin gene is expressed in several nontraditional sites within the endocrine system. In the ovary its expression in the corpora lutea is initiated by ovulation. Ovarian oxytocin concentrations reach maximal levels around day 11 of luteal cycle and fall to a nadir at estrus. PGF2 alpha has the capacity to release oxytocin from the corpus luteum, and oxytocin in turn releases PGF2 alpha from the uterine endometrium or decidua. This positive feedback loop between the ovary and the uterus ensures the completion of luteolysis in species that depend on the presence of the uterus for the termination of luteal lifespan. Immunization against oxytocin has been shown to disrupt this loop, resulting in much-prolonged luteal cycles. In primates and other species in which luteal life span is independent of the uterus, an oxytocin PGF2 alpha interaction may take place within the ovary itself. At parturition a related interaction takes place which ensures the expulsion of the fetus and placenta in an orderly manner. Oxytocin of both pituitary and ovarian origin reaches the uterus via its blood supply and binds to two types of receptors: one on myometrial cells, the occupation of which initiates contractions, and the other on decidual cells, the occupation of which initiates prostaglandin generation. This prostaglandin diffuses into the adjacent myometrium and augments the oxytocin-induced contractions. In conjunction with a direct softening effect by prostaglandins on the cervix the augmented contractions achieve the force needed to dilate the cervix and expel the fetus. An additional source of oxytocin during labor may be the placenta, another non-traditional site for the occurrence of oxytocin.