Peter Husslein

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.

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 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.

The origin of circulating 13,14-dihydro-15-keto-prostaglandin F2α during delivery

Abstract All uterine tissues as well as the fetal membranes and the placenta can form prostaglandins from endogenous precursors in vitro but it is not clear which of the tissues is the main site for the increase in PGF2α production during human parturition. To examine this question, we measured plasma prostaglandin levels before and at intervals after expulsion of the fetus, placenta, and membranes. The concentration of PGFM at the beginning of the second stage of labor was significantly higher than before the onset of labor. Five minutes after the birth of the infant, the concentration had doubled. Thirty minutes after the expulsion of placenta and membranes, plasma PGFM had fallen to the levels at full dilatation; two hours postpartum it was still significantly raised over levels before labor. Since the halflife of PGFM in the circulation is about 7 minutes, these findings indicate that the uterine tissues are important sources of PGFM during labor. In contrast, endogenous oxytocin levels, which were significantly raised over control levels at the second stage of labor, did not change during the third stage, and decline postpartum to control levels. Oxytocin infusion did not influence PGFM levels at 5 and at 30 minutes postpartum, but raised them at 2 hours.

Oxytocin and the initiation of human parturition: IV. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2α during induction of labor by artificial rupture of the membranes☆

The influence of artificial rupture of the membranes on plasma levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and oxytocin was examined in 23 pregnant women at term. Serial blood samples were collected before and 15 minutes, 2 hours, 5 hours, and 8 hours after artificial rupture of the membranes. A significant rise in the concentration of plasma PGFM was observed at 15 minutes in the majority of women (20 of 23), but the magnitude of this early rise or the lack thereof was not related to the subsequent course of labor. The concentration of plasma PGFM at 2 hours was, on the other hand, significantly correlated with the induction-delivery interval. Amniotomy, by itself, induced labor and delivery when the increased PGFM levels were maintained from 2 to 5 hours after the procedure (n = 16). In those cases where Pitocin stimulation was required for adequate uterine contractions, it was found that plasma PGFM levels had declined to initial values at 2 hours. Pitocin infusions then partially reversed this decline. In one patient, the cervix failed to dilate in spite of prolonged Pitocin infusion which did not induce significant uterine contractions, and the infusion did not reverse the marked fall in plasma PGFM after the early but transient rise. Mean plasma oxytocin levels did not rise significantly during labor induced by artificial rupture of the membranes and were, on the average, similar to the levels observed during the first stage of spontaneous or oxytocin-induced labor. Considering the previously demonstrated maximal levels of uterine oxytocin receptors in early labor, the absence of a rise in the plasma oxytocin levels does not negate a role for oxytocin in working synergistically with prostaglandins in the mechanism of labor.