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Publisher Summary Oxytocin is the most potent of all agents known to elicit uterine contractions. Careful analysis of the collective data supports the view that oxytocin plays an important role in both initiation and maintenance of human labor. The low blood levels found in early labor are compatible with physiological secretion rates and are comparable to values found during infusions of exogenous oxytocin for induction of labor. Because the threshold to oxytocin stimulation decreases at the time of parturition because of increases in tissue receptor numbers, the circulating oxytocin levels need not rise to provide the trigger for the labor contractions. The proposed dual role for oxytocin in the mechanism of labor, namely, the stimulation of myometrial contractions and the stimulation of prostaglandin release from the decidua and fetal membranes, provides a unifying concept for the divergent opinions that consider either prostaglandins or oxytocin as the activator of the parturient human uterus.

Es completamente innecesario enfatizar la necesidad de la anticoncepción en un mundo en el que cada año se agrega ochenta millones de individuos. En sólo 25 años la población mundial habrá duplicado su tamaño actual. En muchos lugares del mundo la escasez de alimentos y otros recursos naturales está haciéndose ya evidente, en otras, las consecuencias de las tasas de crecimiento de la población se sienten principalmente en el deterioro del ambiente. En todas partes del mundo las presiones de las poblaciones siempre crecientes y más jóvenes son capaces de crear desorden y violencia social y política.

Tylose gel containing 400 micrograms prostaglandin E2 in 3 ml gel was injected into the cervical canal of 20 patients with high-risk pregnancy and indication for induction of labor, but with unfavorable cervix. Ten were studied after the first gel application, five during repeat injection, and five after application of gel without PGE2. Blood samples were drawn serially during the first 8 hours for determination of oxytocin and 13,14-dihydro,15-ketoprostaglandin-F2 alpha (PGFM). The PGE2 gel increased the Bishop score within 8 hours in all patients; in half of them, artificial rupture of the membranes could be performed and labor induced without further gel application; in the others, it was repeated every 8 hours until a Bishop score of greater than or equal to 8 was achieved. Fourteen of the 15 PGE2-induced patients delivered vaginally. Mean PGFM levels did not increase significantly during the 8 hours of observation, but in patients who responded with rapid progression, an increase was seen after cervical dilation was 6 cm or more. The mean oxytocin levels increased within 60 minutes after PGE2 application and were increased for the remaining observation period. Application of inactive gel had no effect on cervical ripening nor on oxytocin or PGFM levels.

Plasma oxytocin (OT) concentrations were determined in 14 late-pregnant and parturient Angus-Hereford cows. Jugular and utero-ovarian veins were cannulated for simultaneous withdrawal of blood samples. Samples were collected at 10-min intervals for 6 h once weekly beginning 60‐14 days before the date of expected delivery (group 1), or daily 3‐7 days before the due date (group 2). In a third group, samples were collected at 15min intervals every other day for 12 h beginning 1 wk before calving. Basal levels of OT were low, the overall mean for both veins was 0.46 6 0.03 mU/ml until a week before parturition, and then increased to 0.77 6 0.1 mU/ml (P , 0.02). Spurts of OT occurred intermittently on all days. Interpeak intervals averaged 71.0 6 10.7 min until Day 214, and from Day 214 to Day 21 the intervals were 44.0 6 5.3 min (P , 0.05). From Day 260 to Day 225 the amplitudes of OT peaks were low and similar in both veins (mean 1.37 6 0.1 mU/ml). From Day 214 to Day 21 the peak amplitudes were 3.6 6 0.4 mU/ml on average (P , 0.02). During the last 2 wk the utero-ovarian peak of OT was frequently higher than the peripheral peak. In addition, a number of spurts were observed in the utero-ovarian vein

Contents The oxytocin receptor (OTR) plays a central role in the functioning of the reproductive tract in the female ruminant. During the oestrous cycle endometrial OTR is suppressed through most of the cycle, probably in a progesterone-dependent manner, to be massively up-regulated during the few days before and after oestrus. At this time, luteal OT triggers a positive feedback loop, the endometrial OTR mediating the release of luteolytic PGF2α which feeds back to the corpus luteum to cause the secretion of more OT and to induce luteolysis. This feedback is only interrupted if a newly formed blastocyst is present. Ruminant blastocysts secrete the cytokine interferon-τ, which interacts directly with the endometrial epithelial cells, preventing the up-regulation of OTR in late luteal phase. During early pregnancy the levels of OTR in endometrium remain very low whereas myometrial OTR are less affected. OTR in endometrium are up-regulated around day 50 and then progressively increase to reach a maximum at the onset of labour; those in the myometrium are upregulated somewhat later in gestation, around day 100. The OTR in the cervix are differently regulated: their concentrations are very low through most of the cycle and gestation and do not increase until pro-oestrus and at parturition when they abruptly rise to high values. Ligand binding to the mucosal and endometrial OTR causes specific release of prostaglandins, which in turn activate paracrine pathways in the surrounding tissues to induce softening of the connective tissue of the uterine wall during pregnancy, and of the cervix at term. Additionally, local uterine contractions induced by OT and potentiated by prostaglandins may serve a physiological function during pregnancy by improving uterine blood flow. Due to the appearance of gap junctions in myometrium at term the OT-induced contractions become synchronized and well propagated and because of concomitant cervical softening the contractions become expulsive. Although OTR-dependent physiology correlates well with the levels of circulating gonadal steroids, there is no evidence for any direct effect of steroids either on the OTR gene or OTR protein. Instead, progesterone appears to exert an indirect inhibitory effect on the OTR gene, probably mediated via other cell types. This is in contrast to the inhibition by interferon-τ which appears to activate a pathway which directly suppresses the OTR gene expression. The important role of OTR in female uterine physiology, and its value as an indicator molecule, make it imperative to understand the complex molecular mechanisms underlying its regulation. These are likely to be of fundamental importance for many aspects of uterine function both in ruminants and in other species, including the human.

Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA were measured by ribonuclease protection assays in total RNA extracted from intercaruncular and caruncular endometrium, myometrium, cotyledons, and cervical mucosa of pregnant cows. Tissues were obtained at gestational ages of 150 days and 275 days and at term not in labor, at term in labor, and 6-12 h postpartum. Additionally, the effect of oxytocin (OT) on COX-2 expression was determined in intercaruncular endometrium of six third-trimester cows (between 230 and 270 days of pregnancy), three of which were injected with OT (200 IU) and three with saline 2 h before tissues were harvested. Prostaglandin F2alpha (PGF2alpha) metabolite was measured in plasma samples taken at 15-min intervals before and after the injections. Results showed that COX-2 mRNA was expressed in every type of tissue examined, although in different concentrations and beginning at different stages. Other than in seminal vesicular and prostate glands used as positive controls, low concentrations of COX-1 mRNA were detected only in myometrium and caruncles. Cotyledons had the highest concentration of COX-2 transcripts at all stages studied. Caruncles had about half the concentration of COX-2 transcripts that was seen in cotyledons, and on Day 150 even less. COX-2 mRNA expression in both tissues increased with advancing gestation, but there was no difference between samples from term-no-labor and term-in-labor cows. COX-2 mRNA concentrations in endometrium and myometrium were low; they varied randomly during pregnancy with no significant increase until postpartum, when COX-2 transcripts in endometrium had increased severalfold whereas those in myometrium were similar to values before parturition. Cervical mucosa expressed COX-2 mRNA weakly until term but had increased markedly at parturition. Injection of 200 IU of OT induced a substantial increase in endometrial COX-2 mRNA concentration within 2 h; this was associated with linearly increasing plasma concentrations of 13, 14-hydroxy-15-keto-prostaglandin F2alpha, which were still rising at termination of the experiment. The results suggest that endogenous OT is a major factor in induction of COX-2 expression and PGF2alpha release at term and during parturition in cows.

The purpose of this study was to determine the specificity and concentration of oxytocin (OT) and arginine vasopressin (AVP) binding sites in non-pregnant (NP) human and rhesus monkey endometrium, myometrium and fibromyomas, and to determine the cellular localization of OT receptor (OTR). Besides [3H]AVP, [125I]LVA, a specific VP1 receptor subtype antagonist, was used to determine vasopressin receptor (VPR) concentrations. Samples were obtained from 42 pre-menopausal and three pregnant women (5, 13 and 35 weeks gestation), and several NP and pregnant monkeys. Specificity of binding was assessed in competition experiments with unlabelled agonists and antagonists of known pharmacological potency. Cellular localization of OTR was determined by immunohistochemistry. In NP human uterine tissues, [3H]AVP was bound with higher affinity and greater binding capacity than [3H]OT, whereas in pregnant women and in NP and pregnant rhesus monkeys, uterine OT binding capacity was greater. OT and AVP binding sites discriminated very poorly between OT and AVP; [125I]LVA binding sites were more selective than [3H]AVP. Their ligand specificity and binding kinetics indicated the presence of two distinct populations of binding sites for OT and AVP in primate uterus. Endometrium of NP women and monkeys had low OTR and VPR concentrations. Myometrial and endometrial OTR and VPR were down-regulated in midcycle and in early human pregnancy, they were up-regulated in the secretory phase and second half of pregnancy. Immunoreactive OTR in NP uterus was localized in patches of myometrial muscle cells and small numbers of endometrial epithelial cells.

The affinity and specificity of an antagonist of oxytocin, [1-D(CH2)5,Tyr(ME)2,Thr4,Tyr-NH2(9)]ornithine vasotocin (OTA), to oxytocin receptors (OTR) in bovine gestational endometrium was determined in displacement experiments with oxytocin (OT) and vasopressin (AVP) analogues and compared to myometrial OTR. OTA had the highest affinity in both tissues. The effect of OTA on OT-induced increase in plasma concentration of 13,14-dihydro-15-keto-prostaglandin F2alpha metabolite (PGFM) was studied in 24 late-pregnant cows. Treatments consisted of i.v. saline; OT (50 IU); OTA (1200 microg); and OTA (400, 1200, or 4000 microg) injected i.v. 5 min before OT (50 IU) (n = 4 each). Samples were collected from jugular vein at 15-min intervals for 30 min before and 3 h after the injection of OT. Progesterone was measured in once-daily samples taken for 7 days after the experiment. OT caused a twofold increase in plasma PGFM within about 60 min (p < 0.005), with levels returning to baseline at 150-180 min; OTA (1200 microg) caused a gradual lowering of basal plasma PGFM over 180 min (p < 0.05). The 400-microg or 1200-microg dose of OTA did not alter OT-induced PGFM response, whereas the 4000-microg dose inhibited it almost completely (p < 0.005). Plasma progesterone declined after the experiment in all cows, with no differences among groups. Because OTA inhibits OT-induced release of endometrial prostaglandin F2alpha it may be a good tocolytic agent.

Oxytocin (OT) receptor (OTR) concentrations were determined in the cervix of nonpregnant cows on cycle Days 0, 3, 7-8, 17, and 19 (n = 3-4 cows each day); [3H]OT was used as the labeled ligand. Mucosal and muscle layers of the cervix were also analyzed separately for both ligand binding and expression of the OTR gene using a newly developed RNase protection assay (RAP). Cellular localization of OTR protein was determined by immunohistochemistry. All regions of cervix from cows at estrus had high concentrations of OTR; in the luteal phase, all were sharply down-regulated. At estrus the mucosal layer had about 30-fold higher concentrations than the muscle layer. OTR mRNA was readily detected by RAP in the mucosa from estrous cows, while much weaker signals were found in the muscle. On Days 7-17, the OTR mRNA signals in both mucosa and muscle were very faint or nondetectable. Thus, there was a good correlation between ligand binding and mRNA expression, which suggests that OTR concentrations are mainly regulated at the transcriptional level. The epithelial cells at the luminal surface of the mucosa were the principal site of immunoreactive OTR; muscle cells showed significantly weaker signals. Previously, OT was found to stimulate prostaglandin (PG) E2 output in vitro in bovine cervical tissues. Since PGE2 is capable of softening the cervix, our findings suggest that OT may have a novel physiological function to cause softening of the bovine cervix mediated by the release of PGE2.

Brahman cows with known breeding dates received i.v. injections of either 10 or 100 IU oxytocin (OT) on Days 50, 150, 250, or 280 of gestation (n = 6 for each stage). Concentrations of the prostaglandin (PG) F 20 metabolite, 13,14-dihydro-15-keto-prostaglandin (PGFM), and OT were measured in samples of peripheral plasma collected at 15-min intervals for 1 h before and 1 h after treatment and then at 30-min intervals for 3 h. Plasma progesterone was measured daily for 14 days after OT injections on Days 50 and 250 of gestation. The increase in plasma OT after injection was dose-dependent (p = 0.001) but not affected by stage of gestation. Plasma PGFM increased after OT in a dose- and stage-dependent manner (p = 0.0001). At Day 280, the increase in plasma PGFM after 100 IU OT was sevenfold greater than at Day 50. Plasma progesterone declined significantly during the 7th to 12th days postinjection and returned to normal pregnancy values by the 14th day (4.4 ± 0.3 ng/ml) except in two cows treated on Day 50 of gestation that later aborted. In these, plasma progesterone was significantly lower, 2.6 0.1 ng/ml. In a second experiment, the concentration of OT receptors was determined in endometrium collected from purebred Angus or Hereford cows slaughtered on Days 50, 150, 250, and 280 of gestation (n = 3 or 4 at each stage). Endometrial concentrations of OT receptor changed as a function of gestational age, increasing sixfold from Day 50 to Day 280, which was parallel to the increase by OT of plasma PGFM. Thus, endometrial OT receptors are functionally coupled to PGF2, release during pregnancy, and their concentration determines the magnitude of OT-induced PGF2, release during gestation. Consequently, endogenous OT is a factor in the regulation of PGF2. release from the bovine uterus during pregnancy and parturition.

The peptide hormone oxytocin is produced both in the hypothalamus and in certain peripheral organs. The extent of extra-hypothalamic hormone synthesis in the pregnant cow has not previously been examined. In this study we have analyzed different tissues from the pregnant bovine reproductive tract and corpus luteum for the presence of mRNA encoding the oxytocin peptide as well as the oxytocin receptor. In uterine tissues oxytocin mRNA could only be detected sporadically with the help of a reverse transcription-polymerase chain reaction method, implying only very low levels of expression. The caruncles showed a consistently low level of oxytocin gene expression, which appeared up-regulated at term. However, in the corpus luteum there was a significant level of oxytocin gene expression at term, particularly following the onset of labor. The transcript levels were sufficiently high to be measurable by both RNase protection assay and by Northern hybridization; these levels imply a rescue of the oxytocin gene expression seen in the corpora lutea of cyclic and early pregnant cows. At the peptide level this expression was confirmed by immunohistochemistry. A sensitive RNase protection assay was developed to detect transcripts encoding the oxytocin receptor. Transcripts were detected in most uterine tissues, including the caruncles, with highest levels in the endometrium and myometrium at term. No transcripts could be detected in the corpus luteum at any stage of pregnancy, nor in the amnion. The results suggest the possibility of local, paracrine effects of oxytocin within the uterus of the pregnant cow. The rescue of luteal oxytocin at term could act to supplement the circulating hormone of pituitary origin.

OBJECTIVE: Our purpose was to determine whether RU 486 (mifepristone) has direct estrogenic activity in uterine myocytes. STUDY DESIGN: Ovariectomized adult rats were treated with RU 486, and its effect on uterine oxytocin receptor concentration, as a marker of estrogenic activity, was measured. Results were compared with th induction by RU 486 of an estrogen-responsive reporter gene in a cultured Syrian hamster uterine myocyte cell line. RESULTS: Baseline oxytocin receptor concentration was 58.8 ± 7.2 fmol/mg protein (mean ± SEM) and increased to 227 ± 49 fmol/mg with 17β-estradiol (2.5 μg/kg) and to 145 ± 18 fmol/mg afte RU 486 (5 mg/kg) treatment, an effect that was inhibited by the antiestrogen ICI 182,780 (1.5 mg/kg). In the cultured Syrian hamster uterine myocyte cell line cells RU 486 (10 −6 mol/L) caused a 2.17 ± 0.17-fold increase in the expression of the reporter gene versus 113.0 ± 7.4-fold with 17β-estradiol (10 −8 mol/L). The estrogenic activity of RU 486 was dependent on the presence of both estrogen receptor and the promoter's estrogen response element. CONCLUSION: RU 486 has a weak estrogen-like activity in uterine myocytes. This activity may partly explain the therapeutic effects of RU 488 on this target organ.

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.

OBJECTIVES: Our purpose was to determine whether plasma oxytocin concentrations show a daily rhythm. STUDY DESIGN: Ten women between 37 and 39 weeks of gestation volunteered for the study. They were admitted 1 to 2 days before the experiment. Three blood samples were taken with 2-minute intervals each time, at 8 AM, 4 PM, and 12 midnight. Oxytocin, 17 β-estradiol, progesterone, and cortisol were measured by radioimmunoassay with highly specific antibodies. Statistical analysis of variance by Friedman's test was followed by multiple range testing, and p \lt 0.05 was considered significant. RESULTS: Significant daily rhythm was found for plasma cortisol, progesterone, and oxytocin and for the estradiol/progesterone ratio. Oxytocin showed a nocturnal peak and a strong negative correlation with the estradiol/progesterone ratio. CONCLUSIONS: The daily rhythm in plasma oxytocin parallels the rhythm in uterine activity (shown by others), suggesting a causal relationship between the two. Both may in turn be related to the ratio of circulating estradiol and progesterone. (AM J OBSTET GYNECOL 1992;167:1559-63.)

Oxytocin receptors were measured in myometrium and intercaruncular endometrium of cows during pregnancy and partu. rition. Concentrations of estradiol-17�l, estrone, and progesterone in peripheral blood were also measured. Receptor concentrations in the endometrium rose almost 200-fold from Day 20 to term (p < 0.0001, ANOVA), from 40 ± 11 to 7300 ± 1430 finol/mg protein. Myometrial receptor concentrations increased 10-fold from 180 ± 36 flMol/mg on Day 20 to 1850 ± 360 ftnol/mg protein at term (p

The secretory pattern of oxytocin was determined in blood samples taken at 1-minute intervals for 30 minutes from 32 parturient women. The samples were collected in a manner that minimized degradation by plasma oxytocinase, and a highly specific antibody was used for the radioimmunoassay. The results indicated that oxytocin is secreted in discrete pulses of short duration. The frequency of the pulses was significantly higher during spontaneous labor than before the onset of labor. The mean pulse frequencies per 30 minutes were 1.2 +/- 0.54 before labor, 4.2 +/- 0.45 during the first stage, and 6.7 +/- 0.49 during the second and third stages of labor. The mean pulse durations in these three groups were 1.2 +/- 0.20, 1.9 +/- 0.28, and 2.0 +/- 0.26 minutes, respectively. The amplitude of the pulses was variable with no significant differences between the groups, the majority being around 1.0 microU/ml. The spontaneous pulses were of similar magnitude as those measured in 18 women after intravenous injections of 4 to 16 mU of oxytocin, which doses stimulated uterine contractions. We therefore conclude that the pulses of oxytocin observed at increasing frequency during spontaneous labor are of physiologic significance and provide evidence for the participation of oxytocin in the onset and maintenance of spontaneous labor.

Human ovarian tissue and bovine ovarian stroma and follicles bound tritiated oxytocin and tritiated arginine vasopressin with similar affinity, whereas bovine corpora lutea bound tritiated oxytocin only. Competition for the binding of tritiated oxytocin by various agonists and antagonists was suggestive of receptor function. The number of oxytocin binding sites varied cyclically in all tissues. In bovine ovarian stroma and corpora lutea the concentrations were lowest on day 14 and highest on days 17, 19, and 21 after ovulation, with a striking peak in the luteal concentration on day 19. In human ovarian tissues the concentrations also were highest in samples obtained in late luteal phase. In large follicles the concentration of oxytocin binding sites was highest on the day of estrus and lowest on day 7. In bovine ovary the number of arginine vasopressin binding sites was approximately 50% lower than oxytocin binding sites and the cyclic variations were not significant. Human ovarian tissue had similar numbers of oxytocin and arginine vasopressin binding sites. Because bovine ovaries produce oxytocin and arginine vasopressin the results suggest a paracrine or autocrine role for these neuropeptides in luteolysis and ovulation. Although their synthesis in human ovaries is still controversial the presence of binding sites suggests a physiologic role in the regulation of human ovarian function as well.

The oxytocin receptor (OTR) is part of an ancient hormone system expressed in diverse phyla in relation to acute reproductive smooth muscle responses, such as egg-laying, birth, or milk letdown. The regulation of the OTR gene, while correlating with steroid levels in vivo, remains elusive. There appear to be both inhibitory and stimulatory influences acting upon a constitutive pattern of basal expression. We have found no evidence, however, for an effect of the sex steroids either directly on gene transcription, or on the receptor itself at the protein level. In the prostatic carcinoma cell line Du145, we have shown that up-regulation of the OTR gene transcription can be effected by cAMP. In an attempt to characterize the expression of the OTR protein in vivo, we have shown, using ligand-blotting, that the OTR can be expressed at different sizes in transfected cells and in myometrium. Also, in the myometrium at term, immunohistochemistry suggests that there is both an increase in OTR protein per cell, as well as in the number of smooth muscle cells expressing OTR, emphasizing that perinatal changes are the results of both individual gene activation events and gross cellular differentiation. The OTR is a valuable model system reflecting molecular changes in the perinatal period. When we understand how this important molecule is regulated, we will also be a long way towards understanding the mechanisms controlling myometrial contractility at birth. Experimental Physiology (2001) 86.2, 289-296.

Developmental aspects of oxytocin (OT) receptors (OTR) in uterine tissues before puberty are not known. Bovine ovaries secrete some estradiol, but no progesterone, before puberty; the circulating levels of estradiol are between 1 and 3 pg/ml until puberty. Cross-bred Angus-Brahman heifers, in which puberty occurs around 12 months of age, were used to determine the concentrations of OTR from the late fetal stage to adulthood. PGF2alpha release in response to OT was determined in 3-, 6-, and 9-month-old heifers (n = 4 each). Myometrium, endometrium, and cervical mucosa were obtained from 3-week-old, 3-month-old, 6-month-old, and 9-month-old heifers and from adult cows at estrus. Whole uterus and cervix were taken from third trimester fetuses and at birth. [3H]OT binding and specificity, localization of immunoreactive (ir) OTR, OTR messenger RNA, and OT-induced release of PGF2alpha were determined. The uterus from fetuses and the neonate expressed OTR messenger RNA and bound [3H]OT. At 3 weeks of age, OTR concentrations per mg protein were very low, but at 3 months of age they had increased markedly in all three tissues. At 6 and 9 months of age, levels of OTR had risen further and were similar to those in adult cows at estrus. Prepubertal uterus also possessed separate vasopressin VP1 subtype receptors. The ir-OTR was localized in luminal epithelial cells of endometrium and cervical mucosa, most of which were ir positive, whereas in myometrium, clusters of ir-OTR-positive cells were found among large numbers of ir-OTR-negative cells. The PGF2alpha response to OT was insignificant in heifers of all age groups, in contrast to that in cows at estrus. Endometrial cells from 4- to 5-month-old heifers did not respond to OT with PG release in the absence or presence of added arachidonic acid. Tumor promoters, lipopolysaccharide, and interleukin-2 also failed to elicit PG release in vitro, although they induced PG release in similar cell cultures from cyclic cows. In summary, uterine tissues of prepubertal heifers have high levels of OTR, which appear to be developmentally regulated. These receptors are not coupled to PG synthase, or alternatively, the PG synthase gene is not expressed before puberty, possibly because the tissues have had no previous exposure to progesterone.

Previous studies have shown that infusion of oxytocin into normal dogs increased plasma levels of insulin and glucagon. These responses were accompanied by increased rates of glucose production and overall glucose uptake. The purpose of the present study was to determine whether, conversely, changes in glucose metabolism would result in changes in oxytocin secretion. In normal dogs, injection of insulin (0.1 U/kg/iv) resulted in increased secretion of oxytocin which coincided with the hypoglycemic nadir, and the oxytocin levels remained elevated for the remaining 60 min, during which time plasma glucose levels were returning to normal. In dogs made diabetic with streptozocin, injection of insulin (1 U/kg/iv) evoked increased oxytocin secretion which began as the plasma glucose levels were falling from the control value of 400 mg/dl to about 170 mg/dl; the oxytocin levels remained above initial values for at least 90 min, during which period plasma glucose returned to normal glycemic values. In normal dogs, infusion of 2-deoxyglucose, which causes intracellular glucopenia, caused a prompt and sustained increase in plasma oxytocin levels. The data suggest that abrupt decreases in availability of glucose in the central nervous system, as induced experimentally by administration of 2-deoxyglucose or by a rapid fall in peripheral glucose levels, evokes secretion of oxytocin.

Oxytocin has multiple actions in bovine reproductive tract and it was our purpose to determine the nature of these actions and their significance for the physiology of bovine reproduction. The bovine oxytocin receptors (OTR) gene was cloned and its expression studied during the cycle and pregnancy. OTR mRNA changed in parallel with OTR with control occurring mainly at the transcriptional level. However, the endocrine regulation of OTR were found in endometrium and cervical mucosa at estrus and at parturition. In both tissues OTR were suppressed in the luteal phase and early pregnancy. Whereas cervical OTR remained suppressed throughout pregnancy, endometrial OTR began to increase soon after implantation and reached higher concentrations in midpregnancy than at estrus. OTR in caruncles did not increase until third trimester, and OTR in cervical mucosa, cotyledons and fetal membranes increased only at term. Myometrial OTR showed less variation and OTR were present throughout the cycle and pregnancy but increased significantly during mid- and late pregnancy. OTR were localized in endometrial epithelial cells and lumina epithelial cells of cervical mucosa as determined by immunohistochemistry. Endometrial OTR were functional throughout pregnancy and mediated PGF release from day 50 onwards in a receptor density related manner. OTR in cervical mucosa mediated PGE release both in vivo and in vitro, as shown in cyclic cows. The ontogeny of uterine OTR was studied from third trimester fetal stage until puberty. OTR were present in endometrium and cervical mucosa in high concentrations throughout this period; myometrial OTR began to increase somewhat later but also reached adult values by 6-mo of age. In the prepuberal heifers OT injections failed to initiate PGF2a, release. The influence of steroids on the effect of OT was examined. Ovariectomy and E2 were without effect, but P4 with or without E2 induced a massive PGF2a release in response to OT in spite of reduced OTR. Bovine cyclooxygenases (COX-1 and COX-2) were cloned and their expression studied in the endometrium of prepuberal heifers and pregnant cows. Untreated and E2 treated prepuberal heifers did not express COX-2 but P4 treated heifers did express the mRNA for COX-2, albeit weakly. During the second half of pregnancy COX-2 mRNA was strongly expressed in cotyledons and somewhat less in caruncles, whereas endometrium, myometrium and cervical mucosa showed only weak, if any, COX-2 mRNA under basal conditions. However, 2 h after OT injection significant increases in COX-2 mRNA were found in endometrial RNA. Thus OT is capable of inducing the expression of the inducible COX-2 gene, and hence the conversion of arachidonic acid to prostanoids. The results indicate that the functions of OT are numerous and probably essential for successful pregnancy and parturition.

The concentrations of plasma oxytocin and prostaglandin F2 alpha metabolite (PGFM) were measured in 10 parturients with and 10 without lumbar epidural analgesia. A blood sample was taken immediately before analgesia and another 60 min later. The control patients were matched for the stage of cervical dilatation at the time of the first blood sample; the second was drawn 60 min later. Plasma PGFM decreased significantly after lumbar epidural anesthesia and increased in controls resulting in a highly significant difference between the groups (P < 0.005). Plasma oxytocin concentrations levels also changed in opposite directions in the two groups but the difference did not reach statistical significance (P < 0.1). Uterine activity increased in the controls and decreased in the analgesia group resulting in a significant difference between the groups (P < 0.05). All subjects delivered vaginally. The total duration of labor was longer in the analgesia group (7.8 +/- 1.0 h vs. 4.7 +/- 0.6 h; P < 0.05) as was the duration after analgesia (5.1 +/- 0.9 h vs. 2.5 +/- 0.8 h; P < 0.05), whereas the duration of the second stage was not significantly different. We conclude that lumbar epidural anesthesia results in suppression of PGF2 alpha release which may be the cause of the diminished uterine activity and the prolonged duration of the first stage of labor.

The binding of [3H]oxytocin ([3H]-OT) and [3H]arginine vasopressin ([ 3H]-AVP) by bovine endometrial and myometrial membrane preparations obtained on days 0, 7, 14, 17, and 21 after estrus or mating was investigated. [3H]OT was bound with higher affinity than [3H]AVP by both tissues; the mean dissociation constants (KdS) were 0.95 x 10(-9) M and 1.56 x 10(-9) M for OT and AVP, respectively, P less than 0.0001, with no significant variations in the KdS during the cycle. The concentration of [3H]OT binding sites was on the average 50% higher than [3H]AVP across the cycle in both tissues. Endometrial receptor levels varied significantly during the cycle; it was lowest on days 7 and 14, rose significantly on day 17, and peaked on day 21. Myometrial receptor levels decreased from levels at estrus on days 7 and 14, but the changes were not significant. The ratio between endometrial and myometrial receptor concentrations changed from about 10 at estrus to less than 1 in the luteal phase. In early pregnancy, the receptor levels did not differ from nonpregnant levels on days 7 and 14, but on day 17 the endometrial receptor concentrations were significantly lower, and on day 21 those in both tissues were significantly lower. The endometrial OT and AVP receptor concentrations were inversely correlated with plasma progesterone levels (P = 0.005) with no correlation to plasma estradiol, whereas the myometrial receptor concentrations showed no correlation to plasma progesterone but an inverse correlation with plasma estradiol (P = 0.004). We conclude that the endometrial OT and AVP receptor concentrations are more tightly controlled by progesterone than myometrium, and that the bovine conceptus suppresses endometrial OT and AVP receptor concentrations in the preattachment stage either by a local action on the endometrium or indirectly via an antiluteolytic effect.

SummaryVasoactive intestinal peptide (VIP) immunoreactivity has been localised in neuronal vesicles within the hypothalamus and the pituitary, suggesting a role for VIP in the regulation of anterior and posterior pituitary function. VIP has been shown to be a secretagogue for prolactin release, but not for LH or FSH. We investigated the effect of exogenous VIP on plasma levels of oxytocin, vasopressin, ACTH, growth hormone and thyroid stimulating hormone in non-pregnant women. Intravenous infusion of VIP resulted in a significant increase in the concentration of both oxytocin and vasopressin in peripheral blood, while no change was observed in the concentrations of thyroid stimulating hormone, growth hormone or ACTH. Hormone release from the neurohypophysis induced by VIP in man is in accordance with observations in rats and cats and supports our hypothesis that endogenous VIP participates in the regulation of posterior pituitary lobe function.

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.

To investigate whether a putative oxytocin (OT) receptor blocker 1-deamino-[2-D-tyrosine (OEt)-4 threonine-8-ornithine]oxytocin (dTVT) inhibits OT binding to its receptors, we studied binding of [3H]OT to late-pregnant human, guinea pig, and rat myometrial and decidual membranes and competition of dTVT with this binding. Decidua as well as myometrium of all three species bound [3H]OT with high affinity (Kd 1-3 nM) and limited capacity. The concentration of binding sites in decidual membranes was slightly lower than in myometrial membranes in human and guinea pig uterus and twice that of myometrial membranes in day 20 pregnant rat uterus. dTVT competed with [3H]OT with highest affinity in guinea pig myomterium and decidua, the potency ratios ([dTVT]50: [OT]50) being 1.9 and 3.3, respectively. The potency ratios in rat uterine tissues and human decidua were slightly higher (4 to 5) and highest in human myometrium, 23.3. Excess dTVT completely inhibited [3H]OT binding in all six tissues, indicating binding to the same receptor sites. Because of the high-affinity binding of dTVT to oxytocin receptors in human decidua and myometrium, this oxytocin analogue may be a very effective tocolytic agent in the treatment of threatened preterm labor.

The concentration and distribution of specific [3H]oxytocin-binding sites in the nonpregnant human uterus were studied. Oxytocin was bound with an apparent Kd of about 1 nM in the crude membrane fractions of the fundus and corpus. A second class of sites with lower affinity and higher capacity for oxytocin also was found. Consistent with its high uterotonic potency in nonpregnant uteri, arginine vasopressin was as effective as oxytocin in inhibiting [3H]oxytocin binding to corpus and fundus membrane preparations. The concentrations of high affinity binding sites in fundus and corpus were similar and were significantly higher than those of membrane fractions from isthmus or Fallopian tubes. The lowest concentration of sites was found in the cervix. Endometrial membrane preparations contained oxytocin-binding sites in about the same concentration as that in the myometrium. The concentrations of oxytocin receptors in all parts of the nonpregnant uterus were somewhat higher in the luteal phase than in the follicular phase. Concentrations were lowest in postmenopausal uteri. The concentrations of oxytocin receptors in nonpregnant uteri were 50-100 times lower than those in uteri near the end of gestation. These differences correspond to the differences in sensitivity to oxytocin between luteal phase and follicular phase and between the nonpregnant and late term uterus. These findings add support to the evidence that the binding sites for oxytocin represent true oxytocin receptors.

Rupture of membranes at term, whether spontaneous or artificial, causes rapid and sustained increase in prostaglandin F2 alpha (PGF2 alpha) metabolite (PGFM) levels and is associated with augmentation of uterine contractions. To investigate why premature rupture of membranes (PROM) often fails to initiate uterine contractions, we measured plasma concentrations of PGFM and oxytocin (OT) in patients with PROM near term. Serial blood samples were taken before and after PROM as well as before and after local PGE2 gel application for cervical ripening. For comparison, patients with similar criteria with intact membranes were also studied, as were patients in spontaneous labor at term with and without spontaneous rupture of membranes. PROM was always associated with an initial, marked increase in plasma PGFM. Whether or not this increased PGF2 alpha production was maintained was related to the cervical status at the time of PROM. In patients with unripe cervix PGFM levels returned to initial levels within 2 hours and no contractions were elicited; when the cervix was 3 cm or more dilated, PGFM levels remained high and contractions began within 1 to 3 hours. PROM had no significant effect on plasma OT levels. When PGE2 gel was applied to ripen the cervix, PGFM levels increased moderately within 30 minutes in all patients regardless of the status of the membranes. In patients with intact membranes the concentration of PGFM in plasma declined to initial levels within 4 hours, whereas in patients with PROM, PGFM levels remained increased throughout the study period.(ABSTRACT TRUNCATED AT 250 WORDS)

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.)

We had previously shown that the hypothalamo-neurohypophyseal vasopressin secreting system is suppressed in aged rats. In the present study, using aged (26 months) male Fischer 344 (F344) rats, we showed that in contrast to vasopressin, oxytocin plasma concentration and hypothalamic content were unaltered in comparison with young (2-3 months) rats; however, based on data from our past and current studies, the neurohypophyseal concentrations of both hormones were found to be decreased in aged rats. We also compared the effect of aging on the oxytocin and vasopressin in secretory functions. Superfusion technique was employed to examine oxytocin and vasopressin release from isolated neural lobes of young (2-3 months) and old (26 months) male F344 and young (2-3 months), middle-aged (12 months) and old (30 months) Sprague-Dawley (SD) rats. Aging affected basal release of oxytocin and vasopressin in a differential manner. Expressed per gland, basal release of oxytocin increased in aged rats of both strains; whereas vasopressin release decreased in SD, and did not change in F344, old rats. The vasopressin responses to electrical stimulation, 56 mM K+ and initial traumatic release were decreased in aged rats; whereas oxytocin responses were either unaltered or decreased much less. All age-related changes were more pronounced in SD than in F344 rats. Thus, while the aging process is associated with a significant impairment in the vasopressin secretory function, the oxytocin secretory function is much less affected by that process. Significant strain differences were observed in the effects of aging on oxytocin and vasopressin release.

Contractile elements are found in the ovaries of many species, but it has not been possible to ascertain whether these elements are of importance in the process of ovulation. In this report, we describe changes in intraovarian pressure recorded continuously in vivo in unanesthetized rabbits under normal conditions and under the influence of intravenously injected human chorionic gonadotropin (hCG), as well as following the ovulatory stimulus of normal copulation. The recordings were made by means of small latex balloons (0.02- to 0.04-ml volume) attached to indwelling catheters, inserted into the ovarian stroma, and secured with 6-0 nylon sutures. All 24 rabbits studied showed changes in intraovarian pressure indicative of ovarian contractile activity. The intraovarian pressure changes followed a characteristic pattern which was different from the changes in intratubal pressure, recorded simultaneously from the lumen of the ipsilateral fallopian tube, indicating that the contractions of both organs occurred independently. In normal animals, before an ovulatory stimulus was applied, the ovarian contractility pattern consisted of a series of rapid contractions (average amplitude, 6 mm Hg; average frequency; 8 per minute) occurring with intervals of quiescence lasting from 11 to 36 minutes. The base line tonus was frequently elevated during these series of contractions. Mating or an injection of hCG had no immediate effect on intraovarian pressure but, 6 to 8 hours after the stimulus was applied, ovarian contractile activity increased significantly in all rabbits. This enhanced activity persisted for several hours before returning to initial levels approximately 15 to 18 hours after mating or the hCG injection. This demonstration of increased contractile activity about the time of ovulation suggests that ovarian contractions participate in the process of follicular rupture and the extrusion of ova at ovulation. Prostaglandin F2alpha, norepinephrine, and oxytocin were effective in inducing ovarian contractions.

The plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F 2α (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 F 2α (PGF 2α ) 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 PGF 2α are required for adequate stimulation of the human uterus during labor. In addition, the data suggest that oxytocin rather than PGF 2α may be the major stimulus that initiates labor, whereas PGF 2α appears responsible for the progress of labor.

Summary. The concentrations of 13,14-dihydro-15-keto-prostaglandin F2α (PGFM) and oxytocin were measured by radioimmunoassay in the peripheral plasma of 21 women with low Bishop scores in whom cervical ripening and labour were induced with a cervical cap containing 1.5 mg of prostaglandin (PG) E2, left in place for 6 h. Blood samples were taken before and at 3, 6, 9 and 24 h after the cap was applied. Four women (control group) had a cap without PGE2. Labour began in 13 women receiving PGE2, 12 of whom were delivered within 24 h. In these women plasma PGFM rose progressively to levels seen during spontaneous labour, paralleling the changes in cervical dilatation. The increase became significant at 6 h, when cervical dilatation was 4.5 cm (SEM 0.5). Plasma oxytocin also increased significantly while the cap was in place and then decreased. Plasma PGFM and oxytocin did not change in the control subjects, and in the eight women needing further induction of labour the initial rises were transient and not statistically significant.

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.

Electromyograms were obtained from three different locations on the uterus of conscious, unrestrained rats during the 4 days estrous cycle. Intrauterine pressure changes were monitored simultaneously by means of indwelling intraluminal balloons (vol. 0.02 to 0.05 ml.). Electrical activity consisted of bursts of action potentials that were usually initiated at either end of the uterus. Propagated burst activity gave rise to cyclic intrauterine pressure changes, whereas bursts appearing at one electrode only did not elicit any measurable contractions. The rate of intrauterine pressure development depended on the propagation velocity, whereas the tension achieved was related to the duration of burst activity. All three parameters of electrical activity studied, namely, the duration and frequency of spike bursts, as well as their rate of propagation, varied significantly during the cycle. Regional differences were also subject to cyclic variations; thus, in proestrus the bursts originated predominantly at the cervical end, whereas in diestrus they were usually initiated at the ovarian end. Oxytocin stimulated the frequency and duration of bursts along the whole uterus and elicited corresponding changes in intrauterine pressure. Response to oxytocin was dose dependent and modified by cycle stage. Norepinephrine caused a transient prolongation of burst activity that was not dose dependent; epinephrine had a marked dose-dependent inhibitory action. The response to catecholamines did not vary significantly during the cycle. The variations in electrical and mechanical activity were characteristic for each stage of the ovarian cycle and could be correlated with the well-known hormonal changes. High circulating estrogen levels in proestrus are associated with infrequent but rapidly propagated spike bursts, whereas low levels in estrus are associated with frequent and sometimes nonpropaged bursts. The rise in plasma estrogen in diestrus coincides with a decrease in the frequency of burst activity, and the elevated progesterone levels are probably causally related to the significant drop in propagation velocity and the increase in duration of bursts observed in diestrus. These findings are consistent with the concept that estrogen withdrawal activates the estrogen-primed, quiescent myometrium, and that progesterone has an effect similar to that of estrogen withdrawal—at least in the rat.

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.

The effect of estrogen and progesterone on prostaglandin-induced uterine contractions was studied in ovariectomized rats fitted with intrauterine recording balloons. The effects of the three prostaglandins, PGE 1 , PGE 2 , and PGF 2α , injected intravenously were very similar. Pretreatment with estradiol benzoate (1 μg per rat per day) resulted in a considerable reduction of the contractile response to the prostaglandins and was frequently associated with tachyphylactic reactions. Progesterone pretreatment (5 mg. per rat per day), on the other hand, markedly increased the uterine response to prostaglandins and no tachyphylaxis was observed. Intact pregnant rats were studied at mid-gestation; the uterine response in these rats was similar to the response in progesterone-treated rats.

Vasoactive intestinal polypeptide (VIP)ergic nerves innervate both the neurohypophysis and the hypothalamus. To test the hypothesis that VIP is a releasing factor for neurohypophyseal hormones, rats were given intracerebroventricular (icv) infusions of VIP in doses varying from 0.3 pmol/kg.min to 3 nmol/kg.min for 5 min (0.001-10 micrograms/rat). Serial blood samples were drawn from the vena cava for measurement of oxytocin (OT), vasopressin (AVP), and VIP by RIA. After the VIP infusions mean plasma OT and AVP levels rose in a dose-dependent manner; the rise was significant for both hormones at the dose of 300 pmol/kg.min. Peak levels after infusion of 3 nmol/kg.min were greater for OT than AVP [96.1 +/- 14.7 vs. 33.9 +/- 9 microU/ml (mean +/- SE); n = 6]. In addition, the concentration of plasma OT increased more promptly than that of AVP. Plasma OT was significantly raised over control values at 5 min, whereas plasma AVP was not increased until 15 min after the VIP infusion began. The concentration of VIP in peripheral plasma rose somewhat after icv infusions (maximum, 300 pmol/liter 30 min after 10 micrograms/rat), but the rise was only 5% of that observed after systemic infusions of equimolar doses of VIP (maximum, 6000 pmol/liter 5 min after 10 micrograms/rat). Peak plasma OT levels after administration of 3 nmol/kg.min VIP were significantly higher after icv than after systemic infusion of the same dose of VIP reported previously. Intravenous injection of 0.5 ml VIP antiserum with a binding capacity of VIP of 2.3 micrograms/ml before the icv administration of VIP (1 microgram/rat) did not prevent the VIP-induced rise in plasma OT and AVP. These observations suggest a central site of action for VIP in OT and AVP release, probably in the hypothalamus. The results are in harmony with the hypothesis that endogenous VIP is a physiological regulator of OT and AVP release in rats.

Two modes of cervical application of a gel containing PGE2 have been compared in a total of 30 patients with indication for induction of labor and unripe cervix. Fifteen patients had gel injected endocervically; in 10 patients the gel contained 400 micrograms PGE2, in 5 controls the gel was inactive. Fifteen subjects had a 15 ml Foley catheter passed through the cervix and placed extra-amniotically; in 10 of them 3 ml gel with 400 or 800 micrograms PGE2 was injected, while 5 controls received inactive gel. Plasma levels of 13,14-dihydro-15-keto-PGE2 alpha (PGFM) were measured in blood samples drawn before and 1/2, 1, 2, 4, 6, and 8 hours after gel application. Neither the Foley catheter nor the application of inactive gel caused significant changes in the cervical scores or the PGFM levels. PGE2 in the endocervix increased cervical scores without altering plasma PGFM levels. Extra-amniotic PGE2 caused a more rapid increase of the cervical scores and a progressive rise in PGFM levels. The plasma (PGFM) levels were found to be related to the degree and to the rate of cervical dilatation. The correlation with cervical dilatation was highly significant. Labor began spontaneously or after artificial rupture of the membranes in 80% of the extra-amniotic, and 50% of the endocervical PGE2-group, but in none of the controls. These data indicate that increased uterine PGF2 alpha production is not necessary for the early stages of cervical ripening, whereas dilatation beyond 4 cm does not proceed without such increase.

We have measured oxytocin release during lactation in the ewe in response to normal tactile sucking stimuli as well as exteroceptive stimuli emanating from the lamb. Four puerperal ewes that had indwelling catheter inserted in the femoral artery while still pregnant were used. Each nursed a single lamb. Each was studied 2 or 3 times between Days 1 and 15 of lactation during a 2.5-h experimental period that was preceded by a 2-h separation from the lamb in the early morning. Samples were taken before and after the lamb was brought within sight and sound of the ewe but without contact, and then 0.5, 1, 5, 10, 15, 30, and 60 min after suckling began. When another suckling episode intervened, the same sampling schedule was immediately restarted. Suckling occurred in an intermittent fashion; 3 to 4 episodes of 2.9 +/- 2.0 (SD)-min duration took place with variable intervals during the 2.5-h experimental period. Exteroceptive stimuli emanating from the lamb caused plasma oxytocin to rise significantly from basal levels of 10.0 +/- 4.5 to 21.8 +/- 5.7 pg/ml (mean +/- SE, n 10, p less than 0.05). This rise was not seen on Day 1 and in only half of the ewes on Day 2, but thereafter the rise occurred in every instance. A further rise in plasma oxytocin was observed in almost all instances (86%) at suckling. Peak levels were usually observed within 1 min. They were quite variable, ranging from 15 pg/ml to 287 pg/ml, and not related to the milk yield, but were significantly greater than spontaneous pulses observed in nonlactating puerperal sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

1-l-Penicillamine-oxytocin and 1- deaminopenicillamine-oxytocin are analogues of oxytocin that have been found to be potent inhibitors of the oxytocic activity of oxytocin in the rat. The 2 analogues were tested on the rabbit uterus in vivo with regard to the uterine response both to endogenously released oxytocin and to intravenously administered synthetic oxytocin. They were found to be devoid of inhibitory activity when administered in molar ratios of inhibitor to oxytocin between 170:1 and 10000:1. Both analogues had an oxytocic effect on the rabbit uterus in vivo but were approximately 500 to 1000 times less potent than oxytocin in the same preparation. Neither analogue inhibited the milk-ejection effect of oxytocin as judged by the milk yield obtained by the pups from unanesthetized mothers. Both analogues had milkejecting activity estimated on the basis of the milk yield in anesthetized rabbits. This activity was about 50 to 100 times less than that of synthetic oxytocin. A sensitive chronic prepar...

SUMMARY Progesterone determinations were carried out in twenty-eight samples of uterine venous blood collected from women between the 9th and 22nd weeks of pregnancy. The mean progesterone concentration was 35·4 μg./100 ml. plasma (range 8–97), which is ten times as high as the concentration in the peripheral blood.

A method of estimating oxytocin output following physiological stimuli is described which is applicable to experiments in conscious, undisturbed and unrestrained animals. The method consists of recording the uterine responses in puerperal rabbits with a permanently inserted intrauterine balloon as an index of neurohypophysial activation. Previous work has been confirmed on the essential role of oxytocin in milk ejection in rabbits. Only negligible amounts of milk are obtained by the young without any endogenous or exogenous oxytocin, but normal release of oxytocin can occur in spite of diminished or completely inhibited milk flow. The amount of oxytocin released during suckling depends on the strength of the stimulus in a characteristic fashion, and the strength of stimuli again depends both on the number of young suckling simultaneously and on their physical maturity. In the early puerperium (up to 3–4 days post-partum) each suckling young evokes a response comparable to that of 0.5–1.0 mU of oxytocin injected intravenously, whether suckling alone or together with its litter-mates. Only a few grams of milk are removed by each young at that time. After this period, the suckling of 1 or 2 young separately still elicits the release of only a small amount of oxytocin (1–2 mU), but during suckling of a whole litter from 50 to 100 mU are liberated, which corresponds to 10–15 mU for each young. The full milk yield can only be obtained by each young while suckling simultaneously with the whole litter. The amount of oxytocin released is independent of the duration of suckling, of the quantity of milk available, and of the milk flow. Once lactation has been established, the oxytocin output during suckling on an »once-daily« regime remains fairly constant at least for a large part of the lactation period. It is possible that at the end of the lactating period, the amount secreted during suckling is increased to about 250 mU or even more.

Ethanol has previously been shown to inhibit uterine contractions during labor and lactation. Administration of ethanol during the menstrual cycle resulted in marked reduction of the uterine activity, especially during menstruation, when the activity is strongest. The uterine response to oxytocin and vasopressin was not inhibited, and by infusion of vasopressin the pretreatment activity could be restored in spite of continued alcohol administration.

Summary. Determinations of the various phosphorus fractious in the guinea pig placenta in a series of experiments on the placental transfer of phosphate have shown that the orthophosphate concentration is very high in the placental tissue as compared with the maternal and foetal plasma. The concentration increases slowly from the 29th to the 59th day of gestation and may decrease thereafter. Thirty minutes after intravenous injection of radioactive phosphate into the mother the orthophosphate in the placenta has reached a specific activity of one third of that of the inorganic phosphate in the maternal plasma. It has the highest specific activity of the placental phosphorus fractions. Adenosine diphosphate and triphosphate are found in approximately the same concentrations as in the uterine muscle during pregnancy in the rat, the rabbit and the human. The labile phosphorus of these compounds is in equilibrium with the orthophosphate with regard to radioactive phosphorus. Glucose-1-phosphate is present in a low concentration, but it acquires a high relative specific activity. More glucose-6-phosphate is present, but with a low relative specific activity. The inorganic phosphate in the foetal plasma obtains in thirty minutes a specific activity of about half that of the placental orthophosphate.