Maternal plasma prostaglandin E2 metabolite levels during human pregnancy and parturition

Summary. Because of methodological problems associated with the measurement in biological fluids of both prostaglandin E₂ (PGE₂) and its unstable principal circulating metabolite 13,14-dihydro-15-keto-PGE₂ (PGEM), there is little reliable information on these prostaglandins in human pregnancy and parturition. The recent discovery of a stable PGEM degradation product 11-deoxy-13,14-dihydro-15-keto-11β, 16-cyclo-PGE₂ (bicyclo-PGEM) has provided a means of studying endogenous plasma levels of PGEM which circumvents the problems encountered with direct measurements of PGE₂ and PGEM. Using a radioimmunoassay for bicyclo-PGEM we have therefore determined maternal peripheral plasma PGE₂ metabolite levels during human gestation. PGE₂ metabolite levels did not alter significantly during the second or third trimesters nor during labour. This contrasts with maternal peripheral plasma levels of the principal circulating metabolite of PGF_2α 13,14-dihydro-15-keto-PGF_2α (PGFM) which increases several fold during labour. Compared t o PGE₂ therefore. PGF_2α may be quantitatively the more significant prostaglandin associated with human parturition.     

Effect of cervical application of prostaglandin (PG) E2 on plasma 13,14-dihydro-15-keto-PGF2α and oxytocin in pregnant women at term

Summary. The concentrations of 13,14-dihydro-15-keto-prostaglandin F_2α (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.     

Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2α

Summary. Menstrual fluid was collected in a contraceptive diaphragm from 16 women with primary dysmenorrhoea and 12 matched control subjects without dysmenorrhoea. Prostaglandins F_2α (PGF_2α), E₂ (PGE₂) and 6-oxo-prostaglandin F_1α (6-oxo-PGF_lα) were extracted and measured using gas-chromatography: mass spectrometry (GC:MS). The concentrations of both PGF_2α and PGE₂ were higher on days 1 and 2 in the dysmenorrhoea group than in the control group and the concentration of PGF_2α was higher on day 1 than on day 2 in the dysmenorrhoea group. The concentrations of 6-oxo-PGF_1α (the stable metabolite of PGI₂) were low in both groups. These results confirm suggestions that PGF_2α is important in the aetiology of dysmenorrhoea and also indicate that PGE₂ may be involved.     

The treatment of premenstrual tension with mefenamic acid: analysis of prostaglandin concentrations

Summary. Eighty patients with premenstrual tension were treated prospectively with mefenamic acid for a mean period of 13 months. Most of them (86%) reported significant relief of premenstrual tension. Symptoms of dysfunctional menorrhagia or primary dysmenorrhoea were also alleviated. In 19 patients, the plasma concentrations of prostaglandin (PG) E₂, PGF_2α and 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) were measured at intervals throughout three menstrual cycles. During the first cycle the patients received no treatment; in the subsequent two cycles they received either mefenamic acid or placebo in a randomized double-blind crossover manner. Similar measurements were made in 22 matched control subjects. The plasma concentrations of PGE₂, PGF_2α and PGFM were significantly lower in the 19 patients in all three menstrual cycles compared with the values in the control subjects. Excess synthesis of prostaglandins of the 1 series may occur in premenstrual tension and, by precursor depletion, result in decreased synthesis of the 2-series prostaglandins.     

The Safety of Vaginal Prostaglandin F2α for the Stimulation of Labour

Summary: In an audit of 15,102 consecutive deliveries between 1986 and 1991, 3,168 labours were induced with intravenous oxytocin and 824 with 40 mg prostaglandin F₂a (PGF₂α) vaginal gel. Four hundred and twenty women received PGF₂α alone and 404 received PGF₂α followed by oxytocin. The main aim of the study was to audit the safety of PGF₂01 gel to stimulate labour. There were no maternal or neonatal complications attributable to this therapy. In particular, there were no cases of uterine rupture or hyperstimulation requiring surgical or pharmacological intervention. There was little difference in the evidence for fetal distress between induction methods. Although the prostaglandin and oxytocin groups were not comparable in all respects, the results of this large retrospective study confirmed the results of smaller prospective randomized trials showing a significantly shorter labour and reduced analgesia, surgical delivery and postpartum haemorrhage rates in women treated with PGF₂α alone. This is the largest reported series of PGF₂α induced labours and provides evidence of its safety and is in keeping with physiological data suggesting that PGF₂α is the main prostaglandin and oxytocic associated with normal progressive labour. Its apparent safety and potential to reduce both intervention in labour and postpartum complications merits greater attention.     

Twin pregnancy as a model for studies in fetal cortisol concentrations in labour: relation to prostaglandins, prolactin and ACTH

Summary. Cortisol and prostaglandins were measured in umbilical cord blood obtained from 50 twin pregnancies at caesarean section performed either before or during labour. Umbilical artery cortisol concentrations did not differ between twin I and II before labour or in the latent stage. During active labour cortisol levels were significantly higher in twin I than in twin II. Maternal cortisol levels did not correlate with cord blood cortisol levels in either twin before active labour, nor did the rise in maternal cortisol correlate with the cortisol level in twin I; maternal cortisol levels did, however, correlate with cortisol levels in twin II during active labour. Prostaglandins E(PGE), F_2α(PGF_2α), 13,14-dihydro-15-keto F_2αPGFM) and ACTH were measured in cord vein blood. PGE values did not differ between twin I and II before active labour. During active labour PGE levels were significantly greater in twin I and correlated with raised cortisol levels. No differences were seen at any stage in PGE and PGFM levels between twins I and II although PGFM levels increased in both twins during active labour. ACTH and prolactin levels did not increase during labour and were similar in twins I and II. The rise in fetal cortisol during active labour is primarily of fetal origin and PGE may be involved in stimulating cortisol production in the fetus.     

Are leukotrienes involved in human uterine contractility?

Summary. The effects of leukotrienes (LT) on the contractility of human and rat myometrial strips in vitro were compared with the effects of prostaglandins (PGs) and oxytocin. Preparations of human myometrial membranes were investigated for the presence and characteristics of LTC₄ receptors. Neither the peptido-leukotrienes (LTC₄, LTD₄, LTE₄) nor LTB₄ had any consistent effect, stimulatory or inhibitory, on human pregnant or non-pregnant myometrium, at doses up to 1·25 μM; nor did they have any effect in rat non-pregnant myometrium. As expected, PGE₂, PGF_2α (0·3 μM) and oxytocin (5 nM) stimulated human pregnant myometrium. PGF_2α stimulated and PGE₂ inhibited human non-pregnant myometrium but oxytocin had no effect; all three compounds stimulated rat non-pregnant myometrium. The binding of ³H-LTC₄ to human myometrium was specific (LTC₄> LTD₄ >>> LTE₄, LTB₄, PGE₂, PGF_2α, arachidonic acid) but of low affinity compared with the binding of ³H-PGE₂ to the same membrane preparations. These data support the view that leukotrienes have little direct influence on myometrial contractility.     

Induction of labour: a comparison of a single prostaglandin E2 vaginal tablet with amniotomy and intravenous oxytocin

Summary. In a randomized controlled study of 100 women of low parity and favourable induction features, induction of labour by means of a single vaginal tablet containing 3 mg of prostaglandin E₂ (PGE₂) was compared with the conventional method of amniotomy and intravenous oxytocin. Four of the patients (8%) who received the prostaglandin tablet required additional intravenous oxytocin to achieve delivery. The prostaglandin group had a longer mean overall induction-delivery interval but a shorter amniotomy-delivery interval than the oxytocin group. One patient in the PGE₂ group and two in the oxytocin group required caesarean section. The PGE₂ treated patients expressed a higher level of satisfaction with their method of induction, they required less analgesia, had less blood loss at delivery and their babies had a lower incidence of neonatal jaundice.     

The actions of prostaglandins and their interactions with angiotensin II in the isolated perfused human placental cotyledon

Summary. The prostaglandins PGE₁, PGE ₂, PGD ₂, PGF _2α., U46619 and 6_β-PGI_l were administered as bolus injections both separately and in combination with angiotensin II into the fetal circulation of isolated human placental cotyledons perfused in vitro . PGF_2α, and PGD₂, caused small dosedependent increases in fetal perfusion pressure when compared with U46619 which acted as an extremely potent vasoconstrictor of the fetal-placental vasculature. PGE₁, caused very small dose-dependent decreases in fetal perfusion pressure when injected on its own. In combination with angiotensin 11, PGE₁, PGD₂, and 6_β-PG1₁, caused significant, dose-related attenuations of the angiotensin II vasoconstrictive response whereas PGE₂, PGF_2α, and U46619 potentiated the response. Injections of angiotensin II after the infusion of indomethacin into the fetal circulation resulted in a potentiation of angiotensin II induced vasoconstriction. The results indicate that prostaglandins exert their effects on the fetal-placental circulation by modulating the actions of angiotensin II.     

The actions of prostaglandins and their interactions with angiotensin II in the isolated perfused human placental cotyledon

Summary. The prostaglandins PGE₁, PGE ₂, PGD ₂, PGF _2α., U46619 and 6_β-PGI_l were administered as bolus injections both separately and in combination with angiotensin II into the fetal circulation of isolated human placental cotyledons perfused in vitro . PGF_2α, and PGD₂, caused small dosedependent increases in fetal perfusion pressure when compared with U46619 which acted as an extremely potent vasoconstrictor of the fetal-placental vasculature. PGE₁, caused very small dose-dependent decreases in fetal perfusion pressure when injected on its own. In combination with angiotensin 11, PGE₁, PGD₂, and 6_β-PG1₁, caused significant, dose-related attenuations of the angiotensin II vasoconstrictive response whereas PGE₂, PGF_2α, and U46619 potentiated the response. Injections of angiotensin II after the infusion of indomethacin into the fetal circulation resulted in a potentiation of angiotensin II induced vasoconstriction. The results indicate that prostaglandins exert their effects on the fetal-placental circulation by modulating the actions of angiotensin II.     

Comparison of Prostaglandin E2 Vaginal Tablet with Amniotomy and Intravenous Oxytocin for Induction of Labour

Summary: Prostaglandins have been increasingly used in obstetrical practice for cervical ripening and induction of labour. We set out to investigate the effectiveness of prostaglandin E₂ (PGE₂) vaginal pessaries in inducing labour in the Chinese population in Hong Kong. In the period August, 1991 to August, 1992, we recruited 206 pregnant Chinese women who required induction of labour for various obstetrical indications into the trial. The study group had induction of labour by PGE₂ vaginal pessaries and the control group underwent amniotomy plus oxytocin infusion. These patients were alternately assigned either method of induction. They were further divided into primiparous and multiparous (parity 1 and 2 only) groups.
Only 101 primiparas and 99 multiparas were available in the final analysis of the trial. Various aspects of labour, delivery, maternal and fetal outcome were compared. For primiparas, the traditional combined induction was the preferred method. For multiparas, both induction methods were quite satisfactory and there was a trend toward lesser blood loss and pethidine requirement in the PGE₂ users.     

Abnormal concentrations of prostaglandins in amniotic fluid during delayed labour in multigravid patients

Summary. Concentrations of prostaglandins E (PGE), F_2α (PGF), 13,14-dihydro-15-keto prostaglandin F_2α (PGFM), 6-keto F_1α and thromboxane B₂ were measured by specific radioimmunoassay in samples of amniotic fluid from 22 multigravid patients during labour. Normal labour in 10 patients was associated with a significant increase of PGE, PGF and PGFM with close correlation to cervical dilatation ( P < 0.05). In the 12 patients with clinically delayed labour, in the absence of cephalopelvic disproportion, there were significantly lower PGF ( P <0.002) and PGFM ( P < 0.05) concentrations obtained while no differences were observed in the other prostanoids measured. Administration of oxytocin to the latter group to enhance labour did not have any effect on the concentrations of prostaglandins obtained in spite of an improvement in intrauterine pressures and accelerated progress of labour.     

Topographical distribution of prostaglandin E receptors in human myometrium

Summary. The binding of radiolabelled prostaglandin (PG) F_2α and PGE₂ by human myometrium was measured in vitro and the distribution and characteristics of the binding sites in non-pregnant and pregnant uteri were studied. PGF_2α binding sites were of low affinity (Kd 30 nM) and could be occupied by PG of the E series with higher affinity than PGF_2α itself. PGE binding sites were of high affinity (Kd 1·5 nM) and highly specific for PG of the E series, suggesting that they represent true PGE receptors. The concentration of PGE receptors was higher in nonpregnant than in pregnant uteri at term. In non-pregnant uteri the concentration of PGE receptors was highest in the fundus and decreased towards the cervix; in term pregnant uteri the concentration was constant in all areas. In both non-pregnant and pregnant uteri there was a significantly lower PGE binding affinity in cervix than in myometrium from the fundus-corpus area. The concentrations and affinity of PGE receptors were similar during the proliferative and secretory phases of the menstrual cycle and were not influenced by age of the patient. PGE receptors were not influenced by the presence or absence of primary dysmcnorrhoca but appeared to be increased in unexplained menorrhagia.     

The Use of Prostaglandin F2α for the Induction of Mid-Trimester Abortion

Summary: Ninety-eight patients were given prostaglandin F_2α for the induction of mid-trimester abortion. In 42 the PGF_2α was administered by the extra-amniotic route and 37 aborted. A further 56 received the PGF_2α intra-amniotically and 55 aborted. Dose regimens are compared.     

Oral Prostaglandin E2in Induction of Labour

Summary: In a randomised study of 207 patients, labour was induced with oral prostaglandin E₂in 107 and intravenous oxytocin (Syntocinon) in the remainder, half in each group with medication alone, the other half with fore-water amniotomy as well. Prostaglandin and oxytocin were found to be more effective when preceded by amniotomy. Once labour was established, the time taken to achieve vaginal delivery was the same with either drug, as also the number of successful vaginal deliveries. There were 6 failed inductions, but no statistical significance in the percentage differences between PGE₂ and oxytocin could be found. The two perinatal deaths which occurred could not be attributed to either drug. Oral PGE₂is therefore as effective as intravenous oxytocin with no observed hypertonus and little side-effects.     

Concentration of 13,14-dihydro-15-keto-prostaglandin E2 in the maternal peripheral plasma during labour of spontaneous onset

Summary. The concentration of 13, 14-dihydro-15-keto-PGE₂ (PGEM) was measured by radioimmunoassay in pregnant women in the third trimester, in women at term but not in labour and during labour of spontaneous onset. The plasma concentration of PGEM in pregnant women was elevated above that in a non-pregnant control group. Before the onset of labour no increase of PGEM concentration could be identified. Women in labour had higher PGEM plasma concentrations than before the onset of labour, although there was no progressive increase. Immediately after delivery PGEM levels reached a maximum, which decreased significantly to pre-labour values within 30 min. Artificial rupture of the membranes had no influence on plasma PGEM levels. It is concluded that labour is associated with an increased synthesis of PGE₂ and that PGE₂ may be inved in the mechanism of placental separation. The rapid disaearance of high PGEM levels after labour confirms that PGE₂ is probably synthesized mainly in the fetal compartment.     

Erythromycin inhibits prostaglandin F2alpha-induced contractions of myometrium isolated from non-pregnant rats

Objective The aim of this study was to investigate the effects of erythromycin on prostaglandin F_2α (PGF_2α)-induced contractions of isolated myometrial strips from non-pregnant rats.
Design In vitro pharmacological study.
Setting Firat University Faculty of Medicine.
Sample Myometrium samples were taken from 55 adult Wistar rats.
Methods Myometrial strips were isolated from mature, non-pregnant Wistar rats. Isometric contractions of these strips were induced with 1 μM PGF_2α. Effects of 0.01, 0.1, 0.2, 0.5 and 1 mM erythromycin on the frequency and amplitude of these PGF_2α-induced contractions were recorded.
Main outcome measures The inhibition of prostaglandin F_2α-induced contractions in vitro .
Results Application of 0.01 mM erythromycin had no effect on either amplitude or frequency of contractions. However, 0.1, 0.2, 0.5 and 1 mM erythromycin decreased the frequency and amplitude of PGF_2α-induced contractions. The inhibitory effect of erythromycin on amplitude was 27%, 38%, 54% and 83% (   P < 0.05  ), and that on frequency was 10%, 16%, 32% and 61% (   P < 0.05  ) at 0.1, 0.2, 0.5 and 1 mM concentrations, respectively.
Conclusion The results of this study demonstrate that erythromycin inhibits PGF_2α-induced contractions in rat myometrium. Because PGF_2α-induced contractions have been suggested to be involved in the pathogenesis of primary dysmenorrhoea, effects of erythromycin in this clinical entity may present a new approach for the treatment.     

Labour Induction with Intracervical Prostaglandin E2 Gel and Intravenous Oxytocin in Women with a Very Unfavourable Cervix

Summary: Two hundred and sixty-three gravid women having a very unfavourable cervix and requiring labour induction were studied; 80 primigravidas and 56 multigravidas were administered a single dose of intracervical prostaglandin E₂ gel (PGE₂) and 72 primigravidas and 55 multigravidas had labour induced with an escalating oxytocin infusion. After 24 hours 73.8% of the primigravidas induced with PGE₂ had delivered vaginally compared with only 52.8% of those induced with oxytocin. The incidence of Caesarean sections was very high (47.2%) in the primigravidas receiving an oxytocin infusion. In the multigravidas, there was no significant difference in the proportion of women who had delivered vaginally within 24 hours and in the percentage of Caesarean sections in the 2 induction groups. After 12 hours, a significant increase in the cervical score was seen in all women receiving PGE₂ intracervically. The fetal outcome and perinatal mortality were not affected by the mode of induction. Intracervical PGE₂ appears to be more effective than oxytocin in inducing labour in primigravidas having an unfavourable cervix, whereas in multigravidas, both methods appears to be equally effective.     

A Double Blind Dose Trial of Intravaginal Prostaglandin F2α for Cervical Ripening and the Induction of Labour

Summary: A randomised double-blind trial involving 90 patients was set up to compare the efficacy of 25 mg PG F_2α, 50 mg PG F_2α and a placebo on cervical ripening when given in a vaginal tylose gel on the evening before surgical induction of labour. Preliminary stretching of the cervix and sweeping of the fetal membranes was not undertaken. In the 30 control patients, labour was not initiated and the mean improvement in the cervical score before surgical induction the next morning was 0.86. In the group of 30 patients receiving 25 mg PG F_2α, labour commenced during the night in 9 patients and the mean improvement in the cervical score was 3.76 (P < 0.0005); the corresponding figures for the 30 patients receiving 50 mg of PG F_2α were 10 patients coming into labour and cervical score improvement of 4.63 (P < 0.0005). he difference in the mean improvement of the cervical score between the 2 prostaglandin groups was not significant. Significantly fewer prostaglandin-treated patients needed augmentation during labour with intravenous oxytocin (P < 0.025) and there was a significant increase in the spontaneous delivery rate in the combined prostaglandin-treated group (P < 0.025). There was no statistical difference in the outcome of labour between the 2 prostaglandin groups. It was not possible to predict the patients whose cervices would not respond to PG F_2α pretreatment (15%) or those in whom labour would be initiated (30%). No side effects were experienced.     

Interruption of first trimester human pregnancy following Epostane therapy. Effect of prostaglandin E2 pessaries

Summary. The effect of Epostane, a competitive inhibitor of the 3β hydroxy steroid dehydrogenase enzyme system in combination with prostaglandin E₂ (PGE₂) for induction of abortion in early first trimester pregnancy has been studied in a group of 20 women awaiting termination of pregnancy. The women were consecutively assigned to four treatment groups. The first group was treated with PGE₂ alone, administered vaginally as a lipid based (Witepsol) pessary. The remaining three groups received Epostane at differing doses for 5 days, and were treated with PGE₂ on the fourth day. Significant falls in serum progesterone and oestradiol occurred in the Epostane-treated patients. Abortion was induced in one of the five control patients and in three of 10 patients treated with low doses (300–400 mg) of Epostane. Intra-utrine pressure monitoring showed an increased reactivity to PGE₂ in the treated groups. At the highest dose (600 mig) of Epostane, serum progesterone and oestradiol showed the greatest decline to 8% and 21% of the pretreatment values, a prompt and sustained pressure response occurred to PGE₂ and abortion was induced in all five patients. A critical degree of progesterone suppression appears to sensitize the myometrium to exogenous prostaglandin. This combined treatment is an effective method of early pregnancy termination and may have a role in the management of mid-trimester abortion.