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.     

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

Concentrations of prostaglandins E (PGE), F2 alpha (PGF), 13,14-dihydro-15-keto prostaglandin F2 alpha (PGFM), 6-keto F1 alpha 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 less than 0.05). In the 12 patients with clinically delayed labour, in the absence of cephalopelvic disproportion, there were significantly lower PGF (P less than 0.002) and PGFM (P less than 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.     

The influence of spontaneous and induced labour on the rise in prostaglandins at amniotomy

Summary. Maternal peripheral plasma levels of 13, 14-dihydro-15-keto-prostaglandin F (PGFM) were measured immediately before and 5 min after amniotomy. Three groups of women were studied: women in late pregnancy; women in spontaneous labour; and women who had received intravaginal prostaglandin E₂ (PGE₂) pessary. There was no significant difference in the magnitude of the rise in PGFM after amniotomy in late pregnancy or during spontaneous labour suggesting that labour has no influence on the release of prostaglandin F_2α (PGF_2α) induced by artificial rupture of the fetal membranes. However, local administration of PGE₂ before amniotomy caused a greater rise in PGFM suggesting that PGE₂ can influence the release and/or metabolism of PGF_2α.     

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.     

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.     

The Effect of Intravaginal Prostaglandin F2α on Labour after Spontaneous and Artificial Rupture of the Membranes

Summary: The effect on labour of 50 mg intravaginal PG F_2α or a standard intravenous oxytocin regimen was compared in 2 randomised trials involving a total of 83 patients, 23 of whom had experienced spontaneous rupture of the membranes (S.R.O.M.) and 60 of whom had artificial rupture of the membranes (A.R.M.) to induce labour. In each trial, labour had not been initiated by membrane rupture alone. In both trials only 20% of the patients receiving PG F_2α required further augmentation of labour with intravenous oxytocin. The mean length of labour in patients receiving PG F_2α was 2.5 hours shorter in the A.R.M. trial and 3.0 hours shorter in the S.R.O.M. trial than the mean length of labour in patients receiving intravenous oxytocin (P < 0.01). In the A.R.M. trial, the PG F_2α-treated group had significantly less analgesic requirements (P < 0.001). Although more normal deliveries occurred in the patients treated with PG F_2α than oxytocin in both trials, die numbers did not reach statistical significance.
No side effects occurred in the PG F_2α-treated patients or their babies and this method was much preferred by patients and nursing staff alike.     

Plasma prostanoids in pregnancy-induced hypertension

Summary. The concentrations of 13,14-dihydro-15-oxo-prostaglandin F_2α (PGFM), 6-oxo-prostaglandin F1_α,_a (6-oxo-PGF1_α) and thromboxane B₂ (T×B₂) were measured by radioimmunoassay in peripheral plasma from 183 pregnant women attending routine antenatal clinics. A total of 141 patients (47 nulliparous, 94 parous) remained normotensive and had uncomplicated pregnancies. The results from this group showed that there was no significant difference in the concentration of any metabolite in relation to parity or gestational age. The concentrations (pmol/1; means±SD) were PGFM 373±105, 6-oxo-PGF_1α 391±104 and T×B₂ 373±121. Nineteen patients (12 nulliparous, 7 parous) who had pregnancy-induced hypertension (PIH) by the time of sampling (three) or who subsequently developed the symptom (mean time from sampling to diagnosis 11 weeks, range 1–24 weeks) had significantly higher levels of 6-oxo-PGF_lα(574±216; P<0.0005, Student's test) and T×B₂ (603±268; P <0.0005). The concentrations in seven nulliparous patients with PIH and proteinuria were 656±276 for 6-oxo-PGF_3α and 754±228 pmol/1 for T×B₂.     

Determinants of umbilical cord arterial 8-iso-prostaglandin F2alpha concentrations

Objective To determine the concentration of 8-isoPGF_2α in cord blood as a measure of oxidative stress during labour, and to compare them with other established parameters of in vivo lipid peroxidation and with the acid-base status of the newborn.
Method Umbilical cord arterial and venous blood samples were collected from 81 singleton term deliveries for determination of 8-isoPGF_2α, malondialdehyde and organic hydroperoxides. In addition, metabolites derived from the oxidative metabolism of purines during hypoxia-reoxygenation and routine cord blood of oxygen saturation, pH, pO₂, pCO₂, HCO₃ and base excess were measured.
Results Arterial concentrations of 8-isoPGF_2α were significantly higher in cases with fetal distress, tight nuchal cord (   P < 0.001  ), the umbilical coiling index, and male sex (   P < 0.05  ) (R²= 0.48). No correlation was found with any parameter of acid-base status. In arterial and venous blood the concentrations of organic hydroperoxides and hypoxanthine significantly correlated with the fetal nuchal cord (   P < 0.001  ) (R²= 0.26 and 0.16, respectively).
Conclusion Our findings indicate that 8-isoPGF_2α in cord arterial blood is a suitable parameter to quantify a possible oxidative stress in the fetus during labour. Measurements of the F₂-isoprostane concentrations in cord blood at labour provide a clinically useful method to assess the perinatal outcome.     

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.     

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.     

Oral Prostaglandins E2 and F2a in the Induction of Labour

Summary: Oral prostaglandins E₂ and F_2a were used to augment amniotomy in the induction of labour in 173 patients. The success rate was significantly higher with prostaglandin E₂ than with prostaglandin F_2a (89% and 75%, respectively). This was achieved despite a significantly lower incidence of gastrointestinal side effects. No serious maternal or fetal complications occurred with either drug. It is concluded that oral prostaglandin E₂ is more efficient than oral prostaglandin F_2a in the induction of labour.     

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 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.     

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.     

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.     

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

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 2 alpha (PGF 2 alpha), 13,14-dihydro-15-keto F 2 alpha (PGFM) 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.     

Vaginal and abdominal delivery increases maternal urinary 6-keto-prostaglandin F1α excretion

Summary. To study the role of the antiaggregatory and vasodilatory prostacyclin (PGI₂) during human delivery, serial urine samples collected from 13 women delivered vaginally and from eight delivered abdominally were assayed for 6-keto-prostaglandin F_1α (6-keto-PGF_1α a breakdown product of PGI₂) by high-performance-liquid-chromatography and radioimmunoassay. In women delivered vaginally the mean urinary 6-keto-PGF_1α concentration was 41.9 (SE 8.3) ng/mmol creatinine, before the onset of labour and increased progressively to a maximum of 186.5 (SE 47.6) ng/mmol creatinine 2 h after delivery irrespective of the use of oxytocin and epidural analgesia. In women delivered by caesarean section under epidural anaesthesia, the urinary 6-keto-PGF_1α rose from 33.4 (SE 4.2) ng/mmol creatinine to 2153 (SE 314) ng/mmol creatinine 2 h after section. In both groups the increased levels had fallen by 24 h postpartum to levels below those found before delivery. In neonatal urine 6-keto-PGF_1α concentrations were some 12–30 times higher than those in postpartum urine. Thus, vaginal and abdominal delivery is accompanied by significant increases in maternal PGI₂ release, perhaps in the myometrium and/or intrauterine tissues. This may be of significance in the regulation of fetoplacental blood flow and in the prevention of intra- and postpartum thrombosis.     

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.     

Prostaglandins in umbilical plasma at elective caesarean section.

Prostaglandin E (PGE), prostaglandin F (PGF) and 13,14-dihydro-15-ketoprostaglandin F (PGFM) have been measured in umbilical cord plasma obtained immediately after delivery by elective Caesarean section. Umbilical venous plasma levels of PGE were significantly greater than the corresponding arterial levels (p less than 0.02); there were no significant arterio-venous differences for PGF or PGFM. In general, concentrations of PGFM exceeded those of PGE which in turn were greater than concentrations of PGF. Umbilical venous levels of PGE and both arterial and venous levels of PGF and PGFM were significantly greater after spontaneous labour with vaginal delivery than after elective Caesarean section.