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

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, PGF2 alpha and 13,14-dihydro-15-keto-prostaglandin F2 alpha (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, PGF2 alpha 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 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.     

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.     

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.     

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.     

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.     

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.     

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.     

Amniotic fluid prostaglandins do not reflect human fetal lung maturation

Summary. Experimental data suggest the involvement of classic prostaglandins (PG), prostacyclin (PGI,) and thromboxane A₂ (Tx A₂ ) in fetal pulmonary development. To explore this possibility in man, we assayed serial amniotic fluid samples from 33 women for 13, 14 -dihydro-15-keto-PGF_2α (M-PGF_2α a metabolite of PGF_2α), 6-keto-PGF_1α (a breakdown product of prostacyclin (PGI₂)), and thromboxane B₂ (a metabolite of TxA₂) as well as for the lecithin/sphingomyelin (L/S) ratio and phosphatidylglycerol. No difference in these prostanoids was seen between the samples with the immature (< 2) or mature 2) L/S ratio, or between the samples with undetectable or detectable phosphatidylglycerol. The L/S ratio matured in 16 women and phosphatidylglycerol became detectable in 19 women during serial smpling, but even in these women the changes in the amniotic fluid prostanoids were inconsistent. It is concluded that the amniotic fluid M-PGF_2α, 6-keto-PGF_1α, and TxB₂ do not reflect fetal pulmonary maturity.     

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.     

Involvement of prostaglandins in vasopressin stimulation of the human uterus

The involvement of prostaglandins (PG) in the vasopressin (VP) action on the human uterus was investigated in healthy women during three menstruations. Intrauterine pressure was recorded and total pressure area measured. Repeated plasma samples were taken for estimations of arginine(A)- and lysine(L)-VP, 15-keto-13,14-dihydro-PGF_2α and 11- ketotetranor PGF metabolites. During the first menstruation LVP was infused in a dose of 0.08 μg/min. During the second menstruation the infusion of LVP was repeated with the same dose, but 70 min before infusion the women received an oral dose of 500 mg of naproxen. During the third menstruation PGF_2α was administered intravenously in a dose of 25 μg/min. LVP infusion per se caused a significant increase in uterine activity and plasma levels of LVP and PG metabolites. When the women were pretreated with naproxen practically the same uterine activity was induced and closely similar plasma levels of LVP were obtained, but the levels of PG metabolites decreased significantly in comparison with the first series of experiments. Infusion of PGF_2α caused an increase in uterine activity but no change in the plasma levels of AVP. The results indicate that uterine stimulation with VP is possible without an obligatory last step of PG synthesis and release. The results also support the concept that an elevated VP level in primary dysmenorrhoea may be of aetiological importance and is not just released as a 'stress'-hormone because of the dysmenorrhoeic pain.     

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.     

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.     

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.     

Thromboxane A2 and prostacyclin levels in molar pregnancy

Summary. Plasma levels of thromboxane (TX) A₂ and prostacyclin (PGI₂), as measured by radioimmunoassay of their respective stable metabolites TXB₂ and 6–keto PGF_1α, were studied in six molar pregnancies immediately before, immediately following and 24 h after evacuation of the uterus. The mean (SD) levels for TXB₂ were 150 (41), 137 (32) and 125 (25) pg/ml respectively, and for 6–keto PGF_1α the respective values were 225 (52), 226 (127) and 213 (49) pg/ml. There was no significant difference in the levels of prostanoids between the samples taken at the various time intervals. The concentration of these prostanoids in molar intravesicular fluid was also determined. Their respective mean (SD) pg/ml values were 3682 (760) for TXB₂ and 2969 (744) for 6–keto PGF_1α. In 15 normal pregnancies of equivalent gestation, the mean amniotic fluid levels of TXB₂ and 6–keto PGF_lα were 34 (17) and 146 (86) pg/ml respectively. The ability of molar trophoblast to generate the prostanoids from [¹⁴C]arachidonic acid in vitro was also demonstrated. Mean (SD) values for TXB₂ and 6-keto PGF_1α were 12.2 (2.6) and 13.2 (1.8) pg/mg protein/min, respectively. It is likely that the high concentrations of prostanoids in vesicular fluid reflect the synthesizing ability of the villus vesicles. The mole contributes little to the circulatory prostanoids possibly because its villi are deficient in blood circulation.     

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.     

Multiple Dose Extraamniotic Prostaglandin Gel for Second Trimester Termination of Pregnancy

Summary: Multiple doses of PGF_2α gel were administered into the extraamniotic space in 30 patients to induce mid-trimester termination of pregnancy. In 18 of these patients, repeat doses of gel were given only in the absence of uterine contractions and in 12 patients the gel was administered every 4 hours, irrespective of uterine activity. The mean time to abortion in all patients was 13.9 hours; no benefit seemed to accrue from using routine 4-hourly doses and it is recommended that repeat doses are given only when contractions are absent. The latter technique compares favourably with the use of other natural prostaglandins and prostaglandin analogues.     

Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen

Summary. The release of 6-keto-prostaglandin F_1α(6-keto-PGF_1α), a metabolite of prostacyclin (PGI₂) and thromboxane B2 (TxB2), a metabolite of thromboxane A2 (TxA2), was estimated in endometrial biopsies taken from 12 menorrhagic and 12 healthy women during the luteal phase of the cycle. The releases of 6-keto-PGF_1α and TxB2 were normal, but the ratio TxB2/6-keto-PGF_1α was inversely related to menstrual blood loss in women with measured menstrual blood loss exceeding 70 ml. In the second part of the study, 24 women with excessive menstrual bleeding (13 with primary menorrhagia, 10 with uterine fibro-myomas, one with haemostatic factor VIII deficiency) were treated at random with ibuprofen (600mg/day and 1200mg/day) and with a placebo. Ibuprofen 1200 mg/day reduced (P<0.01) median blood loss from 146 ml (range 71–374 ml) to 110 ml (30–288 ml) in primary menorrhagia but had no effect on blood loss in women with uterine fibroids and factor VIII deficiency. Blood loss was normal in six women and was not affected by ibuprofen. Thus, our data suggest that there is a PGI₂ dominance in the endometrium of patients with menorrhagia. In addition, primary, but neither fibromyoma nor coagulation defect-associated menorrhagia, can be treated by ibuprofen.     

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.