Changes in the plasma prostaglandin F2 alpha metabolite before and during spontaneous labor and labor induced by amniotomy, oxytocin and prostaglandin E2

To elucidate the role of endogenous prostaglandin F2 alpha in spontaneous and induced labor, plasma concentrations of 13, 14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were determined before the onset of labor, at onset of labor, during active labor, at the crowning of the fetal head, and 1 and 2 hours after delivery. Patients in spontaneous labor and labor induced by amniotomy, oxytocin, and prostaglandin E2 were studied. The levels of plasma PGFM in patients who entered spontaneous labor fell 2 to 3 weeks before delivery, whereas those in the induced labor group did not change until the time of induction. Although the levels of PGFM rose gradually with the progress of labor in all cases, the levels in the spontaneous labor were significantly lower in each stage than in the corresponding stage of induced labor. These results suggest that endogenous prostaglandin F2 alpha (PGF2 alpha) production decreases 2-3 weeks prior to the spontaneous onset of labor and is increased again as labor progresses, that the patterns of PGF2 alpha production are similar to each other during spontaneous labor and labor induced by various methods. Therefore, it is felt that endogenous PGF2 alpha may participate in the progress of all kinds of labor.     

Plasma levels of 13,14-dihydro-15-keto prostaglandin F2 alpha, estrogens, and progesterone during stretch-induced labor at term

The uterus of six healthy multiparous women at term was mechanically stretched by a rubber catheter and balloon. Apparent labor was inaugurated in all cases within 5 hours and increased progressively with time. Advanced cervical softening and dilatation were also evident after the stretch treatment. Significant increases in the levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were observed with the progress of treatment (P less than 0.01). Plasma estrogens and progesterone levels did not change significantly during the treatment (P greater than 0.05). Stretching and/or resulting uterine contractions appear to induce the secretion of prostaglandin F2 alpha (PGF) from the organ, which in turn seems to be involved in both cervical softening, and the onset and progress of labor, under stable conditions of plasma estrogens and progesterone.     

Amniotic fluid concentrations of prostaglandin F2 alpha, 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and 11-deoxy-13,14-dihydro-15-keto-11, 16-cyclo-prostaglandin E2 (PGEM-LL) in preterm labor

Although prostaglandins (PGs) are considered the key mediators of human parturition at term, there is a paucity of data regarding their participation in the mechanisms responsible for preterm labor. The purpose of this study was to establish if preterm labor is associated with changes in the amniotic fluid concentrations of prostaglandins. PGF2 alpha, 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and 11-deoxy-13,14-dihydro-15-keto-11,16-cyclo-prostaglandin E2 (PGEM-ll) were measured by using specific and sensitive radioimmunoassays. Amniotic fluid was retrieved by transabdominal amniocentesis from 55 women with preterm labor and intact membranes. Patients were divided into three groups according to the response to tocolysis and the presence or absence of an intra-amniotic infection. Amniotic fluid concentrations of PGFM and PGEM-ll were significantly greater in women with preterm labor and intra-amniotic infection than in women without infection. In addition, patients unresponsive to tocolysis without intra-amniotic infection also had a significantly greater concentration of PGFM and PGEM-ll in amniotic fluid than those responsive to tocolysis. Amniotic fluid concentrations of PGF2 alpha were greater in women with intra-amniotic infection than in women without intra-amniotic infection. In the absence of intra-amniotic infection, no difference in amniotic fluid PGF2 alpha concentrations could be found between women who responded to tocolytic treatment and those who did not.     

Disappearance of prostaglandins F2alpha and 15-methyl F2alpha from amniotic fluid as measured by radiommunoassay.

A sensitive and relatively specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F2alpha was used to determine the levels of the drug in amniotic fluid after it had been injected intra-amniotically for termination of second trimester pregnancy. The disappearance of the free acid (tham salt) and methyl ester of the prostaglandin analogue were similar. The results of this preliminary study suggest that the drug rapidly equilibrates in the fluid and this followed by a slow removal from the amniotic sac. A comparison with a similar study with PGF2Alpha revealed that the analogue had a longer half-life in the amniotic fluid.     

Effect of dexcloprostenol on endogenous prostaglandin F2alpha release in dairy heifers

Cloprostenol was previously believed to be unable to release endogenous prostaglandin F2alpha (PGF2alpha) when administered during early bovine diestrus. A prostaglandin release is, however, seen in late diestrus. The aim of this study is to find out whether dexcloprostoenol (containing the only biologically active isomer, d-isomer, of cloprostenol) induces endogenous PGF2alpha release during early and late diestrus. Twelve heifers of the Finnish Ayrshire breed were allocated into two equal groups. Their estrous cycles were synchronized with dexcloprostenol. A further luteolysis was induced with 0.15 mg of dexcloprostenol either on Day 7 (group D7 or early diestrus) or on Day 14 (group D14 or late diestrus) after ovulation. Blood for progesterone and the PGF2alpha metabolite 15-ketodihydro-PGF2alpha determinations was collected immediately before dexcloprostenol treatment and thereafter every second hour for 48 h. Five of the six heifers in both groups showed significantly increased blood levels of 15-ketodihydro-PGF2alpha at some time during the 48-h experimental period. The intervals from treatment to the first significant increases of the PGF2alpha metabolite were 32.8+/-2.3 h (min. 30 h, max. 36 h) and 20.0+/-4.2 h (min. 14 h, max. 24 h) in groups D7 and D14, respectively (P < 0.01). We have concluded that dexcloprostenol induced endogenous PGF2alpha release in most cases, regardless the time of its administration (early or late diestrus). This release, however, differs from that observed during spontaneous luteolysis.     

Post-partum release of prostaglandin F(2alpha) and uterine involution in the cow

Peripheral plasma levels of the main blood plasma metabolite of PGF(2alpha) (15-keto-13,14-dihydro-PGF(2alpha)) and progesterone were investigated during the immediate, post-partum period in 59 normally calving cows. Uterine involution was monitored by weekly rectal palpations. The levels of the prostaglandin metabolite were high at parturition and remained thereafter elevated for periods varying up to 7-23 days. Uterine involution was completed during periods ranging from 16-53 days. According to the clinical findings, the animals were divided into three groups. Group A comprises 46 animals which had an uncomplicated, puerperal period. A significant (p<0.001) correlation between the duration of elevated prostaglandin levels and the time for completed uterine involution (Y=29.6 - 1.3 (X - 13.5)) was found for these animals. Group B animals (n=8) had periods of varying length with uterine discharge during the first 30 days post-partum. When compared to group A animals, the animals in group B had comparatively longer periods of prostaglandin release and also longer periods for completion of uterine involution. Group C animals (n=5) at times had palpable, thin-walled, cystlike structures in the ovaries during the first 30 days post-partum. In this group of animals, the periods of high prostaglandin levels, as well as for the completion of uterine involution, were similar to those for the animals in group A. Progesterone levels remained low during the immediate post-partum period and in no case were elevated levels found until the prostaglandin release had ceased.     

Differential regulation of prostaglandin production by inhibitors and stimulators in amiotic fluids during normal and dysfunctional labor

The regulatory effect of amniotic fluid factors on prostaglandin production by sheep seminal vesicle prostaglandin synthetase was determined using samples obtained before and after the onset of labor. Variations in the enzymes incubation conditions permitted the effects on both prostaglandin E (PGE) and prostaglandin F (PGF) production to be assessed. Amniotic fluid obtained before the onset of labor and during early labor resulted in a net stimulation of PGE production and no difference was observed between these two groups. Samples obtained before and during early labor had no effect of PGF production. However, when samples obtained late in labor were tested, there was a greater stimulation of PGF and less of PGE compared to early labor suggesting a preference for PGF production rather than PGE in late labo. When samples obtained from patients in dysfunctional labor were compared to normal labor, no difference on the effect of either PGE or PGF production was observed. This implies that the decreased PGF previously described in dysfunctional labor is due to an intrinsic abnormality of the fetal membranes rather than inhibition of prostaglandin production by factors mediated via the amniotic fluid.     

Amniotic fluid prostaglandin E2 in preterm labor

These studies were designed to determine amniotic fluid concentrations of prostaglandin E2 (PGE) in women with preterm labor. Amniotic fluid was retrieved by transabdominal amniocentesis from 68 women with preterm labor (less than 37 weeks). Patients were divided into three groups according to the response to tocolysis and the presence or absence of an intraamniotic infection. Amniotic fluid concentrations of PGE2 were significantly greater in women with preterm labor and intraamniotic infection than in women without infection. Patients unresponsive to tocolysis without intraamniotic infection had a significantly greater concentration of PGE2 in amniotic fluid than those responsive to tocolysis.     

Stimulation of myometrial and decidual prostaglandin production by amniotic fluid from term,but not midtrimester pregnancies

The effect of amniotic fluid obtained from second trimester (16–20 wks) and term pregnancies (38–41 wks) on the production of PGE and F by human amnion, decidua and myometrium at term was determined using tissue slices incubated in vitro. Midpregnancy amniotic fluid neither inhibited nor stimulated the prostanoid production by any of the tissues. In contrast, term amniotic fluid obtained before as well as after the onset of labor markedly increased the production of both PGE and PGF in decidua and myometrium from levels in Krebs solution. The prostanoid production (PGE + PGF) in amnoin was not significantly increased but the proportion of PGF was raised during incubations in term amniotic fluid. In decidua and myometrium the increase in PGE and PGF production in term amniotic fluid was approximately 200 and 400 percent respectively, from control values in Krebs solution. We propose that the stimulatory activity in term amniotic fluid in responsible for the accelerated synthesis of prostaglandins after of membranes, which is reflected in raised PGF metabolite levels in maternal circulation. It may also be the reason for the rise in amniotic fluid prostaglandin levels around the 35th week of gestation, and perhaps for the onset of labor.     

Effects of indomethacin, prostaglandin E2, prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha on hatching of mouse blastocysts

The present study has been performed to investigate how PGs would participate the hatching process. Effects of indomethacin, an antagonist to PGs biosynthesis, on the hatching of mouse blastocysts were examined in vitro. Furthermore, it was studied that prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) or 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were added to the culture media with indomethacin. The hatching was inhibited by indomethacin yet the inhibition was reversible. In the groups with indomethacin and PGE2, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. In the groups with indomethacin and PGF2 alpha, inhibition of hatching was improved in comparison with the group with indomethacin. In the groups with indomethacin and 6-keto-PGF1 alpha, no improvement was seen. The above results indicated that PGF2 alpha possibly had an accelerating effect on hatching and a high concentration of PGE2 would exert cytotoxic effect on blastocysts.     

Formation of 6,15-diketoprostaglandin F1 alpha from prostaglandin G2 by bovine aortic endothelial cells

Besides 6-ketoprostaglandin F1 alpha, bovine aortic endothelial cells also produced considerable amounts of 6,15-diketoprostaglandin F1 alpha from arachidonic acid, either exogenously added or released from cellular phospholipids. Incubations of particulate fractions of endothelial cells with the cyclic endoperoxides prostaglandin G2 and prostaglandin H2 showed that 6,15-diketoprostaglandin F1 alpha is formed by the action of prostaglandin I2 synthetase on prostaglandin G2. The labile metabolite 15-hydroperoxyprostaglandin I2 is then converted nonenzymatically to the 15-keto derivative. In the presence of reduced glutathione, quantitative analysis of both metabolites by gas chromatography-mass spectrometry showed a significant decrease of 6,15-diketoprostaglandin F1 alpha formation, whereas prostaglandin I2 synthesis was markedly increased. This shift seems to be due to a stimulation of peroxidase by GSH, a well known cofactor of this enzyme. Thus, it seems that a decreased endothelial prostaglandin I2 formation may occur when cellular glutathione levels are reduced as a consequence of oxidant injury and lipid peroxidation. Additionally, ferrous ions seems to be involved in the regulation of endothelial prostaglandin I2 synthesis, since Desferal, a specific ferrous ion chelator that might have antimetastatic properties, produced a pronounced shift from 6,15-diketoprostaglandin F1 alpha to the 6-keto derivative, i.e., prostaglandin I2.     

Radioimmunoassay of main urinary metabolite of prostaglandin F2alpha in normal subjects

Radioimmunoassay of 5alpha, 7alpha-dihydroxy-11-keto-tetranor-prosta-1,16-dioic acid, main urinary metabolite of prostaglandin F2alpha (PGF2alpha-MUM), was performed in normal subjects. Twenty-four hours secretion of PGF2alpha-MUM were 29.04 +/- 9.73 microgram in males and 18.22 +/- 5.88 microgram in females on an average. And an oral administration of aspirin resulted in the remarkable decrease of PGF2alpha-MUM in both sexes.     

F2-isoprostane induced prostaglandin formation in the rabbit

F(2)-isoprostanes, non-enzymatic free radical mediated products of arachidonic acid, have shown to form during various oxidant stress status and have potent biological effects. This study investigates to what extent 8-iso-PGF(2alpha) (a major F(2)-isoprostane), a bioactive product of lipid peroxidation can modify endogenous prostaglandin F(2alpha) (PGF(2alpha)) formation since prostaglandins are inflammatory as well as potent vasoregulatory substances that modulate diverse important physiological functions, and also form during acute and chronic inflammation. An immediate appearance and disappearance of 8-iso-PGF(2alpha) was seen in both plasma and urine within a short interval after i.v. administration of 43 microg/kg of 8-iso-PGF(2alpha) to the rabbits. A successive but differential formation of PGF(2alpha) resulted in a rapid and pulsatile increase of plasma 15-keto-dihydro-PGF(2alpha), a major metabolite of primary PGF(2alpha). Later, this compound was excreted efficiently as intact compound into the urine during the 3 h of experiment. A 8-fold increase of PGF(2alpha) metabolite in plasma at 10 min and 12-fold increase in the urine at 30-60 after the i.v. administration of 8-iso-PGF(2alpha) was observed which continued throughout the 3 h of experiment. This observation suggests that pharmacologically administered or endogenously produced 8-iso-PGF(2alpha) during oxidant stress induces prostaglandin formation presumably through the classical cyclooxygenase-catalysed arachidonic acid oxidation which might be inflammatory itself to the cells and exerts further vasoconstrictive effects.     

F prostaglandin levels in amniotic fluid in premature labour

The concentration of prostaglandin F (PGF) in amniotic fluid was measured by radioimmunoassay in 27 patients admitted in premature labour. There was a strong correlation between PGF levels in amniotic fluid and both cervical dilatation (r = 0.81; P < 0.001) and duration of labour (r = 0.79; P < 0.001). Cervical dilatation greater than 7 cm was associated with levels exceeding 2000 pg/ml. When contractions were present for less than one hour, levels of PGF were below 50 pg/ml. Low levels of PGF were found in amniotic fluid from a separate group of three patients, of whom two had cervical incompetence. It is concluded that the onset of premature labour is not associated with elevated levels of PGF in amniotic fluid. During premature labour, concentrations rise to an extent comparable to that observed in labour at term.     

Ability of human plasma to inhibit prostaglandin F2 alpha in asthma

Human plasma has been reported to inhibit the conversion of arachidonic acid into prostaglandin (PG) E2 and PGF2 alpha. In the present study the plasma inhibitory activity was determined in three groups (16 each) of plasma obtained from normal healthy volunteers, treated asthmatics and untreated asthmatic patients. The result showed that plasma from all three groups were equally effective in inhibiting the biosynthesis of PGE2. Plasma of normal volunteers and treated asthmatics also inhibited PGF2 alpha biosynthesis. In contrast the plasma obtained from untreated asthmatics was considerably less active in inhibiting the biosynthesis of PGF2 alpha than plasma from the other two groups.     

Comparison of intra-amniotic prostaglandin F2 alpha and hypertonic saline for induction of second-trimester abortion.

The efficacy and safety of intra-amniotic prostaglandin (PG) F2 alpha (25 mg repeated in six hours) and hypertonic saline (200 ml 20% NaC1) were compared in an international multicentre randomised study organised by the World Health Organisation''s prostaglandin task force. Both hypertonic saline and PGF2alpha were found to be effective in terminating second-trimester pregnancy. The main advantage of PGF2alpha however, was its greater efficacy, with significantly higher success rates in the first 48 hours. Out of 717 women given PGF2alpha 614 (85-6%) aborted within 48 hours; by 24 hours 439 (61-2%) had aborted, and by 36 hours 574 (80-1%) had aborted. Out of 796 women given hypertonic saline 641 (80-5%) aborted within 48 hours; however, by 24 and 36 hours, respectively, only 161 (20-2%) and 462 (58%) had aborted. Although PGF2alpha was associated with a somewhat higher frequency of minor side effects than hypertonic saline, notably vomiting and diarrhoea, these were within acceptable limits. Only 59 women (8-2%) in the prostaglandin group had more than four episodes of vomiting and 11 (1-5%) more than four episodes of diarrhoea. Ohter side effects occurred only occasionally. No difference was found between the two groups in the frequency of incomplete abortion or excessive bleeding.     

Gestational changes in the progesterone and prostaglandin F levels of the guinea-pig

In 87 guinea-pigs the gestational changes were measured in the progesterone (P) and prostaglandin F (PGF) levels of the peripheral and uterine vein plasmas, ovaries, uterus, placenta, fetal membranes and amniotic fluid. In the ovaries, the peripheral and uterine vein plasma, placenta and uterus, P-concentrations increase during early pregnancy and after a plateau decrease significantly as term approaches. In contrast, the uterine-vein PGF-levels remain low throughout pregnancy and only increase near term. Thus, in the guinea-pig, as in the classic species of P-action, normal pregnancy is characterized by high P and low PGF levels and labor by low P and high PGF levels. Of special interest are the additional findings that in the guinea-pig the uterine tissue P-levels are only a fraction of the peripheral plasma levels and the placental PGF-levels far exceed those of the uterus and fetal membranes. To promote the biological interpretation of the endogenous changes in the regulatory profile of the pregnant guinea-pig, current studies examine the functional consequences of the experimentally induced changes in P and PGF-levels.     

Conditions of the cervix for the increase of plasma levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha after amniotomy at term

Amniotomy was performed in 12 multiparas at term but not in labor. In 6 of these patients (group I), the fetal head and cervix condition were favorable for amniotomy, and in the other 6 (group II), they were not favorable. In all group I patients, a sudden and progressive descent of the fetal head, and onset and progress of labor were noted within 5 hours. Plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) levels increased significantly (P less than 0.05) in 4 of these cases with time. In group II patients, descent of the head was less than that in group I patients (P less than 0.05), and neither strong labor nor rise of PGFM levels was noted within 5 hours. These data support our view that amniotomy at an appropriate time results in the onset and progress of labor, and the rise of plasma PGFM in virtue of the sudden and exponential increase of the head to cervix force, but amniotomy at an inappropriate time does not, because this force is unchanged.     

Is prostaglandin F2 alpha involved in the increased myometrial contractility of primary dysmenorrhoea?

The concentrations of prostaglandin F2 alpha (PGF2 alpha) and E2 (PGE2) in menstrual fluid collected daily from 13 women with primary dysmenorrhoea and 11 matched controls, were compared with the pattern of uterine contractility during the hour following the menstrual fluid collection. The intra-uterine pressure (IUP) was measured using a micro-transducer catheter and the tracings analysed. On Day 2 the concentration of PGF2 alpha correlated with the peak area, but not with amplitude, duration or rate of contraction. These findings add additional support to the hypothesis that increased production of PGF2 alpha could contribute to the increased uterine contractility in primary dysmenorrhoea.     

Role of prostaglandin F2alpha in ovulation.

Using radioimmunoassay procedures, the levels of plasma, uterine and ovarian prostaglandin (PG) F2alpha, and those of plasma estradiol and progesterone were measured in intact, hysterectomized or ovariectomized immature female rats pretreated with PMS and subsequent HCG. Occurrence of ovulation was confirmed at 8 hours after the HCG administration not only in the intact rats but also in the hysterectomzied rats. The levels of plasma estradiol and progesterone, and of uterine and ovarian PGF2alpha rose with the PMS injection alone, but they did not reach the peaks before the HCG administration. Both plasma estradiol and uterine PGF2alpha showed a peak at 2 hours after the HCG injection. These peaks were antecedent 2 or 6 hours before the peaks of ovarian and plasma PGF2alpha, respectively. However, such increase of uterine PGF2alpha does not seem to be indispensable for ovulation, because ovulation could occur in the hysterectomized rats. The levels of ovarian PGF2alpha showed a high plateau from 4 to 8 hours after the HCG injection, and then rapidly decreased after ovulation. The levels of plasma PGF2alpha peaked not only in the intact rats but also in the hysterectomized rats at 8 hours after the HCG treatment. But in the ovariectomized rats, this plasma PGF2alpha peak at 8 hours disappeared and there was no statistical change of plasma PGF2alpha throughout the PMS-HCG treatment. Plasma progesterone gradually increased and reached the maximum at 10 hours after the HCG injection. These results conclude that the main source of increased plasma PGF2alpha during the ovulatory process induced with the PMS-HCG treatment is the ovary, and it is strongly suggested that a rapid increase of PGF2alpha in the ovary may play some important role(s) in the ovulatory process.