The use of oral prostaglandin E2 in the management of intrauterine fetal death

12 otherwise healthy patients with intrauterine fetal death 1 to 6 weeks earlier were treated with oral prostaglandin E2. 9 of the 12 patients delivered within 48 hours after treatment began. 2 others delivered with 48 hours after unsuccessful treatment ceased. In a third patient the cervix relaxed after treatment, and the uterine contents were removed by curettage. No serious complications, such as hemorrhage occurred. The uterus seemed surprisingly responsive to oral prostaglandin E2 in cases of intrauterine fetal death.     

Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death

In established intrauterine fetal death, 20 patients were treated with prostaglandin E₂ gel administered extraamniotically. The results were compared with those of another group of 20 patients who had received combined treatment. In this group, one or more of the following agents had been administered: - i.v. oxytocin, 20% NaCl solution or Premarin instilled intraamniotically, introduction of a balloon catheter or Rivanol administered extraamniotically. Average induction-abortion interval for the PG group was about 12 hours while for the second group it was about 30 hours. The side effects observed were slight in both groups. The results show that administration of PG-gel can be used with advantage in fetal demise because of the relatively short induction-abortion intervals obtained, the insignificant side effects and the low dose of PG required.     

Hormone changes in relation to the time of fetal death after prostaglandin-induced abortion

The changes in unconjugated estradiol-17β and estriol, progesterone and chorionic somatomammotropin (HCS) in peripheral plasma have been studied in 18 women at 30-minute intervals following intra-uterine prostaglandin E₂ administration for therapeutic termination of second trimester pregnancy. The hormonal changes were related to the time of fetal death detected by the disappearance of fetal heart pulsations. Prostaglandin E₂ was given by the intra-amniotic route with urea (5 patients) or with intravenous oxytocin (5 patients), or by the extra-amniotic route with intravenous oxytocin (8 patients). Fetal death occurred rapidly with intra-amniotic PGE₂, but usually at a late stage with extra-amniotic PGE₂. Three fetuses in the extra-amniotic group died at or just before abortion. A variety of fetal heart changes were noted and the time of fetal death did not appear to influence the time of abortion within each treatment subgroup.Estradiol and estriol showed a slight but persistent fall over 24 hours prior to induction of abortion. A more rapid fall usually occurred after induction, with a consistent fall around the time of fetal death. Progesterone and HCS usually fell much less before and immediately after fetal death. A marked rise in estradiol sometimes occurred before fetal death, particularly in the intra-amniotic PGE₂ and urea subgroup. Estriol levels declined more rapidly before than after fetal death, whereas fetal death had less consistent effects on the other hormones. All hormones had usually fallen considerably at the time of abortion, and in some individuals marked fluctuations in hormone levels were seen.     

Induction of labour with sulprostone after foetal death and in hydatidiform mole

Induction of uterine contractions was carried out with an intravenous infusion of sulprostone, a 16-phenoxy derivate of methylsulphonylamid prostaglandin E₂ in 21 patients after intrauterine foetal death and in seven patients having hydatidiform mole. The mean total dose of sulprostone was estimated as 1100–1300 μg in different groups. The mean induction-delivery time was 7–13 hours. Expellation of the foetus occurred in 20 out of 21 cases during 24 hours after commencement of sulprostone infusion. In all patients having molar pregnancy uterine contractions induced with sulprostone opened the uterine cervix for evacuation. The drug was clinically well tolerated without any serious side-effects.     

Controlled trial of induction of labor by vaginal suppositories containing prostaglandin E2

A group of 84 women at 39 – 43 weeks of pregnancy were randomly allocated to a blind trial of induction of labor with vaginal suppositories containing inert material or either 0.2 mg or 0.4 mg of prostaglandin E₂. The suppositories were self-administered every two hours during waking hours on two successive days until labor started or 15 had been used. Side-effects were absent. Labor was established within 48 hr of insertion of the first suppository in 9.3% of control patients, 65.4% of those treated with 0.2 mg PGE₂ and 85.7% of those treated with 0.4 mg PGE₂. The mean Apgar scores in the three groups were the same. The mean total dose of PGE₂ were 2.0 mg (0.2 mg group) and 2.3 mg (0.4 mg group). It is concluded that vaginal PGE₂ is an effective and acceptable method of inducing labor at term.     

Characteristics of arachidonic acid metabolism of human endothelial cells in culture

Human umbilical endothelial cells in culture retain differentiated morphological and functional characterization in primary culture and even in the early subcultures, after which they begin to degenerate. We have studied the morphological and biochemical characterization (ability to produce prostacyclin, prostaglandin E₂ and thromboxane A₂ in culture) of endothelial cells in the first seven subcultures. In addition the influence of serum and endothelial cell growth factor added to the culture medium have been evaluated. With 20% normal human serum, cell proliferation is faster than with the same concentration of human fetal or bovine fetal serum.After the 3rd passage, morphological and growth alterations become observable in the endothelial cells. However, prostacyclin, prostaglandin E₂ and thromboxane A₂ production showed no variations during the study.     

Oral Administration of Prostaglandins for the Induction of Labour

Prostaglandins E₂ and F₂α administered by mouth were used to induce labour in 100 patients between 35 and 44 weeks of gestation. The usual effective dose of prostaglandin E₂ was 0·5 and of F₂α 5 mg. These were repeated every two hours until labour was established. Induction was successful in 79 out of 80 women treated with oral prostaglandin E₂ and in 16 out of 20 women treated with F₂α     

Termination of pregnancy in cases of fetal death in utero by intravenous prostaglandin F2α

Delivery was induced by an intravenous infusion of prostaglandin F_2α (PGF_2α) in gradually increasing doses in 30 consecutive cases of fetal death in utero after the 28th week of gestation. Twenty patients delivered during the first day of prostaglandin administration, 9 on the second day, and 1 patient not until the third day of infusion. It is concluded, that intravenous PGF_2α appears to be superior to oxytocin in termination of pregnancy under these conditions.     

Temporal changes in serum estradiol and prolactin in immature female rats given a single injection of estradiol benzoate

Serum concentrations of estradiol 17β(E₂) measured by immunoassay reached peak levels (100pg/ml) within one hour in immature female rats given a subcutaneous injection of lug 17βestradiol-3-benzoate (EB). Hypophysectomy did not alter the E₂ concentration, but lower peak levels were found in ovariectomized females. In animals with ovaries a secondary rise in serum E₂ was apparent 12 hours after the injection of EB; from 12 to 48 hours E₂ decreased linearly. A dose of Bug EB caused an abrupt rise in E₂ (180pg/ml) within 30 minutes, but during the next 24 hours rather wide fluctuations in serum levels were found. In animals acclimated to a reversed light schedule and given 5ug EB early in the dark period, E₂ decreased linearly over a period of 72 hours. Prolactin increased in response to the E₂: a rhythm was suggested by the occurrence of increases during the dark periods. The results indicate that statistically significant fluctuations in both E₂ and prolactin occur after a single injection of EB and that measurements at a single point in time are inadequate to determine the true pattern of hormonal changes.     

Effects of protein kinase C activation on prostaglandin production and cyclooxygenase mRNA levels in ovine astroglia

We examined effects of protein kinase C (PKC) activation by phorbol dibutyrate (PDB) on prostaglandin production in astroglia. Astroglia were cultured from sheep fetal cortex and grown in Eagle's basal media supplemented with 10% fetal calf serum (BME-C). Prostaglandin F_2a (PGF_2α) levels in media were determined at 2–24 hours after exposure to PDB. PDB increased production of PGF_2α at 10⁻⁸M and 10⁻⁶M. In addition, PDB increased the ratio of membrane to cytosolic PKC. Coapplication of H7 [1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine] (10⁻⁴M) with PDB (10⁻⁶M) inhibited PDB-induced PGF_2a production. To investigate the role of protein synthesis in increased prostaglandin production by PDB, astroglia were coincubated with actinomycin D (1 mg/ml) or cycloheximide (10 mg/ml). At 4 hrs, both actinomycin D and cycloheximide inhibited increases in PGF_2a in response to PDB application. In addition, COX-2 mRNA levels and COX activity levels were examined. PDB increased COX-2 mRNA levels by 2 hours, and COX activity tripled after 12 hr exposure to PDB. In addition, the increase in COX activity was blocked by cycloheximide. In summary, PKC activation promotes enhanced prostaglandin production via an increase in COX synthesis.     

An in vitro system to screen for diarrheagenic chemicals

We examined an in vitro system to screen for diarrheagenic chemicals using an established intestinal cell line (T₈₄ human colonic carcinoma). The cells were grown on Millicell-PCF (polycarbonate membrane) wells. The cells were seeded at approximately 5 × 10₆ cells/30mm well and incubated for 9–11 days in a 5% C0₂ incubator saturated with water at 37°C. The culture medium was a 1:1 mixture of Ham's F12 and Dulbecco's MEM with 5% fetal bovine serum and 25 pglml gentamicin sulfate. The well containing cells was removed from the incubator and mounted in a modified Ussing chamber for measurement of shortcircuit current (I_sc). Chemical-induced increases in Psc are usually indicative of electrogenic epithelial Cl^– secretion, which is associated with diarrheagenic effects in animals and humans. T₈₄ cells grown on Millicell-PCF membrane responded with an increase in Isc after basolateral addition of the cholinergic (muscarznic) agonist carbachol, prostaglandin E₂, 16,16-dimethylprostaglandin E₂, and forskolin, while non-diarrheagenic prostaglandin D₂ did not affect I_sc. Based on our results, this in vitro system has the potential to be adapted as a rapid screen for detecting diarrheagenic chemicals.Abbreviations dmPGE₂ 16,16-dimethylPGE₂ - EC₅₀ 50% of maximum effective concentration - EDTA ethylenediaminetetraacetate - I_SC short-circuit current - PGD₂ prostaglandin D₂ - PGE₂ prostaglandin E₂ - PD potential difference - R_T transepithelial resistance     

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E₂ (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92 %) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE₂-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64 %) of the 22 patients that were left to be induced after cervical softening and in 26 (57 %) of the 47 women without cervical priming. The Cesarean section rate was 10% (n=5) in the PGE₂-gel group and 12% (_n=6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE₂ pretreatment.     

Teratological studies with prostaglandin E2 in chick embryos

Prostaglandin E₂ (20–100 μg) was lethal to a relatively high percentage of chick embryos when administered at 48 hours incubation; no such effect was observed after 72 hours incubation. A relatively high incidence of abnormal embryos, which increased with the dose-levels of prostaglandin, was induced at both 48 and 72 hours incubation compared to the controls. However, this difference was statistically significant only in embryos treated with 100 μg prostaglandin at 48 hours incubation. The embryos showed no signs of growth retardation.     

hCG-induced prostaglandin E2 and F2 alpha release in adult rat testis: role in Leydig cell desensitization to hCG.

Testicular levels of prostaglandin E₂ and F_2α were measured in decapsulated adult rat testis following hCG stimulation. Basal levels were, respectively, 342 ± 74 and 502 ± 89 pg/testis. Following hCG administration these basal values are not significantly modified up to 2 hours. From 2 to 24 hours the concentrations are clearly increased above the basal level: at 12 hrs they are 1925 ± 165 for E₂ and 3200 ± 190 for F_2α. Levels are back to normal at 48 hrs and remain so until 144 hrs. An identical pattern of prostaglandin release is observed in vitro in Leydig cell preparations isolated at different times following in vivo hCG injection. This suggests that prostaglandins are secreted by Leydig cells. In hypophysectomized animals the release of both prostaglandins E₂ and F_2α is similar to controls indicating that prostaglandin secretion is not directly linked to testosterone production. alternatively testosterone injections (10 mg) does not modify prostaglandin levels. Binding sites for prostaglandins E₁, E₂ and F_2α are present on the Leydig cells and consequently Leydig cell function may be modulated by endogenous or exogenous prostaglandins. Their level is slightly increased at 24 hrs following hCG stimulation. Since the acute changes in prostaglandin E₂ and F_2α secretion occur during the period of “desensitization” and of acute “down regulation” of the LH-hCG receptor in the Leydig cells it is suggested that prostaglandins are involved in both phenomena.     

Changes in prostaglandin E1 stimulation of glucose oxidation in rat adipocytes during maturation and aging

Prostaglandin E₁ stimulates glucose oxidation in isolated rat adipocytes in a time and concentration dependent manner. Maximal stimulation requires 2 hours exposure to prostaglandin, although effects can be detected by 0.5 hours or earlier. In contrast to prostaglandin E₁, prostaglandin F₂α has essentially no effect on glucose oxidation. Maximal stimulation by prostaglandin E₁ at all ages tested occurs at concentrations of 10^?5 ? 10^?4M. Stimulation is greatest in cells of mature (10–12 month old) animals at 81 ± 9% above basal levels of glucose oxidation. This is to reduced to 48 ± 8% in cells of senescent (23–26 month old) animals, and at 23 ± 18% in cells of young (2–3 month old) rats is not significantly different from basal oxidation in most animals. These results are consistent with data for adipocytes and other cell types indicating that responsiveness to certain hormones is altered during maturation and aging.     

The PGE2 vaginal film: An alternative to conventional induction in multiparae with poor cervical scores

In a study involving 50 multiparous subjects with poor cervical scores (⪕3), induction of labour by conventional amniotomy and oxytocin was compared with preinduction cervical ripening using a single administration of prostaglandin E₂ (850ug) in a new vaginal film formulation. Indications for elective delivery, maternal characteristics and distribution of cervical scores in the two groups were similar. Significant changes in mean cervical score were achieved within 12 hours of film insertion. In this group, 11 subjects (45.8%) established labour within 12 hours and a further 8(33.3%) did so before 24 hours so that only 5 cases required amniotomy and oxytocin. Instrumental delivery was less in this group and none of these subjects required Caesarean section for a failure of induction. No adverse maternal or fetal side effects were observed. Convenience, ease of administration and stability of this new prostaglandin formulation make it a useful alternative to conventional induction of labour in the multiparous patient with a poor cervical score.     

Arrest of oogenesis in the bug Rhodnius prolixus challenged with the fungus Aspergillus niger is mediated by immune response-derived PGE2

In this work we characterized the immune response of the insect Rhodnius prolixus to a direct injection into the hemocoel of the non-entomopathogenic fungus Aspergillus niger, and evaluated its consequences on host oogenesis. These animals were able to respond by mounting effective cellular and humoral responses to this fungus; these responses were shown, however, to have reproductive fitness costs, as the number of eggs laid per female was significantly reduced. The disturbance of egg formation during infectious process correlated with an elevation in the titer of hemolymph prostaglandin E₂ 48 h post-challenge. Administration of Zymosan A as an immunogenic non-infectious challenge produced similar effects on phenoloxidase and prophenoloxidase activities, oocyte development and prostaglandin E₂ titer, precluding the hypothesis of an effect mediated by fungal metabolites in animals challenged with fungus. Ovaries at 48 h post-challenge showed absence of vitellogenic ovarian follicles, and the in vivo administration of prostaglandin E₂ or its receptor agonist misoprostol, partially reproduced this phenotype. Together these data led us to hypothesize that immune-derived prostaglandin E₂ raised from the insect response to the fungal challenge is involved in disturbing follicle development, contributing to a reduction in host reproductive output and acting as a host-derived adaptive effector to infection.     

Cervical mucus concentration of prostaglandins E2 and F2α after pretreatment with mifepristone in the first trimester of pregnancy

Cervical dilatation and softening after pretreatment with mifepristone are well documented. As this effect is similar to that observed after local application of prostaglandin E₂ (PGE₂) it is tempting to speculate that the effect of mifepristone is mediated via an increase of the endogenous secretion of prostaglandins from the cervical mucosa. Eighteen healthy women in the first trimester of pregnancy were treated with oral mifepristone (200 mg) 48 and 24 hours before legal abortion by vacuum aspiration and 18 women in the same age of gestation without any pretreatment served as controls. Cervical mucus was collected for measurement of prostaglandins by radioimmunoassay before administration of the drug and in connection with vacuum aspiration. The cervical dilatation at the time of surgery was significantly increased in women given mifepristone as compared with untreated women (7.6 versus 5.8 mm). The wet weight of collected cervical mucus was significantly increased in mifepristone treated women. The amount of PGE₂ and prostaglandin F_2α per sample was unchanged in mifepristone-treated women, whereas the concentration was lower as an effect of dilution due to an increased yield in cervical secretion observed after mifepristone treatment. The present observation does not give any support to the hypothesis that mifepristone-induced cervical maturation is mediated via an increase in cervical prostaglandin production.     

Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death.

In established intrauterine fetal death, 20 patients were treated with prostaglandin E2 gel administered extraamniotically. The results were compared with those of another group of 20 patients who had received combined treatment. In this group, one or more of the following agents had been administered :- i.v. oxytocin, 20% NaCl solution or Premarin instilled intraamniotically, introduction of a balloon catheter or Rivanol administered extraamniotically. Average induction-abortion interval for the PG group was about 12 hours while for the second group it was about 30 hours. The side effects observed were slight in both groups. The results show that administration of PG-gel can be used with advantage in fetal demise because of the relatively short induction-abortion intervals obtained, the insignificant side effects and the low dose of PG required.     

Luteolytic activity of a synthetic prostaglandin and PGF2α in heifers

Two experiments involving 44 cycling heifers were conducted to evaluate the luteolytic activity of a synthetic prostaglandin, AY 24366, and PGF_2α. Activity was assessed by the decline in progesterone level of peripheral blood and occurrence of estrus. Progesterone concentrations of jugular blood plasma were quantified by radioimmunoassay. In the first experiment, 36 heifers were treated during diestrus with AY 24366 (A - 10mg intrauterine, B - 30mg intramuscular and C - 60mg im) or with PGF_2α (D - 5mg, iu, E - 15mg im and F - 30mg im). Mean progesterone 0, 24 and 48 hours after treatment were A - 6.33, 5.55 and 5.06; B - 6.35, 2.79 and 3.92; C - 5.23, 2.69 and 3.91; D - 5.19, 1.50 and 1.51; E - 4.69, 0.85 and 0.61; F - 6.66, 0.80 and 0.48 ng/ml. Standing estrus was observed in 1, 1, 1, 4, 5 and 6 females in groups A, B, C, D, E and F respectively within 72 hours of treatment. PGF_2α resulted in significantly (P<0.01) lower progesterone at 24 and 48 hours than AY 24366. However, im administration of the latter did significantly (P<0.05) lower progesterone at 24 hours. In the second trial six heifers were treated with either 120 or 180mg of AY 24366 im on day 12 of the cycle. Mean progesterone declined from 3.84 to 2.12 ng/ml (P<0.01) by 6 hours and to 1.59 ng/ml by 12 hours. Thereafter the decline was gradual and reached a level of 0.65 ng/ml at 72 hours. All six heifers showed standing estrus at 78±2 hours and were inseminated. Two in each group conceived. Doses of 15mg PGF_2α and 120mg AY 24366 were effective in causing luteal regression, however, the latter caused respiratory discomfort for 5 to 10 minutes post treatment.