The effect of prostaglandins on the bioconversion of arachidonic acid in cervical tissue in early human pregnancy

The aim of the present study was to investigate in late first trimester and early second trimester patients whether whole cell homogenates of cervical tissue incubated with 14C-arachidonic acid was affected by pretreatment for 12 to 14 hours with PGE2 and 9-deoxo- 16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2). After extraction, purification and separation, identification of the compounds found during incubation was achieved using radio-gas liquid chromatography and gas-liquid chromatography-mass spectrometry. Treatment with 9-methylene PGE2 accomplished a reduced production of 14C-labelled PGF2 alpha, -PGE2 and TxB2, while pretreatment with PGE2 induced increase in the production of 14C-6-keto-PGF1 alpha when cervical tissue homogenates were compared with specimens obtained from non-pretreated patients. Recently we reported a significantly increased formation of so far unidentified metabolite(s) in homogenates of human cervical tissue specimens obtained at or near term when compared with corresponding specimens obtained during early pregnancy. With both types of prostaglandin pretreatment there was a tendency of increased formation of these metabolites. It seems possible that the influence on the biochemistry of cervical tissue induced by PGE2 and 9-methylene PGE2 is mediated via the endogenous arachidonic acid cascade towards non-prostaglandin compound(s).     

Plasma levels of 9-deoxo-16,15-dimethyl-9-methylene-PGE2 in connection with its development as an abortifacient

Gaschromatographic-mass spectrometric quantitation of 9-deoxo-16,16-dimethyl-9-methylene-PGE₂ in plasma samples obtained during constant intravenous infusion of the drug revealed that a plasma level of about 20 ng/ml was associated with high enough uterine contractility for induction of second trimester abortions. This level was therefore aimed for during the development of formulations and dose schedules for interruption of pregnancy with this drug. For the first time it was possible to induce second trimester abortions through oral administration of a prostaglandin analog, although the plasma levels were low giving a moderate success rate (about 50%) within 25 hours. Rectal administration of 20 mg of the drug at 6 hours intervals resulted in high enough plasma levels for second trimester abortions. Highly efficient dose schedules for interruption of early first trimester (“menses induction”) and second trimester pregnancies through vaginal administration were developed. The frequency of side effects in the early first trimester were so low that “home treatment” was possible. Formulations suitable for 3, 6 or 12 hours preoperative dilatation of the cervix were also developed.     

Preoperative dilatation of the cervix by single vaginal administration of 15-methyl-PGF2alpha-methyl ester.

Two different vaginal suppositories have been developed suitable for one single treatment for preoperative dilatation of the cervix prior to vacuum aspiration in late first trimester abortion. The study included 60 patients equally distributed in one control group (Group I) where vacuum aspiration was performed without pretreatment; one group (Group II) where the patients obtained 2.0 mg 15-methyl-PGF2alpha-methyl ester in a rapid releasing base six hours prior to operation and one group (Group III) where the prostaglandin dose was increased to 2.5 mg 15-methyl-PGF2alpha-methyl ester and a more slow releasing base was used and the operation performed after 12 hours. The mean cervical dilatation at operation was in Group II 9 mm and in Group III 11 mm in comparison with 4.8 mm in the control group. The bleeding at the operation was also significantly reduced.     

Preoperative dilatation of the cervix by single vaginal administration of 15-methyl-PGF2α-methyl ester

Two different vaginal suppositories have been developed suitable for one single treatment for preoperative dilatation of the cervix prior to vacuum aspiration in late first trimester abortion. The study included 60 patients equally distributed in one control group (Group I) where vacuum aspiration was performed without pretreatment; one group (Group II) where the patients obtained 2.0 mg 15-methyl-PGF_2α-methyl ester in a rapid releasing base six hours prior to operation and one group (Group III) where the prostaglandin dose was increased to 2.5 mg 15-methyl-PGF_2α-methyl ester and a more slow releasing base was used and the operation performed after 12 hours. The mean cervical dilatation at operation was in Group II 9 mm and in Group III 11 mm in comparison with 4.8 mm in the control group. The bleeding at the operation was also significantly reduced.     

Effects of 9-deoxo-16,16-dimethyl-9-methylene PGE2 on muscle contractile activity and collagen synthesis in the human cervix

The in vitro effects of a stable PGE-analogue (9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) on human cervical tissue was investigated. The influence of the analogue on collagen biosynthesis was studied by measuring the incorporation of 3H-proline, while smooth muscle effects were evaluated by isometric recording of contractile activity. The specimens were obtained by needle biopsy from women in early and late pregnancy and from nonpregnant women of fertile age. 9-methylene PGE2 compared with controls increased the incorporation of 3H-proline in the secretory phase and before the 9th week of pregnancy, whereas radiolabelling was decreased in the follicular phase, in the 9th-12th week and at term. With respect to incorporation of 3H-proline,9-methylene PGE2 was equipotent to PGE2. 9-methylene PGE2 inhibited spontaneous contractile activity in early as well as in late pregnancy but increased muscular activity in nonpregnant patients. The inhibitory effects of the analogue was similar to that of PGE2 but the natural compound was considerably more potent in this respect.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm.

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E2 suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE2 suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE2 suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2 degrees F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last adminstration of PGE2. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE2 suppositories is a very effective abortifacient technque during the midtrimester, however the use of PGE2 in conjunction with a diaphragm did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE2 suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

On the mechanism of action of 15-methyl-PGF2 alpha as an abortifacient.

Several hours following administration of long acting vaginal suppositories containing 3.0 mg of 15-methyl-PGF2 alpha for interruption of second trimester pregnancies there is an up to 10-fold increase in endogenous production of PGE2 and PGF2 alpha before abortion as reflected by gas chromatographic-mass spectrometric determination of the major plasma metabolites of PGE2 and PGF2 alpha. The data suggest that this increased formation of endogenous prostaglandins contributes to the induced uterine activity during the latter part of the abortion process.     

Vaginally administered PGF2alpha for cervical dilatation in nulliparas prior to suction curettage

Because of the need for an atraumatic method to dilate the cervix when performing artificial abortion by suction curettage, cervical dilatation following vaginally administered PGF2alpha was studied. A 50 mg PGF2alpha vaginal suppository was administered to 40 (treated group) first trimester nulliparas 3 hours prior to progressive cervical dilatation from a 19 (circumference in mm) Pratt dilator to a 35 Pratt dialator. The smallest-sized dilator that met resistance was interpreted as being the amount of clinically significant cervical dilatation. The results were compared to 20 (control group) first trimester nulliparas who received no PGF2alpha studied in an identical manner. Independent of gestational age, treated patients were dilated significantly more than the control patients. When subjects of similar gestational age were compared, PGF2alpha treated subjects were more often dilated sufficiently to perform abortion (55%) by suction curettage than control group subjects (5%). Those PGF2alpha subjects needing further dilatation to accept an appropriate sized cannula for their gestational age needed less dilatation than did those subjects of similar gestational age in the control group. No serious complications of PGF2alpha per se were observed and the most frequent side effects, vomiting and diarrhea, did not appear severe enough to limit the clinical practicability of the method.     

Letter: On the administration of prostaglandins as a pre-operative means of cervical dilatation

Prostaglandin (PG) administration by the intramuscular or extraamniotic route has been reported to be a safe and reliable means of effecting cervical dilatation prior to 1st trimester abortion by suction curettage. At the Mulago Hospital, Kampala, a minimum of 5 cases of 1st trimester abortions were performed weekly using the Karman cannula (KC), a flexible polyethylene catheter which lessens the risk of cervical dilatation. In none of the cases was cervical dilatation required for insertion of a KC of sufficient diameter. Paracervical block with procaine 2% (10 ml) was used for analgesia; in rare cases, 10 mg of diazepan was administered orally or intravenously as a preoperative medication. Complications encountered included: 1) perforation of the uterine fundus; 2) metritis; and 3) retained products of conception. With proper instrumentation, cervical dilatation is no longer required for 1st trimester abortions. PG administered for cervical dilatation is no longer justified because it is time consuming, a source of additional expense, inconvenient, and is associated with uterine cramps and gastrointestinal side effects. In occasional cases, as in undue cervical resistance, the use of PGs may be justified.     

Vaginally administered 16, 16-dimethyl-prostaglandin E2 as an agent for pre-operative cervical dilatation.

Twenty-one women in the 10th-12th week of pregnancy were treated prior to vacuum aspiration with vaginal suppositories containing 16, 16-dimethyl-PGE2 (free acid). An average total dose of 3.4 mg led to abortion or adequate cervical dilatation in all patients. Based upon previous experience with the compound, no prophylactic anti-emetic or anti-diarrhetic medication was given. Gastrointestinal side effects were minimal. Excessive bleeding was not observed. In two cases, slight temperature elevation was noted prior to abortion. The low incidence of side effects in combination with the effectiveness of the compound help to make this method an attractive therapeutic adjunct to vacuum aspiration beyond the 10th week of gestation. Under the experimental conditions of this study, the results suggest that vaginally administered 16, 16-dimethyl-PGE2 can be a safe and effective method for cervical dilatation before vacuum aspiration.     

Cervical dilatation with prostaglandin analogues prior to vaginal termination of first trimester pregnancy in nulliparous patients.

Dilatation of the cervix with prostaglandin analogues prior to vaginal termination of pregnancy was attempted in 125 nulliparous women in the first trimester of pregnancy. The patients were divided into five groups (25 in each group) and given a single extra-amniotic dose of one of the following prostaglandin analogues 14-16 hours prior to the evacuation of the uterus by vacuum aspiration. (Group A) 15 (S) 15 methyl PGE2 (free acid); (Group B) 15 (S) 15 methyl PGE2 methyl ester; (Group C) 15 (S) 15 methyl PGF2alpha (free acid); (Group D) 15 (S) 15 methyl PGF2alpha methyl ester and(Group E) a mixture of 15 (S) 15 methyl PGE2methyl ester and 15 (S) 15 methyl PGF2alpha methyl ester. Evacuation of the uterus without mechanical dilatation of the cervix was possible in 111 (90%) of the patients. In an additional 10 patients (8%) there was some degree of cervical dilatation and further mechanical dilatation could be performed easily. With the combination of 15 (S) 15 methyl PGE2 methyl ester and 15 (S) 15 methyl PGF2alpha methyl ester the incidence of gastrointestinal side effects and pyrexia were considerably reduced.     

Vaginally administered 16, 16-dimethyl-prostaglandin E2 as an agent for pre-operative cervical dilatation

Twenty-one women in the 10th–12th week of pregnancy were treated prior to vacuum aspiration with vaginal suppositories containing 16, 16-dimethyl-PGE₂ (free acid). An average total dose of 3.4 mg led to abortion or adequate cervical dilatation in all patients. Based upon previous experience with the compound, no prophylactic anti-emetic or anti-diarrhetic medication was given. Gastrointestinal side effects were minimal. Excessive bleeding was not observed. In two cases, slight temperature elevation was noted prior to abortion. The low incidence of side effects in combination with the effectiveness of the compound help to make this method an attractive therapeutic adjunct to vacuum aspiration beyond the 10th week of gestation. Under the experimental conditions of this study, the results suggest that vaginally administered 16, 16-dimethyl-PGE₂ can be a safe and effective method for cervical dilatation before vacuum aspiration.     

Vaginally administered 16, 16-dimethyl-prostaglandin E2 as an agent for pre-operative cervical dilatation

Twenty-one women in the 10th–12th week of pregnancy were treated prior to vacuum aspiration with vaginal suppositories containing 16, 16-dimethyl-PGE₂ (free acid). An average total dose of 3.4 mg led to abortion or adequate cervical dilatation in all patients. Based upon previous experience with the compound, no prophylactic anti-emetic or anti-diarrhetic medication was given. Gastrointestinal side effects were minimal. Excessive bleeding was not observed. In two cases, slight temperature elevation was noted prior to abortion. The low incidence of side effects in combination with the effectiveness of the compound help to make this method an attractive therapeutic adjunct to vacuum aspiration beyond the 10th week of gestation. Under the experimental conditions of this study, the results suggest that vaginally administered 16, 16-dimethyl-PGE₂ can be a safe and effective method for cervical dilatation before vacuum aspiration.     

Pregnancy termination

During pregnancy, the antiprogestin mifepristone will induce uterine contractions, increase the sensitivity of the myometrium to prostaglandin, and ripen the cervix. These effects indicate that mifepristone can be used for termination of pregnancy. The clinical experience has shown that mifepristone is sufficiently effective for this purpose only if combined with a suitable prostaglandin, e.g. gemeprost or misoprostol. The combined treatment has been used for termination of early pregnancy (up to 63 days of amenorrhea) and for termination of second trimester pregnancy. During early pregnancy, the recommended dose of mifepristone is 600 mg (although 200 mg seems sufficient), followed 36-48 h later by 0.4-0.8 mg misoprostol administered either orally or vaginally, or vaginal administration of 1.0 mg gemeprost. For termination of second trimester pregnancy, the treatment with mifepristone is most commonly combined with 1.0 mg gemeprost repeated at 3-6-h intervals. The combined treatment is as effective and safe during early pregnancy as is the alternative vacuum aspiration and is also equally acceptable if the woman is allowed to choose the method she prefers. During the second trimester, the pretreatment will significantly reduce the duration of labor, dose of prostaglandin, and the frequency of side effects.     

Vaginally administered 16,16-dimethyl-PGE2 for the induction of midtrimester abortion

Thirty patients in the 13th–20th week of gestation underwent therapeutic abortion utilizing vaginally administered 16,16-dimethyl-PGE₂ (free acid) suppositories. The first 15 patients obtained individual doses in the range of 400–1200 μg given every three hours (mean total dose 4.2 mg). In the following 15 patients a fixed dose schedule was used (800 μg followed by 1000 μg every three hours; mean total dose 5.3 mg). All but one of the 30 patients aborted. The mean induction-abortion interval for all patients was 16.8±6.9 hours (mean ± S.D.) With the fixed dose regime the success rate was 100% and the induction-abortion interval 16.0±5.9 hours. Because gastro-intestinal side effects were minimal, neither anti-emetic nor anti-diarrheic medication was required. A slight elevation of temperature was noted in five patients. The uterine response to the vaginal administration of this compound was characterized by a gradual increase in uterine tonus followed by sustained stimulation. The results are interpreted to suggest that the vaginal administration of 16,16-dimethyl-PGE₂ is a useful alternate method for the induction of second trimester abortion. Moreover, this compound seems to cause fewer gastro-intestinal side effects than other prostaglandins administered by the vaginal route at our department.     

Clinical experiences with a new gel for intracervical application of prostaglandin E2 before therapeutic abortion or induction of term labor

A new gel for intracervical application of prostaglandin E₂ (PGE₂) has been elaborated and evaluated. The main component of the gel is a cross-linked starch polymer to which prostaglandins can be added and preserved for long-term storage (> 12 months).In a double blind study, 20 patients requiring legal abortion in late first trimester were given gel containing 0.25 mg PGE₂ or gel without PGE₂. The gel was applied within the cervical canal. In all patients receiving PGE₂-gel, a rapid ripening of the cervix occurred which facilitated the subsequent dilatation and evacuation. In patients receiving gel without PGE₂ cervix did not ripen. In a subsequent open study, 30 patients were treated with PGE₂-gel before therapeutic abortion. The same degree of cervical ripening was registered as for the patients receiving PGE₂-gel in the double blind study.In 50 patients at term, intracervical application of 3 ml gel containing 0.50 mg PGE₂ induced labor in 27 cases, i.e. 54 per cent of the patients. In the remaining undelivered women, a prominent cervical ripening occurred within 24 hours. No side effects of the treatment were observed.We conclude the new PGE₂-gel to be a promising future alternative in the treatment of patients with an unfavorable cervix, prior to surgical evacuation of the uterus in late first trimester abortion, as well as before induction of labor at term.     

Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries in the early second trimester

The use of gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries for the termination of pregnancy in the early second trimester has been further investigated. Of 113 women between 12 and 16 weeks gestation, 93 (82%) aborted within 24 hours of the administration of 4.4 +/- 0.1 1 mg gemeprost pessaries. The mean induction-abortion interval was 881 +/- 31 minutes. Successful abortion was achieved in 16 of the remaining 20 women after a second course of gemeprost pessaries without the need for oxytocin supplementation. There were no serious complications. Crampy abdominal pain and vaginal bleeding started after 275 and 756 minutes respectively. Twenty-two (19%) patients did not require pain relief during treatment, but 90 (80%) required parenteral opiates. Vomiting and diarrhoea occurred in 16 (14%) and 23 (20%) cases respectively. The safe induction of therapeutic abortion in 96% of women using vaginal prostaglandin alone offers an acceptable alternative to surgical evacuation in the early second trimester.     

Termination of second trimester pregnancy with intra-muscular administration of 16 phenoxy-omega-17,18,19,20 tetranor PGE2 methylsulfonylamide.

A new prostaglandin analogue, 16 phenoxy-omega-17,18,19,20 tetranor PGE2 methylsulfonylamide was used for the termination of second trimester pregnancy in 60 patients. The drug was injected intramuscularly in doses of 0.5 mg 4 hourly, 1 mg 8 hourly or 1 mg 6 hourly for a maximum of 36 hours. Fifty five patients aborted. The incidence of gastrointestinal side effects was low and there were no complications.     

Prostaglandin-induced pregnancy termination: Further studies using gemeprost (16, 16 dimethyl-trans-Δ-PGE1 methyl ester vaginal pessaries in the early second trimester

The use of gemeprost (16, 16 dimethyl-trans-Δ²-PGE₁ methyl ester) vaginal pessaries for the termination of pregnancy in the early second trimester has been further investigated. Of 113 women between 12 and 16 weeks gestation, 93 (82%) aborted within 24 hours of the administration of 4.4 ± 0.1 1mg gemeprost pessaries. The mean induction — abortion interval was 881 ± 31 minutes. Successful abortion was achieved in 16 of the remaining 20 women after a second course of gemeprost pessaries without the need for oxytocin supplementation. There were no serious complications. Crampy abdominal pain and vaginal bleeding started after 275 and 756 minutes respectively. Twenty-two (19%) patients did not require pain relief during treatment, but 90 (80%) required parenteral opiates. Vomiting and diarrhoea occured in 16 (14%) and 23 (20%) cases respectively. The safe induction of therapeutic abortion in 96% of women using vaginal prostaglandin alone offers an acceptable alternative to surgical evacuation in the early second trimester.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

This investigation was conducted to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F2 alpha. Both 15-methyl PGF2 alpha and 15-methyl PGF methyl ester can be absorbed from the vagina in sufficient amounts to induce abortion. The potency of the methyl ester was approximately twice that of the free acid. The most successful treatment schedule consisted of an initial dose of 0.5 mg of the methyl ester followed by 1.0 or 2.0 mg every third hour. On this treatment all patients aborted within 24 hours. Initially 200 ug of 15-methyl-PGF2 alpha was given. The dose was increased to 400 ug or occassionally to 500 ug depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100% abortion rate and the mean induction-abortion interval was 16.1 hours. Both routes were associated with a higher frequency of side effects than that reported for intraamniotic administration of 15-methyl-PGF2 alpha. It seems justified to conclude that the intraamniotic route is preferable after the 14th week when the uterine cavity is easy to puncture, but that vaginal or intramuscular injections of the compounds could be an alternative in late first trimester and early second trimester cases.