Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PFG_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Effect of 15(S)15-methyl-PGF2α-methyl ester vaginal suppositories on circulating hormone levels in early pregnancy

Intravaginal administration of 15-methyl-PGF_2α-methyl ester in the form of suppositories terminated pregnancy in 70 percent of the cases whose last menstrual periods ranged from 35 to 56 days. The use of these suppositories in 49 patients, between 57 to 80 days of gestation, dilated the cervix by 10 mm or more, in one hundred percent of the cases. A decrease in circulating levels of estradiol-17β and progesterone was observed following 15-methyl-PGF_2α administration. The mean estradiol-17β levels declined by about 55.9 percent at 9 hours whereas, the corresponding fall in progesterone was 32.7 percent. This was indicative of a direct action of 15-methyl-PGF_2α on the corpus luteum. The vaginal use of 15-methyl-PGF_2α-methyl ester suppositories thus appears to be a promising method for the termination of early pregnancy and for pre-operative cervical dilatation. The termination of early pregnancy appears to be partly due to the luteolytic effect of 15-methyl-PGF_2α besides stimulating uterine contractions.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 μg initially and 300 μg every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 g initially and 300 g every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Serial intramuscular injections of 15(S)-15-methyl-prostaglandin F2α in the induction of abortion

Abortion was successfully induced in 62 of 68 patients in the 9th to the 26th week of pregnancy by serial intramuscular administration of 15(S)-15-methyl-prostaglandin F_2α (15-ME-PGF_2α). In 6 patients who failed to abort after 24 hours of prostaglandin administration, a concomitant infusion of oxytocin was initiated; 5 of these patients aborted within 12 hours of the combined therapy. A single patient failed to abort, even with the combined therapy, and underwent surgical evacuation. The mean abortion time in the 67 successful inductions was 14.56 hours. Parous patients aborted somewhat faster, mean 13.98 hours, as compared to nulliparous patients, mean 15.02 hours, but this difference was not statistically significant. In this study initial intramuscular injection of 100 μg 15-ME-PGF_2α was followed in 1 hour by 250 μg and then 250 μg every 2 hours with concomitant oxytocin therapy initiated after 24 hours. The results with this dose schedule were compared to the results obtained in a previous study with a higher dose schedule, an initial dose of 100 μg 15-ME-PGF_2α, followed in 1 hour by 250 μg then 500 μg every 2 hours. There was no significant difference in the mean abortion time and the incidence of side effects between the 2 dose schedules. The mean abortion time for patients with gestational ages of 16 weeks and less was the same with both dose schedules, however patients with gestational ages of 17 weeks and higher aborted somewhat faster with the higher dose schedule. It might therefore be advisable for patients with gestations of 17 weeks and higher to be treated with the higher dose schedule. In earlier gestations patients could be started on the lower schedule, and if abortion had not occurred within 15 hours the dose of 15-ME-PGF_2α could then be increased to 500 μg every 2 hours.     

Induction of midtrimester abortion by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F2α (THAM) suppositories

Midtrimester abortion was successfully induced in 13 of 22 patients by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F_2α (THAM) suppositories. Nine patients, 4 nulliparas and 5 multiparas, failed to abort after 24 hours of prostaglandin administration and a concomitant infusion of oxytocin was initiated. Seven of the nine patients aborted within 7 hours of the combined therapy and one patient on methadone maintainence aborted after 17.5 hours of combined therapy, 41.5 hours after the first dose of prostaglandin. A single patient failed to abort, despite the concomitant prostaglandin-oxytocin administration and underwent surgical evacuation. The mean abortion time for the 21 successful abortions was 22.56 hours. Nulliparous patients aborted somewhat faster, mean 21.79 hours, than multiparous patients, mean 23.80 hours, but this difference was not statistically significant. In this study, one patient aborted in less than 12 hours, and 62% of the successful cases aborted within 24 hours. The plasma levels of 15-ME-PGF_2α were analyzed by radioimmunoassay in 10 patients. Plasma prostaglandin levels rose significantly 30 minutes after the insertion of the first suppository, but there was a wide variation in levels from patient to patient. It was observed that the 2 patients with the highest levels had the fastest abortion times and episodes of gastro-intestinal side effects appeared related to a rise in prostaglandin levels. Sixty-four percent of the patients in this study had no gastro-intestinal side effect related to prostaglandin administration.     

A radioimmunoassay of 15 (S) 15 methyl prostaglandin F2α

A sensitive and relative specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α has been developed to enable the measurements of the concentrations of the drug in biological fluids after its administration for therapeutic abortion. The precision, accuracy and specificity of the assay are described.     

Induced abortion in the 8–9th week of pregnancy with vaginally administered 15-methyl PGF2α methyl ester

15(S)15-methyl PGF_2α methyl ester was self-administered vaginally to terminate pregnancy in 42 women in the 8–9th week of gestation. Ten patients received a total of 6 mg of the compound over 15 hours (Group I) while the remaining 32 patients received 5.5 mg of the prostaglandin compound during a shorter period of time or 9 hours (Group II). If parts of the conceptus were expelled during treatment, surgical intervention was excluded. All patients were followed closely after treatment with repeated serum HCG assays and clinical examinations. All patients in Group II and eight out of ten patients in Group I aborted following treatment. In 33 of the 42 patients, the serum HCG levels and the clinical course following the expulsion of the conceptus indicated that abortion was complete. Gastro-intestinal side effects were minimal if anti-diarrheic agents were given prophylactically. The incidence of uterine pain was variable but could in most cases be controlled by oral or rectal administration of analgetics. The results of this study suggest that the use of this compound for termination of pregnancy may be safely extended through the 9th week of gestation and in certain cases be an alternative to the normal operative procedure.     

Intrauterine instillation of prostaglandin F2α in early pregnancy

Intrauterine PGF_2α (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidence of infection was high occurring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF_2α instillation and 90% 14 days later. The mean plasma estradiol-17β fell 26% over the initial eight hour period and 75% over the next 14 days.     

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.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F2α — A two dose schedule study

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F_2α (15 me F_2α) was attempted in fifty patients. One group (25 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F_2α was similar in both groups; over 90% of the patients aborted with a single dose. There was a higher incidence of vomiting, diarrhoea and incomplete abortions in the group treated with 2.5 mg 15 me F_2α. Although the mean injection-abortion interval in the 2.5 mg group was shorter, it is concluded that intra-amniotic administration of 1 mg 15 me F_2α provides a better regime, giving high efficacy with a single dose, a low incidence of side effects and greater safety in case of inadvertent entry of the intra-amniotic dose into systemic circulation.     

Disappearance of prostaglandins F2α and 15-methyl F2α from amniotic fluid as measured by radioimmunoassay

A sensitive and relatively specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α 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 is followed by a slow removal from the amniotic sac. A comparison with a similar study with PGF_2α, revealed that the analogue had a longer half-life in the amniotic fluid.     

Prostaglandin F2α (PGF2α) and prolactin secretion in rats

Plasma prolactin and F-prostaglandins (PGF) were measured in anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF_2α (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpromazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF_2α administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpromazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. These results indicate that PGF_2α can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpromazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.     

Post-conceptional induction of menses with a single vaginal suppository of (15S)-15-methyl prostaglandin F2α methyl ester

The induction of post-conceptional menses needs a technically simple method which would avoid avoid instrumentation of the uterus. One possible method investigated in this study is the abortifacient effect of a single dose long-acting vaginal suppository containing 3.0 mg of (15S)-15-methyl prostaglandin F₂α methyl ester. Pregnancy was terminated successfully in 13 of the 14 subjects. Two successful patients required curettage for prolonged bleeding and retained products of conception. Prolonged vaginal bleeding and the uncertainty of endpoints with particular reference to human chorionic gonadotropin (HCG) constitute the major problem with this non-invasive method, and are discussed in the light of the data obtained.     

Hormone changes occurring during second trimester abortion induced with 15(S)-15-methyl prostaglandin F2α

Changes in progesterone, human placental lactogen (HPL), cortisol and estradiol-17β were measured during second trimester abortion induced by I.M. 15-methyl PGF2α. A rapid decline in progesterone and HPL was found, indicating perhaps an initial effect on the placenta. A rapid rise in cortisol was found, but it is not clear if this is due to stress or part of the termination mechanism. The changes of estradiol were not as distinct and may reflect opposite effects of the prostaglandin on the placenta and adrenals. Similar hormonal changes were observed regardless of the duration of gestation.     

The origin of circulating 13,14-dihydro-15-keto-prostaglandin F2α during delivery

All uterine tissues as well as the fetal membranes and the placenta can form prostaglandins from endogenous precursors but it is not clear which of the tissues is the main site for the increase in PGF_2α production during human parturition. To examine this question, we measured plasma prostaglandin levels before and at intervals after expulsion of the fetus, placenta, and membranes. The concentration of PGFM at the beginning of the second stage of labor was significantly higher than before the onset of labor. Five minutes after the birth of the infant, the concentration had doubled. Thirty minutes after the expulsion of placenta and membranes, plasma PGFM had fallen to the levels at full dilatation; two hours postpartum it was still significantly raised over levels before labor. Since the halflife of PGFM in the circulation is about 7 minutes, these findings indicate that the uterine tissues are important sources of PGFM during labor. In contrast, endogenous oxytocin levels, which were significantly raised over control levels at the second stage of labor, did not change during the third stage, and decline postpartum to control levels. Oxytocin infusion did not influence PGFM levels at 5 and at 30 minutes postpartum, but raised them at 2 hours.     

15(S)15-Methyl protaglandin F2α for termination of very early human pregnancy. A comparative study of a single intramuscular injection and vaginal suppositories

The results of a comparative study of the efficacy and acceptability of 15(S)15-methyl prostaglandin F_2α (15-Me-PGF_2α) administered as a single i.m. injection or vaginal suppositories (15-Me-PGF_2α methyl ester) every 3rd hr for termination of very early human pregnancy is reported. The amenorrhoic period varied from 37 to 60 days. (30 cases) received 0.6 mg as a single i.m. injection without any pretreatment. Restrospectively 24 of the 30 women were in fat pregnant and 22 of them aborted. received suppositories (1.0 or 1.5 mg per suppository). In this group all women were pregnant and they all aborted.Symptoms such as pain, bleeding, vomiting and diarrhea started in general earlier in the i.m. group and they were more marked. In the present series the efficacy and acceptability were highest for the vaginal route of administration.     

Termination of pregnancy in cats with prostaglandin F2α

Two subcutaneous injections of Prostaglandin F_2α THAM salt 24 hours apart terminated pregnancies in cats after the 40th day of gestation. Injections of 0.50 or 1.00 mg. PGF_2α THAM salt/Kg. body weight were the most effective in terminating pregnancies. Parturition or abortion occurred within 24 hours after the initial injection in 9 cats and after the 2nd injection in 4 cats.     

Cardiovascular actions of prostaglandins F2α; 15-me-F2α; F1α; F2β and F1β in the cat

Prostaglandin F_2α (5μg/kg, i.v.) causes an increase in pulmonary arterial pressure, decrease in systemic arterial pressure, and reflex bradycardia in the anesthetized cat. The same dose of the 15-methyl analogue of PGF_2α produces the same triad of effects but of greater magnitude and duration. Although prostaglandins F_1α, F_2β and F_1β also cause the same cardiovascular effects as F_2α, there is a decrease in potency for all parameters measured, with PGF_2α>PGF_1α>PGF_2β>PGF_1β. When compared to the actions of PGF_2α in producing an increase in pulmonary arterial pressure, PGs F_1α, F_2β and F_1β were less potent by approximately 10, 100, and 1000 fold respectively.