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.     

Treatment with a single vaginal suppository containing 15-methyl PGF2α methyl ester at expected time of menstruation

Termination of early pregnancy, by vaginal administration of prostaglandin analogues, one to three weeks after the first missed menstrual period, has advantages and disadvantages in comparison with vacuum aspiration. Some of these may be reduced if the patient is treated earlier. In the present study the effect and safety of one vaginal administration of 2.5 to 3 mg 15-methyl-PGF_2α methyl ester around the expected time of menstruation was evaluated in 16 women exposed to the risk of pregnancy.The overall number of treatment cycles was 35 and pregnancy was confirmed by plasma β-HCG in eight. The treatment resulted in bleeding in all the pregnant cycles while in the nonpregnant ones it only provoked spotting and bleeding did not begin until the expected time of menstruation. Treatment with 2.5 mg 15-methyl-PGF_2α methyl ester resulted in complete abortion in one of three women. If the dose was increased to 3 mg all five treated women aborted. In nonpregnant patients no changes in the levels of estradiol-17β or progesterone at any time during the 24-hour observation period were found. Serum cortisol and prolactin but not TSH levels started to increase two hours after the start of treatment and reached a maximum after five hours. The increase coincided with the onset of uterine pain.Ovulatory cycles as judged from basal body temperature occurred in the first menstrual cycle following treatment in all nonpregnant patients. Although possible to use as a “once a month treatment” it seems preferable since the dose is the same, to postpone treatment until menstruation is delayed for a week or more.     

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.     

Additional studies on pregnancy termination and inhibition of the monkey corpus luteum with 5-oxa-17-phenyl-18,19,20-trinor-PGF1α methyl ester and structurally related prostaglandins

Oral administration of 5-oxa-17-phenyl-18,19,20-trinor-PGF_1α methyl ester (PGF-analog) resulted in a consistent and dose-dependent inhibition of corpus luteum progesterone production in nonpregnant rhesus monkeys concomitantly treated with human chorionic gonadotropin. Similarly, vaginal suppositories containing PGF-analog also inhibited the monkey corpus luteum. Side effects by the oral route of administration were minimal, whereas side effects of following vaginal treatment with PGF-analog were higher. Five prostaglandings with structural similarity to PGF-analog were studied for their ability to inhibit the monkey corpus luteum, but none showed an advantage over the parent molecule. PGF-analog did not synergize with 9-deoxo-16,16-dimethyl-9-methylene-PGE₂ for the inhibition of the monkey corpus luteum, nor did it synergize with (15S)-15-methyl-PGF₂α methyl ester for the interruption of early pregnancy in the monkey. 9-Deoxo-9-methylene-5-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester did not terminate early gestation in the monkey at doses of 8 or 24 mg.     

Effects of (15S)-15-methyl prostaglandin F2 methyl ester and estrogens upon the corpus luteum and conceptus of the rhesus monkey

The corpus luteum inhibiting properties of eighteen 15-methyl prostaglandin analogs were determined in the rhesus monkey during concomitant stimulation of the corpus luteum with chorionic gonadotropin. The methyl ester of (15S)-15-methyl PGF_2^α (15M-PGF_2^α, 12.5 mg/monkey) lowered serum progesterone to 12% of pretreatment values within 24 hours, however progesterone returned to normal limits within 48 hours. Elongation of the top side-chain by two carbons (2a,2b-dihomo-15M-PGF_2^α methyl ester, 13 mg/monkey), substitution of a hydroxymethyl group at carbon 1 (2-decarboxy-2-hydroxymethyl-15M-PGF_2^α, 12 mg/monkey), or the formation of the carbon 1 amide (15M-PGF_2^α amide, 12.5 mg/monkey) improved the inhibitory activity of 15M-PGF_2^α; serum progesterone for these 3 analogs was depressed to 15–30% of pretreatment levels within 24 hours, and did not return to control values. Luteal function was not inhibited (12 or more mg/monkey) when the 15-methyl group was placed in the R configuration, the top side chain was shortened by two carbons, an amino group was substituted for carbon 1, the 5-oxa modification was added, or the 1,9-lactone was formed. Some other modifications of 15M-PGF_2^α were also inactive, although not all were tested at equivalent doses: 2,2-difluoro; 4,5-cis-didehydro; 9,11-dideoxy-9α,11α-dichloro; 11-deoxy; 17-phenyl; 1,15-lactone; and the p-benzamidophenyl ester of 2a,2b-dihomo-15M-PGF_2^α. (15S)-15-Methyl PGE₂ methyl ester (1 mg/monkey) depressed serum progesterone concentrations to 42% of pretreatment values within 24 hours; 2a,2b-dihomo-11-deoxy-(15S)-15-methyl PGE₂ methyl ester was inactive (5 mg/monkey). A corpus luteum inhibiting action of certain 15-methyl prostaglandins can be demonstrated in the rhesus monkey.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

The present investigation was undertaken to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F_2α.1. . Both 15-methyl-PGF_2α and 15-methyl-PGF_2α 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.2. . Initially 200 μg of 15-methyl-PGF_2α was given. The dose was increased to 400 μg or occasionally to 500 μg depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100 per cent 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 intra-amniotic administration of 15-methyl-PGF_2α. It seems justified to conclude that the intra-amniotic 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.     

Induction of second trimester abortion: Comparison between vaginal 15-methyl-PGF2α methyl ester and intra-amniotic PGF2α

The efficiency and acceptability of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was compared with intra-amniotic administration of 50 mg of PGF_2α in 100 patients with a second trimester pregnancy termination. Within 24 hours, 78 per cent of the patients in the vaginal group and 92 per cent in the intra-amniotic group had aborted. The mean induction-abortion interval was 17.9 hours in the vaginal group and 15.8 hours in the intra-amniotic group.Gastrointestinal side-effects were more frequent, but the procedure was less painful, with vaginal 15-methyl PGF_2α methyl ester than with intra-amniotic PGF_2α.The vaginal route is technically simple for adaptation to large-scale use, but the high frequency of gastrointestinal side-effects still limits the acceptability of 15-methyl PGF_2α methyl ester in vaginal administration.     

Abortifacient efficiency of 15(S)15-methyl-prostaglandin F2α-methyl ester administered vaginally during early pregnancy

Forty early pregnancies (menses delay 13 – 27 days) were terminated by administering four vaginal suppositories each containing 1.0 or 1.5 mg of 15(S)15-methyl-prostaglandin F_2α-methyl ester, one every third hour. In 14 cases serial measurements of serum estradiol and progesterone were performed during and after therapy. Uterine contractions and bleeding started 1 – 17 hours after administration of the first suppository. Abortion was complete after one week in five women (13 %), and after two weeks in 30 (75 %). A curettage was performed on eight women, residual placentral fragments were found in seven and pregnancy continued in one woman. Mild diarrhoea (65 %) and vomiting (40 %) were the major side-effects, despite premedication. Estradiol and progesterone levels fell progressively during the therapy. Self-administration of 4 or 6 mg of the methyl ester caused too low a rate of complete abortion for use in practice, but it may be a valuable and practical agent for preoperative dilation of the cervix.     

Administration of prostaglandins by various routes for induction of abortion merits and demerits

Prostaglandin F_2α and its methyl analogues were used for induction of abortion in 598 patients with gestational age from 9 to 20 weeks. Different routes of administration were studied and varous dosages given. The incidence of gastrointestinal side effects were within acceptable range for all methods. Both intra-amniotic injections of 50 mg PGF_2α and 2.5 mg 15-methyl PGF_2α as well as intramuscular and vaginal administration of 15-methyl PGF_2α or its methyl ester, respectively, were highly effective in termination of pregnancy. The intramuscular route was, however, associated with the highest frequency of gastrointestinal side effects. If both efficacy and side effects were taken into consideration, the intra-amniotic and vaginal routes were superior. The ease of administration as well as the applicability over a wider range of gestation in termination of pregnancy may, however, in many situations speak in favour of the repeated vaginal administration of 15-methyl PGF_2α methyl ester.     

Serum hormone levels in women undergoing abortion with intra-amniotic,extra-amniotic or intra-muscular administration of 15(S)15-methyl-prostaglandin F2α

The serum levels of estradiol-17β, progesterone and HPL have been estimated by specific radioimmunoassay in thirty women undergoing abortion with 15-methyl-PGF_2α given by intra-amniotic, extra-amniotic or intra-muscular route. A significant decline in the levels of these hormones was observed in 27 cases in which the pregnancy was terminated. However, in the remaining three cases, 15-methyl-PGF_2α was found to be unsuccesful, and no significant change in the hormone levels was evident. The decline in these hormones was more marked by intra-muscular route, than that observed by the other routes. The pattern of estradiol-17β decline was more consistent when compared with progesterone and HPL. The levels of progesterone and HPL, in a few cases, rather showed an increase in the initial hours of 15-methyl-PGF_2α administration before the decline began and this pattern was more prominent on extra-amniotic administration. In general, the decline in the hormone levels was slower in cases which took longer time for abortion than cases with shorter induction-abortion time (IAT).The decline in estradiol-17β levels was about 65 percent at six hour of intra-muscular administration of 15-methyl-PGF_2α, whereas the corresponding fall with intra-amniotic and extra-amniotic routes was 29 and 22 percent, respectively. However, the net drop in its levels during IAT was not significantly different (range 70 to 80 percent) by the three routes. About 38 percent fall in progesterone levels was observed at six hour of intra-muscular administration whereas, by intra-amniotic the fall was 19 percent. The net decline in progesterone levels, during IAT, was in the range of 46 to 60 percent by the three routes. Similarly, intra-muscular 15-methyl-PGF_2α evoked a sharper decline in HPL levels as compared with other routes. The total decline during IAT was 58 to 66 percent. The results, thus indicated that the abortion with 15-methyl-PGF_2α was associated with a fall in the serum hormone levels, which could be resultant effect of alterations in the hormone production by the foeto-placental unit. This along with the uterine contractions may play a significant role in the abortifacient action of 15-methyl-PGF_2α.     

Plasma levels of the methyl ester of 15-methyl PGF2α in connection with intravenous and vaginal administration to the human

After intravenous injection of the methyl ester of 15-methyl-PGF_2α the drug initially disappeared faster than the corresponding free acid, but still after one hour, about 1% of the active drug is circulating in plasma. Vaginal administration of single suppositories containing 1 mg of 15-methyl-PGF_2α methyl ester and determination of plasma levels using gas chromatography - mass spectrometry demonstrated that the highest plasma levels were reached after 1.5 - 3 hours.Vaginal suppositories were administered according to different dose schedules for induction of abortion and plasma levels of 15-methyl-PGF_2α and it's ester were determined. There seemed to be a gross correlation between given doses and obtained plasma level. The data will serve as basis for further development of vaginal delivery devices.     

On the mechanism of action of 15-methyl-PGF2α as an abortifacient

Several hours following administration of long acting vaginal suppositories containing 3.0 mg of 15-methyl-PGF_2α for interruption of second trimester pregnancies there is an up to 10-fold increase in endogenous production of PGE₂ and PGF_2α before abortion as reflected by gas chromatographic-mass spectrometric determination of the major plasma metabolites of PGE₂ and PGF_2α. The data suggest that this increased formation of endogenous prostaglandins contributes to the induced uterine activity during the latter part of the abortion process.     

Role of endogenous prostaglandins in pregnancy termination by 15-methyl PGF2α

Thirty pregnant women with foetal death in utero received 15-methyl PGF_2α to terminate their pregnancies. Two groups (15 cases each) matched for age, gravidity and age of pregnancy were studied. One group received indomethacin suppositories before and during the PG induction while the second group received the prostaglandin analogue therapy only. The group which received the prostaglandin biosynthesis inhibitor showed a longer induction-termination interval, more PG ampoules were used and the number of failed cases was higher. Thus, the Release of Endogenous prostaglandins seems to play a complementary role in the therapeutic termination of pregnancy.     

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.     

Synthesis of 2, 3-dinor-PGFα metabolites

Thir report described the preparation of various 2,3-dinor-PGFα prostaglandins. Of particular importance is the synthesis of 2,3-dinor-15(S)-15-methyl PGF₂α, the primary metabolite in the enzymatic degradation of 15(S)-15-methyl-PGF₂α (1). Introduction of the three carbon β,γ-unsaturated carboxyl side chain was achieved in a one-step Wittig reaction. The 2,3-dinor structural assignments were established by carbon magnetic resonance (crm) spectroscopy.     

Effect of prostaglandins on in vitro synthesis of progesterone and oestradiol-17β in placenta from early human pregnancy

In vitro synthesis of progesterone and estradiol-17β from endogenous precursors was studied in the placenta from women in early stage of gestation (< 7 weeks). Radioimmunoassay techniques were used to measure progesterone and estradiol-17β.It was shown that placental tissue from as early as six weeks of gestation can synthesize both progesterone and estradiol-17β in vitro. Prostaglandins F_2α and E₂ in concentration of 100 μg/ml of the incubation media did not have any significant effect on the in vitro synthesis of progesterone and estradiol-17β in the placental tissue.It seems unlikely that the abortifacient effect of natural prostaglandins PGE₂ and PGF_2α is due to their direct action on the synthesis of progesterone and estradiol-17β in the placenta.     

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.     

Effects of PGF2α and PGF2α, 1–15 lactone on the corpus luteum and on early pregnancy in the rhesus monkey

The effects of prostaglandin (PG)F_2α and PGF_2α, 1–15 lactone were compared in luteal phase, non-pregnant and in early pregnant rhesus monkeys. Animals treated with either PG after pretreatment with human chorionic gonadotropin (hCG) had peripheral plasma progesterone concentrations that were not statistically different from those in animals treated with hCG and vehicle. However, menstrual cycle lengths in monkeys treated with PGF_2α, 1–15 lactone were significantly (P <0.02) shorter than those in vehicle treated animals. In the absence of hCG pretreatment, plasma progesterone concentrations were significantly (P <0.008) lower by the second day after the initial treatment with either PGF_2α or PGF_2α, 1–15 lactone than in vehicle treated monkeys. Menstrual cycle lengths in monkeys treated with either PG were significantly (P <0.04) shorter than those in animals treated with vehicle. There were no changes in plasma progesterone concentrations in early pregnant monkeys treated with PGF_2α, and pregnancy was not interrupted. In contrast, plasma progesterone declined and pregnancy was terminated in 5 of 6 early pregnant monkeys treated with PGF_2α, 1–15 lactone. These data indicate that PGF_2α, 1–15 lactone decreases menstrual cycle lengths in non-pregnant rhesus monkeys. More importantly, PGF_2α, 1–15 lactone terminates early pregnancy in the monkey at a dose which is less than an ineffective dose of PGF_2α.     

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.     

Induction of 20α-hydroxysteroid dehydrogenase in rat corpora lutea of pregnancy by prostaglandin F2α

20α-OH-SDH is a marker of luteolysis in rat corpora lutea and appearance of this enzyme is inhibited by prolactin but stimulated by LH or hCG. PGF₂α induced 20 α-OH-SDH activity in corpora lutea of pregnant rats and a significant fall in peripheral plasma progesterone concentrations when administered i.m. for two consecutive days. Rats treated with PGF₂ α on days 8 and 9 of pregnancy were resorbing implants by day 10. Exogenous progesterone, but not estrogen, prevented implant resorption, yet 20 α-OH-SDH appeared in the corpora marking luteolysis. HCG, LH and prolactin, but not FSH, prevented pregnancy termination and inhibited induction of 20 α-OH-SDH in rats treated with PGF₂ α in early pregnancy. PGF₂α also induced 20α-OH-SDH in luteal tissue of intact and hypophysectomized rats treated on days 14 and 15 of pregnancy, but neither exogenous steroids or gonadotrophins blocked the induction of the enzyme in rats treated at this time. The increase in lutein 20α-OH-SDH activity during the peripartal period was partially blocked by administration of the prostaglandin biosynthesis inhibitor, indomethacin, suggesting a role for endogenous prostaglandins in the induction of 20α-OH-SDH at term. It appears that PGF₂α acts directly on the ovary to induce 20α-OH-SDH activity by preventing the luteotrophic action of prolactin. Other luteal NADPH-dependent dehydrogenase activities are not markedly stimulated following PGF₂α administration.