Prostaglandins and post-abortion luteolysis in early pregnancy.

This study was undertaken to determine if post-abortion luteolysis in early pregnancy could be accelerated by the administration of 15(S)15-methyl-PGF2alpha(15-me-PGF2alpha) or delayed following pretreatment with indomethacin. Thirty-nine women were divided into four groups: 7 women were given 400mug 15-me-PGF2alpha extra-amniotically one hour prior to vacuum aspiration; 14 were pretreated with oral indomethacin (50 mg X4) over 24 hours; 7 were given indomethacin (50mg X 6) over 36 hours and 11 served as controls. Plasma progesterone and estradiol were measured at fixed intervals before and after abortion. There was a rapid drop in the plasma progesterone within the first hour after abortion followed by an exponential decline over the next 23 hours. The plasma estradiol fell rapidly duriing the same period. Under the experimental conditions of this study neither 15-me-PGF2alpha nor indomethacin exerted a significant effect on the decline in luteal function. These results are interpreted as suggesting that factors other than prostaglandins have a more significant role in post-abortion luteolysis.     

Prostaglandins and post-abortion luteolysis in early pregnancy

This study was undertaken to determine if post-abortion luteolysis in early pregnancy could be accelerated by the administration of 15(S)15-methyl-PGF₂ (15-me-PGF₂) or delayed following pretreatment with indomethacin. Thirty-nine women were divided into four groups: 7 women were given 400g 15-me-PGF₂ extra-amniotically one hour prior to vacuum aspiration; 14 were pretreated with oral indomethacin (50 mg X4) over 24 hours; 7 were given indomethacin (50mg X 6) over 36 hours and 11 served as controls. Plasma progesterone and estradiol were measured at fixed intervals before and after abortion. There was a rapid drop in the plasma progesterone within the first hour after abortion followed by an exponential decline over the next 23 hours. The plasma estradiol fell rapidly during the same period. Under the experimental conditions of this study, neither 15-me-PGF₂ nor indomethacin exerted a significant effect on the decline in luteal function. These results are interpreted as suggesting that factors other than prostaglandins have a more significant role in post-abortion luteolysis.     

Termination of early gestation with vaginal prostaglandin F2α tablets

The abortifacient activity of prostaglandin F_2α was investigated by placing one or two 50 mg tablets of prostaglandin F_2α in THAM salt into the vagina of nine women less than 4 weeks pregnant at intervals of 2 to 4 hours for a 24 hour period. Serum levels of HCG, estradiol (E₂), progesterone and 17α-hydroxyprogesterone were measured by radioimmunoassay prior to starting therapy and at frequent intervals thereafter for 48 hours. All but two patients had significant side-effects, mainly diarrhea and vomiting, indicating that systemic absorption took place. Although bleeding was induced in 8 of 9 women, only 3 had complete abortions. A D&C was performed on all patients 48 hours after starting therapy. A significant fall in HCG levels was noted only in the patients who aborted. Only 3 of the 9 women had significant changes in steroid levels. A fall in progesterone and 17α-hydroxyprogesterone occurred in the 3 women who aborted and took place following the fall in HCG. Estradiol levels remained in the same range in all subjects. These findings indicate that prostaglandin F_2α when administered in this vehicle and this dosage is relatively ineffective as an abortifacient. When effective, its action would appear to be due to contractions of uterine muscle and not secondarily to luteolysis.     

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.     

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.     

The simultaneous use of two prostaglandin radioimmunoassays employing two antisera of differing specificity: II. Relative Stability of Prostaglandins E1, E2 and F1α in Cell Cultures of BALB/c 3T3 and SV3T3 Mouse Fibroblasts.

Progesterone and the main plasma metabolite of PGF_2α, 15-keto-13,14-dihydro-PGF_2α, were determined at hourly intervals in the peripheral circulation during luteolysis in two heifers. The prostaglandin release was found to occur during 2–3 days as rapid pulses with a duration of 1–5 hours prior to and during luteolysis, which was indicated by decreasing levels of progesterone.     

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.     

Intra-amniotic prostaglandin F2α and urea for abortion

Prostaglandin F_2α (PGF_2α) 20 mg combined with urea 80 g was injected intra-amniotically in 20 patients to induce mid-trimester abortion. Abortion resulted in all subjects within 24 hours in a mean time of 12 hours 38 minutes (range 5 hours 50 minutes to 20 hours 45 minutes).Plasma sex steroids were evaluated before and hourly for 5 hours after the injection. A progressive decline in levels occurred with time. Decreases in plasma progesterone, estrone, estradiol and estriol were significant as soon as one hour after injection.Gastrointestinal side effects occurred with a greater frequency than when a comparable dose of PGF_2α is given alone and 2 patients had small cervical lacerations requiring suture. Further studies are indicated to establish whether a lower dose of PGF_2α will be associated with fewer side effects and be as effective.     

Effect of intravenous infusion of 15-methyl-PGF2α on plasma hormone levels during early pregnancy

Ten pregnant women (7th–8th week of pregnancy) obtained an intravenous infusion of 15-methyl-prostaglandin-F_2α (2.5 μg/min) until clinical signs of abortion occurred or up to 7 hours. Surgical removal of the products of conception was performed 4–7 hours after the start of the infusion. Blood samples were taken prior to and during the infusion and then during the post-abortion period. The plasma levels of both progesterone and estradiol exhibited a significant decrease (p<0.001 and p<0.05, respectively) one hour after the beginning of infusion and remained reduced by approximately 35 and 45 per cent, respectively, during the entire infusion period. A drop in the levels of both steroids was seen after surgical interruption. This was followed by a gradual decrease to non-pregnancy levels. The levels of cortisol increased significantly (p<0.01) by approximately 60 per cent, starting with the second hour of infusion. Following surgical interruption, the levels dropped to pre-infusion values. 17-Hydroxyprogesterone levels increased (p<0.05) above the pretreatment levels by approximately 25 per cent, starting with the third hour of infusion. These levels were not correlated with those of cortisol during the infusion period. Following surgical interruption the plasma levels of 17-hydroxyprogesterone returned to non-pregnancy levels.     

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.     

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.     

The effect of a 10 cm2, 0.5% 15-ME-PGF2α methyl ester intravaginal silastic device on abortion and plasma prostaglandin concentration

Intravaginal insetion of a 10 cm² silastic device with an 0.5% concentration of 15(S)-15-methyl-prostaglandin F_2α methyl ester alone successfully induced abortion in 27 of 48 patients in the midtrimester and in an additional 11 patients with a concomitant infusion of oxytocin. The mean abortion time for the 38 successful induction was 15.35 hours. In 8 of the 10 patients who failed to abort even with concomitant oxytocin therapy, abortion was induced by serial intramuscular injections of 15-ME-PGF_α; the remaining 2 failures underwent surgical evaccution. The plasma levels of 15-ME-PGF_2α methyl ester in the 11 patients studied varied widely over the first 2 hours after insertion of the device. The maximum mean level was achieved at 2 hours, maintained at 4 hours and then dropped sharply at 8 hours and declined over the abortion period in undelivered patients. Vomiting and diarrhea were the most common side effects and in general well tolerated by the patients. However, there was an adverse reaction in a single patient who experienced almost constant nausea, vomiting and diarrhea. The device was removed 1 hour 50 minutes after insertion and the patient aborted spontaneously 7 hours later. Intravaginal insertion of a silastic device is an effective means of prostaglandin abortion, but their investigation is required to determine the most effective device which would provide a slow, continuous release of the prostaglandin.     

Comparative luteolytic activity of estradiol cyclopentylpropionate and prostaglandin F2α in diestrous cows

The effect of estradiol cyclopentylpropionate (EC) on corpus luteum (CL) function in diestrous cows was evaluated. Two doses of EC (4 and 20 mg) were given by intramuscular (IM) injection and one dose of EC (4 mg) was given by intrauterine (IU) infusion. Control cows were treated with physiologic sterile saline (PSS) IU or corn oil IU (negative controls) or prostaglandin F_2α (PGF_2α, 30 mg IM, positive control). A total of 24 cows, four per treatment, were treated on days 8 to 12 of the estrous cycle (day 0 equals day of estrus). Luteal function was monitored by serum progesterone through 96 hours after treatment. A decrease in serum progesterone from pretreatment diestrous concentrations to less than 1.0 ng/ml was considered indicative of luteolysis.Intrauterine injection of PSS and corn oil had no effect on luteal function. Neither IM nor IU administration of EC caused consistent or rapid luteolytic effects. Prostaglandin F_2α consistently induced rapid luteal regression. These results indicate that EC should not be considered luteolytic in the same sense as is PGF_2α.     

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.     

Effect of estrogen and progesterone treatment on the depressor response to prostaglandin E2 in ovariectomized women

The effect of exogenous estrogen and progesterone on the response of the systemic arterial pressure to prostaglandin E₂ (PGE₂) was studied in 15 ovariectomized women. All experiments were performed on the 7th postoperative day. Arterial blood pressure was measured in all women in supine position at one minute intervals by an automatic recorder. PGE₂ infused intravenously in all subjects for 10 minutes. Ten of the women who were given intramuscular injections of either estradiol benzoate (10 mg) or inert vechicle 60–65 hours before the experiment, showed a significant decline in both systolic and diastolic blood pressure during the PGE₂ infusion. In contrast, the remaining of the women who were injected with progesterone intramuscularly also 60–65 hours before the experiment, did not present any significant alterations in blood pressure during or after the infusion of PGE₂. These results suggest that, in ovariectomized women, progesterone treatment prevents the depressor response to PGE₂. This may be due to increased inactivation of PGE₂ by various tissues.     

Effect of in vivo prostaglandin treatment on 3H-PGF2α uptake in hamster corpora lutea

Pregnant hamsters were administered (SC) prostaglandin or vehicle on the morning of the 4th day of pregnancy. Serum progesterone was significantly depressed (p<.01) at 0.5, 2, and 6 hours after treatment with 100 μg PGF_2α. Serum progesterone levels were unchanged 2 hours and 6 hours after treatment with 100 μg PGF_2β and 2 hours after treatment with 1 mg PGF_2β. Progesterone levels were depressed to less than 1 ng/ml 6 hours after treatment with 1 mg PGF_2β. The specific uptake of ³H-PGF_2α in whole hamster corpora lutea was significantly depressed 2 hours and 6 hours following 100 μg PGF_2α treatment. A 15% depression in specific uptake occurred 0.5 hour post-treatment. Treatment with 100 μg PGF_2β resulted in no change. Administration of 1 mg PGF_2β resulted in depressed ³H-PGF_2α uptake at both 2 and 6 hours post-treatment.Prostacyclin (PGI₂) treatment resulted in no change in either ³H-PGF_2α specific uptake or serum progesterone 2 hours after 100 μg treatment SC. These parameters were both reduced approximately 30% 6 hours post-treatment. Treatment with 6-keto-PGF_1α resulted in a complete lack of measurable ³H-PGF_2α uptake and serum progesterone levels less than 1 ng/ml at both 2 and 6 hours after treatment with 1 mg SC.     

Midtrimester abortion induced by a single intra-amniotic instillation of two dose schedules of 15(S)-15-methyl-prostaglandin F2α

Midtrimester abortion was successfully induced in a series of 20 patient by intra-amniotic instillation of 15(S)-15-methyl-prostaglandin F_2α with a mean abortion time of 17.78 hours. The patients in this study were divided into two groups, Groups I received on initial dose of 2.5 mg 15-ME-PGF_2α and aborted in a mean time of 16.26 hours. The patients in Group II received 3.0 mg 15-ME-PGF_2α and aborted in a mean time of 18.94 hours. There was no significant difference in the abortion time, occurrence of side effects or the initiation of uterine activity between Group I and Group II. Parous patients aborted somewhat faster than nulliparous patients but this difference was not significant. In this study 80% of the patients aborted in 24 hours or less, and the intra-amniotic instillation of 15-ME-PGF_2α was an effective abortifacient technique from the 15th to the 23rd week of gestation. The uterine response to intra-amniotic instillation of 15-ME-PGF_2α was characterized by the gradual appearance of low amplitude, high frequency contractions accompanied by a rise in baseline intrauterine tonus. Uterine activity developed gradually and peaked at 1:50 hours after intra-amniotic instillation of 15-ME-PGF_2α. In this small series 15-ME-PGF_2α administered via intra-amniotic instillation did not appear to have a distinct advantage over the naturally occurring PGF_2α administered by the same method for the induction of midtrimester abortion; a larger series is indicated to define the advantages of either technique.     

Induced abortion in cattle

Several procedures were used to abort cattle during the second and third trimesters of gestation. The treatment to abortion interval was better (P<0.05) when dexamethasone trimethyiacetate (DTMA) injections repeated at either 6 or 4 day intervals than when a single injection of DTMA was followed 6 days later by the administration of stilboestrol. The treatment to abortion interval was not significantly shorter when DTMA was repeated after 4 days rather than 5 days (0.10<P>0.05). Prostaglandin F_2α produced abortion 1 to 4 days following direct administration into the foetai fluids.Peripheral plasma progesterone concentration had a tendency to rise immediately following the second injection of DTMA given at a 6 day interval. This was followed by a decline. Two injections of DTMA given at 4 day intervals resuited in a decline in progesterone concentration. Abortion occurred when plasma progesterone concentrations were about 1 ng/ml in cows treated with DTMA. In cows treated with prostagiandin F_2α the plasma progesterone concentration fell rapidly within one day of administration to approximately 2 ng/ml, at which concentration abortion took place.     

An intra-corpus luteum site for the luteolytic action of prostaglandin F2α in the rhesus monkey

It has not been possible to demonstrate prostaglandin F₂α (PGF₂α) participation in primate luteolysis under conditions of systemic administration or of acute intraluteal injection. These study designs were hampered by the short biological half-life in the first instance and brevity of administration in the latter. In this study, luteolysis has resulted from chronic, intraluteal delivery of PGF₂ α. Using the Alzet osmotic pump-cannula system, normally cycling rhesus monkeys were continuously infused, until menses occurred, with PGF₂ α (10 ng/1/hr) directly into the corpus luteum (CL, n=6), into the stroma of the ovary bot bearing the corpus luteum (NCL, n=3), or subcutaneously (SC, n=5). An additional 5 monkeys received vehicle (V) into the corpus luteum. All experiments commenced 5–7 days after the preovulatory estradiol surge. Luteal function was assessed by the daily measurements of plasma progesterone, estradiol, and LH. Intraluteal PGF₂α caused premature functional luteolysis in all monkeys, as reflected by a highly significant decline in circulating progesterone and estradiol and the early onset of menstruation, when compared to the other groups. V, NCL, and SC infusions had no effect on either circulating steroid levels or luteal phase lengths. None of the experimental groups showed any change in plasma LH concentrations. These are the first data to indicate that PGF₂α can induce functional luteolysis in the primate, and the site of action appears to be the corpus luteum.     

Intrapulse temporality between pulses of a metabolite of prostaglandin F2α and circulating concentrations of progesterone before, during, and after spontaneous luteolysis in heifers

Pulses of the prostaglandin F_2α (PGF) metabolite 13,14-dihydro-15-keto-PGF_2α (PGFM) and the intrapulse concentrations of progesterone were characterized hourly during the preluteolytic, luteolytic, and postluteolytic periods in seven heifers. The common hour of the end of preluteolysis and the beginning of luteolysis was based on a progressive progesterone decrease when assessed only at the peaks of successive oscillations. The end of the luteolytic period was defined as a decrease in progesterone to 1 ng/mL. Blood samples were taken hourly from 15 d after ovulation until luteal regression as determined by color-Doppler ultrasonography. Between Hours −2 and 2 (Hour 0 = PGFM peak) of the last PGFM pulse of the preluteolytic period, progesterone decreased between Hours −1 and 0, and then returned to the prepulse concentration. Concentration did not change significantly thereafter until a PGFM pulse early in the luteolytic period; progesterone decreased by Hour 0 and transiently rebounded after Hour 0, but not to the prepulse concentration. In the later portion of the luteolytic period, progesterone also decreased between Hours −1 and 0 but did not rebound. After the defined end of luteolysis, progesterone decreased slightly throughout a PGFM pulse. Results demonstrated for the first time that the patterns of progesterone concentrations within a PGFM pulse differ considerably among the preluteolytic, luteolytic, and postluteolytic periods.