Menstrual induction with the PGF2α-analogue ICI 81008

“Menstrual Induction” (MI) has been studied in 79 volunteers, using the therapeutic principle of “PG-Impact”. The PGF2α analogue: ICI 81008 was administered under strictly aseptic precautions into the uterine cavity during the 4th week of pregnancy. The treatment catheter (inserted through the cervical canal) delivered a single dose of only 100–200 μg ICI 81008 during the pilot study with this new drug. When it was established that the side effects were acceptable, this moderately effective dose was increased at first to 200–300 μg and eventually to 400 μg.At the 400 μg dose level, 29 (76%) of the 38 study patients had complete and 8 (21%) incomplete abortions, while 1 (3%) failed to bleed. Those 9 women who had incomplete abortions or failed to abort were curetted. In comparison with PGF2α (428 cases) and PGE₂ (114 cases), ICI 81008 (38 cases at the 400 μg level) provoked lesser side effects, excepting the transient increase in blood pressure.All patients (whose intrauterine pressure was measured) responded to the ICI 81008-impact with rapidly developing high level uterine contracture. Plasma progesterone decreased significantly if treatment was successful and insignificantly in cases of treatment failure. In current studies, the efficacy of the vaginal delivery system of ICI 81008 is examined.     

Luteolysis induced in pigtail monkeys (Macaca nemestrina) with prostaglandin f 2 alpha, ICI 80996 and ICI 81008.

Non-pregnant pigtail monkeys (M. nemestrina) were given ICI 80996 subcutaneously and ICI 81008 and PGF2alpha subcutaneously or intravaginally, once daily on days 20-30 inclusive, or two or three times on days 24 or 26 only. Doses of 50 mug/kg of ICI 80996, 100 mug/kg of ICI 81008 and approx. 1 mg/kg of PGF2alpha were used. In the majority of monkeys treated subcutaneously a rapid fall in circulating progesterone concentrations and earlier than normal menstrual bleeding occurred. When given per vaginam, ICI 81008 was as effective as when given subcutaneously, though PGF2alpha was less effective intravaginally than by the subcutaneous route.     

Menstrual induction by the vaginal application of ICI 81008 gel

After ～2 weeks menstrual delay (positive Pregnosticon Tests) “menstrual induction” was attempted in 75 gravidas by repeated vaginal application of a gel, containing 200 or 400 μg/ml ICI 81008. After ～10 minutes, following the 1st vaginal delivery of 400 μg ICI 81008, the uterus responded to this PGF2α analogue with sustained contracture. The highest success rate in induced bleeding (93%) and pregnancy termination (79%), without supportive therapy, was achieved when 400 μg ICI 81008 was administered 2 to 5 times at 4 hour intervals. Those gravidas (21%), who failed in induced menstruation, or stopped bleeding within 24 hours after treatment, had positive Pregnosticon Tests on day 14 and were curetted. The side effects, mostly vomiting and increased blood pressure, were transient and subjectively and medically acceptable. While the vaginal application of the drug is apparently less effective than the intrauterine (1), it has the advantage of simple delivery and the potential of self-administration.     

Pregnancy termination in the rat “model” by a synthetic prostaglandin analogue ICI 81008

The abortifacient efficacy of the PGF2α analogue ICI 81008 had been examined in 378 Spraque-Dawley rats. Of the 3 systemic routes of administration studied: intramuscular (i.m.), subcutaneous (s.c.) and per vaginam (p.v.), the p.v. treatment had been the most effective. Complete abortions were provoked invariably by a single p.v. dose of 20 μg ICI 81008 in the broad gestational range of 6 to 10 days of pregnancy and the “abortion rate” (AbR) remained 86% at day 12. The reduction of the p.v. dose to 10 μg only decreased efficacy slightly and its increase to 40 μg improved it. The analogue ICI 81008 was highly more effective than the natural PGs: F2α and E₂, in spite of their comparable oxytocic actions on the excised uterus. This high efficacy of ICI 81008 in p.v. formulation, without apparent side effects, is a therapeutic promise which demands early clinical investigation.At day 3 the AbR decreased to 0% and at day 14 to 30%. Plotting AbR, as a function of the gestational timing of treatment, yielded a reversed U shape curve, which reflected upon the mechanism of ICI 81008 action. The pituitary, the corpus luteum and the blastocyst are equally indispensable and accessible to drugs at days 3 and 6 of gestation. Yet the efficacy of ICI 81008 increased from 0% to 100% during this 3 days period, suggesting that the primary target of ICI 81008 is the uterine environment of the implanted conceptus. Thus the earlier premise had been substantiated that in inducing abortion PGs provoke: reduction of uterine microcirculation, sustained contracture, suppression of feto-placental endocrine function (including luteotrophic support), luteolysis, progesterone (P)-withdrawal and the evolution of uterine activity.However, progesterone treatment prevented the effect of ICI 81008, completely or partly, depending on the dose of PG administered. Furthermore, extensive studies of the ICI research team showed that ICI 81008 can provoke luteolysis without pregnancy, suggesting that under certain conditions the ovary is the primary target of this drug. If this effect on the ovary also involves a microcirculatory disturbance, then the mechanism of action of ICI 81008 is retained, in a variety of species and reproductive conditions, and only the threshold of the organ serving as primary target changes.From the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MissouriThis work was supported by the Agency for International Development Contract AID/csd 3160 and the National Institute of Health Career Award, HD 20169-11.     

The effect of the prostaglandin F2alpha analogue ICI 81008 on uterine small arteries and on blood pressure.

The effects of PGF2alpha and its analogue ICI 81008 have been compared on the small arteries of the omentum uteri on the rat. The vessels measured 20-80 mum in diameter and were examined by intra-vital-microscopy. While the maximum responses of PGF2alpha and ICI 81008 were similar, the duration of the effect of ICI 81008 was significantly longer (P is less than 0.001). At 15 minutes after the administration of the drugs the effect of ICI 81008 was still almost maximal, while the PGF2alpha response disappeared.     

The effect of the prostaglandin F2α analogue ICI 81008 on uterine small arteries and on blood pressure

The effects of PGF2α and its analogue ICI 81008^* have been compared on the small arteries of the omentum uteri on the rat. The vessels measured 20–80 μm in diameter and were examined by intra-vital-microscopy. While the maximum responses of PGF2α and ICI 81008 were similar, the duration of the effect of ICI 81008 was significantly longer (P< 0.001). At 15 minutes after the administration of the drugs the effect of ICI 81008 was still almost maximal, while the PGF2α response disappeared.     

Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-delta2-PGE1 methyl ester)

ONO-802 was infused into the uterine cavity for the termination of early pregnancy in 45 healthy volunteers. Forty two (93%) of the 45 cases had complete abortions and two had incomplete abortions. Nine (20%) of the 45 volunteers complained of nausea, 7 (16%) vomited and 5 (11%) complained of abdominal pain. Neither diarrhea nor weakness was observed. These results suggest that ONO-802 is more acceptable for the termination of early pregnancy than is PGF2alpha.     

Progesterone withdrawal induced by ICI 81008 in pregnant rats

Of a total of 343 pregnant rats treated with the prostaglandin F2 analogue ICI 81008, 137 aborted, while 83 had reduced and 123 intact litter. These biological variations depended primarily on the gestational timing of treatment and on the dose and route of administration of this synthetic PG. In comparison with the 107 controls, all experimental rats which aborted had a drastic reduction in plasma progesterone levels which was highly significant (P<0.001) until day 18. In contrast, those animals which escaped suboptimal ICI 81008 treatment with a partly resorbed litter, only had a moderate reduction in progesterone which was statistically significant (P<0.01) until day 16 when the levels of this steroid normally begin to decrease. Ineffective treatment did not affect progesterone levels and intact pregnancy. In contrast to progesterone, there was no correlation between plasma estradiol-17β levels and the consequences of ICI 81008 treatment.

ICI 81008 was most effective between the 6th and 12th days of gestation, when plasma progesterone in the normal controls showed a nadir. Effective treatment reduced plasma progesterone within 6 hours. Evidently the pharmacologically provoked endocrine imbalance precedes the cessation of characteristic gestational weight gain, uterine bleeding and abortion which only manifest 24 to 48 hours after treatment.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2alpha for termination of early pregnancy in out-patient.

15-me-PGF2alpha 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 mug and 80% induced with 300 mug. After 3 weeks, abortion was complete in 90% induced with 125 mug, in 70% induced with 200 mug and in 100% induced with 300 mug. One failure occurred in patients treated with 200 mug and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF2alpha is as effective as natural PGF2alpha in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Response of the midpregnant human uterus to systemic administration of 15(S)-15-methyl-prostaglandin F2alpha

The contractile response of the midpregnant human uterus to a new (PG) prostaglandin analogue, 15(S)-methyl-PGF2alpha (15-me-PGF2alpha), was investigated and compared to the effect of natural PGF2alpha. It was found that the threshold dose of 15-me-PGF2alpha was around 10 mcg when given as a single intravenous injection, which is approximately 1/10 of the corresponding dose of PGF2alpha. It was also found that higher intravenous doses of 15-me-PGFalpha resulted in a uterine response of longer duration than that following PGF2alpha. Intramuscular injection of the analogue at doses of 1.0-1.5 mg induced a marked uterine stimulation sustained for 5-7 hours without causing local reaction. Intravenous infusion of 5 mcg/min of 15-me-PGF2alpha stimulated a level of uterine activity equivalent to that of 75 mcg/min of PGF1alpha. The incidence of gastrointestinal side effects was the same in the 2 treatment groups. However, there seemed to be a tendency toward a significantly higher abortion rate with the analogue.     

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.     

Progesterone withdrawal induced by ICI 81008 in pregnant rats.

Of a total of 343 pregnant rats treated with the prostaglandin F2alpha analogue ICI 81008, 137 aborted, while 83 had reduced and 123 intact litter. These biological variations depended primarily on the gestational timing of treatment and on the dose and route of administration of this synthetic PG. In comparison with the 107 controls, all experimental rats which aborted had a drastic reduction in plasma progesterone levels which was highly significant (P is less than 0.001) until day 18. In contrast, those animals which escaped suboptimal ICI 81001 treatment with a partly resorbed litter, only had a moderate reduction in progesterone which was statistically significant (P is less than 0.01) until day 16 when levels of this steroid normally begin to decrease. Ineffective treatment did not affect progesterone levels and intact pregnancy. In contrast to progesterone, there was no correlation between plasma estradiol-17beta levels and the consequences of ICI 81008 treatment.     

Comparison of the effects of PGF(2)alpha and bromocryptine in pregnant beagle bitches

Termination of pregnancy (abortion) was successful in four of four bitches that received PGF(2)alpha (125 mug/kg bid s.c.) and in two or four bitches that received bromocryptine (62.5 mug/kg bid po) for up to 6 d beginning 43 to 45 d post ovulation. Four sham-treated controls whelped normally at term. The incidence of side effects, primarily emesis and loose stools, was similar for both experimental groups. Bitches that failed to abort following treatment with bromocryptine whelped normally at term.     

Absence of uterokinetic effects of prostaglandin F 2 alpha on oxytocin-reactive uterus in the mare

In most cyclic females, prostaglandin F(2alpha) (PGF(2alpha)) triggers a uterine motility response resembling that of oxytocin (OT). To determine if PGF(2alpha) is a uterokinetic substance in the cycling mare, uterine motility was measured by intrauterine balloon technique in 12 conscious, normally cyclic mares. After 60 min of saline infusion, continuous intravenous (i.v.) infusion with OT (1 i.u./min) was followed by PGF(2alpha) (200 mug/min) for 60 min each. The experiment was repeated 3 wk later except with PGF(2alpha) preceeding OT. A second group of mares was administered OT (60 i.u.) either i.v., intramuscularly (i.m.), or intrauterinely (i.u.). Plasma samples were studied for progesterone concentration. Control uterine motility for the first group of mares was (mean +/- SEM) 545.83 +/- 45.10 mm(2). Significant (P<0.05) elevation in uterine motility was recorded for OT (1118.60 +/- 70.56 mm(2)) regardless if PGF(2alpha) preceded OT infusion or vice-versa. No significant difference (P>0.05) was seen in motility after PGF(2alpha) (423.33 +/- 31.12 mm(2)) infusion. The uterokinetic effect of OT was greatest when OT was administered i.v. (1696.50 +/- 195.46 mm(2)) followed by i.m. (819.82 +/- 39.96 mm(2)), and it was least effective when administered i.u. (607.83 +/- 21.56 mm(2)) as compared to control uterine motility (279.78 +/- 22.33 mm(2)). Skin electrical resistance values rose from 0 to 2000 ohms with PGF(2alpha) infusion (but not with OT), indicating that PGF(2alpha) was bioactive. It was concluded that PGF(2alpha) was not a uterokinetic substance in the cyclic mare.     

Dose and time dependent luteotropic and luteolytic action of prostaglandin F2alpha in the luteinized rabbit ovary.

The mechanism of stimulatory and inhibitory action of PGF2alpha on ovarian steroidogenesis both under in vitro and in vivo conditions has been studied in the pseudopregnant rabbits. Short term incubation of the ovaries with PGF2alpha (2.82 times 10(-5)M) resulted in an increased synthesis of progesterone and 20alpha-OH P. The addition of PGF2alpha in the medium and further incubation of the ovaries obtained from rabbits that had been constantly infused with PGF2alpha (0.5 mug/min.) for two hours resulted in increased synthesis of these progestins. The ratio of progesterone to 20alpha -OH P was also enhanced under these conditions and thus supported the luteotropic action of small doses of PGF2 under short term incubations. However, as the amount of PGF2alpha infused was increased to 5 mug/min., the addition of PGF2alpha under in vitro conditions strikingly decreased the production of these progestins. The ratio decreased the production of these progestins. The ratio of progesterone to 20alpha -OH P was also decreased and thus was indicative of luteolytic action of higher doses of PGF2alpha. High doses of PGF2alpha (5.64 times 10(-4)M) failed to cause any significant change in the progestin synthesis under short term incubation. These results thus suggest that the luteotropic and luteolytic action of PGF2alpha in the luteinized rabbit ovary is dose and time dependent.     

Effect of prostaglandin F2 alpha (PGF2 alpha) on sources of progesterone and pregnancy in intact, ovariectomized and hysterectomized 90-100 day pregnant ewes.

A single dose of 8 or 16 mg of PGF2 alpha per 58 kg body weight was injected intramuscular into intact, ovariectomized or hysterectomized 90-100 day pregnant sheep in three separate experiments. Both doses of PGF2 alpha decreased the weights of the corpora lutea (P less than or equal to 0.05) and the concentration of progesterone in ovarian venous plasma at 72 hr (P less than or equal to 0.05) compared to the 0 hr sample within treatment groups and to control ewes at 72 hr in intact and hysterectomized pregnant ewes. In hysterectomized pregnant ewes, progesterone in jugular plasma declined (P less than or equal to 0.05) from 0 to 72 hr but never fell below 4 mg/ml and this decrease in progesterone after 8 or 16 mg PGF2 alpha was greater than in control hysterectomized ewes (P less than or equal to 0.05). There was a significant decrease in progesterone over time in jugular or uterine venous plasma in the presence of absence of the ovaries in 90-100 day pregnant ewes (P less than or equal to 0.05) but the profiles of progesterone were not different between vehicle and PGF2 alpha-treated ewes (P greater than or equal to 0.05). Uterine venous progesterone never declined below 30 ng/ml in the presence or absence of the ovaries and there was a significant quadratic increase (P less than or equal to 0.05) in uterine venous progesterone toward the end of the 72 hr sampling period indicating an increase in steroidogenic activity of the placenta. PGF2 alpha did not affect the number of abortions in intact or ovariectomized pregnant ewes (P greater than 0.05). Thus, the corpus luteum of sheep at 90-100 days of pregnancy is functional and responsive to PGF2 alpha, placentomes are functional but do not appear to be responsive to the doses of PGF2 alpha tested and PGF2 alpha was not an abortifacient over the 72 hr treatment period.     

Uterine motility in the cow during the estrous cycle. II. Comparative effects of prostaglandins F(2alpha), E(2), and cloprostenol

Intrauterine pressure (IUP) changes were recorded in nonlactating, cyclic dairy cows using transcervically placed intraluminal pressure microtransducers. Spontaneous activity was recorded for the first 30 min. Prostaglandins (PG) F(2alpha) (5 mug/kg), E(2) (5 mug/kg), or cloprostenol (0.1 mug/kg) were then injected intravenously (i.v.) at diestrus, proestrus, estrus, and metestrus, and their effects were recorded. The drug administrations did not alter the duration of the estrous cycle of the cows. Single doses of PGF(2alpha) and E(2) significantly increased uterine activity at all stages of the estrous cycle, while cloprostenol had no effect. PGF(2alpha) and PGE(2) increased IUP, frequency, and amplitude during all stages of the estrous cycle. The spontaneous pattern resumed within 20 min postinjection. Partial uterine refractoriness occurred with both PGs. The results indicate that low doses of natural prostaglandins stimulate uterine activity during the estrous cycle in cattle.     

Mid-trimester abortion with 15 (S) methyl prostaglandin F 2 alpha

The efficacy of intramuscular administration of 15 methyl (15S) prostaglandin F2alpha (PGF2a) in midtrimester pregnancy termination was evaluated in 16 healthy patients (mean age, 23.3; mean parity, 1.4; mean number of menstrual weeks, 16.1) by measuring dose response; oxytocin conversion; abortion time; side effects; intrauterine dynamics and progesterone withdrawal. Labor was monitored using extraovular balloon placed transvaginally; transcervically; and connected to a Physiograph machine. Patients not aborting within 48 hours after the first dose were considered failures. Blood samples were collected at 0, 3, and 6 hours and at abortion time for plasma progesterone measurement. Average dose given was 789 +or- 60 micrograms. Only 9 of 10 patients aborted within the prescribed 48 hours: 7 were complete abortions, and 2 were incomplete and required suction curettage. Mean induction to abortion time was 20.2 +or- 2.7 hours. Nausea, vomiting and diarrhea were the main side effects. The findings suggest that 15 methyl PGF2a in the dosages and routes prescribed is not as efficient as PGF2a. It is also suggested that prostaglandin affects the myometrium at 2 levels: 1) a membrane effect, and 2) a more fundamental intracellular regulatory effect which is necessary to initiate labor.     

Effects of gonadotropin releasing hormone and prostaglandin F(2)alpha on the reproductive performance in postpartum cows

A study was conducted to determine whether treatment with gonadotropin releasing hormone (GnRH) in combination with prostaglandin F(2)alpha (PGF(2)alpha) could enhance ovarian activity and uterine involution in postpartum dairy cows to reduce the calving interval. Cows were randomly assigned to one of three treatment groups. Cows (n = 8) in Group 1 received 100 mug GnRH intramuscularly (i.m.) twice on Day 20 and Day 35 postpartum, and 25 mg PGF(2)alpha i.m. on Day 47 postpartum. Group 2 (n = 8) received a single i.m. injection of 100 mug GnRH on Day 25 postpartum and 25 mg PGF(2)alpha i.m. on Day 37 postpartum. The Control Group (n = 9) did not receive hormonal treatment. Palpation per rectum of the reproductive organs and serum progesterone (P) determination were performed twice a week to monitor ovarian activity and uterine involution. Postpartum interval to the first ovulation was short in treated groups (Group 1, 21.0 d; Group 2, 26.3 d) compared with Control Group (30.1 d, P < 0.05). Likewise, mean frequency of ovulation was increased in both treated groups compared with the Control Group (P < 0.05). Cows in treated groups required fewer days to complete uterine involution than in the Control Group. The mean interval to the first service, the conception rate at first service and the number of services per conception showed no significant differences among the three groups, but the mean days from calving to conception were shorter for the treated groups (78.7 d in Group 1; 83.3 d in Group 2) than (109.1 d, P < 0.05) for the Control Group. Our results suggest that combined treatment with GnRH and PGF(2)alpha may enhance ovarian activity in the postpartum cow, resulting in improved reproductive performance.     

Action of prostaglandin F2alpha on pregnancy in hamsters: luteolytic and extra-ovarian effects.

Pregnancies in hamsters may be terminated by 10 mug PGF2alpha administered b.i.d. on days 4, k and 6 of gestation. Small (250 mug and above) daily injections of progesterone on the same days will reverse this PG effect; in contradistinction, 10 mg of progesterone per day failed to maintain normal pregnancies in hamsters spayed on day 5. Daily administration of 3 mg of progesterone and 1 mug of estrone essentially normalized the gestation; administration of PGF2alpha at 10 mg on days 5, 6 and 7 of pregnancy in steroid-maintained rats, resulted in pregnancy termination in all animals, while 1 mg was partly effective. These data demonstrate an extra-ovarian site of action of prostaglandin F2alpha on pregnancy in hamsters.