On the mechanism of midtrimester abortions induced by the prostaglandin “impact”

Using Csapo's technique a single dose of 24.3±1.1mg PG F_2α had been delivered intraamniotically to 20 sedated 15.9±0.6 weeks pregnant patients, to provoke a “PG Impact” (PGI), a consequent progesterone (P) withdrawal and a conversion of the pharmacologically refractory normal pregnant uterus into a reactive organ. The side effects were occasional and acceptable and no further PG F_2α treatment was needed except in 4 cases (5–10mg). Only after the Oxytocin Test showed that the uterus is becoming reactive was 50mU/min oxytocin infused i.v., to facilitate the evolution of IUP to 93±3mm Hg and thus promote clinical progress. All the 20 patients aborted both the fetus and the placenta in 16.5±2.1 hours, but 8 women retained small placental residues to be removed by curettage. The Csapo Score was high, 92±2.As early as 3 hours after PGI, the plasma P levels already decreased significantly. They continued to decline throughout the IAT and reach a 72% withdrawal when the fetus was aborted. Fifteen patients, whose P-withdrawal was rapid aborted before the mean IAT, while those 5 women whose P-withdrawal was slow aborted after this time. Thus, the rate of P-withdrawal was directly, while parity and gestational age indirectly related to the IAT. Studies are in progress to elucidate further the abortifacient action of PG F_2α and through this knowledge promote predictable therapy.     

The effect of luteectomy-induced progesterone-withdrawal on the oxytocin and prostaglandin response of the first trimester pregnant human uterus

In 9 normal 1st trimester pregnant patients strong stimulation with a single intravenous dose of 250 mU oxytocin, or 100 mc prostaglandin F2alpha (PGF2alpha), only provoked barely detectable and transient contractures, rather than advanced cyclic intrauterine pressure (IUP). Evidently, the normal early pregnant human uterus is not an "inert" muscle organ, but is "refractory" to stimulants. Luteectomy-induced rapid and continued progesterone(P)-withdrawals in 5 of the 9 patients "converted" these "refractory" uteri to "responsive" organs. This "conversion" was revealed by advanced cyclic IUP during the OR and PGR within 24-28 hours after luteectomy. Abortion occurred in 60.6+ or - 7.6 hours. "Conversion" was delayed in those 2 patients whose P-withdrawal was slow and who only aborted after 140.5 + or - 13.5 hours. The remaining 2 patients, whose luteectomy-induced P-withdrawal was moderate and transient showed no "conversion" and failed to abort. The rate and degree of P-withdrawal in these 3 groups of patients was a function of gestational age. Apparently the normal pregnant human uterus is a suppressed organ, refractory to stimulants. Continued P-withdrawal suspends suppression, lowers threshold and thus "converts" the refractory uterus to a reactive organ. Once "converted" the pregnant human uterus becomes spontaneously active under endogenous stimulation and expels its contents, a process which can be hastened by exogenous stimulants.     

The termination of first trimester pregnancy by extraovular “Prostaglandin-impact”

In 30 sedated volunteers first trimester pregnancy had been successfully terminated with Csapo's method of “Prostaglandin-Impact” (1). The patients were 24.1±0.4 years of age, 9.2±0.4 weeks pregnant, para 0.4±0.1. They all received an extraovular dose of 10 mg PG F2α, under intravenous sedation (100 mg pethidium hydrochloride, 50 mg DPP hydrochloride and 0.5 mg atropinum sulfate). Those 15 (out of 30) patients, whose clinical progress was slow received at 8 hours after the first PG Impact (PGI) a 2nd dose of 5 mg PG F2α, increasing the total average dose to 12.5± 0.5 mg.PGI invariably provoked a rapid and high level uterine contracture. At 4 hours after PGI plasma progesterone (P) already decreased by 20% and cyclic intrauterine pressure was in distinct evolution. At 8 hours after PGI, 15 of the 30 patients showed advanced clinical progress and 33% decrease in P levels. These women aborted in 10.2±1.1 hours, when their P levels decreased by 45% (P < 0.001). Abortion was complete in 13 and incomplete in 2 of the patients. The remaining 15 women, whose clinical progress was indistinct at 8 hours after PGI and whose P levels only decreased by 25% received a 2nd dose of 5 mg PG F2α. These women aborted after 18.5±1.5 hours, 9 completely and 6 incompletely, when their P levels decreased (as in the previous group) by 45% (P < 0.001).All the 30 patients aborted after a short IAT of 14.3±1.2 hours. Abortion was complete in 22 women, while 8 retained various amounts of placental tissue. The “Abortion Score” was high, 94.7±1.6. Only 13 patients had side effects, shortly after PGI, manifesting in vomiting and nausea, which were transient and mild. There were no complications during the study and followup. These findings confirm earlier results (1). When supplemented by extensive field trials, the technique of extraovular PGI might be broadly considered for the non-surgical termination of 1st trimester pregnancy.     

Massive initial prostaglandin impact in postconceptional therapy

The abortifacient effect of an initial PGF2alpha impact was examined in 10 obstetrically normal first trimester pregnant patients. Sedated patients were given extraamniotically an average initial dose of 8.1 + or - 0.8 mg PGF2alpha during a 10 minute instillation. Side effects occurred occasionally but were minimal. Uterine contracture developed rapidly reaching an average pressure of 83.2 + or - 11.3mm Hg in about 20 minutes and then slightly declined in time. Superimposed on the contracture response were gradually increasing cyclic changes in intrauterine pressure which reached a magnitude of 129.8 + or - 12.2mm Hg by 10 hours after initial treatment. Initial therapy was augmented in some cases by an average of 4mg PGF2alpha; only 4 patients required oxytocin supportive therapy. The patients aborted in an average of 10.9 + or - 2.0 hours. 7 aborted completely, 2 left behind small placental residues, and 1 retained the placenta during a period of 11.5 hours. An (AbS) abortion score of 92 was obtained in the study which is the highest in 6 consecutive studies using various methods of PGF2alpha administration. Plasma estradiol-17beta and progesterone levels decreased continuously during the instillation abortion time in the complete aborters, while the incomplete aborters showed lesser changes. It is concluded that massive intrauterine PGF2alpha injection is a more efficacious and acceptable form of postconceptional therapy than protracted treatment. Such therapy appears to convert the refractory uterus into a spontaneously active and pharmacologiclly reactive organ by inducing vasoconstriction, myometrial stretch, and fetoplacental insufficiency.     

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.     

Effect of PGF2alpha, indomethacin, tamoxifen, or estradiol-17beta on incidence of abortion, progesterone, and pregnancy-specific protein B (PSPB) secretion in 88- to 90-day pregnant sheep

One objective of this experiment was to evaluate our hypotheses that estradiol-17beta regulates secretion of pregnancy specific protein B (PSPB) and that secretion of progesterone during pregnancy is regulated by a prostanoid by examining the effects of prostaglandin F2alpha (PGF2alpha), a luteolyic agent; indomethacin, a prostanoid synthesis inhibitor; tamoxifen, an estrogen receptor antagonist; estradiol 17-beta; and interaction of these factors on the incidence of abortion and progesterone and PSPB secretion. Another objective was to determine if there is a luteal source of PSPB. Weights of corpora lutea were decreased (P < or = 0.05) by PGF2alpha, indomethacin, PGF2alpha + tamoxifen, PGF2alpha + indomethacin, and PGF2alpha + estradiol-17beta but not (P > or = 0.05) by tamoxifen or estradiol-17beta alone. No ewe treated with PGF2alpha alone aborted (P > or = 0.05). Forty percent of ewes treated with PGF2alpha + estradiol-17beta aborted (P < or = 0.05), but ewes were not aborted by any other treatment within the 72-h sampling period. Profiles of progesterone in jugular venous blood differed (P < or = 0.05) among control, indomethacin-, tamoxifen-, and PGF2alpha + indomethacin-treated ewes. Progesterone in jugular venous blood of control ewes decreased (P < or = 0.05) by 24 h, followed by a quadratic increase (P < or = 0.05) from 24 to 62 h. Progesterone in jugular venous blood of indomethacin-, PGF2alpha-, PGF2alpha- + tamoxifen-, PGF2alpha + indomethacin-, PGF2alpha + estradiol-17beta-, and tamoxifen-treated ewes was reduced (P < or = 0.05) by 18 h and did not vary (P > or = 0.05) for the remainder of the 72-h sampling period. Progesterone in vena cava and in uterine venous blood was reduced (P < or = 0.05) at 72 h in PGF2alpha-, indomethacin-, tamoxifen-, PGF2alpha + indomethacin-, PGF2alpha + tamoxifen-, and PGF2alpha + estradiol-17beta-treated ewes. Weights of placentomes did not differ among treatment groups (P > or = 0.05). Profiles of PSPB in inferior vena cava blood differed (P < or = 0.05) among control, estradiol-17beta-, indomethacin-, tamoxifen-, PGF2alpha + indomethacin-, and PGF2alpha + tamoxifen-treated 88- to 90-day pregnant ewes. Concentrations of PSPB in inferior vena cava blood were increased (P < or = 0.05) in indomethacin-, estradiol-17beta-, tamoxifen-, PGF2alpha + tamoxifen-, and PGF2alpha + indomethacin-treated 88- to 90-day pregnant ewes within 6 h and did not vary (P > or = 0.05) for the remainder of the 72-h sampling period. Concentrations of PSPB in uterine venous blood of indomethacin-, tamoxifen-, PGF2alpha + tamoxifen-, and PGF2alpha + indomethacin-treated ewes were greater (P < or = 0.05) at 72 h than at 0 h. PSPB in ovarian venous blood did not differ (P > or = 0.05) adjacent or opposite to the ovary with the corpus luteum. It is concluded from these data that estrogen regulates placental secretion of PSPB and that a prostanoid, presumably prostaglandin E, regulates placental secretion of progesterone during 88-90 days of gestation in sheep and that there is no luteal source of PSPB.     

Fetal viability does not affect the onset of stretch-induced labor and the increase in amniotic fluid prostaglandin F2 alpha and plasma prostaglandin F2 alpha metabolite levels.

The role of the fetus in the onset and progress of stretch-induced labor and in the change in amniotic fluid prostaglandin F2 alpha and plasma prostaglandin F2 alpha metabolite levels was evaluated in six normal pregnant women (group 1) and six women whose fetuses had been dead for more than one week (group 2). The uterus was distended by a balloon inflated with physiologic saline. Regular uterine contractions occurred, and increased in all patients. Within 21 hours, all patients delivered a normal baby in group 1 and a macerated fetus in group 2. There was no significant difference in induction-delivery interval between the two groups. Both groups showed a significant and similar range of increases in the levels of amniotic fluid prostaglandin F2 alpha and plasma prostaglandin F2 alpha metabolite during treatment (P less than 0.001). Thus, the fetus has no functional role in the onset and progress of stretch-induced labor or in the rise of amniotic fluid prostaglandin F2 alpha and plasma prostaglandin F2 alpha metabolite levels.     

Trilostane but not prostaglandin F2alpha (PGF2alpha) or cortisol aborts 90-day-pregnant lutectomized sheep

Ewes were lutectomized and treatments were started 72 h later. Pregnant ewes were treated with vehicle; prostaglandin F2alpha (PGF2alpha); cortisol (C); trilostane (TR), a 3beta-hydroxy-steroid dehydrogenase inhibitor; PGF2alpha + C; TR + PGF2alpha; TR + C, or TR + PGF2 + C. TR, TR + PGF2alpha, TR + C, and TR + PGF2alpha + C aborted (P < or = 0.05) all ewes receiving TR. One ewe treated with PGF2alpha aborted (P > or = 0.05). The average time to abortion of TR-treated ewes was 50.8 h (P < or = 0.05) after initiation of treatments. All aborted ewes had retained placentas (P < or = 0.05) except one ewe in the TR + PGF2alpha, treatment group. TR was given every 12 h starting at 72 h postlutectomy until 96 h postlutectomy. TR reduced (P < or = 0.05) progesterone. Estradiol-17beta was increased (P < or = 0.05) 2 h after the first two TR treatments and declined 2 h later and was followed by a sustained increase (P < or = 0.05) in estradiol-17beta, which was coincident with the onset of abortions. Estradiol-17beta was increased (P < or = 0.05) by PGF2alpha but did not decrease (P > or = 0.05) placental secretion of progesterone. It is concluded that TR but not PGF2alpha is an abortifacient in 90-day-pregnant lutectomized ewes and that abortion occurs only when there is a decrease in circulating progesterone and an increase in circulating estradiol-17beta.     

The effect of uterine stretch on first trimester abortions induced by extraovular prostaglandin impact

In 20 obstetrically normal 1st trimester pregnant volunteers abortion had been induced successfully in 19, by Prostaglandin-Impact (PGI) technique (1). A total average dose of 12.3±0.9 mg PG F2α, delivered into the extraovular (E.O.) space, reduced the plasma P levels from an initial value of 29.4±2.5 ng/ml to 12.8±1.6 ng/ml (P < 0.001) within 17.4±1.6 hours instillation-abortion time (IAT). Of the 20 women 13 aborted completely, 6 incompletely, and 1 progressed to 2 cm cervical dilatation: yielding an “Abortion Score” (AbS) of 86.0±4.6.Of the 20 gravidas, 10 only received PGI (Control Group), while the remaining 10 were exposed to uterine stretch, in addition to PGI (Experimental Group). Stretch had been accomplished by a “stretch balloon” filled with 200 ml saline. Comparing the Control and Experimental Groups revealed that stretch shortens the IAT and improves the AbS. This effect is very probably achieved through a stretch induced increase in the endogenous PG-synthesis of the uterus (1). This preliminary finding exposes the possibility, that pregnancy termination can be promoted by an increased involvement of endogenous PGs in the activation of the myometrium, provoked through stretch. The validity of this premise is under current examination.     

Prostacyclin induces a surprising long-lasting motility in quiescent uterine strips (indomethacin-treated) isolated from ovariectomized rats

Dose-response curves for several prostaglandins (PGI2; PGD2; PGF2 and PGE2); BaCl2 or prostaglandin metabolites (15-keto-PGF2 alpha; 13,14-diOH-15-keto-PGF2 alpha; 6-keto-PGF1 alpha and 6-keto PGE1 in quiescent (indomethacin-treated) uterine strips from ovariectomized rats, were constructed. All PGs tested as well as BaCl2, triggered at different concentrations, evident phasic contractions. Within the range of concentrations tested the portion of the curves for the metabolites of PGF2 alpha was shifted to the right of that for PGF2 alpha itself; the curve for 6-keto-PGF1 alpha was displaced to the right of the curve for PGI2 and that for 6-keto-PGE1 to the left. It was also demonstrated that the uterine motility elicited by 10(-5) M PGF2 alpha and its metabolites was long lasting (more than 3 hours) and so it was the activity evoked by PGI2;6-keto-PGF1 alpha and BaCl2, but not the contractions following 6-keto-PGE1, which disappeared much earlier. The contractile tension after PGF2 alpha; 15-keto-PGF2 alpha; 13,14-diOH-15-keto-PGF2 alpha and PGI2, increased as time progressed whilst that evoked by 6-keto-PGF1 alpha or BaCl2 fluctuated during the same period around more constant levels. The surprising sustained and gradually increasing contractile activity after a single dose of an unstable prostaglandin such as PGI2, on the isolated rat uterus rendered quiescent by indomethacin, is discussed in terms of an effect associated to its transformation into more stable metabolites (6-keto-PGF1 alpha, or another not tested) or as a consequence of a factor which might protects prostacyclin from inactivation.     

The effect of acetylsalicylic acid and indomethacin on the catecholamine- and oxytocin-induced contractility and prostaglandin (6-keto-PGF1 alpha, PGF2 alpha)-production of human pregnant myometrial strips

The effects of acetylsalicylic acid (ASA) and indomethacin (IND) on the epinephrine and oxytocin stimulated contractility and prostaglandin (6-keto-PGF1 alpha, PGF2 alpha) production of superfused myometrial strips from the pregnant human uterus at term are reported. Without preincubation in ASA or IND epinephrine dose-dependently (10 ng/ml to 1 microgram/ml) stimulated the contractility and significantly increased the PG-release of the myometrial strips. The epinephrine induced increase in contractility was correlated to a higher increase in PGF2a production and a decreased 6-keto-PGF1 alpha/PGF2 alpha ratio (5.4 to 1.8). Superfusion of oxytocin increased myometrial contractions and PGF2 alpha release according to dose (3-12 microU/ml). However, 6-keto-PGF1 alpha production was not affected by oxytocin. Myometrial strips preincubated with ASA (100 micrograms/ml) or IND (10 micrograms/ml) demonstrated little spontaneous activity and the PG production was below the detection limit of the RIA. The stimulating effect of epinephrine and oxytocin on the contractility and PGF2 alpha release of the myometrial strips was inhibited significantly. During continuous superfusion of the ASA and IND preincubated myometrial strips with Tyrode's solution the inhibitory effect on spontaneous, epinephrine-, and oxytocin-stimulated contractility and PGF2 alpha release gradually declined over a period of 2 hours. This decrease of the inhibitory effect was more significant in ASA preincubated specimens. Our results demonstrate that spontaneous, epinephrine-, and oxytocin-stimulated contractility and PG release of human myometrial strips can be inhibited by ASA and IND and that this inhibitory effect is reversible. Furthermore our results suggest that in pregnant human myometrium the inhibition of PGF2 alpha production by ASA and IND is more pronounced than that of 6-keto-PGF1 alpha (PGI2).     

The effects of prostacyclin (PGI2) on tissues which detect prostaglandins (PG'S).

The effects of prostacyclin (PGI2) and its stable metabolite 6-oxo-PGF1alpha on various bioassay tissues are compared with those of PGE2 and PGF2alpha, using the cascade superfusion method. On vascular smooth muscle, PGI2 caused relaxation of all tissues tested except the rabbit aorta. PGE2 relaxed rabbit coeliac and mesenteric artery but contracted bovine coronary artery and had no effect on rabbit aorta. 6-oxo-PGF1alpha was ineffective at the concentrations tested. On gastro-intestinal smooth muscle, PGI2 contracted strips of rat and hamster stomach and the chick rectum. It was less potent than PGE2 or PGF2alpha. None of these substances contracted the cat terminal ileum. 6-oxo-PGF1alpha was inactive on these tissues at the doses tested. PGI2 was less active than PGE2 or PGF2alpha in contracting guinea-pig trachea and rat uterus; 6-oxo-PGF1alpha was active only on the rat uterus. Thus, PGI2 can be distinguished from the other stable prostaglandins using the cascade method of superfusion.     

Effect of mifepristone on pregnancy,pregnancy-specific protein B (PSPB), progesterone,estradiol-17beta,prostaglandin F2alpha (PGF2alpha) and prostaglandin E (PGE) in ovariectomized 90-day pregnant ewes

The objective of this experiment was to determine the effect of mifepristone, a progesterone receptor antagonist, on pregnancy and secretion of steroids, pregnancy-specific protein B (PSPB) and prostaglandins at mid-pregnancy in ewes. Ninety-day pregnant ewes were ovariectomized (OVX) and treatments were initiated 72 h post-OVX. Ewes received (1) vehicle, (2) prostaglandin F2alpha (PGF2alpha, 8 mg/58 kg/bw, i.m.) 84 h post-OVX, (3) mifepristone (50 mg intrajugular at 72, 84, 96, and 108 h post-OVX), (4) mifepristone (50mg) + PGF2alpha, (5) mifepristone (100 mg intrajugular at 72, 84, 96, and 108 h), and (6) mifepristone (100 mg) + PGF2alpha. Ewes treated with vehicle or PGF2alpha alone did not abort (P > or = 0.05). But, 60, 80, 60, and 100% of ewes treated with mifepristone (50 mg), mifepristone (50 mg) + PGF2alpha, mifepristone (100 mg), and mifepristone (100 mg) + PGF2alpha, respectively, aborted (P < or = 0.05). Profiles of progesterone, estradiol-17beta, prostaglandin E (PGE), or PSPB did not differ (P > or = 0.05) among treatment groups. Profiles of PGF2alpha of treatment groups receiving mifepristone with or without PGF2alpha differed (P < 0.05) from vehicle or PGF2alpha alone-treated ewes. It is concluded that progesterone actions are necessary to suppress uterine/placental secretion of PGF2alpha and that maintenance of critical progesterone: estradiol-17beta and PGE:PGF2alpha ratios are necessary for maintenance of pregnancy.     

Effect of the aromatase inhibitor CGS-16949A on pregnancy and secretion of progesterone, estradiol-17beta, prostaglandins E and F2alpha (PGE; PGF2alpha) and pregnancy specific protein B (PSPB) in 90-day ovariectomized pregnant ewes

The aromatase inhibitor CGS-16949A was used to determine whether CGS-16949A altered secretion of progesterone, estradiol-17beta, PGE (PGE1 + PGE2), PGF2alpha and PSPB. Ninety day pregnant ewes were ovariectomized and received vehicle, PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A. None of the ewes treated with PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A aborted (P > or = 0.05) during the 108-h experimental period. Treatment with CGS-16949A lowered (P < or = 0.05) progesterone in jugular venous plasma but concentrations of progesterone were not affected (P > or = 0.05) by treatment with PGF2alpha. Concentrations of estradiol-17beta and PSPB in jugular venous plasma and PGE in inferior vena cava plasma were decreased (P < or = 0.05) by treatment with CGS-16949A. Concentrations of PGF2alpha in inferior vena cava plasma were not affected (P > or = 0.05) by treatment with CGS-16949A. Decreases in estradiol-17beta occurred before decreases in PSPB, which was then followed by decreases in PGE (P < or = 0.05). It is concluded that these data support the hypothesis that estradiol-17beta regulates placental secretion of PSPB; PSPB regulates placental secretion of PGE; and PGE regulates placental secretion of progesterone during mid-pregnancy in ewes.     

Effect of prostaglandin F2alpha (PGF2alpha), indomethacin, tamoxifen or estradiol-17beta on prostaglandin E (PGE), PGF2alpha and estradiol-17beta secretion in 88 to 90-day pregnant sheep

Treatment with PGF2alpha plus estradiol-17beta aborts 90-day pregnant ewes, whereas PGF2alpha or estradiol-17beta alone does not abort ewes. The objective of this experiment was to evaluate whether tamoxifen, an estrogen receptor antagonist, estradiol-17beta, prostaglandin F2alpha (PGF2alpha), indomethacin, or some of their interactions affected ovine uterine/placental secretion of PGF2alpha, estradiol-17beta or prostaglandins E (PGE), because a single treatment with PGF2alpha and estradiol-17beta given every 6 h aborts 90-day pregnant ewes. Concentrations of PGF2alpha in uterine venous blood were increased (P < or = 0.05) by estradiol-17beta, PGF2alpha + estradiol-17beta, and PGF2alpha + tamoxifen, and decreased (P < or = 0.05) by indomethacin or PGF2alpha + indomethacin at 72 h when compared to the 0 h samples. Concentrations of PGE in uterine venous blood were decreased (P < or = 0.05) by indomethacin and PGF2alpha + indomethacin and increased (P < or = 0.05) by PGF2alpha + estradiol-17beta at 72 h when compared to the 0 h samples. Concentrations of PGF2alpha in inferior vena cava blood at 6 h were increased (P < or = 0.05) by PGF2alpha either alone or in combination with indomethacin, tamoxifen, or estradiol-17beta, which is due to the PGF2alpha injected. Concentrations of PGF2alpha in inferior vena cava blood in PGF2alpha + estradiol-17beta-treated 88- to 90-day pregnant ewes increased (P < or = 0.05) linearly over the 72-h sampling period and averaged 4.0 + 0.4 ng/ml. Concentrations of PGF2alpha in inferior vena cava blood of control, PGF2alpha, tamoxifen, PGF2alpha + indomethacin, PGF2alpha + tamoxifen, and estradiol-17beta-treated ewes did not differ (P > or = 0.05) and averaged 0.4 + 0.04 ng/ml. Profiles of PGE in inferior vena cava blood of 88- to 90-day pregnant ewes treated with vehicle, PGF2alpha, estradiol-17beta, tamoxifen, tamoxifen + PGF2alpha, or estradiol-17beta + PGF2alpha did not differ (P > or = 0.05). Concentrations of PGE in inferior vena cava blood of 88- to 90-day pregnant ewes treated with indomethacin or PGF2alpha + indomethacin were lower (P < or = 0.05) than in control ewes. Concentrations of estradiol-17beta in jugular venous plasma of PGF2alpha + estradiol-17beta-treated 88- to 90-day pregnant ewes increased linearly and differed (P < or = 0.05) from controls. Profiles of estradiol-17beta in jugular venous plasma of PGF2alpha, indomethacin, tamoxifen, and PGF2alpha + tamoxifen and PGF2alpha + indomethacin, estradiol-17beta, and controls did not differ (P > or = 0.05). It is concluded that treatment with a single injection of PGF2alpha and estradiol-17beta given every 6 h causes a linear increase in PGF2alpha and estradiol-17beta.     

Menstrual induction with PGF2 alpha and PGE2.

The "prostaglandin impact" (PGI), a massive intrauterine dose of PG, converts the refractory pregnant uterus into a reactive organ by provoking a regulatory imbalance. This regulatory conversion releases the endogenous mechanism of menstruation or abortion. During initial studies, PGI successfully provoked menstrual induction (MI) in 22 and subsequently in 65 volunteers. These results were confirmed and complemented by 2 independent trials in 14 and 36 gravidas respectively. The best clinical outcome was obtained in 20 volunteers, when a "PG-Pellet" (a mini-suppositorium) was inserted in utero, containing only 2.5 mg PGF2alpha. These 157 trials in sedated volunteers had the common features of over 90% efficiency, transient and medically acceptable side effects and infrequent complications. The present study of 542 volunteers focused upon the collection of clinical data regarding efficacy, side effects and complications of MI. All patients had committee approval for legal abortion, during the 2nd week of their missed menstrual period. They volunteered to participate because of their preference for pharmacological rather than surgical pregnancy termination. The clinical outcome of the 542 MI with 5 mg PGF2alpha (428 cases) and 1.5 mg PGE2 (114 cases) was identical. On the average, 95% of the gravidas had complete evacuation of the uterus with the clinical symptoms of delayed menstruation rather than abortion; they experienced spontaneous menstruation in 34 days after having received a single dose of PG.     

Pharmacological activity of PGI2 and its metabolite 6-oxo-PGF1alpha on human uterus and fallopian tubes.

The actions of prostacyclin (PGI2) and its stable metabolite 6-OXO-PGF1alpha were investigated in strips of normal human uterus and in fallopian tubes. Both compounds were also compared with natural prostaglandins (PGE2, PGF2alpha and PGD2). PGI2 showed biphasic response both in uterus and fallopian tubes qualitatively and quantitatively similar to that induced by PGE2 and PGD2; prostacyclin was also able to inhibit the spasmus induced by PGF2alpha but not that induced by BaCl2 and vasopressin. 6-0XO-PGF1alpha on the other hand induced only small contractions on both tissues investigated. The authors discusse the possible implication of these findings in the physiology of the reproductive system.     

Effects of hyperthermia on fetal and maternal plasma prostaglandin concentrations and uterine activity in sheep

The exposure of pregnant sheep to high ambient temperatures (43 degrees C) for 8 hours, sufficient to significantly elevate maternal and fetal body temperature +2.0 degrees C (p less than 0.001) and +1.9 degrees C (p less than 0.001) respectively, resulted in significant increases in PGE2 plasma concentrations in both the maternal and fetal circulations. Plasma PGF2 alpha concentrations were significantly raised in the fetal circulation but not the maternal during hyperthermia. The increase in prostaglandin concentrations were correlated with the magnitude of the increase in maternal and fetal body temperature. Uterine activity also increased during hyperthermia, probably as a result of the increase in prostaglandin concentrations. We propose that increased synthesis and release of prostaglandins from the uterus and/or placenta is an adaptive response to hyperthermia, and may protect the fetus from the consequences of heat stress.     

Comparison of intra-amniotic prostaglandin F2 alpha and hypertonic saline for induction of second-trimester abortion.

The efficacy and safety of intra-amniotic prostaglandin (PG) F2 alpha (25 mg repeated in six hours) and hypertonic saline (200 ml 20% NaC1) were compared in an international multicentre randomised study organised by the World Health Organisation''s prostaglandin task force. Both hypertonic saline and PGF2alpha were found to be effective in terminating second-trimester pregnancy. The main advantage of PGF2alpha however, was its greater efficacy, with significantly higher success rates in the first 48 hours. Out of 717 women given PGF2alpha 614 (85-6%) aborted within 48 hours; by 24 hours 439 (61-2%) had aborted, and by 36 hours 574 (80-1%) had aborted. Out of 796 women given hypertonic saline 641 (80-5%) aborted within 48 hours; however, by 24 and 36 hours, respectively, only 161 (20-2%) and 462 (58%) had aborted. Although PGF2alpha was associated with a somewhat higher frequency of minor side effects than hypertonic saline, notably vomiting and diarrhoea, these were within acceptable limits. Only 59 women (8-2%) in the prostaglandin group had more than four episodes of vomiting and 11 (1-5%) more than four episodes of diarrhoea. Ohter side effects occurred only occasionally. No difference was found between the two groups in the frequency of incomplete abortion or excessive bleeding.     

The effect of prostaglandin I on the contractility of the term pregnant human myometrium

Small myometrial strips were dissected from the upper and lower segments of the term pregnant human uterus. The specimens were superfused in organ chambers and contractile activity was recorded isometrically. In strips from the upper segment, prostacyclin (PGI2), induced an initial excitatory response followed in the majority of experiments by transient inhibition. In the lower segment the response was generally the same although direct inhibition without initial stimulation occurred in some cases. During the period of inhibition the specimens were refractory to iterated exposure to PGI2. Furthermore, during this period of PGI2-induced inhibition the muscle strip was also refractory to PGE2 but responded to PGF2 alpha and oxytocin by stimulation. After inhibition of spontaneous contractile activity induced by indomethacin PGI2 induced an excitatory response. The results do not indicate any critical change in the myometrial responsiveness of the upper uterine segment to PGI2 during labor. In strips from the lower segment obtained before labor there tended to be a dominance of non-responders and inhibition only as compared to the results during labor. Nevertheless, whether or not PGI2 under physiological or pharmacological conditions has any significant influence on the contractility of the term pregnant human uterus, still remains obscure. As judged from earlier reports from our laboratory and the present study it is evident that the uterine vessels are considerably more sensitive to the action of PGI2 than the myometrium.