Effect of prostaglandin F2 alpha on the secretion of human prolactin

This study examines the role of PGF2a (prostaglandin F2alpha) in increasing the secretion rate of human prolactin. 11 women (mean gestational period, 18 weeks) seeking pregnancy termination were divided into 4 groups: 1) Group 1 consisted of 6 women who received 30 mg initially of PGF2a injected intramuscularly and an additional 15 mg after 24 hours if abortion had not occured; mean induction to termination period was 38 hours; 2) Group 2 comprised of 3 women who received PGF2a (500-1500 ug) via the transcervical route at 1 to 2 hourly interval; average number of injections was 20; mean induction to termination period, 24 hours; 3) Group 3 had 2 women receiving hypertonic saline by intraamniotic injection; mean induction to termination period was 51 hours; 4) Group 4 had 4 women who served as controls; mean observation period, 20 hours. Venous blood samples were heparinized in tubes at intervals of 2 to 3 hours. A homologous radioimmunoassay using highly purified human prolactin (for iodination and standards) plus rabbit antihuman prolactin measured serum prolactin. Spikes of serum prolactin up to 550 ng/ml were observed at irregular intervals in 5 women in Group 1; the spikes were less frequent and of smaller amplitude in Groups 3 and 4. The increase in serum prolactin was dramatic and more sustained in Group 2 patients and peaked towards the end of the prostaglandin infusion. Serum prolactin of Group 2 patients were significantly higher than those of Groups 3 and 4 (p0.01). 5 of 9 women whose pregnancies were terminated by PGF2a lactated. However, there was no significant difference between the mean serum prolactin levels in women who lactated (136 ng/ml) and those who did not (120 ng/ml). Although PGF2a is not a lactogenic hormone, this study shows that PGF2a stimulates the secretion of human prolactin during second trimester pregnancy. The fact that the transcervical route caused a significant increase in serum prolactin and the intraamniotic route did not is attributed to the increased systemic absorption of PGF2a following transcervical administration. No correlation was seen between the presence or absence of lactation and the serum prolactin level following pregnancy termination with PGF2a.     

Late midtrimester medical pregnancy terminations: three different procedures with prostaglandin F2 alpha and laminaria tents

One hundred twenty eight women underwent midtrimester induced abortion with: 1) combined regimen of intramniotic prostaglandin (PG) F2a injection and intracervical laminaria tents (group A, 50 women), 2) intramniotic PGF2a injection only (group B, 51 women) and 3) laminaria tents followed by intracervical PGF2a tablets insertion (group C, 27 women). The mean induction-abortion time (+/- SE) was 24.9 +/- 1.7 hours for group A, 28.2 +/- 2.2 hours for group B (p greater than 0.05) and 42.1 +/- 3.4 hours for group C, significantly longer than goup A and B (p less than 0.001 and p less than 0.01 respectively). In 48 hours 98% of the patients of group A, 90% of group B (p less than 0.05) and 59% of group C (p less than 0.001) completed the abortion procedure. Parous women of group A and B presented similar induction - abortion time, while in nulliparous the use of laminaria shortened the abortion procedure significantly (p less than 0.05). The complications rate was low. In conclusion, the intracervical PGF2a insertion is a simple but very slow abortion procedure with high failure rates. The intramniotic PGF2a injection is a successful method for late midtrimester medical pregnancy termination and the concurrent use of laminaria tents shortens the abortion procedure, particularly in nulliparous, reduces the number of prostaglandins' reinjections and increases the incidence of successful abortion within 48 hours.     

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.     

Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries in the early second trimester

The use of gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries for the termination of pregnancy in the early second trimester has been further investigated. Of 113 women between 12 and 16 weeks gestation, 93 (82%) aborted within 24 hours of the administration of 4.4 +/- 0.1 1 mg gemeprost pessaries. The mean induction-abortion interval was 881 +/- 31 minutes. Successful abortion was achieved in 16 of the remaining 20 women after a second course of gemeprost pessaries without the need for oxytocin supplementation. There were no serious complications. Crampy abdominal pain and vaginal bleeding started after 275 and 756 minutes respectively. Twenty-two (19%) patients did not require pain relief during treatment, but 90 (80%) required parenteral opiates. Vomiting and diarrhoea occurred in 16 (14%) and 23 (20%) cases respectively. The safe induction of therapeutic abortion in 96% of women using vaginal prostaglandin alone offers an acceptable alternative to surgical evacuation in the early second trimester.     

Single intraamniotic injections of prostaglandin F-2-alpha as an abortifacient agent: size of effective dose and effect of parity

This report discusses the authors' experience with intraamniotic administration of single doses of the prostaglandin PGF2alpha as an abortifacient agent. 98 healthy women between the 12th and 26th week of pregnancy admitted to the Clinical Research Unit of the North Carolina Memorial Hospital were given a single intraamniotic dose of PGF2a administered through an indwelling polyethelene catheter inserted either transabdominally or transvaginally. The drug was given as Tham salt with the first 5 mg of any dose being given at the rate of 1 mg/minute for 5 minutes, followed by more rapid administration of the balance of the dose. Abortion which did not occur within 48 hours was considered a failure. Each patient received 1 of the following dosages: 25, 40, 50, and 75. 9 (64%) of 14 patients given 25 mg PGF2a aborted within the 48-hour period. The percentages of abortion in the doses 40, 50, and 75 mg were 88.9% (9 patients), 96.7% (60 patients) and 93.3% (15 patients) respectively. As these figures were almost similar, the 84 patients were combined as a single group (84 patients) relative to the injection-abortion time, effect of parity, and stage of gestation at which the abortion was carried out. Half of the patients in this combined group aborted in approximately 21 hours; more than 90% at the end of 32 hours; and 95% at the end of the 48 hours post-injection. For comparison, the cumulative abortion curve of 552 patients who had intraamniotic saline for abortion showed that 50% of the women aborted within 31 hours, 84% within 48 hours, and 97% within 72 hours. Prostaglandin induced abortions thus are shown to reach the 50% level 10 hours before the saline patients, and the 90% level about 21 hours before the saline patients. Significant side effects (presented elsewhere) were observed in all groups, with the incidence increasing at higher dosages. Mean induction-abortion time for nulliparas at all dosages was 17.4 hours; for multiparas, 20.4 hours. There was no clear relationship between gestational age and parity. The study shows that the effective dose for inducing abortion with PGF2a lies within the 40 to 50 mg dose range.     

Single extra-amniotic injection of prostaglandin E2 in viscous gel to induce mid-trimester abortion.

In a preliminary study a single extra-amniotic injection of 1.5 mg of prostaglandin E-2 incorporated into an aqueous viscous gel was given to 24 patients aborted within 24 hours, and the mean induction-abortion interval (plus or minus S.E. of mean) was 13.5 plus or minus 1.5 hours. Vomiting occurred in seven patients, and transient severe uterine cramps, pallor, nausea, and shivering occurred in one patient immediately after injection. Complete abortion occurred in 20patients. A delay in the time taken to abort seemed to be associated with an immediate and rapid rise in uterine tone after the injection which required prompt analgesia; this probably reflected rapid decidual absorption and dissolution of the prostaglandins away from their site of action. The degree of distention of the catheter-retaining balloon did not influence abortion times.     

A retrospective study of 932 second trimester terminations using gemeprost (16,16 dimethyl-trans delta 2 PGE1 methyl ester).

A retrospective study of 932 second trimester terminations between 12-27 weeks gestation was carried out to determine the efficacy of gemeprost for second trimester termination. A single course of 5 x 1 mg gemeprost pessaries was administered every three hours. If abortion had not occurred after the first course of pessaries, a further course of 5 x 1 mg pessaries was administered. Intravenous oxytocin was administered after 36 hours if abortion had not occurred. Eighty per cent and ninety five per cent of patients aborted within 24 and 48 hours respectively. Of the remaining 5 per cent of women, 3 per cent aborted with escalating doses of oxytocin. In the remaining 18 (2 per cent) women, the pregnancies were electively terminated with an alternative method. The median induction-abortion interval was 18.0 hours and 15.0 hours in nulliparous and parous women respectively (P less than 0.0001). The number of pessaries required to induce abortion was not influenced by parity. Significantly more parous women bled more than 500 ml. The incidence of pelvic sepsis (0.1 per cent) and cervical tear (0.1 per cent) was low. Twenty six per cent of women had diarrhoea and 23 per cent vomited following administration of prostaglandin. This study confirmed the efficacy of gemeprost for second trimester termination of pregnancy. This method of termination is safe, non-invasive, simple and has a low complication rate.     

Blood production rates of estrogens in women with differing ratios of urinary estrogen conjugates.

On the basis of the ratios of the estrogen conjugates in their urine (estriol/estrone + estradiol: E3/[E1+E2]), 19 women were divided into two groups: 9 women had ratios less than 0.6 and 10 women had ratios greater than 1.3. All women had measurements made of endogenous estrogens in their plasma by radioimmunoassay. They were then given constant infusions of 3H-estrone, 3H-estradiol and 14C-estriol during days 5-7 and days 20-22 of their cycles, and metabolic clearance rates (MCR) and blood production rates (PB) of estrone, estradiol and estriol were determined. Despite the wide disparity in their ratios of urinary estrogens, no differences could be found between the groups for the MCR's and PB's for all estrogens at either time of the cycle. The mean ratios of PB's (PB3/[PB2+PB1]) of estrone, estradiol and estriol ranged from 0.07 to 0.10 for each group during the cycle. The amounts of estriol entering the blood are small compared to the amounts of estrone and estradiol and do not correlate with the ratios of their urinary conjugates.     

Endocrinology of pregnancy in the orang-utan (Pongo pygmaeus) and its evolutionary significance

Urinary concentrations of estrone, estradiol-17Β, estriol, pregnanediol-3α-glucuronide, and chorionic gonadotrophin (CG) were measured by radio-immunoassy through five pregnancies in four multiparous orang-utans. The excretion of all three estrogen metabolites increased substantially during pregnancy. Although estrone was the major metabolite during early pregnancy, estriol excretion increased considerably, to reach 10 times the concentration of estrone at term. Estradiol-17Β was of comparatively minor importance. Maximum CG excretion occurred during the first trimester and low but constant levels were present in urine throughout the remainder of pregnancy. An early peak of pregnanediol-3α-glucuronide excretion coincided with the CG peak and then rose steadily to reach a plateau 8 weeks prepartum which was maintained until term. Urinary excretion of all five hormones decreased rapidly immediately following parturition. These data suggest that the pattern of urinary steroid and CG excretion during pregnancy in the orang-utan closely resembles that in the other great apes and women.     

Vaginally administered 16,16-dimethyl-PGE2 for the induction of midtrimester abortion

Thirty patients in the 13th–20th week of gestation underwent therapeutic abortion utilizing vaginally administered 16,16-dimethyl-PGE₂ (free acid) suppositories. The first 15 patients obtained individual doses in the range of 400–1200 μg given every three hours (mean total dose 4.2 mg). In the following 15 patients a fixed dose schedule was used (800 μg followed by 1000 μg every three hours; mean total dose 5.3 mg). All but one of the 30 patients aborted. The mean induction-abortion interval for all patients was 16.8±6.9 hours (mean ± S.D.) With the fixed dose regime the success rate was 100% and the induction-abortion interval 16.0±5.9 hours. Because gastro-intestinal side effects were minimal, neither anti-emetic nor anti-diarrheic medication was required. A slight elevation of temperature was noted in five patients. The uterine response to the vaginal administration of this compound was characterized by a gradual increase in uterine tonus followed by sustained stimulation. The results are interpreted to suggest that the vaginal administration of 16,16-dimethyl-PGE₂ is a useful alternate method for the induction of second trimester abortion. Moreover, this compound seems to cause fewer gastro-intestinal side effects than other prostaglandins administered by the vaginal route at our department.     

Mid-trimester abortion with intra-amniotic prostaglandin F2 alpha and intravenous oxytocin infusion

Induction of abortion in mid-trimester pregnancies were performed on 26 patients. The first 12 patients were treated by intra-amniotic instillation of Prostaglandin F2 alpha, with a mean dosage of 40.2 mg. and mean abortion time of 24 hours and 41 minutes (ten patients). Fourteen additional mid-trimester abortions were performed using identical protocol plus the addition of oxytocin by intravenous infusion two hours after injection of the prostaglandin. All patients aborted, with mean dosage of PGF2 alpha of 28.2 mg. and mean abortion time of 15 hours and 37 minutes.     

Preparturient changes in plasma concentrations of estrone,estradiol-17β and estradiol-17α in the fetal calf: Effects of dexamethasone infusion

The concentrations of total estrogens in fetal calf plasma were determined during a 6–10 day period immediately before delivery. Comparison was made between levels found in untreated calves and calves infused with dexamethasone at the rate of 0.1, 1.0 and 10 mg/24 hours. In untreated calves the plasma estrone, estradiol-17β and estradiol-17α levels remained relatively constant at 38 ± 7 ng ml^?1 (mean ± SEM n = 3), 46 ± 6 ng ml^?1 and 29 ± 5 ng ml^?1 respectively. Infusion with dexamethasone at 0.1 mg/24 hr (3 calves) and 1.0 mg/24 hr (3 calves) was without dramatic effect on plasma estrogen levels. However, in one fetus infused with 10.0 mg/24 hr the dexamethasone treatment may have caused a transitory rise in the levels of all estrogens examined.     

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.     

Longitudinal studies on the phenomenon of postmenopausal estrogen production

Longitudinal studies on the phenomenon of postmenopausal estrogen pr oduction are presented. Cytohormonal screening was repeated after 1-4 years in 5633 women. The outcome of the 2nd smear was determined by the cytologic characteristics of the 1st smear and by body weight. A thin woman with an atrophic 1st smear had only 4.8% probability of showing an estrogenic 2nd smear, whereas a grossly obese woman with an estrogenic 1st smear had a 26.2% chance of showing an estrogenic 2nd smear. Series of 8-12 cytologic smears were studied within 2 months in 80 women. Evidence indicated that the phenomenon of postmenopausal estrogenic smears tended to be continuous. 24-hour urine specimens from 100 normal women were analyzed and the cytologic-biochemical relationships were studied. Persistent estrogenic smears predicted higher excretion of estrone and estriol and slightly lower excretion of androsterone and etiocholanolone.     

The efficacy and acceptability of the "prostaglandin impact" in inducing complete abortion during the second week after the missed menstrual period

Clinical research was undertaken using PGF2a (prostaglandin) to induce abortion in 22 pregnant women at 12 +/- 1 days following their missed menstrual period. The PG was administered in a 5 mg single intrauterine dose through the cervix for a 10-minute period. The PG administration caused increased uterine contraction within 20 minutes and raised intrauterine pressure which was sustained for 2 hours. During the initiation of the intrauterine pressure, bleeding started and progesterone and estradiol levels decreased and continued to do so. In those patients who had been sedated, side effects were minimal. At 24 hours following the PG administration, progesterone had been withdrawn at a rate of 44%, bleeding was continuing, and cervical dilatation was at approximately 1 cm. Complete abortion was achieved in 20 out of the 22 women. It is believed that the abortion was effected through the action of endogenous PG, due to the withdrawal effect on progesterone of the exogenously-administered PG.     

Laminaria augmentation of intra-amniotic prostaglandin F2α for the induction of mid-trimester abortion

From interpretation of 24-hour dose-response curves, it is improbable that mid-trimester abortion rates greater than about 80% can be accomplished with any one dose schedule of Prostaglandin F2α (PGF2α). To determine whether augmentation of intra-amniotic PGF2α with laminaria would improve the abortion rate, the results of a group of 22 gravidas treated with intra-amniotic PGF2α were compared to those of a group of 21 subjects treated with laminaria and an identical dose schedule of PGF2α. Patients with laminaria not only had a shorter mean abortion time (14.6 hours), but 95% aborted within 24 hours and all patients aborted within 24.5 hours of the initial PGF2α injection. Patients without laminaria had a longer mean abortion time (18.9 hours); only 68% aborted within 24 hours and one failed to abort within the 48-hour trial period. No significant differences in the frequency or severity of complications between the two groups were observed. Uterine contractility over the initial 6 hours of the induction was similar in the two groups. Therefore, augmenting the intra-amniotic PGF2α method with laminaria appears practicable.     

The stimulatory action of the prostaglandins on the production of oestrogens by the human placenta perfused in vitro

The effect of prostaglandins (PGs) on estrogen production by the human placenta perfused in vitro is investigated in this study. 5 placentas obtained by natural delivery at term were perfused within the 1st 30 minutes following delivery. 10 mg of testosterone was added at the beginning of the experiment and varying amounts of PGF2alpha, PGE1, and PGE2 at the end of the 1st hour of perfusion (maintained for 2 to 2-1/2 hours). Fluorimetric measurements of estrone and estradiol were done following chromatography on a celite column of 50 ml samples of perfusate taken every 30 minutes. Placentas perfused in a similar manner but receiving 10 mg testosterone only were used as controls. The results show that addition of 1 mg of PGE2 (3 x 10 -6 M) or PGF2alpha significantly increased the level of estrogens in the perfusion fluid compared with the control placentas. It is possible that this stimulatory effect facilitates uterine contractions during parturition. The increase appeared to be of long duration and to have a dose-response relationship. However, the perfusion of the whole organ appears not to be a very good model for studying the quantitative effect of a stimulator or the relationship between different doses used and responses obtained because of the variation of 1 placenta to another. To investigate the possibility that PGs are possible mediators between human chorionic gonadotropins or luteinizing hormones and adenyl-cyclase, the authors conducted experiments where PGE1 and PGF2alpha were added to minced placentas together with DB cyclic AMP or NADPH generating factors. Only in the 2nd case was an additive effect observed, suggesting that this effect on estrogen production is brought about by the stimulation of adenyl-cyclase observed in placental homogenates by investigators Satoh and Ryan.     

Quantitative evaluation of steroid extrogens by study of the vaginal epithelium thickness and mitotic index in mice

The potency of estrone, estradiol, estriol, and equilenin, administered to mice subcutaneously or intravaginally, was quantitated by vaginal mitotic index and by epithelial thickness; results were compared with those previously obtained in the classical tests of rat vaginal cornification and uterotrophic activity in mice. Ovariectomized mice received .002-.7 mcg estrogens in oil sc, or .16-6250 pg in alcohol solution intravaginally. 19 hours later .1 mg colchicine was given to arrest cells in metaphase. 24 hours after estrogen treatment, vaginas were a positive log-dose response in both tests and by both routes. Estradiol by both routes increased vaginal thickness but without linear dose-response, increased vaginal mitosis with a less definite dose response, but generated a negative dose response in mitotic index. Equilenin had a positive but nonlinear effect by both routes in both tests. Comparing the activities of these estrogens by routes, estradiol was more active by subcutaneous than by intravaginal routes; estriol and equilenin were more active vaginally than subcutaneously. Estradiol was 3-7 times more active than estrone intravaginally and 25-45 times more active subcutaneously. Estriol was less active than estrone; equilenin was as active as estrone intravaginally, but less active subcutaneously. In comparison with the rat vaginal cornification or mouse uterotrophy tests, estradiol sc, estriol and equilenin sc and especially vaginally, are much more active.     

Prostaglandin F2α-induced stimulation of estrone and estradiol-17β secretion in cattle

Four of 5 Holstein heifers given intra-ovarian injections of 300 μg of prostaglandin F_2α (PGF_2α) showed transient, but statistically significant, depressions in plasma progesterone levels which returned to near normal levels within 24 hr. The same 4 animals also exhibited significant elevations in plasma estrone and estradiol-17β levels during the initial 24 hr. period following treatment, although no animals were observed in estrus during this time. Plasma levels of progesterone, estrone, estradiol-17β and PGF showed little change in control heifers receiving intra-ovarian injections of the buffer solution used as a vehicle for PGF_2α. It is concluded that PGF_2α stimulates estrogen secretion, presumably by follicular elements of the ovary.     

Estrogens and prostaglandin F2alpha in the semen and blood plasma of stallions

A study was performed to determine the levels of estrogens and prostaglandin F(2)alpha in the stallion ejaculate. Simultaneous semen and blood plasma samples were collected from 19 stallions, 2 weeks apart, during the breeding season. Although not statistically different, the total mean estrogen content tended to be higher in seminal plasma (4447 pg/ml) than in blood (2497 pg/ml). A tendency was found for higher mean estrone sulphate concentrations than for total free steroid in both seminal (4116.1 vs 330.5 pg/ml) and blood plasma (2447.1 vs 49.5 pm/ml). Mean concentrations of estrone in ejaculate and blood plasma were 257.1 +/- 267.0 (SD) and 9.5 +/- 5.4 pg/ml, respectively. Estradiol-17beta concentrations were 73.4 +/- 87.4 and 40.0 +/- 27.6 pg/ml in ejaculates and blood plasma, respectively. Mean PGF(2)alpha concentrations tended to be much higher than total estrogens (1106.8 +/- 1636.4, SD, vs approximately 260 ng/ejaculate, respectively). To our knowledge this is the first report of PGF(2)alpha and estrogen concentrations in the stallion ejaculate.