Marc Bygdeman

The relation between fertility and prostaglandin content of seminal fluid in man.

The relationship of prostaglandin levels in human seminal fluid to fertility, an accepted one, was tested by dividing 150 men into 3 clinical groups: 1) Group A, 29 fertile men; 2) Group B, 100 men in noninvestigated infertile marriages; and 3) Group C, 21 men in infertile marriages with no abnormal clinical or laboratory findings. Thin layer chromatography was used to measure the various prostaglandin compounds, after alkali treatment. Prostaglandin E content of semen samples below 11 mcg/ml was considered low; the percentage of samples in each group displaying this low content was: 0% in A, 17% in B, and 41% in C. The groups of men also differed statistically significantly from each other, with A and C being most highly significant. In all 3 groups, the concentration of 19-hydroxy and dehydrated prostaglandins remained constant. Because Group C members had been studied extensively for causes of infertility, the finding of low prostaglandin E content in seminal fluid compared with controls (A) and noninvestigated infertile male partners (B) shows that the E compounds are important for reproduction.

Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle

Study objective. To evaluate the effect of treatment with ethinylesteradiol‐levonorgestrel or danazol on ovarian function, gonadotrophin release and endometrial development during the time when a pregnancy may occur following unprotected intercourse.

Verifying the effectiveness of medical abortion; ultrasound versus hCG testing

OBJECTIVES The combination of mifepristone and misoprostol is an established method for termination of pregnancy. However, there is no general agreement about how best to evaluate the treatment outcome. STUDY DESIGN In 217 women with an unwanted pregnancy below 49 days of amenorrhoea, ultrasound examination and serum hCG test were performed before treatment and at follow-up. RESULTS Treatment was successful in 98.2%. At follow-up their hCG dropped to a mean of 3% (S.D. 3) of initial levels and the endometrium measured a mean of 10 mm (S.D. 4). Interpretation of endometrium was difficult in some cases because of inhomogeneous structure. Using hCG was reliable in 98.5% of successful abortions. For ultrasound the corresponding figure was 89.8% for the cases with a confirmed intrauterine pregnancy before treatment but only 66% if all pregnancies were included. CONCLUSION Measuring serum hCG before treatment and at follow-up is more effective than ultrasound to confirm a successful medically induced abortion in early pregnancy.

Induction of abortion by extra-amniotic prostaglandin administration

Abstract Abortion was induced by intermittent extra-amniotic administration of prostaglandin F 2α in 70 women. It was found that the best results were obtained by separate doses of 250–750 ug PGF 2α given in volumes of 1–6 ml every 1–4 hours via a self retaining Foley catheter. A radiological study revealed that a small volume of PGF 2α solution injected into the lower uterine segment induces local contractions which force the pool of solution upwards to spread between the uterine wall and the foetal membranes. This mechanism is believed to facilitate the development of forceful reasonably coordinated contractions that result in expulsion of the conceptus. In the second trimester, abortion occurred within a mean period of 24 hours in 88% of the cases. The incidence of generalized side-effects in terms of vomiting and diarrhoea was very low compared to that during continuous intravenous infusion of the compound. In 10 late first or early second trimester pregnancies PGF 2α or PGE 2 was injected extra-amniotically during a limited period to dilate the cervix as a pre-operative measure. The stimulating action of prostaglandins on uterine contractility induced a cervical dilatation that made subsequent instrumental evacuation a simple procedure. This form of pre-operative treatment may be utilized to avoid complications in “border-line cases” where the size of the uterus renders primary evacuation hazardous.

Vascular changes in the human endometrium following the administration of the progesterone antagonist RU 486

Eleven healthy women were assigned to one of two groups. They received 50 mg RU 486 orally per day either on cycle days 7 to 10 (preovulatory group n = 5) or on cycle days 20 to 23 (postovulatory group, n = 6). An endometrial biopsy was taken on the fourth day of the RU-treatment in the preovulatory group and on the second (n = 2) or fourth (n = 4) treatment day in the postovulatory group. Biopsies from 34 untreated women representing matched samples from early and mid preovulatory phase (n = 10) and mid and late postovulatory phase (n = 24) were used as control. The ultrastructure of the endometrial capillaries was investigated by morphometric methods. The administration of RU 486 during the preovulatory phase did not modify the vascular structure. However, when given in the postovulatory phase, necrosis occurred in the capillary endothelial cells with and without regressive changes of the adjacent stroma. The area and diameter of the capillary lumen and the area of the adventitia was smaller than in the control material (p less than 0.01). The result of the study suggests that RU 486, when administered in the postovulatory phase, directly affects the capillary vessels of the endometrium.

Pharmacokinetics of prostaglandins

Naturally occurring prostaglandins (PGs) are rapidly metabolized in the human circulation. For clinical use a number of PG analogues have therefore been developed which are resistant to rapid inactivation. Among these are carboprost, gemeprost and misoprostol. Following intramuscular injection of carboprost, plasma levels peaked after 20 minutes and declined slowly thereafter. In amniotic fluid the half-life was between 31 and 37 hours. Gemeprost is administered vaginally, and maximum plasma levels were reached after 2-3 hours, with detectable levels for at least 6-8 hours. Pharmacokinetic data on misoprostol are available following oral, vaginal and sublingual administration. Following oral treatment, plasma levels peaked at about 30 minutes, while after vaginal administration of the tablets the levels increased gradually and reached maximum levels after 70-80 minutes, but remained detectable for a significantly longer time. After sublingual administration the peak concentration was the same as for oral treatment but declined significantly more slowly. Endocervical administration of PGE(2) might be regarded as a local therapy, while following vaginal administration increased plasma levels of metabolites can generally be found. The plasma profile varies with the vehicle used.

Induction of abortion by intra-amniotic administration of prostaglandin F2α

Abstract Legal abortion was induced in 37 pregnant women in the second trimester by intra-amniotic administration of prostaglandin F 2α . The effect of different dose schedules on uterine contractility and clinical outcome was studied. Doses in the order of 5–25 mg were employed demonstrating a marked and prolonged stimulatory effect on the uterus. The contractions became rather effective and fairly regular within 6 hours and were sustained for about 20 hours. The induction trial was successful in 89% of the cases with a mean induction-abortion interval of 28 hours. The possible mechanism of action and the results obtained by different doses are discussed. More experience is still required before a suitable dose schedule can be finally settled. This procedure seems to offer certain advantages over the currently used methods for termination of pregnancy in the second trimester.

A comparison of two stable prostaglandin E analogues for termination of early pregnancy and for cervical dilatation

Termination of pregnancy with prostaglandin E analogues is in general associated with a lower frequency of gastrointestinal side effects than if corresponding F analogues are used. Their clinical use has, however, been limited by stability problems. In the present study the efficacy of different dose schedules of two new stable E analogues for termination of early pregnancy and for preoperative dilatation of the cervical canal was evaluated in 389 women. In early pregnant patients, vaginal administration of 75 mg of 9-deoxo-16, 16-dimethyl-9-methylene PGE2 repeated after six hours or three intramuscular injections of 0.5 mg 16-phenoxy-omega-17, 18, 19, 20-tetranor PGE2 methyl sulfonylamide administered in three-hour intervals resulted in a complete abortion in 94 to 100 per cent of the patients. Both treatments were associated with a low frequency of side effects. The 9-methylene analogue had the advantage of causing less uterine pain than 16-phenoxy-omega-17, 18, 19, 20-tetranor PGE2 methyl sulfonylamide with the dose schedules used. Single vaginal administration of 30 mg of 9-deoxo-16, 16-dimethyl-9-methylene PGE2 and one intramuscular injection of 0.5 mg of the methyl sulfonylamide analogue 12 hours prior to vacuum aspiration were equally effective in dilating the cervix in late first trimester pregnant patients. For both compounds, the frequency of side effects were lower than that previously reported for different PGF analogues administered by non-invasive routes.

The effect of the prostaglandin F compounds on the contractility of the pregnant human uterus

The aim of this paper was to study the influence of prostaglandins compounds on the pregnant human uterus in situ. Recordings of uterine motility were made on 14 pregnant women by measuring the amniotic pressure. PGE1 alpha and PGF2 alpha were administered intravenously as single injections. It was found that PGF2 alpha and, to a minor extent, PGE1 alpha had a stimulating effect characterized by an increment of tone. The threshold dose to induce contractility was 8 times greater for PGF2 alpha than it was for PGE1.

Development of a vaginal suppository suitable for single administration for interruption of second trimester pregnancy

Abstract Extra- and intra-amniotic administration of prostaglandins are accepted methods for interruption of second trimester pregnancy. However, an equally effective nonsurgical method would give important advantages especially for large scale programs. Repeated vaginal administration of suppositories containing either 15-methyl PGF2α methyl ester or 16,16-dimethyl PGE2 has been effective in inducing abortion during the first and second trimesters of pregnancy. By using different bases for the suppository and different amounts of 15-methyl PGF2α methyl ester, a long-acting vaginal suppository has been developed. Recording of uterine contractility and measurement of plasma concentration showed sufficient release of 15-methyl PGF2α methyl ester for 12 to 24 hours. One suppository containing 3.0 to 3.5 mg 15-methyl PGF2α methyl ester in 2.2 or 2.5 g of the base Witepsol E-76 was given to 25 second trimester patients. Twenty-three patients (92%) aborted within 24 hours following one suppository. The mean induction-abortion interval was 12.4 hours. The abortion process was completed in the remaining two patients by one to three intramuscular injections of 15-methyl PGF2α. The incidence of gastrointestinal side effects was low. The mean frequency of vomiting and diarrhea per patient was 1.7 and 0.7, respectively. The results of this single dose vaginal suppository has been encouraging and appears to be an important break-through in the research for an ideal abortifacient.