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Human seminal plasma contains eight different prostaglandins belonging to the F series, i.e. PGF1a, PGF2a, 19-hydroxy-PGF1a, 19-hydroxy PGF2a, as well as the corresponding 8ß-isomers. A systematic description of the mass spectrometric fragmentation of the 8ß-isomers has not been previously reported. In the present study the prostaglandins were separated from human seminal plasma and analysed as methylester, trimethylsilylethers with gas chromatography mass spectrometry. All the eight F and 19-hydroxy F prostaglandins fragmented in the same manner, but the relative abundances of the formed ions varied in a typical way. Thus, the mass spectra of 8ß-PGF1aand 8ß-19-hydroxy PGF1adiffered clearly from those of their 8a-isomers, which could be used for identification and should be considered in selected ion monitoring. The ratio between the seminal plasma levels of 8ß- and 8a-isomers of 19-hydroxy F1awas much higher than the corresponding ratio for the PGF1a.

The finding that exogenous prostaglandins have a potent and specific stimulatory action on uterine contractility in the human female as well as data suggesting increased concentrations of endogenous prostaglandins in amniotic fluid and blood serum during labor indicate that these compounds may play a role in human parturition. However, earlier results on blood levels of prostaglandin F2α(PGF2α) remain controversial because of the possible formation of PGF2αby platelets and blood cells during isolation of the plasma or serum. It seems that measurement of the PGF2αmetabolite 15-keto-13, 14-dihydro-PGF2αby a gas chromatographic-mass spectrometric technique offers a more reliable method for monitoring PGF2αbiosynthesis. During the last month preceding labor, the concentration of 15-keto-13, 14-dihydro-PGF2αincreased slightly. During active labor the plasma level of the metabolite increased ten- to thirtyfold. One hour after delivery the concentration had decreased by 20 to 75 per cent. The presented data support the view that endogenously produced PGF2αresults in increased uterine activity during the last month of pregnancy and during labor.

In the present study the efficacy and safety of three different prostaglandin E analogues for termination of early pregnancy (up to 49 days of amenorrhea) was evaluated. The study comprised 198 women. Most of the patients were treated at the hospital, but on an out-patient basis. After a thorough explanation, 45 patients agreed to undergo the treatment at home. Each patient received one of three alternative treatments1) Intramuscular injections of 16-phenoxy-ω-17,18,19,20-tetranor-PGE2 methyl sulfonylamide (16-phenoxy-PGE2). 0.5 mg three times at 3-hour intervals;2) Vaginal suppositories containing 1.0 mg 16,16-dimethyl-trans-A2-PGE2 methyl ester, five times at 3-hour intervals;3) Vaginal suppositories containing 9-deoxo-16,16-dimeth-yl-9-methylene-PGE2, 75 mg followed by 30 mg 6 hours later, or 60 mg plus 45 mg with the same time interval.The last analogue in the same dose was used in the home-treated patients. All three compounds were equally effective in terminating early pregnancy. The frequency of complete abortion varied between 92 and 94% for patients treated in the hospital and was 98% in the home-treated patients. The frequency of gastro-intestinal side effects was also very similar and much lower than we have previously reported for 15-methyl-PGF2α methyl ester administered by the vaginal route. Uterine pain necessitating analgesic injections in the hospital-treated patients was higher (56%) following intramuscular injections of 16-phenoxy-PGE2 than following vaginal administration of the other two analogues (32 - 34%). In the patients treated at home, the corresponding figure was much lower (4%). Temperature elevation was most common following treatment with 9-methylene-PGE2 but never exceeded 40°C. It is concluded that in women who are positive to a non-surgical procedure for termination of early pregnancy, the therapy was well accepted.

Termination of abnormal pregnancy has long been a major gynecological problem. Both surgical and non-surgical procedures are associated with a significant risk for both minor and major complications. Treatment with natural prostaglandins and especially prostaglandin analogues administered by non-invasive routes seems to be an attractive alternative to methods in current use. In the present study 68 consecutive patients with a missed abortion or hydatiform mole were treated with vaginal suppositories containing either 15-methyl-PGF2α, methyl ester or 9-deoxo-16,16-dimethyl-9-methylene PGE2. When the uterine size at treatment was 13 weeks or less, vacuum aspiration was performed 12 hours after start of prostaglandin therapy (group I: 41 patients). When the uterus was larger, curettage was performed only after abortion (group II: 27 patients). In group I approximately 45% of the patients aborted within 12 hours from the start of prostaglandin treatment. In the remaining patients the cervical canal was sufficiently dilated and the uterus contracted to allow an easy evacuation. In group II all patients aborted within 26 hours from start of therapy. No serious complications were observed. Both prostaglandin analogues seemed equally effective in terminating an abnormal pregnancy. The E analogue has the advantage of causing significantly fewer gastro-intestinal side effects than the F analogue, though temperature elevation is more common with the former. It may be concluded that vaginal administration of prostaglandin analogues is a simple and effective therapy for termination of abnormal pregnancy and seems to offer considerable advantages over methods in current use.

The semen quality of men who participated in an infertility investigation in 1956 was compared with that from men from similar populations in the years 1966, 1976, and 1986. The sperm parameters studied included total sperm count and sperm morphology. A significant reduction over this 30-year period was observed for both parameters. The total sperm count decreased from 467 million in 1956 to 305 million in 1986 (mean,p < 0.0001) and the percentage of sperm with normal morphology diminished from 53% to 37% (mean, p < 0.0001) during the same period. This Swedish study, like studies in other industrialized countries, indicates a decline in semen quality over the past few decades.

Suppositories of 15-methyl PGF2αmethyl ester in triglyceride Mere administered vaginally to 75 women in whom 31 to 49 days had elapsed since their lust menstrual period. Three or four suppositories of 0.5, 1.0, or 1.5 mg were given at intervals of 3 hours. Pregnancy was later confirmed in 63 of the women. In the pregnant women vaginal bleeding usually started 3 to 6 hours after the initiation of therapy and continued for 1(1 to 14 days. Patients were followed for 2 to 4 weeks with serial measurements of serum progesterone and hCG. There were no failures in the trial, but in 2 cases the treatment resulted in incomplete abortion. In 2 other patients curettage was performed due to prolonged bleeding, but histologic examination revealed no remaining signs of pregnancy. Gastrointestinal side effects were well within acceptable limits, and no serious complications occurred. Clinical signs of pelvic inflammatory disease were not found. The vaginal use of 15-methyl PGF2αmethyl ester seems promising as a reliable outpatient nonsurgical self-administered procedure for termination of early pregnancy.

Summary A new PGE2-gel, based on a cross-linked starch powder, has been developed. This gel seems to have solved several of the pharmaceutical and practical problems connected with local administration of prostaglandins. In a three-center study 120 nulliparous patients were given 0.5 mg PGE2 in 2.2 ml gel intracervically prior to dilatation of the cervix and evacuation of the uterus in late first trimester. Considerable cervical dilatation was obtained within 15 h. The frequency of side effects, including pain and gastro-intestinal discomfort was low. The technique can be recommended for outpatients.

Summary An industrially manufactured ready-to-use PGE2 gel for cervical ripening was clinically evaluated. The study included 42 primiparous and eight multiparous women with an unfavourable cervix (Bishop score ⩽ 5) admitted to hospital for induction of labour on medical grounds. PGE2, 0.5 mg, in 2 ml triacetin gel was instilled into the cervical canal. In nine patients (18%) the gel induced labour and subsequent delivery. In the remaining women the mean Bishop score increased from 3.0 to 7.7 during a 24-h period and labour was induced by either i.v. oxytocin or PGF2α. None of the 50 patients experienced gastrointestinal side effects during pretreatment with PGE2. In 50% of the patients slight uterine contractility was noticed. All patients went into labour. The incidence of Cesarean section was 10%. Except for two patients treated because of intrauterine fetal death there was no perinatal mortality. The 5-min Apgar score was 8 or more in all newborn but 1. The main advantage of the new gel is that it is ready to use without any mixing procedure. Moreover, the stability of PGE2 is sufficient to allow routine clinical use.

Summary In a randomized double-blind study we evaluated the effects on cervical ripening and labor induction of 0.5 mg PGE2 in gel given intracervically and 2.0 mg PGE2 given as a vaginal suppository. All patients were at term with unfavorable cervical scores. The indications for induction were toxemia, diabetes mellitus, Rh-immunization, or intrauterine growth retardation. Significantly better results for both cervical priming and labor induction were obtained after intracervical PGE2-gel application than after treatment with placebo or vaginal suppositories. Eleven out of 19 patients (58%) were delivered within 24 h after intracervical PGE2-gel compared to two out of 19 patients given placebo (p < 0.01). In patients not delivered 24 h after the start of treatment, the mean cervical score had changed from 3.7 to 6.0 (p < 0.05) after PGE2-gel application compared to a change from 3.9 to 4.3 after placebo treatment (n.s.). The outcome after treatment with PGE2 suppositories did not differ significantly from that with placebo treatment.

15(S)15-methyl-PGF2α-methyl ester was administered as vaginal suppositories to terminate very early gestation in 16 outpatients who were thought to be pregnant. All patients received between 2.5 and 5.0 mg. of the prostaglandin compound. Pregnancy was confirmed later in 10 of the women. In these patients vaginal bleeding started 3 to 6 hours after the start of therapy and continued for an average of 8 days. By subjective assessment, the amount of bleeding during this time was equal to or slightly heavier than that of a normal menstruation for each woman. Patients were followed for 2 to 4 weeks with serial measurements of serum progesterone and HCG. There were no failures at early pregnancy interruption. Gastrointestinal side effects rarely were encountered; no serious complications occurred and no curettage had to be performed because of heavy bleeding. The vaginal use of the methyl ester of 15(S)15-methyl-PGF2αfor the termination of early pregnancy seems promising as a reliable and practical outpatient procedure.

The in vitro conversion of [14C]arachidonic acid by endocervical mucosa and cervical tissue specimens obtained in first trimester (9-12 w) and term pregnant patients (37 - 39 w) was studied in whole-cell homogenates. All radiolabelled products of the arachidonic acid cascade were extracted, purified and separated utilizing silicic acid chromatography, thin-layer chromatography and reversed phase partition chromatography and identified with radio-gas chromatography and gas chromatography-mass specto-metry. Both types of tissue produced PGF2α and PGE2, as well as TxB2. In cervical tissue specimens there was a significant increase in the production of all these three prostaglan-dins as the pregnancy progressed, whereas no such difference was seen in homogenates of endocervical mucosa. In both endocervical mucosa and cervical tissue specimens there was a highly significant increase in the production of a so-far unknown compound(s), in samples from term patients as compared with samples from first-trimester patients. The possible participation of this metabolite of [14C]arachidonic acid in the regulation of cervical ripening is discussed.

The aim of the present study was to investigate the effects of tamoxifen on pituitary and luteal function and on the bleeding pattern when administered continuously in the secretory phase. The study included 16 women with regular menstrual cycles followed during one control, one treatment and one follow-up cycle. Each volunteer received 20 mg tamoxifen twice daily from cycle day 18 to menstruation in the treatment cycle. The luteal phase was slightly, but significantly prolonged during treatment, and FSH, progesterone, 17-hydroxyprogesterone, 20α-dihydro progesterone, estrone, estrone sulphate and estradiol significantly elevated in comparison with corresponding data during the control cycle. The results indicate that estrogen may be of some importance for the regulation of the life span of the corpus luteum in the human. The significantly elevated levels of pregnanediol glucuronide and estrone glucuronide during the follow-up cycle are most likely a result of either a direct effect of remaining circulating tamoxifen levels on the ovary, or mediated through the increased release of FSH. If estrogens are of importance for the process of implantation, which has recently been suggested in subhuman primates, also in the human remains unclear. Studies on the effect of anti-estrogens on the endometrium during the secretory phase of the cycle are ongoing.

The effects of intravenous infusions of the stable prostaglandin analogue 9-deoxo-16,16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) in a dosage of 10 or 24 µg/min were studied in the consicious euhydrated, dehydrated, and hyperhydrated with the simultaneous administration of exogenous arginine vasopressin (AVP), sheep. The infusions decreased urine osmolality and increased urine flow and renal free water clearance. The results indicate that 9-methylene-PGE2 exhibits its diuretic effect by antagonizing the antidiuretic action of AVP. In the hyperhydrated sheep receiving AVP the syndrome of inappropriate antidiuretic hormone release (SIADH) was simulated. As the prostaglandin analogue effectively blocked the antidiuretic effect of the AVP-administration it appears that 9-methylene-PGE2 may play a future role as a diuretic agent, especially in conditions characterized by water retention and dilutional hyponatremia such as SIADH.

Human fetal tissue fragments from cortex cerebri and cerebellum were grafted to the anterior chamber of the eye of adult athymic nude rats. The grafts were obtained from tissue fragments recovered after elective routine abortions, performed in weeks 8-11 of gestation. Both cerebellar and cortex cerebri grafts survived and developed in the anterior chamber of the eye for 1-4 months. The transplants slowly became vascularized from the host iris. The grafts developed blood vessels with laminin-immunoreactive walls and contained relatively high amounts of glial fibrillary acidic protein- and neurofilament-immunoreactivity in the neuropil after 4 months in oculo. Recordings of extracellular action potentials from the grafts revealed spontaneously active neurons with action-potential waveforms similar to those observed in immature rodents. Morphologically, the grafts showed no signs of rejection. Clusters and bands of large neurons resembling Purkinje cells and dense aggregates of smaller granule-like cells could be found in the cerebellar grafts. Large neurons were also seen in the cortex grafts. Taken together, these data suggest that the athymic rat may serve as a useful tool for studies of central nervous system tissue from otherwise immunologically incompatible species.

Summary.Five men with cystic fibrosis delivered semen samples which were analysed for the content of the four main groups of prostaglandins (PGs). No PGs could be found in any of the specimens. The results of the present study provide further evidence that the seminal vesicles constitute the dominant site of production of PGs in human semen.

The intraperitoneal instillation of 32% dextran 70 (HyskonR, Pharmacia AB, Sweden) has previously been reported to prevent the formation of postoperative adhesions. Against this background, the present study was undertaken to evaluate the efficacy of HyskonR in counteracting peritoneal adhesions following tubal microsurgery. 105 infertile women were operated upon in a prospective, randomized, controlled, double-blind, multicenter study. The intra-ab-dominal adhesions present from the beginning were classified by means of a standardized scoring scale and the extent of adhesions was again evaluated at follow-up laparoscopy 4-10 weeks later. A reduction in the extent of the intra-abdominal adhesions (statistically highly significant) was revealed in both the Hyskon group and the saline control group. The extent of adhesions in the Hyskon group was not lesser than in the saline group, however. The pregnancy rates in the two groups were also similar.

Clinical studies on the effect of locally administered prostaglandin E2 and F2α on the sensitivity and reactivity of the non-pregnant human uterus were performed in 16 volunteers. With the use of the flaccid microballoon technique, uterine recordings were made at frequent intervals throughout the menstrual cycle. As little as 0.25 μg PGE2 or 1.0 μg PGFM2α effected an increase in uterine motility during most of the proliferative and secretory phases of the menstrual cycle. However, a marked decrease in sensitivity and suppression of reactivity to either prostaglandin compound was observed around ovulation. Moreover, an inhibition of uterine contractility in response to PGE2 but not to PGF2α was noted during active menstrual bleeding. Circulating levels of estrogen could be correlated generally with these uterine responses. Endogenous prostaglandins normally occur in the secretory endometrium in levels compatible with the amount of exogenously administered prostaglandins which elicited increased, decreased, or unchanged uterine activity in this study. These findings suggest that local prostaglandin E2 and F2α in concert with variable levels of circulating estrogen, may play important roles in the cyclic regulation of uterine motility during the menstrual cycle.

An attempt to define the role of the prostaglandins in human parturition must necessarily be fragmentary at the present time. However, there is no doubt that considerable progress has been made during the last few years and that the prostaglandins have been established as important key intermediates in the complex hormonal and mechanical events integrated in the process. Improved chemical methods for the determination of prostaglandins in body fluids and tissues as well as some evidence of indirect nature have contributed to a better understanding of this complex problem.

Human cortex cerebri and cerebelli xenografts from first-trimester fetal tissue fragments were used to study the effects of ethanol on single human central neurons. Transplants were placed into the anterior eye chamber of athymic nude rats and allowed to develop for 3 to 11 months. Immunohistologic analysis revealed graft structures that stained positively for a number of neuronal, transmitter-related, glial and vascular markers. Superfusion of ethanol (EtOH) elicited a reversible and dose-dependent depression of action potential discharge. At least two populations of neurons could be identified--a more sensitive group with an EC50 of 3.0 mM and a less sensitive group with an EC50 of 22.4 mM. These EtOH levels are within the range eliciting behavioral signs of intoxication in humans. EtOH-induced depressions could be antagonized by administration of the benzodiazepine inverse agonist Ro 15-4513. This study represents the first demonstration, to our knowledge, of the electrophysiologic actions of EtOH on single neurons from human brain, and provides dose-response data collected with known concentrations of EtOH as well as evidence for the blockade of these EtOH effects by the Roche compound.

The effect of single intravenous and intramuscular injections as well as intra-amniotic and vaginal administration of PGE1on the motility of the midpregnant human uterus was studied. Recording of uterine motility was made by measuring the amniotic pressure. Intravenous and intramuscular PGE1stimulated the uterus predominantly by elevation of tone. The threshold dose of intravenous injection was found to be around 20 μg. One hundred micrograms caused a long-lasting sustained contracture. The influence of intravenous injection of PGE2was compared with that of PGE1and found to be approximately the same both qualitatively and quantitatively. Intra-amniotic or vaginal administration of PGE1in high doses had no effect whatsoever on the pregnant uterus.

The effect of intravenous infusion of the pure prostaglandin compounds PGE1and PGE2on the motility of the pregnant human uterus was studied. Recording of uterine motility was made by measuring the amniotic pressure. Nine midpregnant and 8 term pregnant patients were studied. Both PGE1and PGE2stimulated uterine motility in all experiments. The potency of PGE1was approximately the same as that of PGE2. The midpregnant uterus was somewhat more sensitive to both compounds than the uterus at term. Threshold dose at midpregnancy was 2 to 4 μg per minute and at term 4 to 8 μg per minute. At midpregnancy the PGE compounds preferably induced an increment of tone but to some extent also an irregular uterine activity. At term the effect on amplitude and frequency of contractions was more dominant but unphysiologic elevation of tone frequently occurred. The latter reaction renders the PGE substances less suitable for induction of labor, whereas their tendency to cause longlasting uterine contracture might offer a group of new pharmacologic agents for the treatment of uterine atonicity after delivery.

Progesterone has an inhibitory action on the spontaneous motility and pharmacological reactivity of isolated myometrial strips from women in early pregnancy. This effect is similar to that observed on isolated uterine preparations from other species, such as rabbit, rat and mouse.

The influence of single intravenous injections of two prostaglandin F compounds (PGF1αand PGF2α) on the motility of the pregnant human uterus in situ was studied. It was found that PGF2αand to some minor extent PGF1αhad a stimulatory effect, predominantly in terms of elevation of tone. The threshold dose of PGF2αwas approximately 8 times higher than that of PGE1.

The effect on uterine contractility of prostaglandin E1 (PGF2α) and F2α (PGF2α) was studied in 19 non-pregnant women. Uterine motility was recorded by the micro balloon method and the prostaglandins administered by single intravenous injections in increasing doses.1. Doses above threshold levels of both PGE1 and PGF2α always resulted in stimulation of the uterus primarily in terms of tone elevation.2. A short drop of tone during 40-60 seconds immediately following the injection was obtained in a few experiments after high doses of PGE1. This response preceeded the normal stimulatory effect.3. The threshold dose for PGE1 was approximately 20 μg and that for PGF2α around 50 μg or lower.4. The non-pregnant uterus is probably more sensitive to PGF2α than the midpregnant uterus.5. The number of experiments were too few to allow conclusions as to differences in uterine sensitivity during the various phases of the menstrual cycle.6. Administration of oxytocin and vasopressin did not enchance the uterine sensitivity to stimulation by PGE1.

The influence of prostaglandin E1 (PGE1), oxytocin and methyl ergometrin maleate (Mether-gin®) on the contractility of the pregnant human uterus was compared in in vivo experiments on 8 early pregnant and 14 midpregnant women. The substances were administered intravenously in separate injections. With the doses used PGE1 and oxytocin caused a marked elevation of tone whereas Methergin® had a less significant effect. The duration of the elevation of tone after PGE1 was approximately three times longer than that after oxytocin but considerably shorter than after Methergin®. The motility pattern following Methergin® was characterized by small irregular contractions which differed completely from that after PGE1 and oxytocin. The pharmacological effect of PGE1 on the midpregnant uterus suggests that this substance might reduce blood loss and shorten the period of time for placental separation during the third stage of labour. However, this assumption could not be confirmed as judged from a small clinical pilot study carried out on 188 women.