Transcervical polidocanol as a nonsurgical method of female sterilization: a pilot study.

We have studied the effects of transcervically administered polidocanol on uterine and fallopian tube morphology in Wistar rats and Rhesus monkeys. Polidocanol is a synthetic, long-chain fatty acid that is widely used as a sclerosing agent in Europe. The goal of the study was to determine whether polidocanol would safely cause tubal occlusion in an animal model. Twenty female Wistar rats and three female Rhesus monkeys underwent transcervical injection of polidocanol or physiological saline. The animals were followed for 30 days and then a lower laparotomy was performed, with excision of the entire upper reproductive tract. Specimens were subsequently examined for macroscopic and microscopic changes. Only cyclic changes were observed in the control animals of both species. Fifteen macroscopic and 37 microscopic changes were observed in the uterine horns of the 10 rats treated with polidocanol. There was no observed effect in the monkey fallopian tube. These results suggest that species differences that exist between rodents and primates may influence the effects of transcervical polidocanol. Experiments using a primate model are needed as proof of concept prior to human studies of candidate agents for transcervical tubal sterilization.

Danazol mimics antigestagen action in first trimester termination of pregnancy.

BACKGROUND: Based on steroid receptor binding and biologic activity, danazol was suspected to be an antigestagen. OBJECTIVE: To compare with placebo test in first trimester termination of pregnancy (TOP) as a method for predilatation of the cervix prior to application of misoprostol. METHODS: 52 patients were randomised into two groups. Thereby, 26 women received 200 mg danazol vaginal suppositories three times during 2 days before administering 200 microg misoprostol and undergoing mechanical dilatation and vacuum aspiration 5h later. The other 26 received placebo suppositories and the same treatment otherwise. RESULT: The uterine cervix was wider and less dilatation and time was needed for the surgical termination in the group pretreated with danazol. There were six cases of complete abortion within 5h of administering misoprostol in the danazol group; and none in the placebo group. After danazol treatment, 16 women exhibited signs of abortion versus four receiving the inert suppositories. CONCLUSION: Pretreatment with 200mg danazol suppositories three times starting 36 h before administering misoprostol for cervical dilatation enhances the effect of prostaglandin on cervical dilatation and uterine contractions in a manner similar to antigestagens.

Progesterone and ovulation.

The role of progesterone (P) in the mechanism of ovulation is controversial at best. The contraceptive application of P was established in rodents in 1936 and with orally absorbed progestogenes was put to human use. There were hints on the proovulatory actions of P administered before the time of ovulation in rats by 1948. Similarly, in 1954 the observation of high P level in the preovulatory follicle pointed to a role in ovulation. Neither of these two observations was further investigated and the positive feedback effect of P exerted on gonadotropins was described in 1968. Still the positive feedback between P and gonadotropins were not recognized as a physiologic mechanism, much less utilized pharmacologically. The apparent contradiction between these two different actions of P continues upto now. The paper sets out to expose this controversy and tries to resolve it using extensive literary data and the author's experiences with synthetic progestogenes in contraception, in the treatment of infertility and with the antigestagen mifepristone in blocking ovulation. The precise mechanisms lying behind these applications are explored and discussed in detail. The putative role of oestradiol (E2) in the mechanism of eliciting the gonadotropin surge is extensively discussed but refuted as the ovulatory signal. The time sequence between the rise of P and gonadotropins contradicts the common wisdom of LH causing luteinization. The positive feedback effect of P on the E2 sensitized ovulatory axis on the hypothalamic and pituitary level is discussed and its local role in the mechanism of follicular rupture is also taken into account. The final proof seems to be the antiovulatory effect of mifepristone, which blocked both GnRH pulsatility, pituitary sensitivity to GnRH and follicular rupture in several experiments. Thus, the dogma of LH peak causing follicular rupture and subsequent luteinization seems questionable, the putative role of E2 to initiate the ovulatory cascade has to be discarded and P's role as a trigger of the physiological mechanisms leading to ovulation should be firmly recognized.

[Effect of antigestagens on human reproduction]. / Antigesztagének hatása a humán reprodukcióra.

A short history of antihormones is presented first. After reviewing the physiologic role of progesterone in the regulation of human reproduction, the theoretical and practical implications of suspending its actions are depicted. The tested or theoretically possible applications are enumerated. The initial success of contraceptive use of antigestagens is summarized based on their own research and international publications. Obstetric application is hindered by fear of fetal antiglucocorticoid side effects. The very remarkable success in termination of pregnancy is summarized by reviewing partly their own results. The combination of antigestagen plus prostaglandin is able to terminate pregnancies both in the first and second trimester very effectively (in 95% or over) and with very few side effects. It also renders possible the medical termination of unsuccessful pregnancies with diminishing complications. Although the most important applications take place in the regulation of human fertility, the initial results in the treatment of both benign (fibroids, endometriosis) and malignant (endometrial and ductus carcinoma) gynaecological conditions are encouraging. The production of mifepristone is possible in Hungary, but due to marketing considerations and political hurdles its registration and application is not considered yet.

Effects of long-term low-dose mifepristone on reproductive function in women.

Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.

PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.

Amanita poisoning during the second trimester of pregnancy. A case report and a review of the literature.

Amanita phalloides-type mushroom poisoning is well recognized as causing acute liver injury and often death. Less is known, however, of whether maternal Amanita poisoning is associated with fetal damage or not. In August 1991 four members of a family were hospitalized with food intoxication caused by Amanita phalloides and Amanita verna. One of them died from hepatic and renal failure. The survivors included a 26-year-old woman in the 23rd week of pregnancy. Her clinical symptoms and blood chemistry data (lowest prothrombin activity 23%) indicated intoxication of medium severity. The management consisted of i.v. hydration, forced diuresis, and administration of silibinin, high-dose penicillin, thioctic acid, hydrocortisone, vitamin K, and fresh frozen plasma. Sonographic and obstetric controls failed to show any fetal abnormalities in the acute phase of poisoning. In the 38th week of pregnancy she gave birth to a healthy baby, who has subsequently undergone an undisturbed development. This observation indicated that severe fetal damage did not occur in maternal Amanita poisoning in the second trimester of pregnancy. Thus, at least from the second trimester on, maternal Amanita poisoning is not necessarily an indication for induced abortion.

[Ovulation inhibition with RU 486]. / Ovulatiogátlás RU 486-tal.

Starting from the theory, that progesterone (P) may be one of the triggers of physiologic ovulation, P receptor blocking agent Mifepristone was administered to 7 regularly menstruating women, 2 days before the expected time of ovulation. Ovulation was monitored by ultrasound folliculometry and determination of serum estradiol (E2), P and luteinizing hormone (LH) levels. The luteal phase was checked by measuring urinary pregnandiol glucuronide excretion. Administration of the drug was properly timed in 5 cases, none of the existing follicles ruptured, one got luteinized and 4 had undergone atresia. According to these findings P seems to be a trigger of ovulatory events.

[Prediction of ovulation based on the serum estradiol level and the diameter of the follicle]. / Az ovulatio elörejelzése a szérum ösztradiol szintje, illetve a folliculus átméröje alapján.

Experiences with the methods are summarized. Follicular growth was monitored by ultrasound folliculometry (USFM) and estimation of serum estradiol (E2 values in physiologic cycles. USFM was found to predict follicular rupture-ovulation--more precisely than E2 values. Cases of disturbed folliculogenesis (persisting and luteinized unruptured follicle, cysts) are described. The wider use of USFM in Hungary is urged, because appropriate equipment is available while the chances of continuous hormonal monitoring are rather limited.

Disparate effects of naloxone in hypothalamic amenorrhoea of athletes.

Of 30 amenorrhoeic women athletes, 28 were considered to have hypothalamic amenorrhoea according to their low gonadotropin, estradiol (E2) and normal testosterone and prolactin (PRL) values. Gonadotropin-releasing hormone (LH-RH 100 micrograms i.v.) and naloxone (4 mg i.v. bolus followed by 2.8 mg/h infusion) tests were administered consecutively. Fifteen subjects reacted to the naloxone test with at least a fivefold increase in LH values; these values were consistently above those of the LH-RH test. The other 13 women reacted similarly to the releasing hormone but not to naloxone. While there were no differences between basal LH values in the two groups, E2 levels tended to be lower in non-responders, but since 1/3 of the values fell below the threshold of sensitivity of the E2 assay, no significance could be calculated. The obvious difference among the subjects could be E2 -mediated, the non-responders representing a deeper level of hypothalamic amenorrhoea. The naloxone test seems to be useful for differentiating between different forms of this condition.

Pituitary, ovarian and endometrial effects of graded doses of medroxyprogesterone acetate administered on cycle days 7 to 10.

Eighteen apparently healthy women with normal menstrual cycles were studied during a control cycle and then during a treatment cycle, in which graded doses (2.5, 5.0 and 10 mg/day) of medroxyprogesterone acetate (MPA) were administered orally on cycle days 7 to 10. In both the control and the treatment cycle peripheral blood was drawn daily for the assay of luteinizing hormone (LH), estradiol (E2) and progesterone (PROG) and an endometrial biopsy was taken on cycle day 11. The lowest dose of MPA (2.5 mg X 4) did not influence the various cycle characteristics. Administration of higher doses (5.0 or 10 mg X 4) resulted in a lengthening of the duration of E2-peak (P less than 0.05), an increase in the area under the E2-peak (P less than 0.05), a decrease in the area under the PROG-curve (P less than 0.05) and a reduction in the height of the LH-peak (P less than 0.05). Furthermore, in 5 of these 12 subjects there was no ovulatory-like PROG-pattern during the cycle in which MPA was administered for 4 days. Morphometric analysis of the endometrial biopsy specimens revealed that the administration of MPA increased the diameter of endometrial glands (P less than 0.01) and the number of vacuolated glandular cells (P less than 0.001), decreased the number of glandular (P less than 0.01) and stromal (P less than 0.05) mitoses and reduced pseudostratification (P less than 0.001). There was no change in the number of endometrial glands and in glandular epithelial height. No leukocytic infiltration was observed. Dating of the biopsies indicated that all control biopsies were proliferative and all, but one (a suppressed proliferation including predecidual reaction), biopsies obtained after MPA administration were early secretory. The most conspicuous effect of MPA administration was a marked increase in subnuclear vacuolation, which could be demonstrated even at the lowest dose (P less than 0.01).

Pharmacokinetics, pharmacodynamic and endometrial effects of a single dose of 200 mg norethisterone enanthate.

Ovulation was confirmed by daily analyses of the peripheral plasma levels of estradiol (E2)4) and progesterone (P) in a pre-treatment cycle of 14 subjects. An endometrial biopsy was taken either in the proliferative or in the secretory phase of the cycle. On the 5th day of a subsequent cycle 200 mg norethisterone enanthate (NET-EN) was administered intramuscularly. The levels of E2, P and those of NET were analyzed during the next 19 days and again during 44-60 days following the injection. The endometrial biopsy was repeated on the 23rd and 59th day of the treated cycle. The levels of NET reached a peak of 34.3 nmol/1 on the sixth post-injection day and decreased to below detectable limits in 3 of 12 subjects by the end of the observation. Ovarian activity was completely suppressed in all women during the first period, but returned to different levels in 11 subjects during the second. Four of them exhibited ovulatory steroid pattern. The morphologic changes of the endometrium reflected the progestogen effect in the first post-injection period but were characteristic of the ovarian reaction in the second.

[The expediency of using natural oestrogens in combined oral contraceptive tablets]. / Celszeru-e termeszetes osztrogenek alkalmazasa kombinalt oralis fogamzasgatlo tablettaban?

PIP: A randomized, double-blind, prospective, clinical examination was performed on 325 female volunteers requesting contraception. In addition to 4 mg estradiol + 2 mg estriol and 50 mcg ethinyl estradiol, 2 types of oral contraceptives (OCs) containing 3 mg norethisterone acetate were used through 16 cycles. Both preparations proved to be effective as no pregnancies resulted during treatment. No significant differences in complications were observed; however, there were changes in menstrual bleeding and amenorrhea and these occurred significantly more often in the group treated with natural estrogens. OCs with natural estrogens proved to more advantageous than pure synthetic preparations. (author's modified)^ieng

[Use of terbutaline sulfate (Bricalyn Astra-Egyt) for betamimetic tocolysis]. / Die Anwendung von Terbutalin-Sulfat (Bricanyl ASTRA-EGYT) zur betamimetischen Tokolyse.

The authors have undertaken controlled prospective clinical studies into Bricanyl treatment of 40 women with imminent abortion. Their conclusion has been that Bricanyl was an effective tocolytic for both intravenous and oral application. Thirty-eight cases were followed up to birth, with 30 mature infants being born plus seven premature birth (four of these immature). Abortion occurred in one case. Three foetuses were perinatally lost in the immature group. There were no side-effects which might have necessitated discontinuation of therapy. All tocolysed patients came under ECG control, and pathological changes were recorded from 17 in 31 women. Another checkup after birth revealed that all ECG findings had been restored to normal. Repeated warnings are given by the authors against application of betamimetics on an outpatient basis.