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Assessment of the therapeutic effect of epimestrol and epimestrol associated with clomiphene in female sterility.

In 24 women with disturbances of ovulation treated for sterility with Epimestrol, ovulation was achieved in 3 patients but none of these became pregnant after therapy. Since it has been suggested that the association of Clomiphene with a weak estrogen might improve the pregnancy rate, we decided to administer Clomiphene associated with Epimestrol. Using this combined therapy in 58 patients, 32 out of the 58 women ovulated and 17 conceived. The overall rate of pregnancy using the combined therapy was no better than that obtained when Clomiphene alone is administered. From this study it is concluded that: (1) Epimestrol is not an effective method for the induction of ovulation, and (2) addition of Epimestrol to Clomiphene is of no clinical benefit.

Clomiphene

[Comparative clinical studies on clomiphen, cyclofenil and epimestrol (author's transl)].

Report on the treatment of 310 anovulatory woment in 1173 treatment cycles with Clomiphen, Cyclofenil and Epimestrol. 63% of the patients had a biphasic basal body temperature record after treatment in 718 cycles. Patients with secondary amenorrhea of the first or the second degree had a satisfactory ovulation rate in 71% of the cases only by treatment with Clomiphen. In women with anovulatory cycles an overall ovulation rate of 75% was observed with all three medications. In 73 patients 78 pregnancies occurred. Of these, 38 pregnancies followed Cyclofenil, 25 pregnancies followed Clomiphen and 15 pregnancies followed Epimestrol corresponding to a 15%, 17% and 13% rate in the treated patients. 22 of these pregnancies ended in incomplete abortion. The side effects of Clomiphen especially visual and cystic ovarian and vasomotor side effects are more pronounced than the side effects of Cyclofenil and Epimestrol. The statistical analysis of the clinical results showed that Clomiphen and Cyclofenil had a higher rate of ovulation in secondary amenorrhea of the first or second degree than Epimestrol.

Amenorrhea

Effect of epimestrol on gonadotropin and prolactin plasma levels and response to luteinizing hormone-releasing hormone/thyrotropin-releasing hormone in secondary amenorrhea and oligomenorrhea.

The effects of epimestrol (5 mg every 6 hours for 5 days) on basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl), estradiol, progesterone, and dehydroepiandrosterone sulfate, and on the response to LH-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) stimulation, were studied in 18 cases of secondary amenorrhea and oligomenorrhea of hypothalamic-pituitary origin, in three cases of anorexia nervosa, in two cases of long-lasting progestin-induced amenorrhea, and in one case of precocious menopause. The results in the first 18 patients indicate that epimestrol treatment induces a significant increase in LH and Prl levels after 24 hours, while the FSH increase becomes significant only after 4 days of therapy. Twelve hours after discontinuation of treatment, all three hormone levels decreased significantly to values similar to the basal levels, while the pituitary response to LH-RH indicated a much more marked LH secretion than before treatment. A second test, performed 36 hours after the last drug administration, again showed a significantly higher LH response than that found under basal conditions. No significant variations were observed in the FSH response to LH-RH, nor in the Prl response to TRH. These data suggest that epimestrol interferes at the level of the centers responsible for Prl and gonadotropin secretion in the manner of a weak estrogen.

Adolescent

[Treatment of infertile women with epimestrol (author's transl)].

155 patients have been treated with epimestrol during 593 menstrual cycles in a daily dosage of 5, 10 or 2.5 mg from the 1st to the 10th or from the 5th to the 14th day of the cycle. 143 patients with secondary amenorrhoea, anovulatory cycles, ovulatory oligomenorrhoea, corpus luteum insufficiency, and normal cycles received epimestrol after an average period of 2.4 years of involuntary infertility. The pregnancy rate was 21% (n = 30), the spontaneous abortion rate 13% (n = 4). Twelve further patients not seeking pregnancy were treated with epimestrol because of secondary amenorrhoea and (or) anovulatory bleeding. The results were as follows: 1) In eugonadotropic secondary amenorrhoea 8 out of 12 patients ovulated, 5 out of 10 patients wanting children became pregnant. No patient with hypogonadotropism ovulated. 2) Out of 25 patients with anovulatory cycles or bleeding 13 ovulated and 4 became pregnant. 3) 17 out of 68 oligomenorrhoeic patients became pregnant. 4) In 12 out of 24 patients with corpus luteum insufficiency the hyperthermic phase improved and four patients became pregnant. 5) In 12 patients without anomalous cycles these remained unchanged and there were no pregnancies. 6) No side effects could be observed.

Abortion, Spontaneous

[Treatment of hypothalamically-induced primary amenorrhea with epimestrol].

Eleven patients with hypothalamic primary amenorrhoea, aged between 17 and 23 years, were examined. Each patient was given 10 mg epimestrol (E) orally over a period of 10 days followed by a 20-day pause. This regimen was repeated 6 times. Gonadotropin secretory patterns were investigated between 9 a.m. and 2 p.m. before, during (on the 5th day of treatment in the 4th cycle) and 3 weeks after termination of treatment. In addition LHRH double stimulation tests were carried out before and after treatment to evaluate the acute releasable pool of gonadotropins as well as the pituitary synthesis capacity. In 3 patients with low baseline gonadotropin levels no effect of E on the release of gonadotropins could be found. These patients also showed non-pulsatile secretion with low baseline gonadotropin levels and no response in the LHRH stimulation tests. Similar results could be observed in one patient with low baseline LH levels but FSH levels within the normal range. Variable results were found in 7 patients with both LH and FSH in the normal range: 3 women experienced menstrual bleeding during and/or after E treatment; 1 woman stated that spotting had occurred twice. These 4 patients all showed regular pulsatile LH secretion after cessation of E treatment; the duration of the LH pulses was 60 to 120 minutes. Some hypothalamic activity seems to be essential for a positive response to E in patients with primary amenorrhoea. This activity is characterized by a positive gestagen test as well as baseline gonadotropin levels in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

[Induction of ovulation with Epimestrol (author's transl)].

Epimestrol 5 mg. daily for 10 days was administered in 119 treatment cycles to 21 women with normal gonadotropins and 33 ovulations were induced. Of the 21 patients, 7 had secondary amenorrhea, 10 had anovulatory oligomenorrhea and 4 had ovulatory oligomenorrhea. 17 patients desired pregnancies and 6 became pregnant. There was 1 pregnancy among 5 women with secondary amenorrhea. There were 3 pregnancies among 9 patients with anovulatory oligomenorrhea and 2 pregnancies in 3 patients with ovulatory oligomenorrhea. The pregnancy rate was 35%. Side effects were not observed.

Adult

[Clinico-echographic study of the ovulatory phase, spontaneous and induced, conceptional and non conceptional cycles].

We present the results obtained on 110 menstrual cycles of 87 patients; echography study of ovulation, immunologic LH determination, basal body register card and serial cervical mucus score, since -6 to 0 day. Echography study determined follicular diameter, endometrial bulk and the presence of liquid in the cul-de-sac. We considered only those patients in whom the disappearance of the follicle was observed 24 hours before; being this fact, the indicator of ovulation, related to all other variables. These patients presented spontaneous (47.3%), epimestrol (28.2%) or clomiphene induced (24.5%) cycles, and they turned out to be pregnant or not in that cycle, (34.6%, 25.8% and 37.0% respectively). It was 36 (32.7%) pregnant women in all the The three follicular diameter curves for pregnant cycles, were similar being the preovulatory follicular range 21.5 mm for spontaneous cycles, 18.9 mm for epimestrol induced cycles and 20.7 mm for clomiphene induced cycles. Conceptional range was from 15 to 22 mms, 15 to 22 mm, and 14 to 27 mms, respectively. We didn't observe free fluid in cul-de-sac in 5 pregnant cycles (13.9%). Most of positive LH, are about -2 and -1 (21% and 50%, respectively). There were one pregnant patient and 2 no pregnant patient with repetitive, negative LH. In 50% of patients who became pregnant, the Nadir was on -1 day. In spontaneous conceptional group, bad cervical score was not observed. The good cervical score period is longer on conceptional group than in those with epimestrol. On conceptional group, dissociation between best score day and the day of ovulations was not observed, fact that we observed in non-conceptional group.

Clomiphene

Effect of steroid hormones and antihormones on hypothalamic beta-endorphin concentrations in intact and castrated female rats.

The aim of the present study was to evaluate the effects of estrogens and androgens on hypothalamic beta-endorphin (beta-EP) concentrations. Intact or castrated female rats were chronically (2 weeks) treated with estrogen (estradiol benzoate) and/or antiestrogens (clomiphene, cyclophenil or epimestrol), and with androgens (dihydrotestosterone or dehydroepiandrosterone sulphate) and/or antiandrogen (cyproterone acetate). A group of rats treated with vehicle were studied as comparison. The beta-EP concentrations were measured by radioimmunoassay on acidic extracts of rat hypothalami. The administration of clomiphene and cyclophenil significantly reduced hypothalamic beta-EP concentrations in intact rats, while both drugs or estradiol benzoate increased the peptide concentration in castrated rats. Both intact and castrated rats treated with epimestrol showed hypothalamic beta-EP concentrations higher than vehicle treated rats. The estradiol-induced increase of beta-EP was not changed by the concomitant administration of antiestrogens. The administration of dihydrotestosterone significantly decreased beta-EP concentrations in both intact and castrated female rats, while the treatment with dehydroepiandrosterone sulphate only slightly decreased beta-EP levels in intact female rats. The cyproterone acetate-chronically treated rats showed higher beta-EP concentrations than vehicle-treated rats and these changes were reversed by the concomitant addition of dihydrotestosterone or dehydroepiandrosterone sulphate. These results showed that estrogens play a positive role while androgens negatively influence the hypothalamic beta-EP concentrations in female rats, supporting the view that central beta-EP might be a target of gonadal steroid feedback signals.

Androgen Antagonists

[Analysis of therapeutic success and of obstetrical results in sterile marriages].

In the course of sterility therapy 375 pregnancies were observed in 296 patients. 63 women conceived twice or more. At the first visite the mean age of the patients was 25,8 years, the mean duration of sterility 2,7 years. A primary sterility was observed in 207 and a secondary sterility in 98 cases. The main therapeutic procedure was the induction of ovulation with FSH/LH releasing preparations (Clomiphen, Cyclofenil, Epimestrol) (40,3%), followed by the substitution therapy with human gonadotrophins (22,7%). 78 pregnancies ended by spontaneous and 4 by artificially induced abortion. The abortion rate in this study was 20,8 %, exceeding considerably the normal abortion rate. The rate of extrauterine pregnancies was also increased, being 2,4%. There was no significant difference in the abortion rate of pregnancies with or without induction of ovulation. The age at the time of conception and the duration of therapy had no significant influence on the rate of abortions. In 293 pregnancies the duration of gestation exceeded the 28th week. However, 33,1% of these pregnancies had complications that required hospitalisation. Almost 50% of the complications consisted of threatened abortion. The mean duration of gestation was reduced by 5 days, caused by a relatively high frequency of early births (16,9%). The mode of delivery of our patients was in 68,8% spontaneous delivery, in 16,2% caesarian section, in 15,0% forceps or vacuum extractions. This corresponds to the general mode of delivery of our hospital. Only after gonadotrophin therapy a higher caesarian section rate of 26,8% was noted. Out of the 310 live born children, 9,2% had a weight below 2500 g, owing to a multiple pregnancy rate of 4,1%. 4% of the children showed the signs of dystrophia. The perinatal mortality amounted to 5,1%. However, when the gonadotrophin induced multiple pregnancies are excluded, the rate is 2,7%. Only 2 cases of malformations were observed.

Adult

[The importance of hormone examinations in ovulation induction (author's transl)].

Those hormone-determination methods were reported by the authors which help to make the ovary response visible for the experts during the ovulation induction. They also dealt with the determination of basal temperature measuring, oestrogen, pregnandiol, progesterone, oestradiol-17beta, FSH, LH, epimestrol and clomiphen. After the routine determination of the above mentioned parameter a preprinted sheet was done, where every treated case was illustrated graphically. From these cases some of the typical ones were shown and analyzed. The determination of hormonal releasing curves characteristic of hyperstimulation, and the importance of these most dangerous complication was emphasized.

Adult

[Recent advances in the hormonal treatment of sterility (author's transl)].

The present trends in the utilization of hormones in the treatment of sterility are reviewed, special reference being made to the utilization of gonadotrophins, hypothalamic hormones and gonadal hormones as well as other substances (clomiphene, epimestrol, cyclophenyl) that are also utilized in this type of treatments.

Clomiphene

[Increasing the effectiveness degree of ovulation induction using clomiphene in combination with HCG in cases of functional sterility].

The authors gave functionally infertile women a combined treatment, of Clomiphen + HCG whom 19 had already been treated with Clomiphenor Epimestrol without success. If the number of ovulations considerably increase in consequence of Clomiphen + HCG treatment or the periods of ovulations, aphysiological periods, are of physiological duration the treatment may be successful. In these cases the effectiveness of Clomiphene induction can be intensified with HCG administration

Adult

Anovulation.

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Anovulation