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The role of gestrinone, 2.5 mg twice weekly, in treating proven menorrhagia (greater than 80 ml) was examined in 19 women. They were treated for five cycles (2 placebo, 3 active), taking one capsule twice weekly. Placebo had no effect on menstrual blood loss (MBL). On gestrinone 10 women became amenorrhoeic, in five MBL was markedly reduced (5-74 ml) and four did not respond. In three of the non-responders submucous leiomyomas were found at subsequent hysterectomy. Follow-up periods showed a persistent reduction in MBL for nine women in the first post-treatment menstruation.

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The purpose of this randomized double blind prospective trial was to study the efficacy and safety of two doses of oral gestrinone in the treatment of endometriosis. Six patients received gestrinone 1.25 mg twice weekly (group I) and six patients received gestrinone 2.5 mg twice weekly (group II). Patients underwent pretreatment and post-treatment laparoscopies and their endometriosis scores were recorded. The mean total endometriosis scores declined significantly from 20.0 +/- 5.2 (mean +/- standard error of the mean) pretreatment to 9.5 +/- 3.9 post-treatment in group I and from 19.1 +/- 4.8 pretreatment to 7.1 +/- 2.1 post-treatment in group II. A total of 67% of patients reported side effects. This study suggests that oral gestrinone 1.25 mg or 2.5 mg twice weekly is efficacious and safe in the treatment of endometriosis.

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Medical treatment of fibroma has changed radically in recent years with the introduction of analogs of LH-RH (luteinizing hormone releasing hormone). These agents, which are active only via parenteral administration, have proved remarkably effective, and are devoid of metabolic effects. They do engender some disagreeable adverse reactions, and unfortunately their efficacy is transitory and their cost high. Compared with these analogs, gestrinone, a progestogen as yet unused in treatment of luteal insufficiency, seems very interesting in the treatment of fibromas, due to its prolonged antigonadotropic effect and its antiprogesterone effect. Further studies are required to confirm the first results published by Coutinho.

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Nineteen patients with a laparoscopic diagnosis of endometriosis were treated with gestrinone at a dosage of 2.5 mg twice a week for 6 months. In 7 who reported spotting in the first 3 months, the dose was increased to 2.5 mg three times a week during the second trimester. An endometrial sample was obtained from each patient at the time of laparoscopy (basal) and at 3 and 6 months of treatment. Endometrial structure and ultrastructure were studied. Areas of hemorrhage and of loss of surface epithelium and a lesser degree of involution of the surface epithelium were observed in the 3-month samples of 7 patients with spotting, compared with 12 with amenorrhea. It is hypothesized that incomplete endometrial involution could be due to differences in gestrinone pharmacokinetics in individual patients, in the quality and/or quantity of endometrial cytosolic receptors for sex steroids, or in endocrine compensation to administration of the drug.

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The effect of oral gestrinone, 2.5 mg twice weekly for 6 months, was studied in 11 women with mild or moderate endometriosis laparoscopically confirmed. The mean laparoscopic score decreased from 17.18 to 9.09 (P greater than 0.005). Painful symptoms were relieved in all patients within 2 months from start of therapy. Gonadotropins, prolactin (PRL) 17 beta-estradiol (17 beta-E2), estrone (E1), progesterone (P), androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S) remained in the follicular phase range. Total testosterone (TT) and sex hormone-binding globulin (SHBG) decreased, whereas free testosterone (FT) slightly increased. Metabolic studies showed a decrease of total triglycerides, very low-density lipoprotein (VLDL) triglycerides, and high-density lipoprotein (HDL) and VLDL cholesterol, parallel to the decrease of associated apoproteins. Low-density lipoprotein cholesterol and apoprotein B increased during therapy. The results suggest that gestrinone possesses antiestrogenic, androgenic, and progestigenic effects at therapeutic dosages both by acting on central and peripheral steroid receptors. For its efficacy and good tolerance, gestrinone may be considered an option for treating endometriosis.

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A prospective randomized study was conducted in 100 women with leiomyomas in order to evaluate the effect of gestrinone, a synthetic derivative of ethynil-nor-testosterone. Patients in group A received capsules containing 2.5 mg of gestrinone three times weekly orally. Those in group B received capsules containing 5.0 mg twice weekly, also orally. In group C, patients used by vaginal route tablets containing 5 mg of gestrinone three times weekly. Reduction in uterine volume occurred in all three groups of patients. Of patients who discontinued treatment at 6 months, uterine volume remained lower than pretreatment values in 89%, 18 months after discontinuation. Of those patients who discontinued at 1 year, uterine volume remained below pretreatment levels in 76% 1 year after discontinuation. In patients treated continuously for 24 months, mean uterine volume decreased from a mean 339 cm3 to 273 cm3, a statistically significant difference. The vaginal route showed statistically more significant volume decreases than the oral route for all treatment intervals.

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Thirty-nine infertile patients with laparoscopic diagnosis of endometriosis were allocated randomly to treatment with gestrinone 2.5 mg twice weekly (20 patients) or danazol 600 mg/day (19 patients) for 6 months. If amenorrhea was not obtained after 1 month of treatment, the gestrinone dose was increased to 2.5 mg three times a week (7 patients) and the danazol dose to 800 mg/day (2 patients). One month after the end of the treatment, a repeat laparoscopy was performed only in the women who agreed (7 of the gestrinone treated group, 9 of the danazol group). All of the patients were followed for at least 12 months after the end of the treatment, during which time they attempted to conceive. There was a marked improvement of pain symptoms during the treatment in the patients of both groups. The repeat laparoscopy did not reveal significant differences between the two groups in the reduction of the disease extent. Eighteen months after treatment suspension, the cumulative pregnancy rate was 33% in the patients treated with gestrinone and 40% in those treated with danazol. Pain symptoms recurred during the follow-up in 57% of the gestrinone and 53% of the danazol group. The side effects were more frequent and severe with the danazol treatment, whereas those caused by gestrinone were mostly weight gain and acne. The results of this study suggest that gestrinone is as effective as danazol in the treatment of infertility associated with endometriosis and is better tolerated.

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The recent ability to diagnose asymptomatic endometriosis has produced dilemmas, particularly with respect to the need for treatment. The first placebo-controlled study of drug treatment in asymptomatic endometriosis shows that although spontaneous improvement occurs, it is more likely after treatment with gestrinone.

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There are three major types of peritoneal endometriotic implant as distinguished by their laparoscopic and morphological characteristics; the microscopic or epithelial-type plaque, the vesicular and papular type and the fibrotic, nodular type. Fluctuations in hormone levels during the menstrual cycle and throughout hormonal therapy have differential effects on the three types of implant. After only a short period of treatment with gestrinone the active types of peritoneal endometriotic implant exhibit inactivity and involutionary changes. Regressive changes in the implants may explain the abolition of the symptoms.

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Minor degrees of endometriosis have often been regarded as being of no import and hence remain untreated, but a study of the natural history of endometriosis has demonstrated that 47% (95% confidence limits, 23-71%) of patients (n = 35) given placebo in a double-blind, randomized controlled trial showed progression of the disease when assessed before and after treatment by laparoscopy. The active agent, the progestogen gestrinone, was given at a dose of 2.5 mg twice weekly and resulted in an improvement of the disease (p less than 0.004). Furthermore, follow-up over 12 months showed no significant difference between those patients treated with active agent or placebo, and none between those with persistent disease and those in whom it had been obliterated. These data suggest that a diagnosis of mild endometriosis should be followed by treatment to prevent progressive disease, but that the treatment does not influence subsequent fertility. They indicate that expectant treatment has no place and that even if fertility is not an immediate requirement, active treatment should be instituted, and that the new gestogen, gestrinone is efficacious. Other treatments, such as danazol or luteinizing hormone releasing hormone (LHRH) agonists, or the older contraceptive or pseudopregnancy regimens, must be set against spontaneous improvement (in 5 of 17 patients i.e. 29%) or elimination (in 4 of 17 patients i.e. 24%) in the placebo group. Infertile patients with mild endometriosis have disorders of follicular and luteal function, and in vitro fertilization suggests a reduced fertilization rate.(ABSTRACT TRUNCATED AT 250 WORDS)

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Progestins, including medroxyprogesterone acetate (MPA), danazol and gestrinone, are used in the medical management of endometriosis. Danazol and gestrinone, by inducing progestin-like effects, closely resemble MPA in their actions on intrauterine endometrium. Ectopic endometrium, on the other hand, does not respond to these hormonal stimuli (as determined by estrogen and progestin receptor assays and 17 beta-hydroxysteroid dehydrogenase activity measurements), indicating that the therapeutic effects of steroidal drugs may not be entirely due to an action on the endometrium. At therapeutic doses, these drugs also prevent the midcycle elevation in gonadotropic hormone secretion and suppress ovarian activity (as evidenced by follicular arrest and low and stable estrogen and progesterone secretion). These indirect actions of progestins are probably more important than their direct actions on the endometrium in the treatment of endometriosis. These steroidal drugs also have androgenic effects, though the increase in the free androgen index caused by danazol is significantly larger than that induced by gestrinone or by MPA. In a study involving treatment with danazol (200 mg three times a day), high-dose MPA (100 mg/day) or placebo for 6 months, danazol and MPA were found to have equal clinical efficacy (as judged by relief of symptoms and disappearance of lesions). Danazol therapy, however, caused more androgenic and metabolic side-effects. Those patients who were infertile were also examined at 30 months. The cumulative pregnancy rate in these patients over the duration of the trial was danazol 33%, MPA 42% and placebo 46%, with no significant difference between treatments. Hormonal therapy delayed conception by approximately 8 months.(ABSTRACT TRUNCATED AT 250 WORDS)

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In a study involving over 300 women, gestrinone has been found to induce regression of uterine myomas. Gestrinone was given in doses of 2.5-5 mg (orally or by vaginal pessary), two or three times weekly. The treatment regimen depended upon tumor size and tumor age. Patients with small tumors, i.e. uterine volumes of less than 200 cm3, were treated for 6 months, whereas those with uterine volumes of 200-300 cm3 were treated for 1 year. In severe cases where uterine volumes were greater than 400 cm3, the patients were treated for 2 years. Large myomas of 300 cm3 or more required higher doses of steroid. During the first 6 months of treatment there was a marked reduction in uterine volume, but subsequently the rate of tumor regression was slower. Following discontinuation of treatment, reactivation of tumor growth was slow in most patients. Gestrinone caused amenorrhea in all patients and in most women it lasted throughout therapy. The abdominal discomfort, dyspareunia and dysuria which resulted from the myoma were progressively alleviated during treatment. Most patients experienced at least some side-effects associated with the mild androgenicity of gestrinone. These included weight gain, seborrhea and acne (which developed in most patients). Hirsutism, hoarseness and increase in libido were less common, affecting 10-20% of patients, depending on the dose and duration of treatment. All side effects were reversible.

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In a randomized study, the effect of gestrinone (2 x 2.5 mg/week) was compared with the effect of danazol (3 x 200 mg/day) in treating 30 patients with laparoscopically proven endometriotic implants for 6 months. Therapy was effective in 80%-90% of cases and pregnancy rates were similar, but the incidence of side effects was different in the groups. In addition, buserelin (900 micrograms/day intranasally) was investigated in a multinational, multicenter trial in 275 patients. In 80%, GnRH agonist treatment induced the disappearance or reduction of endometriotic implants. The main side effects were due to estrogenic suppression. Presently, various methods of hormonal treatment are under investigation, especially to determine recurrency rates of endometriosis and long-term side effects.

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In forty-six sterile women, endometriosis externa was diagnosed and classified laparoscopically. 21 patients were treated with Gestrinone 5mg-10mg/week and 25 patients were treated with Danazol 300mg-400mg/day for 6 months. The effects of these hormonal treatments were evaluated by second-look laparoscopy according to adhesion severity, number of blueberry spots and chocolate cyst size, as well as dysmenorrhea and other complaints. The results were as follows; 1) Dysmenorrhea was relieved in 60.0% of the Gestrinone-treated group and 45.5% of the Danazol group. 2) Adhesion was weakened or partially separated spontaneously in 66.7% of the Gestrinone group and 63.6% of the Danazol group. 3) Blueberry spots decreased in number or paled in 61.9% of the Gestrinone group and 75.0% of the Danazol group. 4) Chocolate cyst size became smaller in 60.0% of the Gestrinone group and 77.8% of the Danazol group. 5) Peritoneal fluid volume was not decreased after the hormonal treatments but the prostaglandin E2 concentration in peritoneal fluid was decreased (p less than 0.05) after Gestrinone therapy. 6) The patients complained of some side effects, liver function especially was disturbed in 48.0% of the Danazol group and 9.5% of the Gestrinone group. Hoarseness was complained of in 33.3% of the Gestrinone group and 12.0% of the Danazol group. 7) Finally, 23.8% of the Gestrinone group and 28.0% of the Danazol group conceived after the hormonal treatments.

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In a survey it is reported on the antiprogestins mifepristone (RU 486) and gestrinone (R 2323). Thanks to its high reversible affinity for progesterone receptor mifepristone stops progesterone activity at its target organs. Mifepristone also inhibits ovarian progesterone synthesis. This antiprogesterone was tested clinically with different results for following indications: postcoital contraception, luteolysis, early abortion, ectopic pregnancy, missed abortion, cervix priming, and breast cancer. Gestrinone has antiestrogenic, antiprogesterone, and weak androgenic properties. These effects are related to the affinity for estrogene-, progesterone- and androgene receptor. A suppressory action on gonadotropins has been observed in therapeutic dosages. On the basis of its properties gestrinone is used for treatment of endometriosis, leiomyomas, benign breast diseases and also for contraception.

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We have treated 15 patients with locally advanced or metastatic breast cancer using the synthetic 19-norsteroid gestrinone (2.5 mg orally every 3 days). All patients had assessable disease and endocrine-sensitive tumors, as defined by a previous positive response to endocrine therapy. There were no objective responses. Six patients had disease stabilization and nine had progressive disease on treatment. Seven patients were given endocrine therapy after gestrinone and three have responded. Gestrinone has no significant antitumor activity in hormone-sensitive breast cancer. This, however, does not preclude its use in benign breast disease, particularly since other agents used for benign breast disease can mask occult primary carcinoma.

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A clinicopathologic study of a short-term medical treatment of endometriosis with danazol or gestrinone was performed in 50 patients with endometriosis and infertility. The cellular response to the therapy was evaluated and graded according to morphologic, that is, histologic and ultrastructural, criteria. A 2-month therapy with 1.25 mg of gestrinone daily induced a degree of cellular inactivation and degeneration of the endometriotic implants that was more pronounced than after 4 months of therapy with either gestrinone (2.5 mg twice or thrice weekly) or danazol (600 mg daily). There was no correlation between the morphologic response to treatment and either the hormonal response of the foci during the menstrual cycle before therapy or the change in laparoscopic staging of endometriosis at the end of therapy. It is suggested that a short-term medical treatment should be further evaluated clinically in the treatment of endometriosis and infertility.

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