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PubMed1988

[Laparoscopic diagnosis and evaluation of danazol or gestrinone therapy for endometriosis in sterility].

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.

Adult↗
PubMed2000

Danazol for unexplained infertilty.

BACKGROUND: The androgen, Danazol, was developed in the 1970's as a treatment for endometriosis. Its use was soon advocated in women with unexplained infertility. Two randomized trials were subsequently conducted to assess the effectiveness of danazol in this population. OBJECTIVES: The objective of this review was to assess the effects of danazol on pregnancy rates in women with unexplained subfertility. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched. SELECTION CRITERIA: Randomised trials of danazol compared with placebo or no treatment in women with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers. MAIN RESULTS: Two trials involving 68 women were involved. There was no difference found in pregnancy rate between danazol and placebo (odds ratio 2.57, 95% confidence 0.53 to 12.46). REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate the effect of danazol on pregnancy rates in women with unexplained subfertility. The need to use contraception during danazol treatment, adverse effects and costs are additional considerations.

Danazol↗
PubMed1978

Radioimmunoassay for danazol in human and monkey plasma.

A sensitive method is described for the radioimmunoassay of danazol in monkey and human plasma. Antiserum was developed in rabbits, and a second antibody was used to separate bound from free danazol. The radioimmunoassay was specific for danazol, and the limit of detection ranged from 1.4 to 2.8 ng/ml. Exogeneous danazol could be quantitated accurately in both monkey and human plasma. The radioimmunoassay results agreed with values obtained by inverse isotope dilution after intravenous administration of 14C-danazol to monkeys. The assay was used successfully to measure danazol in plasma from human volunteers receiving 200 mg of danazol.

Animals↗
PubMed1989

Danazol stimulates the release of follicle-stimulating hormone and inhibits the release of prolactin in vitro studies on rat pituitary cell cultures.

The actions of danazol on the release of gonadotropins and prolactin (PRL) were investigated by using a culture of rat anterior pituitary gland cells. The addition of danazol in the range between 10(-9) M and 10(-5) M elevated the levels of follicle-stimulating hormone (FSH) in a dose-dependent manner. Danazol at 10(-5) M caused a 70% increase in FSH levels over the control. The intracellular contents of FSH was also increased by danazol, suggesting its stimulatory effect on both the synthesis and release of FSH. Danazol had no effect on the release of luteinizing hormone (LH). Danazol diminished the sensitivity of gonadotrophs to luteinizing hormone-releasing hormone (LHRH) in that the LHRH-induced release of both FSH and LH was suppressed. The amount of PRL released into medium was decreased by danazol in a dose-dependent way.

Animals↗
PubMed2001

Fatal acute hepatic failure induced by danazol in a patient with endometriosis and aplastic anemia.

We describe a 47-year-old woman with severe aplastic anemia with genital bleeding who developed acute severe hepatitis after the administration of danazol while she was receiving cyclosporin. She had been diagnosed with severe aplastic anemia 1 year previously and, while hospitalized, had received methyl prednisolone pulse therapy, which was not successful. She was then referred to our hospital. She was treated with antithymocyte globulin, cyclosporin, granulocyte colony-stimulating factor, and methyl prednisolone; a good response was achieved after 3 months of this therapy. Subsequently, oral administration of cyclosporin was continued, but she was readmitted to our hospital when pancytopenia gradually developed and the genital bleeding recurred. Danazol was administered for pancytopenia and endometriosis. Four days after the first administration of danazol, epigastric pain occurred, and the danazol was stopped. Eighteen days after the first danazol administration, very severe hepatic injury occurred abruptly. The patient died of hepatic failure. Postmortem examination revealed centrilobular massive necrosis of the liver. Danazol was implicated as the agent responsible for causing the hepatic failure. Drug interactions between danazol and cyclosporin may cause adverse effects.

Anemia, Aplastic↗
PubMed1994

Danazol influences gonadotropin secretion acting at the hypothalamic level.

OBJECTIVES: The purpose of the study was to determine the influence of danazol on gonadotropin secretion. METHODS: Ten endometriotic patients were treated with danazol for 6 months. To evaluate gonadotropin and estradiol secretion, a gonadotropin-releasing hormone (GnRH) test and a clomiphene citrate (CC) challenge test were carried out in the follicular phase before treatment, during the sixth month of treatment and after the reappearance of the second menses. The same tests were also performed, only once, in the follicular phase of ten normal women. RESULTS: GnRH-stimulated gonadotropin response during danazol treatment was significantly higher than that in the same group of women before and after danazol treatment, as well as in controls. Gonadotropin increase after clomiphene citrate administration during danazol treatment was not significant; moreover, LH response was significantly lower than that in the same group of patients before and after danazol treatment, as well as in controls. CONCLUSIONS: Our results suggest that danazol exerts a suppressive effect on gonadotropin secretion acting at the hypothalamic level.

Adult↗
PubMed1988

Inhibitory effects of danazol and medroxyprogesterone acetate on [3H]thymidine incorporation in human endometrial cancer cells.

Effects of medroxyprogesterone acetate (MPA) and danazol (1 nM-10 microM) on cultured cancer cells from human endometrial adenocarcinomas obtained by hysterectomy were simultaneously investigated. Of twenty-four endometrial adenocarcinomas examined, five tumors were successfully maintained in primary cell culture. The addition of MPA as well as danazol in culture of cells from the five tumors resulted in a significant inhibition of [3H]thymidine incorporation in cancer cells from three tumors having progesterone receptors (PR). The minimum effective concentrations of MPA and danazol for the inhibition of [3H]thymidine incorporation were found to be 10 and 100 nM, respectively. The difference in effective concentration could be explained by a higher affinity of MPA to PR than that of danazol in cancer cells. On the other hand, neither danazol nor MPA affected [3H]thymidine incorporation in cultured cells from the remaining two tumors, in which PR was absent in one but present in the other. These findings, together with our previous findings that danazol inhibited the growth of a human endometrial cancer cell line with PR, suggest that a growth-inhibitory effect of danazol on human endometrial cancer cells is mediated through PR in the cells.

Adenocarcinoma↗
PubMed1987

Immune modulation by danazol in autoimmune thrombocytopenia.

Danazol, an attenuated androgen, has recently been introduced into the treatment of autoimmune thrombocytopenia. We studied its effects on T helper/inducer (Thi) and T suppressor/cytotoxic (Tsc) lymphocytes in these patients. Prospectively nine patients were studied with their T-cell subsets measured before and during danazol therapy. Increases in the percentage of Thi lymphocytes (P less than 0.05) and Thi/Tsc ratios (P less than 0.001) were observed at 1 and 3 months of treatment. Retrospectively T-cell subset data on 30 patients not treated with danazol and 36 patients on danazol were compared with those of 35 normal controls. The group not on danazol had lower percentages of Pan T (P less than 0.05), Thi (P less than 0.002), and Thi/Tsc ratios (P less than 0.00005), and had higher percentages of Tsc lymphocytes (P less than 0.01), than those of controls. In the group treated with danazol the percentages of Pan T, Thi, and Tsc lymphocytes were similar to those of controls. The percentage of Thi in the treated group was higher (P less than 0.002) than in the untreated group. Thus, danazol appears to be an effective immune modulator, correcting the abnormality of T-cell subsets seen in autoimmune thrombocytopenia by increasing the percentage of Thi lymphocytes.

Autoimmune Diseases↗
PubMed1992

Progesterone receptor induction by danazol in cultured cancer cells and the rat uterus.

We have previously reported that clinical trials relating to the use of danazol in the management of benign breast disease show a positive correlation between favourable clinical response and an induction of progesterone receptors in the affected tissue which is maintained for a period of at least 6 months subsequent to the cessation of treatment. Further studies designed at elucidating more clearly the actions of danazol at the cellular and molecular levels have confirmed that progesterone receptors are down-regulated by short-term progestin action at the level of the mRNA transcript, but that danazol is subsequently able to produce an enhanced cellular response, inducing progesterone receptors in the presence of oestrogenic agents. Uteri from danazol-treated rats showed a doubling of progesterone receptor concentrations compared with the control uteri. In the mammary cancer cell line T-47D, cells treated with danazol had increased progesterone receptor concentrations of 558.4 +/- 32.0 compared with 152.6 +/- 7.0 fmol/mg protein in the control cells. In both cases, these inductions were observed following a period of progesterone receptor suppression. Short-term molecular studies on T-47D cells indicated that progesterone and danazol initially inhibit mRNA transcription, but that 24 h after treatment an induction is observed. This is especially marked in the danazol-treated cells.

Animals↗
PubMed2006

Danazol inhibits aromatase activity of endometriosis-derived stromal cells by a competitive mechanism.

OBJECTIVE: To evaluate the inhibitory effect of danazol on estrogen (E) production in endometriosis. DESIGN: Prospective randomized study. SETTING: Academic research unit of the department of obstetrics and gynecology in a university hospital. PATIENT(S): Thirteen patients with endometriosis. INTERVENTION(S): Danazol was added to the culture of endometriosis-derived stromal cells or suspensions of microsomes prepared from chocolate cysts. MAIN OUTCOME MEASURE(S): The aromatase activities as well as mRNA and protein levels of aromatase in endometriosis-derived stromal cells or microsomes of endometriosis were examined. RESULT(S): Danazol treatment with a concentration greater than 10(-6) M significantly suppressed aromatase activity of endometriosis-derived stromal cells under basal and prostaglandin E(2) (PGE(2))-stimulated conditions. Danazol (10(-5) M) did not affect mRNA and protein levels of aromatase. Danazol competitively inhibited aromatase activity (by 1.7 x 10(-6) M of calculated Ki and 2.9 x 10(-5) M of Ki') of endometriosis microsomes. CONCLUSION(S): Danazol competitively inhibited aromatase activity in endometriosis-derived stromal cells without affecting either the mRNA or protein levels of aromatase. These results indicate the efficacy of local application of danazol to endometriotic lesions.

Aromatase↗
PubMed1983

Free testosterone levels during danazol therapy.

Danazol is a testosterone (T) derivative widely used in the clinical treatment of endometriosis. Its mechanism of action is poorly understood, but is side effects are mainly androgenic. Previously it was demonstrated that danazol can displace T from sex-hormone-binding globulin (SHBG). The binding properties of danazol to SHBG and albumin were studied with the use of labeled danazol in an aqueous two-phase equilibrium partition system. Levels of total T, SHBG, and albumin were measured in 16 women undergoing danazol treatment for endometriosis. Thereafter, free and protein-bound T levels were calculated. A marked rise in free T was found during danazol therapy as compared with pretreatment levels. The data suggest that many of the effects of danazol could be explained by increased levels of free T during treatment.

Danazol↗
PubMed1992

An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team.

OBJECTIVE: To compare the efficacy and safety of goserelin depot and danazol for endometriosis. DESIGN: Open, randomized comparative trial. SETTING: Multicenter European academic clinical institutions. PATIENTS: A total of 307 patients with laparoscopically diagnosed endometriosis were randomized to goserelin (n = 204) or danazol (n = 103); 249 patients underwent second look laparoscopy (175 received goserelin and 74 danazol) and were analyzed for efficacy. INTERVENTIONS: A 3.6-mg depot of goserelin monthly subcutaneously or oral danazol 200 mg three times a day administered for 24 weeks. MAIN OUTCOME MEASURES: Efficacy assessments were based on changes in visible deposits at laparoscopy before and after treatment and subjective symptom scores at 4-week intervals during treatment and 8-week intervals after treatment for up to 24 weeks. Safety was assessed by adverse event reporting and clinical laboratory measures. RESULTS: There were similar proportions of symptomatic (73%) and asymptomatic (but infertile) (27%) and comparable distribution of different severity of endometriosis randomized to each treatment. Significantly fewer patients randomized to goserelin (6.4%) withdrew during treatment compared with 20.4% randomized to danazol (P less than 0.05). There were significantly reduced visible deposits of endometriosis found post-treatment (P less than 0.0001) within each group but no differences between the treatments. The mean total subjective symptoms scores remained significantly less than entry at 24 weeks post-treatment (P less than 0.05). Hypoestrogenic side effects were more common in those receiving goserelin, particularly hot flushes, but anabolic/androgenic side effects of weight gain and muscle cramps were more common in those receiving danazol. CONCLUSIONS: The monthly administered 3.6-mg depot preparation of goserelin was highly effective at inducing resolution of endometriotic implants and relieving the symptoms of endometriosis with prevention of their return during 24 weeks follow-up in the majority of patients. However, results were not significantly different from those achieved with danazol 600 mg/d.

Adolescent↗
PubMed1989

Gestrinone versus danazol in the treatment of endometriosis.

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.

Adult↗
PubMed2001

Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether beta-cyclodextrins (SBE) and danazol-SBE inclusion complexes.

The aim of the present work was to characterize hygroscopicity, phase solubility and dissolution properties for various substituted sulfobutylether beta-cyclodextrins (SBEs) and danazol-SBE inclusion complexes. Moisture sorption was measured using a symmetric gravimetric analyzer. The complexes were characterized by powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Moisture sorption isotherms for the SBEs and the complexes showed low moisture sorption at RH <60%. The moisture absorption desorption isotherms for the various SBEs showed very little hysteresis, indicating almost complete desorption. Moisture adsorbed by the various SBE was in the order SBE 7>SBE 4>SBE 5 at 95% RH. Powder XRD data for complexes showed the disappearance of characteristic crystalline peaks for danazol or the formation of amorphous entities and DSC showed the disappearance of the peak of fusion of danazol indicating complex formation. Phase solubility of danazol with various substituted SBEs indicated 1:1 stoichiometry of complexes. The apparent stability constant, as determined by the method of Higuchi and Connors, increased as the degree of substitution of SBEs increased and decreased as the temperature increased. The dissolution of the complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of poorly soluble danazol. More than 85% of danazol was released in <10 min, compared to 15% danazol release from the physical mixtures.

Calorimetry, Differential Scanning↗
PubMed1997

Effects of danazol and progesterone on sex hormone-binding globulin mRNA expression in human endometrial cancer cell line Ishikawa.

To ascertain one of the biological effects of danazol and progesterone on the uterine endometrial cancer cell line, Ishikawa, we investigated the effects of these steroids on sex hormone-binding globulin (SHBG) mRNA expression by competitive reverse transcription-polymerase chain reaction-Southern blot analysis (RT-PCR-SBA). Estradiol-17beta (E2) in any concentration given did not exert any significant effect on the expression of SHBG mRNA. Danazol and progesterone significantly (P < 0.05) suppressed the expression of SHBG mRNA dose-dependently starting at a concentration of 10(-6) and 10(-8) M, respectively. Progesterone, in a low concentration (10[-10] M) with E2 (10[-8] M), significantly (P < 0.05) increased the expression of SHBG mRNA, but danazol did not. In contrast, danazol and progesterone in high concentrations (10[-6] to 10[-5] M) with E2 (10[-8] M) significantly (P < 0.05) suppressed its expression. The time course study showed the time-dependent decrease of SHBG mRNA level by danazol and progesterone (10[-6] M) with or without E2 (10[-8] M), except for a temporal increase by progesterone. These findings suggest that danazol and progesterone in a superphysiological milieu down-regulate the intracellular SHBG-related steroidal actions, and that progesterone in a physiological milieu with estrogen up-regulates it in a hormone-dependent cell line. A decrease of intracellular SHBG caused by high-dose danazol or progesterone might partly contribute to the abolition of the intracellular estrogen-dominant milieu, and be related to the inhibition of estrogen-dependent growth of some endometrial cancer cells.

Adenocarcinoma↗
PubMed1982

Endocrinological studies of the hypothalamo-pituitary gonadal axis during danazol treatment in pubertal boys with marked gynecomastia.

The present paper evaluates the variations of the hypothalamo-pituitary gonadal axis during Danazol treatment in pubertal boys with marked gynecomastia (breast size more than 6 cm in diameter). Before treatment a normal sleep-dependent gonadotropin increase was found together with a normal response to LHRH stimulation. Plasma prolactin increased at sleep as well. Plasma testosterone values were normal for pubertal age. During Danazol treatment 200 mg daily for 6 months basal gonadotropin levels, the sleep related hormone increases as well as the response to luteinizing-hormone releasing hormone (LHRH) stimulation were blunted. Concomitantly, testosterone values decreased to values seen in pubertal stage II-III. After 6 months of therapy, 4 of 5 boys treated so far, demonstrated a reduction of the gynecomastia to a maximum of 3 cm in diameter. In 1 boy Danazol treatment was finished after 3 months. Because of increased psychological problems a mastectomy was performed. 6 months after cessation of Danazol treatment a normal sleep dependent gonadotropin rhythm and a normal response to LHRH was found again demonstrating a normalization of the physiologic sleep-related gonadotropin rhythms. Plasma testosterone levels nearly increased to values seen before treatment. From the clinical aspect there were no signs of a recurrence of the marked pubertal gynecomastia in all boys treated with Danazol. These results indicate that Danazol is a specific gonadotropin inhibitor acting at the hypothalamo-pituitary level. No side effects on other hormones or on the development of secondary sex characteristics were noted during and after Danazol treatment.

Adolescent↗
PubMed1997

Prolonged inhibition of normal ovarian cycles in the rat and cynomolgus monkeys following a single s.c. injection of danazol.

In castrated male rats, a single s.c. injection of danazol has been shown to result in an inordinately prolonged inhibition of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations. In the present study, we have examined whether the same and similar routes of administration suppresses ovarian function in normally cycling rats and cynomolgus monkeys. Normally cycling female rats received danazol as a single administration either orally, i.m. or s.c. and a separate group also received danazol in silastic capsules. The duration of the dioestrous interval until the next oestrous smear was followed daily and cycle lengths were compared with vehicle-treated groups. Six normally cycling cynomolgus monkeys were followed by daily observation and blood sampling at 2-3 day intervals. After one normal cycle, danazol (200 mg/kg) was administered as a single s.c. injection. Monkeys were followed until the next menses and one cycle thereafter and blood samples were assayed for oestradiol, progesterone and bioactive LH. Oestrous cycle length in vehicle-treated control rats was 4.7 days. A single administration of danazol s.c. at the higher dose prolonged the dioestrous interval to 31.3 days (P <0.001) and a similar prolongation was observed with this high dose when administered i.m. (27.7 days; P <0.001). In normally cycling monkeys, the menstrual cycle length was 30.2 days, but following a single danazol administration, the mean duration to the next menses was prolonged to 117.5 days (P <0.001). In five out of six monkeys, there was a decrease in LH and an absence of normal oestradiol and progesterone patterns. After this prolonged hiatus, a subsequent menstrual cycle was normal in length and endocrine pattern. A single s.c. administration of danazol resulted in a prolonged suppression of ovarian cyclicity in both normally cycling rats and cynomolgus monkeys.

Animals↗
PubMed1990

A new therapy for pelvic endometriosis and uterine adenomyosis: local effect of vaginal and intrauterine danazol application.

In order to investigate the effect of the local direct action of danazol upon endometriosis, intravaginal and intrauterine application were tried. A vaginal danazol ring containing 2 g to 3.5 g danazol not only reduced both dysmenorrhea and the extent of pelvic endometriosis in all 35 infertile women, but also resulted in conception in 13 out of 35 infertile women while the vaginal ring was in place. Uterine adenomyosis usually fails to respond to oral danazol therapy, but an intrauterine device containing 175 mg of danazol was effective in reducing the size of the uterus and in inducing pregnancy in 66.6% cases. It is noteworthy that this vaginal or intrauterine danazol therapy did not inhibit ovulation, but still effected atrophy of endometriosis and aided in the establishment of pregnancy. These results clearly demonstrate that the main mode of action of danazol is its direct action on endometriotic cells.

Administration, Intravaginal↗