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At least 19 recordsLinked to original sources

PubMed1978

Acquired angioedema associated with rectal carcinoma and its response to danazol therapy. Acquired angioedema treated with danazol.

Cases of the acquired form of angioedema have been recognized as a separate entity since 1972. Previously reported cases have been related to various hematologic malignancies. We have recently studied a patient with rectal carcinoma who manifests a complement pattern compatible with the acquired form of angioedema. No previous personal or family history of allergic disease or angioedema was present. Because the episodes of angioedema were laryngeal in location and required emergency intubation to maintain an adequate airway, a trial of danazol prophylaxis, which has been shown to be effective in hereditary angioedema, was undertaken. His beneficial response to this form of therapy is also documented.

Adenocarcinoma↗

PubMed1992

Some clotting factors in plasma during danazol therapy: free and total protein S, but not C4b-binding protein, are elevated by danazol therapy.

Anabolic steroids are known to increase the plasma concentrations of certain plasma proteins. In four patients given treatment with danazol, an attenuated androgen, the concentrations of heparin cofactor II, Hageman factor (factor XII), protein C, and both free and total protein S increased significantly when tested 39 to 103 days after the start of therapy. The titers of these proteins in samples obtained 21 days to 5 years after therapy was discontinued were similar to those before treatment, except for total protein S, the titer of which remained elevated. No significant changes in the titers of C4b binding protein or plasma plasmin inhibitory activity were found.

Adult↗

PubMed1992

The effects of fetal exposure to danazol.

OBJECTIVE: To assess the consequences of exposure to danazol in utero. Additionally, by assessing the risk, to facilitate the counselling of pregnant women inadvertently exposed to danazol in early pregnancy. DESIGN: Retrospective review of reported case histories. SUBJECTS: 129 women exposed to danazol during pregnancy were identified from individual case reports, data from the Australian Drug Reactions Advisory Committee and the United States Food and Drug Administration and from the reports of danazol exposure made directly to the manufacturers. MAIN OUTCOME MEASURES: Teratogenic effects of fetal exposure to danazol in relation to dosage and duration of exposure. RESULTS: Of the 129 reported pregnancies, 12 miscarried and 23 were aborted. Of the 94 completed pregnancies, 37 resulted in the birth of normal males, 34 in non-virilized females and 23 in virilized females. Virilization occurred in a proportion of female fetuses with a pattern of cliteromegaly, fused labia and urogenital sinus formation. Surgery to the genital tract was usually, but not always, required in childhood. The abnormality has not been reported where danazol therapy had been discontinued before the 8th week of pregnancy. Although more common in the higher dosages, virilization was reported in one case with a 200 mg daily dosage. CONCLUSIONS: Danazol should remain contraindicated in pregnancy and clinicians should give careful contraceptive advice to patients commencing or continuing danazol therapy. Nonetheless it is possible to be cautiously optimistic about the outcome of danazol-exposed pregnancies, particularly if treatment is discontinued before 8 completed weeks gestation.

Abnormalities, Drug-Induced↗

PubMed1977

Danazol inhibits steroidogenesis in the rat testis in vitro.

The effects of danazol on steroidogenesis in vitro in the rat testis were examined by studying: 1) androgen synthesis in rat Leydig cells cultured with danazol, 2) danazol binding to rat testis microsomal cytochrome P-450, and 3) enzyme kinetics of danazol inhibition of the microsomal enzymes of testicular steroidogenesis. Concentrations of danazol as low as 1 micrometer suppressed LH-stimulated testosterone and androstenedione production in cultured Leydig cells. The addition of danazol to a preparation of testicular microsomes elicited a type I cytochrome P-450 binding spectrum, with an apparent spectral dissociation constant (Ks) of 4.8 micrometer. Danazol inhibited progesterone and 17alpha-hydroxy-progesterone binding to microsomal P-450 with apparent spectral inhibition constants of 2.4 micrometer and 2.8 micrometer, respectively. Danazol competitively inhibited 3beta-hydroxy-delta5-steroid dehydrogenase-isomerase (apparent enzymatic inhibition constant, KI = 5.8 micrometer), 17alpha-hydroxylase (KI = 2.4 micrometer), 17,20 lyase (KI = 1.9 micrometer), and 17beta-hydroxysteroid dehydrogenase (KI = 4.4 micrometer). These findings indicate that low concentrations of danazol directly inhibit steroidogenesis in the rat testis in vitro.

Androgens↗

PubMed1978

A radioimmunoassay for danazol (17alpha-pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol).

A method is described for the radioimmunoassay of circulating levels of the pituitary inhibiting agent, danazol. An antigen for danazol was prepared by reacting a 17-carboxy-methyloxime derivative of danazol with bovine serum albumin. By immunizing rabbits with this antigen, antiserum was generated which shows excellent specificity for danazol relative to its known metabolites as well as to many natural steroids. A radioimmunoassay was developed, without using separation or extraction techniques, involving competition for the antiserum between danazol in plasma and 14C-danazol. This assay has been successfully used to measure danazol in a series of normal human subjects receiving the drug at either 100 or 200 mg b.i.d. for 2 weeks. A significant relationship was seen between dosage of danazol and plasma concentrations.

Animals↗

PubMed1979

A comparison of plasma protein changes induced by danazol, pregnancy, and estrogens.

Analysis of 25 plasma proteins was performed on blood drawn from 7 females before and during treatment with danazol. This steroid was found to induce a pattern of plasma protein changes similar to but not identical with that of other 17 alpha-alkylated anabolic steroids. For comparison, the same 25 plasma proteins were analyzed in blood from pregnant women in their third trimester, when the estrogen influence on plasma protein synthesis is most pronounced. Five major types of response were found. 1) Albumin and orosomucoid were not influenced by danazol or, after correction for volume expansion, by pregnancy. 2) Prealbumin, C1-esterase inhibitor, and haptoglobins increased substantially during danazol treatment but were not significantly influenced by pregnancy. 3) Transferrin, antithrombin III, prothrombin, and plasminogen showed marked increases after administration of danazol and during pregnancy. 4) Transcortin, ceruloplasmin, and alpha 1-antitrypsin doubled in pregnancy but were not influenced by danazol. 5) The concentrations of T4-binding globulin, pregnancy zone protein, and sex hormone-binding globulin more than doubled in pregnancy, and all three decreased to one third or less on administration of danazol. The plasma estradiol content fell correspondingly. The different types of plasma protein response found in these two groups of patients fit the hypothesis that hepatocytes contain steroid receptors capable of reacting with estrogens and/or other steroids such as danazol and, thus, influence the biosynthetic rate of many but not all plasma proteins according to a specific pattern. The synthesis of some of the estrogen-sensitive proteins is depressed after intake of danazol, which suggests that there is a competition for the receptors in the hepatocytes as there is for other estrogen target tissues.

Adult↗

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↗

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↗

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↗

PubMed1992

Danazol suppresses both spontaneous and activated human lymphocyte-mediated cytotoxicity.

Danazol is an effective drug in the treatment of endometriosis. Previous reports suggest that it can act by influencing the immune system. Thus, in this study we evaluated whether danazol is able to affect the expression of natural and activated cytotoxicity by human peripheral blood lymphocytes (PBL). A cytotoxicity assay by 51Cr release was performed to determine the effect of danazol on lymphocyte cytotoxic response toward an erythroleukemic cell line (K562). A significant suppression of spontaneous cytotoxicity was observed when lymphocytes were pretreated for 18 h with danazol at the concentration of 5 x 10(-6) M. In addition, danazol could significantly inhibit both IL-2- and INF alpha-activated cytotoxicity at the concentration of 10(-5) M. Following 18 h exposure to danazol, PBL were able to completely recover their spontaneous but not activated cytotoxic potential upon further in vitro incubation (18 h) in absence of the drug. The biological significance of danazol as an inhibitor of immune function under experimentally defined conditions is discussed in relation to its possible role in vivo.

Cytotoxicity, Immunologic↗

PubMed1992

Danazol increases the anticoagulant effect of warfarin.

OBJECTIVE: To report two cases demonstrating an interaction between danazol and warfarin, resulting in the potentiation of warfarin's effect and bleeding complications. DATA SOURCES: Case reports, review articles, and studies identified by MEDLINE. STUDY SELECTION: All published English-language reports involving danazol and warfarin interactions were reviewed. DATA SYNTHESIS: Danazol, a synthetic testosterone derivative, is used in the treatment of endometriosis, fibrocystic breast disease, menorrhagia protein C deficiency, and hemophilia. We describe two cases including an interaction between danazol and warfarin, resulting in bleeding complications. There are at least two other reported cases of this interaction. This interaction may be attributable to several mechanisms. Danazol may inhibit the metabolism of warfarin and/or it may have a direct effect on the coagulation and fibrinolytic systems. CONCLUSIONS: Based on this report and other published cases, clinicians must be aware that danazol may increase the anticoagulant effect of warfarin. Patients receiving warfarin who are prescribed danazol must be monitored closely to prevent excessive anticoagulation and subsequent bleeding. Studies are needed to determine the frequency of this interaction and its underlying mechanisms.

Adult↗

PubMed1992

Nafarelin for endometriosis: a large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up. The Nafarelin European Endometriosis Trial Group (NEET).

OBJECTIVE: To compare the efficacy and safety of nafarelin and danazol for endometriosis. DESIGN: Randomized, double-blind, double-dummy. SETTING: Multiple European institutions. PATIENTS: In total, 307 patients with laparoscopically diagnosed endometriosis received nafarelin (n = 206) or danazol (n = 101); 263 (171 nafarelin, 92 danazol) were analyzed for efficacy. INTERVENTIONS: Intranasal nafarelin 200 micrograms two times a day or oral danazol 200 mg three times a day were administered for 6 months. MAIN OUTCOME MEASURES: Efficacy assessments were based on preadmission and end-of-treatment laparoscopic scores and subjective symptom scores at admission, end of treatment, 1, 3, 6, and 12 months after treatment. Safety was evaluated by adverse events and clinical laboratory tests. RESULTS: In each group, endometriosis growth and symptoms significantly improved during treatment (P less than 0.001). After treatment, symptoms returned in each group, but severity was less than at admission at all time points (P less than or equal to 0.016). Mean body weight increased in the danazol-treated group (P less than 0.001), serum glutamic oxaloacetic transaminase increased in both groups (P less than 0.001 for both) but significantly more in danazol users (P less than 0.002), and more nafarelin recipients had hot flushes (P less than 0.001). CONCLUSIONS: Nafarelin and danazol were equally effective in reducing endometriosis growth and symptoms during treatment and in preventing the return of symptoms during 12-month follow-up.

Administration, Intranasal↗

PubMed1992

Inhibitory and stimulatory actions of danazol in rat ovarian and uterine tissues.

We examined whether danazol has a direct action on ovarian steroid secretion and/or uterine prostaglandin (PG) F2 alpha catabolic activity in immature rats in which the first ovulation was induced and in adult ovariectomized rats. The preovulatory surge of estradiol and progesterone was markedly suppressed together with that of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by danazol administration under conditions that blocked the first ovulation. Uterine weight and PGF2 alpha catabolic activity enhanced by endogenous estrogen were greatly decreased by danazol treatment at a dose that did not block the first ovulation in immature rats. When danazol (30 mg) was given s.c. once daily for 2 days to ovariectomized rats, the uterine weight and PGF2 alpha catabolic activity per uterus were clearly increased, and the compensatory increase in FSH levels as a result of castration was not influenced, although the compensatory increase in LH levels was inhibited. These results demonstrate that danazol has a direct action on the ovary and uterus, and give further support to the view put forward in our previous paper that these actions of danazol may contribute to its therapeutic effects.

Administration, Oral↗

PubMed1979

Danazol binding to rat androgen, glucocorticoid, progesterone, and estrogen receptors: correlation with biologic activity.

Danazol was found to possess androgenic and glucocorticoid activity in rat bioassays. In contrast, danazol displayed no significant estrogenic activity. In support of these findings, danazol bound to the 8 S androgen receptor of rat prostate cytosol and to the glucocorticoid receptor of rat liver cytosol, but danazol did not bind well to the estrogen receptor of the rat uterus. Finally, danazol bound to the progesterone receptor of the rat uterus, but controversy continues as the whether danazol possesses progestational, antiprogestational, or no progestational effects.

Animals↗

PubMed1975

Observations on the effects of 17-alpha-pregn-4-en-20-yno-(2,3-d) isoxazol-17-ol(Danazol) on the female reproductive tract and pituitary gonadotrophs of gerbil (Meriones hurrianae).

Danazol caused leukolysis in adult female gerbils. It brings about suppression of ovarian weight, presumably by inhibiting gonadotrophin secretion from the pituitary gland. Uterotrophic action of Danazol is confirmed in ovariectomized animals. Danazol counteracted the uterotrophic effect of an exogenous oestrogen. Vaginal smears of Danazol-treated animals retained a dioestrous leukocytic pattern indicating the absence of follicular activity. Decreased RNA synthesis in the uterus indicates the possibility that Danazol is anti-oestrogenic. Castration-like changes were noticed in the anterior lobe of the hypophysis after Danazol administration.

Animals↗

PubMed1992

A randomized placebo-controlled double-blind study of danazol in hemophilia A.

A randomized double-blind placebo-controlled crossover trial of danazol was carried out in 19 cases of hemophilia A. Danazol was given for 3 months at a dose of 150 mg/day to patients under 15 years of age, and 300 mg/day to older patients. The basal factor VIII:C level was 8.3 +/- 5.6% (mean +/- SD), and after 3 months of danazol treatment was 15.3 +/- 11.0% (p = 0.02). Six patients (basal factor VIII:C 2-22%) showed a 1.36- to 2.87-fold elevation of factor VIII:C levels after danazol. 0/2, 1/4 and 5/13 cases of severe, moderate and mild disease, respectively, responded. Decreases in the number of bleeding episodes and cryoprecipitate requirement were seen in the responders. No adverse reactions to danazol were encountered. Danazol appears to raise the factor VIII:C levels in selected cases of hemophilia A.

Adolescent↗

PubMed1979

Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications.

Hereditary angioedema (HAE), an auto-somal dominant disorder characterized by attacks of episodic edema is associated with decreased functional levels of the C1 esterase inhibitor. Approximately 85% of patients have lowered antigen levels of a normal inhibitor protein. 15% of patients have normal or elevated antigenic levels of functionless protein. We have examined the response to danazol therapy of patients with the variant HAE phenotypes possessing the abnormal protein in an effort to determine if these patients possess a normal structural C1 inhibitor allele. Four patients with a variant HAE phenotype were treated successfully with danazol. In two patients, distinguished by the presence of a functionless, albumin-bound, C1 inhibitor (phenotype 2), phenotypic analysis of the danazol response by bidirectional immunoelectrophoresis revealed the appearance of the normal C1 inhibitor gene product during danazol therapy. This relatively cathodal C1 inhibitor peak appears in conjunction with the development of nearly normal functional activity. All of the functional C1 inhibitory activity which appeared in the phenotype 2 treatment serum was associated with the electrophoretically normal inhibitor. This normal protein could be separated from the functionless inhibitor protein by immunoadsorption and molecular sieve chromatography. Danazol therapy of the two patients with an electrophoretically normal, functionless C1 inhibitor (phenotype 3) also resulted in a clinical remission associated with development of a significant increment in functional serum C1 inhibitory activity and C1 inhibitor protein. These findings demonstrate that these two HAE phenotypic variants are heterozygous for the normal serum C1 inhibitor, a finding which was not apparent before phenotypic analysis of this serum during danazol therapy. These data provide strong evidence for a basic similarity between the common form of HAE and its phenotypic variants. They also suggest that a structural gene lesion may result in the abnormalities of serum C1 inhibitor function and disease expression in all three of these HAE phenotypes.

Angioedema↗

PubMed1977

Danazol inhibits steroidogenesis.

Danazol was found to inhibit multiple enzymes of steroidogenesis directly in the pregnant mare serum (PMS)-treated hamster ovary and the rat testis and adrenal in vitro. In the PMS-treated hamster ovary, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, and 3beta-hydroxysteroid dehydrogenase. In the rat testis, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase. In the rat adrenal, danazol inhibited 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11beta-hydroxylase. Two hours after a subcutaneous injection of 5 mg/kg of danazol to adult male rats, serum luteinizing hormone levels were significantly increased and serum testosterone levels were significantly suppressed. These findings suggest that in the rodent one of danazol's major pharmacologic effects is the direct inhibition of steroidogenesis.

Adrenal Glands↗