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Danazol for pelvic pain associated with endometriosis.

BACKGROUND: Endometriosis is defined as the presence of endometrial tissue (stromal and glandular) outside the normal uterine cavity. Conventional medical and surgical treatments for endometriosis aim to remove or decrease deposits of ectopic endometrium. The observation that hyperandrogenic states (an excess of male hormone) induce atrophy of the endometrium has led to the use of androgens in the treatment of endometriosis. Danazol is one of these treatments used. The efficacy of danazol is based on its ability to produce a high androgen/low estrogen environment (a pseudo menopause) which results in the atrophy of endometriotic implants and thus an improvement in painful symptoms. OBJECTIVES: To determine the effectiveness of danazol compared to placebo or no treatment in the treatment of the symptoms and signs, other than infertility, of endometriosis in women of reproductive age. SEARCH STRATEGY: The Menstrual Disorders Group search strategy was used to identify randomised controlled trials of the use of danazol in endometriosis. In addition, all reference lists of included trials were searched, and relevant drug companies were contacted for details of unpublished trials SELECTION CRITERIA: Randomised controlled trials in which danazol (alone or as adjunctive therapy) was compared to placebo or no therapy. Trials which only reported infertility outcomes were excluded. DATA COLLECTION AND ANALYSIS: Only four trials met the inclusion criteria and two authors extracted data independently from these trials. All four trials compared danazol to placebo. Two trials used danazol as sole therapy and two trials used danazol as an adjunct to surgery. Although the main outcome was pain improvement other data relating to laparoscopic scores and hormonal parameters were also collected. MAIN RESULTS: Treatment with danazol (including adjunctive surgical therapy) was effective in relieving painful symptoms related to endometriosis when compared to placebo. Laparoscopic scores were improved with danazol treatment (including adjunctive therapy) when compared with either placebo or no treatment. Side effects were more commonly reported in those patients receiving danazol than placebo. REVIEWER'S CONCLUSIONS: Danazol is effective in treating the symptoms and signs of endometriosis. However, its use is limited by the occurrence of androgenic side effects.

Danazol↗

A comparative study of danazol, a regimen of decreasing doses of danazol, and norethindrone in the treatment of objectively proven unexplained menorrhagia.

OBJECTIVE: Our purpose was to compare the efficacy of the recommended dose of danazol, a reduced-dose danazol regimen, and norethindrone in the treatment of objectively proven menorrhagia. Recurrence after discontinuing treatment was also assessed. STUDY DESIGN: The study was a single-blind, randomized, parallel, comparative study. After a placebo run-in period over two menstrual cycles, 57 patients with a baseline mean menstrual blood loss of at least 80 ml per cycle were randomly assigned to receive one of three therapies: danazol, 200 mg/day (n = 19) for three menstrual cycles; danazol, 200 mg/day for one cycle, 100 mg/day for one cycle, and 50 mg/day for one cycle (n = 19); and norethindrone, 5 mg three times daily on days 19 through 26 of the cycle for three consecutive cycles (n = 19). Patients in whom treatment was successful (those experiencing blood loss < 80 ml) were entered in the follow-up phase of the study, receiving placebo for a maximum of four menstrual cycles. RESULTS: The final menstrual blood loss on treatment was significantly less for those patients who received both danazol regimens compared with those who received norethindrone (p = 0.017 for reducing dose danazol vs norethindrone and p = 0.043 for 200 mg of danazol vs norethindrone). Both danazol treatment regimens were significantly more successful in reducing menstrual blood loss to within the normal range than was norethindrone. The reducing-dose danazol regimen was successful in eight of 17 patients (p = 0.027), and 200 mg of danazol was successful in nine of 19 patients (p = 0.029), compared with the two successes of 18 patients treated with norethindrone. Significantly more recipients of 200 mg of danazol than of norethindrone subjectively rated their treatment to be moderately or highly effective (p = 0.033). Both danazol treatment regimens were associated with a higher incidence of adverse events than was norethindrone therapy, although the number of withdrawals were similar and infrequent in the three groups. CONCLUSIONS: Both danazol regimens were significantly more effective than norethindrone in reducing the excessive menstrual blood loss of women with unexplained menorrhagia. A subjective assessment by patients found that only the 200 mg of danazol was judged to be significantly more effective than norethindrone in controlling the heaviness of menstrual bleeding. The reduced-dose danazol regimen did not appear to markedly diminish the incidence of adverse events compared with the 200 mg of danazol regimen.

Adult↗

Danazol concentrations in ovary, uterus, and serum and their effect on the hypothalamic-pituitary-ovarian axis during vaginal administration of a danazol suppository.

OBJECTIVE: To determine danazol concentrations in the ovary, uterus, and serum during daily vaginal administration of a danazol suppository and to examine its effect on the hypothalamic-pituitary-ovarian axis. DESIGN: Sampling of tissues after vaginal or oral administration of danazol and sampling of blood during control and danazol-administration menstrual cycles. SETTING: Outpatient volunteers and inpatients at a public hospital. PARTICIPANTS: Thirty patients who were to undergo hysterectomy and oophorectomy because of uterine leiomyoma and eight regularly menstruating volunteers. INTERVENTIONS: Danazol was administered as a vaginal suppository (100 mg) or orally (400 mg). MAIN OUTCOME MEASURE: Danazol concentrations in the ovary, uterus, and serum, and serum E2 and P levels. RESULTS: Danazol concentrations in the ovary and uterus after daily vaginal administration of a suppository containing 100 mg danazol were comparable to those after daily oral administration of 400 mg danazol, but the serum danazol concentration was much lower. Menstrual cycle patterns of serum E2 and P levels were normal during daily vaginal administration of a danazol suppository. CONCLUSION: Daily administration of a suppository containing 100 mg danazol produces high ovarian and uterine concentrations but low serum concentrations, and no effect was detected on the hypothalamic-pituitary-ovarian axis.

Adult↗

Adrenal steroids in serum during danazol therapy, taking into account cross-reactions between danazol metabolites and serum androgens.

To investigate the changes in the serum androgen concentrations and the Free Androgen Index (FAI) in women during danazol therapy, we measured the serum concentrations of adrenal steroids and danazol metabolites, and then examined the effects of danazol metabolites on assays for serum androgens. Thirteen women who had endometriosis were treated with danazol (300 or 400 mg/day) for 8 to 16 weeks. Blood samples were taken before, during, and after the medication. During the danazol therapy, serum testosterone (T), cortisol (F), and sex-hormone binding globulin (SHBG) significantly decreased (P < 0.05); but serum dehydroepiandrosterone-sulfate (DHEAS) and FAI increased (P < 0.05). The serum concentrations of danazol metabolites were: danazol, 209.0 +/- 28.3 (ng/mL, mean +/- SEM); delta 1-2-hydroxymethyl ethisterone, 114.4 +/- 8.4; and 2-hydroxymethyl ethisterone, 660.0 +/- 54.2. There was considerable cross-reaction between danazol metabolites and androgens [T, androstenedione (A), and dehydroepiandrosterone (DHEA)] in the direct assays. As for the ratios of adrenal steroids in serum, the DHEAS/F, DHEAS/DHEA, and 11-deoxycortisol (S)/F ratios increased (P < 0.05). We conclude that the increase in FAI and DHEAS represents increased native androgenic activity with danazol, and the changes in adrenal steroid ratios in serum indicate the inhibition of 11 beta-hydroxylase and sulfatase activities during danazol therapy.

Adrenal Glands↗

Effects of danazol, gonadotropin-releasing hormone agonist, and a combination of danazol and gonadotropin-releasing hormone agonist on experimental endometriosis.

Effects of danazol, gonadotropin-releasing hormone agonist (leuprolide), and danazol-leuprolide combination on experimental endometriosis were evaluated in female rats. A complete resorption of the fluid and a marked decrease in the volume of endometrium autotransplanted under the renal capsule were found after castration (1.4 +/- 0.1 mm3 in castrated, n = 14, vs 26.7 +/- 5.6 mm3 in intact control, n = 16). Histologic examination indicated atrophy and regression of the endometrial explant. These atrophic changes of endometrial explant were also induced by danazol, leuprolide, and the combination treatment. However, the volume of explants after combination therapy with danazol and leuprolide (1.8 +/- 1.0 mm3, n = 17) was significantly less than that after therapy with danazol (11.6 +/- 2.8 mm3, n = 20) or leuprolide alone (5.9 +/- 1.4 mm3, n = 24). The combination therapy (16/17) was also shown to be superior to danazol (9/20) or leuprolide alone (14/24) to induce the regression of fluid in experimental endometriosis. As expected, administration of leuprolide decreased the serum estradiol level, but use of danazol did not. These findings suggest that a combination therapy of danazol and gonadotropin-releasing hormone agonist, which show different modes of action, may be a potential modality in treatment of patients with advanced endometriosis.

Analysis of Variance↗

Danazol suppression of luteinizing hormone secretion: a role for danazol-androgen receptor interaction within the brain-pituitary complex.

We investigated the relationship between intracellular androgen and estrogen receptors within the brain-pituitary complex and danazol suppression of luteinizing hormone secretion in castrated rats. Danazol did not influence 3H-estradiol-estrogen receptor interactions within the brain and pituitary but did suppress 3H-dihydrotestosterone-androgen receptor interactions within this neuroendocrine complex. To study the significance of these danazol-androgen receptor interactions, the drug was administered to androgen receptor-deficient pseudohermaphrodite or flutamide-treated male rats. In both instances, danazol suppression of luteinizing hormone release was markedly attenuated or absent. These findings point to danazol-androgen receptor interactions within the brain-pituitary complex as a key step in this drug's antigonadotropic actions. Whether the active drug form is danazol itself or a metabolite is subject to further study.

Amygdala↗

Direct effect of danazol on endometrial hyperplasia in adenomyotic women: treatment with danazol containing intrauterine device.

It is well known that danazol has a direct effect on endometriosis tissue and cell. We have been treating adenomyotic women with danazol containing intrauterine device (D-IUD) from June 1993 to August 2000 and significant decrease of dysmenorrhea and serum CA-125 levels were observed. Of fifty-nine adenomyotic women, eight women were also diagnosed by endometrial biopsy as endometrial hyperplasia and one woman was diagnosed as atypical endometrial hyperplasia. In these endometrial hyperplastic patients, endometrial tissues were obtained before insertion and at the time of removal or exchange of D-IUD and examined pathologically. In all of the 9 women, histopathological findings of endometrial hyperplasia disappeared after D-IUD treatment. In particular, in one patient, findings of atypical endometrial hyperplasia also disappeared after D-IUD treatment. She is now closely observed at our clinic using D-IUD. By these evidences, we postulate that D-IUD is one of the treatment choices of endometrial hyperplasia given exposure of the endometrium to such an extraordinary high concentration of danazol released by D-IUD and avoidance of adverse effects of oral danazol or general administration of GnRH and progesterone. In particular, in atypical endometrial hyperplasia case, its mechanisms might give great benefit to patient. However, mechanisms of direct effect of danazol on endometrial hyperplasia remain to be elucidated in the future study.

Adult↗

Levels of androgens and danazol metabolites in serum during danazol therapy.

Thirteen women who had endometriosis were treated with danazol (300 to 400 mg/d). Levels of androgens and danazol metabolites in serum and the influences of danazol metabolites on the assays for serum androgen were investigated during danazol therapy. Serum DHEAS significantly increased (P < 0.05), but serum DHEA slightly decreased. Serum T levels, measured by direct assay, were markedly elevated. However, measured after HPLC separation, the T levels in serum were significantly decreased (P < 0.05). There were considerable cross-reactions between danazol metabolites and androgens (T, DHEA, and A) in RIA. Purification of androgens using column chromatography was necessary to measure serum androgens precisely.

Adult↗

Danazol versus carbon dioxide laser plus postoperative danazol: treatment of infertility due to mild pelvic endometriosis.

The mechanism of action by which mild pelvic endometriosis causes infertility is still unknown. Danazol has been proposed as the sole agent to treat this condition; however, the results for pregnancy rates do not give as much cause for enthusiasm at the present time as they did when this drug was introduced. To ascertain the role of laser via the laparoscopic approach, this retrospective study looks at the pregnancy success rate in two groups of patients. Group I was treated with danazol alone; group II was treated with danazol after laser surgery. Although the success rate is better in group II, the population sample in both groups is modest and does not allow one to draw meaningful statistical conclusions at the present time, but the use of carbon dioxide laser with the laparoscope plus postoperative danazol seems to be a better approach to this condition that affects the infertile female.

Adult↗

The inhibitory effects of danazol, danazol metabolites, gestrinone, and testosterone on the growth of human endometrial cells in vitro.

Danazol and gestrinone are effective drugs in the treatment of endometriosis. Their mechanism of action remains uncertain, but may be related to their androgenic activity. The authors examined the effect of danazol on human endometrial cells cultured in vitro, its two major metabolites, ethisterone and 2 hydroxymethyl ethisterone, gestrinone, and testosterone (T) at 1X and 10X expected plasma concentrations. Danazol and T suppressed growth by 20.8 and 25.0% (P less than 0.01), respectively, at the lower dose, and by 26.9 and 35.5% (P less than 0.01), respectively, at the 10-fold higher dose. No significant suppression of growth occurred with gestrinone, ethisterone, or 2 hydroxymethyl ethisterone. The results provide further evidence that danazol and T (but not gestrinone) may act by a direct effect on endometrial tissue.

Cell Division↗

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↗

Life table analysis of pregnancy rates in women with moderate or severe endometriosis comparing danazol therapy after carbon dioxide laser laparoscopy plus electrocoagulation or laparotomy plus electrocoagulation versus danazol therapy only.

STUDY OBJECTIVE: To assess the effectiveness, in terms of pregnancy rates, of isotopic 13CO2 laser laparoscopy versus traditional laparoscopy or laparotomy in the treatment of infertile women with moderate or severe endometriosis. DESIGN: Prospective 5-year study. SETTING: Medical school-affiliated hospital. PATIENTS: Three hundred nine infertile women with moderate to severe endometriosis. INTERVENTIONS: The patients were treated with one of four options: operative laparoscopy with the 13carbon dioxide (13CO2) laser vaporization and/or resection, operative laparoscopy with simple electrocoagulation and sharp dissection, laparotomy with electrocoagulation and sharp dissection, and medical treatment with danazol. Estimated cumulative pregnancy rates using life table analyses were indicators of treatment of success and compared among treatments. A subgroup of 192 women considered to have endometriosis as the only infertility factor was also evaluated. MEASUREMENTS AND MAIN RESULTS: Pregnancy rates in the laparoscopy group were equal to or higher than those of the laparotomy group, for both the entire population and the endometriosis-only subset. When the CO2 laser was used as an adjuvant option, the rates were better, especially in patients with advanced disease and with endometriosis as the only infertility factor. CONCLUSION: In women with endometriosis as the only infertility factor, laparoscopic surgery with the 13CO2 laser was more effective than nonlaser treatment.

Adult↗

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↗

Danazol: endocrine pharmacology and therapeutic applications.

The options for the medical management of endometriosis have been expanded by the introduction of the synthetic steroid, danazol. The results of large clinical studies suggest that danazol treatment produces significant improvement in the symptoms, signs, and laparoscopic findings of endometriosis. The original studies of the pharmacology of danazol concluded that danazol was a strong antigonadotrophin with mild androgenic effects and no other hormonal properties. Recent studies which emphasize the molecular pharmacology of danazol suggest that this steroid has direct effects on hypothalamic-pituitary function, multiple classes of steroid receptors, gonadal steroidogenesis, and endogenous steroid metabolism. These studies demonstrate that: (1) danazol prevents the midcycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); (2) danazol does not significantly suppress basal LH or FSH in gonadally intact human beings; (3) in castrated animals danazol can prevent the compensatory increase in LH and FSH; (4) danazol binds to androgen, progesterone, and glucocorticoid receptors; (5) danazol does not bind to estrogen receptors; (6) danazol binds to sex hormone-binding globulin and corticosteroid-binding globulin; (7) danazol inhibits multiple enzymes of steroidogenesis; (8) danazol increases the metabolic clearance rate of progesterone; and (9) metabolites of danazol are hormonally active. Given the complex pharmacology of danazol it is inappropriate to continue to refer to danazol as a "selective antigonadotrophin."U

Animals↗

Danazol for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women. OBJECTIVES: To determine the effectiveness and tolerability of danazol when used for heavy menstrual bleeding in women of reproductive years. SEARCH STRATEGY: All studies which might describe randomised controlled trials of danazol for the treatment of heavy menstrual bleeding were obtained by electronic searches of MEDLINE, EMBASE, Current Contents, CINAHL, National Research Register and the Menstrual Disorders and Subfertility Group's Specialist Register of controlled trials (on 6 November 2001). Attempts were also made to identify trials from citation lists of included trials and relevant review articles. In most cases the first author of each included trial was contacted for unpublished additional information. SELECTION CRITERIA: Randomised controlled trials of danazol versus placebo, any other medical (non-surgical) therapy or danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria for this review. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format. MAIN RESULTS: Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7, 28.2) and progestogens (OR 4.05, 95% CI 1.6, 10.2), but this did not appear to affect adherence to treatment. Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8, -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3, -4.8). There were no randomised trials comparing danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system. REVIEWER'S CONCLUSIONS: Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments, though it is uncertain whether it is acceptable to women. The use of danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. Overall no strong recommendations can be made due to the small number of trials, and the small sample sizes of the included trials.

Danazol↗

Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women.

STUDY OBJECTIVE: To assess the long-term benefit and side effects of danazol therapy, and to delineate factors influencing the responses in patients with autoimmune thrombocytopenia. DESIGN: Before and after trial. SETTING: Referral-based hematology clinics and the University of Miami teaching hospitals. PATIENTS: Data were collected on 96 patients (60 women and 36 men, 45 of whom had had splenectomies) receiving danazol therapy for autoimmune thrombocytopenia and analyzed. INTERVENTION: Danazol was added to the previous therapy or begun as an initial therapy. Glucocorticoids were tapered gradually. MEASUREMENTS AND MAIN RESULTS: The overall response rate to danazol was 61.4%. Among responders, the platelet counts (mean +/- SD) before and after danazol treatment were 36 +/- 24 x 10(9)/L and 145 +/- 77 x 10(9)/L, respectively, and the time to response was 2.7 +/- 3 months. Sex, age, and the status of the spleen (absent or present) influenced the responses to danazol. In women, but not in men, response rates improved with advancing age, especially in the nonsplenectomized women. This may be because estrogen levels are high in younger women and low in older women and men. Danazol, when given longer than a year, induced remissions lasting for years even after its discontinuation, but early relapses were frequent when danazol was administered for less than 6 months. Platelet-associated IgG returned to normal range during unmaintained remission. CONCLUSION: Danazol is best suited for long-term medical management of autoimmune thrombocytopenia. It is well tolerated, and lasting, unmaintained remissions often occur after prolonged danazol administration. Age, sex, and the status of the spleen influence the responses. When danazol therapy is used, glucocorticoids can be substantially reduced in dosage or withdrawn. Danazol is a good alternative to splenectomy in elderly persons, especially in women.

Adolescent↗

Danazol distribution in plasma and cell membranes as related to altered cell properties: implications for mechanism.

Concentrations of danazol in patient plasma and red blood cells (RBC) were assayed over a 6-month period in 75 patients on danazol therapy using a high-pressure liquid chromatography (HPLC) method more reliable than previous radioimmunoassay (RIA) methods. It was found that plasma danazol rose regularly for 15 days after the beginning of treatment, reaching a steady state plateau of 175 +/- 76 ng/ml in 20 patients on normal dose, and less for lower dose schedules. After stopping danazol, concentrations declined to near zero in a similar time frame. RBC concentrations on a packed volume basis were similar to plasma levels. However, the membrane ghosts of RBC contained about 50% of the total RBC danazol, implying about 100-fold higher concentration in membranes than in plasma. Similar distributions were obtained in vitro with both RBC and platelets, and were confirmed by 14-C-labeled danazol. These findings tend to support the hypothesis that the benefits of danazol in immune disorders may be attributable in part to its intercalation in the lipid bilayer of the plasma membrane, altering antigen/receptor expression to modulate immune reactions. This hypothesis was first suggested when it was observed that the RBC of patients on danazol therapy showed morphological changes and increased resistance to osmotic lysis. It was later shown that danazol in vitro reduces binding of autoantibodies, and protects against complement-mediated lysis, suggesting direct action of danazol on the membranes. This hypothesis is discussed, and danazol's effect in protecting against complement-mediated lysis is described.

Blood Platelets↗

Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis.

Danazol is routinely administered orally to inhibit ovulation and to treat pelvic endometriosis. However, recent evidence suggests that danazol can act directly on endometriotic tissue in vitro to inhibit DNA synthesis and induce apoptosis. Danazol was administered via the vagina in this study, using a vaginal ring drug delivery system containing 1500 mg of danazol. This therapy was effective for treatment of pelvic endometriosis, especially for deeply infiltrating endometriosis, resulting in a cure of dysmenorrhoea and tenderness in the cul-de-sac within 3 months, and of induration or nodularity in the cul-de-sac within 7 months. Moreover, conception was possible during insertion of the vaginal ring in 17 out of 31 infertile women with deeply infiltrating endometriosis, and in two out of eight infertile women with ovarian endometriotic cysts not adhering to the cul-de-sac and without deeply infiltrating endometriosis. Serum danazol concentrations, high during oral daily 400 mg danazol therapy, but undetectable during vaginal danazol ring therapy, explain why ovulation and conception could occur during insertion of the vaginal danazol ring, and why general side-effects, which are often observed during oral danazol therapy, were not observed during vaginal danazol ring therapy. Danazol seems to be absorbed through the vaginal mucosa and reaches the deeply infiltrating endometriosis via diffusion.

Absorption↗