Continuing Education Activity

Danazol is a drug used to manage endometriosis, a condition in which endometrial cells grow on tissue outside the uterus, including the fallopian tubes and ovaries. It is also used in other gynecological problems like uterine fibroids and fibrocystic breast disease and various hematological diseases such as in patients with persistent/chronic refractory immune thrombocytopenia (ITP) who failed to respond to corticosteroids and/or other treatments and hereditary angioedema. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of danazol therapy in the clinical setting related to essential points.

Objectives:

• Identify the indications for danazol therapy.
• Outline the mechanism of action of danazol.
• Review the potential adverse effects of using danazol
• Summarize some inter-professional team strategies for improving communication to improve outcomes when using danazol.

Indications

Danazol has been historically used to manage endometriosis and other gynecological problems, such as uterine fibroids, fibrocystic breast disease, and heavy menstrual bleeding, for which it has demonstrated greater effectiveness than other medical therapies such as progestogens, NSAIDs, and OCPs.[1][2][3][4] 

Recently, researchers have explored the role of danazol in various hematologic diseases, such as persistent/chronic refractory immune thrombocytopenia (ITP) who failed to respond to corticosteroids or other therapies amegakaryocytic thrombocytic purpura, paroxysmal nocturnal hemoglobinuria, myelofibrosis, and Diamond-Blackfan anemia.[5][6][7][8] Apart from these, danazol has also shown effectiveness in telomere disease and hereditary angioedema.[9][10]

Mechanism of Action

Absorption: Danazol, like other steroids, is well absorbed from the gastrointestinal system. Peak plasma concentration of danazol is reached within 2 to 8 hours post oral administration of 400 mg tablet, with a median Tmax value of 4 hours. Steady-state concentrations require twice-daily dosing of danazol for six days.

Distribution: Danazol is lipophilic and hence has the potential to penetrate deep tissue compartments.

Metabolism and Excretion: Danazol is extensively metabolized in the liver to 2-hydroxymethyl ethisterone. It is mainly excreted in the urine, and a small amount is excreted in the feces. Danazol appears to be metabolized into two primary metabolites; these are 2-hydroxymethyl danazol and ethisterone. It has both urinary and fecal excretion, with urinary excretion accounting for the primary mode of excretion of the primary metabolites, while almost ten different products have been identified in feces. The half-life of danazol has been reported to be at a mean of 9.7 hours, while in patients with endometriosis, six months treatment with 200 mg tablets of danazol three times daily reported the half-life of danazol to be 23.7 hours.

Danazol has multiple mechanisms of action by which it exerts its effect. It is a synthetic steroid and possesses some structural similarities with testosterone. Therefore, some of the biological effects of danazol are related to and in line with other androgens.[11] There is evidence that danazol inhibits steroidogenesis in the adrenal glands, ovaries, and the testis In Vitro. In the porcine ovary, danazol has been shown to inhibit the aromatization of the basal and luteinizing hormone-mediated progesterone secretion by the granulosa cells and luteal cells of the ovary.[11] This phenomenon in the ovary suggests that danazol directly inhibits steroidogenesis in the ovary, independent of its inhibition of gonadotropin secretion.[11] Danazol is also known for its affinity to bind with sex hormone-binding globulin and corticosteroid-binding globulin. This effectively increases the free to plasma bound concentrations of sex hormones and steroids, which increases their effect.

Apart from the androgenic mode of action, danazol has also been shown to induce apoptosis and cytotoxicity and affect the expression of apoptosis regulating proteins in leukemic cells, where it has shown results in inducing apoptosis in chronic lymphocytic leukemia.[12]

Administration

Danazol is supplied as 50, 100, and 200 mg tablets, and the drug is administered orally. For mild endometriosis, two 100 or 200 mg tablets twice daily, and for moderate to severe endometriosis, 400 mg tablets twice daily are recommended, but the dose should be titrated down to the minimum required to maintain amenorrhea. Therapy typically lasts six months but can be extended to 9 months.

For fibrocystic breast disease, a twice-daily dose of 100 mg tablets is recommended. For hereditary angioedema, 200 or 300 mg tablets twice daily prophylactic doses are recommended. The dose should be decreased by 50% in 1 to 3 months according to response and increased if there is an attack up to 200 mg/day, dosages more than 200 mg per day for an extended period are not recommended due to side effects.

Adverse Effects

As a synthetic steroid, danazol has many adverse effects in line with other androgens, making its adverse effects broad and systemic in nature. The most commonly reported side effects of danazol include weight gain, gastrointestinal symptoms including bloating, nausea, vomiting, gastroenteritis, elevated liver function tests, joint pain, muscle spasm, lethargy, headache, and depression.[4] Other than these, gynecologic side effects such as intermenstrual bleeding, breast atrophy, flushes, and androgenic side effects such as hirsutism, decreased breast size, acne, hair loss, oily skin, oily hair, menstrual irregularities and hoarseness, side effects due to weak mineralocorticoid activity such as swelling and edema have also been reported.[13][4]

Also, since this drug is a synthetic steroid, elevated blood pressure can occur and remains an area that merits further investigation, along with its effects on adrenal activity.[13] The androgenic side effects have been shown to resolve after discontinuation of danazol. Danazol is also known to cause decreased plasma clearance of carbamazepine, with elimination half-life increasing from 11 hours to 24.3 hours; therefore, the dose of carbamazepine should be adjusted if co-administered with danazol.[14] 

Thromboembolism, including stroke, thrombotic and thrombophlebitic events (e.g., sagittal sinus thrombosis, stroke), pseudotumor cerebri (benign intracranial hypertension), peliosis hepatitis, benign hepatic adenoma has been reported with danazol use. Elevated concentrations of hepatic enzymes (e.g., alkaline phosphatase, AST, ALT) and/or jaundice have been reported with doses of more than 400 mg daily. Danazol treatment may also cause decreased HDL and increased LDL. Danazol causes possible interference with laboratory measurement of androgens, for example, testosterone. Moreover, danazol is reported to be a CYP3A4 inhibitor; hence its concurrent use with statins has been reported to cause rhabdomyolysis.[15][16][17]

Contraindications

Danazol is contraindicated in pregnancy due to its ability to cause virilization in female fetuses. It has been shown that female fetuses exposed to danazol after eight weeks of gestation were more likely to experience virilization, which followed the pattern of clitoromegaly, fused labia, and fused urogenital sinus formation.[18] Surgery is usually, but not always, required for correction of virilization. Virilization usually occurs at higher doses but can occur at doses as low as 200 mg.[18] 

Being an androgen, danazol should also be avoided in androgen-dependent tumors, e.g., prostate cancer. Danazol also induces the ALA synthase enzyme and induces porphyrin metabolism and, therefore, should be avoided in people with any form of porphyria. Danazol should be avoided with a previous history of hypersensitivity to the drug or its' metabolites. Danazol is also contraindicated during lactation. 

If danazol is being used to treat fibrocystic breast disease, breast cancer should be ruled out first. If any nodule persists or enlarges during danazol treatment, consider and rule out breast carcinoma.

Danazol should not be given to women with undiagnosed vaginal bleeding and patients with severe renal, liver, and cardiac disease.

Monitoring

Danazol has a relatively safer side effect profile than other drugs used to treat similar conditions; however, its use does require monitoring. Danazol can cause liver damage, especially with concomitant use of glucocorticoids.[19] This combination is used in patients with ITP, and therefore, liver function tests should be monitored routinely to detect liver damage. Danazol decreases the clearance of carbamazepine. Thus, the dose of carbamazepine should be adjusted accordingly, and blood levels should be monitored in patients receiving carbamazepine therapy being co-administered with danazol to avoid various side effects of carbamazepine.[14] 

Enhancing Healthcare Team Outcomes

Danazol has been historically used to treat endometriosis but has recently been used in several hematological diseases. There is evidence of its effect in steroid-resistant Diamond-Blackfan anemia, where it showed effectiveness in causing erythroid hyperplasia, possibly by virtue of its androgenic nature.[20] [Level 5] Moreover, there is clear evidence of the drug not causing any long-term hematological problems, even for as long as four decades of use, which speaks for the drug's safety profile.[21] [Level 3]

There is also evidence of its efficacy in acquired amegakaryocytic thrombocytopenic purpura and immune thrombocytopenia purpura, and chronic lymphocytic leukemia, where it is shown to induce apoptosis in leukemic cells.[5][12] Danazol is a cheap and readily available drug with a relatively safer side effect profile than conventional steroids. There are multiple implications of the drug in terms of hematological diseases. Clinicians should have this drug in mind when tackling these diseases, especially those who become resistant to standard therapies.

Recent advances in medicine introduced more effective treatments for endometriosis, for which danazol has been used historically. It is still useful for treatment-resistant varieties of endometriosis, as well as gynecological problems, including heavy menstrual bleeding.[4] [Level 1]

Danazol can prove to be a valuable agent in female patients suffering from both hematological and gynecological problems, as it has shown its efficacy in both fields. 

Since danazol is known to cause liver damage, it should be avoided with other drugs that cause hepatotoxicity, especially in the geriatric and diabetic population, most of which are already prescribed statin drugs for their conditions. Clinicians and pharmacists should maintain a watchful eye for drug interactions and combined toxicity. They should work together with other clinicians and closely monitor their medications to save the patient from liver damage and increase adherence. 

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References

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3.

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8.

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9.

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12.

Podhorecka M, Macheta A, Chocholska S, Bojarska-Junak A, Szymczyk A, Goracy A, Dmoszynska A, Hus M. Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia. Ann Hematol. 2016 Feb;95(3):425-35. [PMC free article: PMC4742499] [PubMed: 26692089]

13.

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20.

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21.

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Disclosure: Salman Ashfaq declares no relevant financial relationships with ineligible companies.

Disclosure: Ahmet Can declares no relevant financial relationships with ineligible companies.