Continuing Education Activity

This activity discusses the drug danazol, a synthetic steroid derivative, in the management of diverse gynecological conditions and hematological disorders. As a therapeutic agent, danazol has proven effective against challenging conditions such as endometriosis, uterine fibroids, and fibrocystic breast disease. Furthermore, its role extends to hematological disorders, notably immune thrombocytopenia (ITP) refractory to conventional treatments and hereditary angioedema. This activity is designed to provide healthcare professionals with a thorough exploration of danazol's clinical applications. The content spans indications, contraindications, pharmacological activity, adverse events, and other essential facets relevant to its therapeutic use.

By examining the complexities of danazol therapy, this activity aims to equip healthcare professionals with critical insights into optimizing patient care. The clinical nuances of danazol administration, emphasizing crucial considerations for its use in managing endometriosis, uterine fibroids, fibrocystic breast disease, immune thrombocytopenia, and hereditary angioedema are discussed. Participants gain valuable knowledge that enhances their ability to make informed decisions in the context of danazol therapy, ultimately contributing to improved patient outcomes.

Objectives:

• Identify appropriate clinical scenarios warranting the use of danazol for endometriosis, uterine fibroids, fibrocystic breast disease, immune thrombocytopenia (ITP), and hereditary angioedema.

• Implement danazol therapy aligning with established guidelines, considering dosing, duration, and potential adverse effects for optimal patient care.

• Assess patients undergoing danazol treatment regularly to evaluate efficacy and monitor adverse reactions and overall treatment outcomes.

• Implement communication with patients about the rationale, expected outcomes, potential adverse effects, and follow-up care related to danazol therapy.

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]

FDA-Approved Indications

• Mild and moderate to severe endometriosis
• Hereditary angioedema

Off-Label Uses

• Fibrocystic breast disease

Mechanism of Action

Danazol has multiple mechanisms of action by which it exerts its effect. Danazol 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] Evidence shows 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 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]

Pharmacokinetics

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 T_max value of 4 hours. Steady-state concentrations require a twice-daily dosing of danazol for 6 days.

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

Metabolism: Danazol is extensively metabolized in the liver to 2-hydroxymethyl ethisterone. The drug is mainly excreted in the urine, and a small amount is excreted in the feces. Danazol appears to be metabolized into 2 primary metabolites: 2-hydroxymethyl danazol and ethisterone. 

Excretion: Danazol undergoes both urinary and fecal excretion, with urinary excretion accounting for the primary mode of excretion of the primary metabolites, while almost 10 different products have been identified in feces. The half-life of danazol has been reported to be at a mean of 9.7 hours. In patients with endometriosis, the half-life of danazol was reported to be 23.7 hours during treatment of 6 months with 200 mg thrice daily. 

Administration

Dosage Forms

Danazol is supplied as 50, 100, and 200 mg tablets and administered orally. 

Adult Dosing

Mild endometriosis: 100 to 200 mg orally daily, 2 or 3 times daily for 3 to 9 months. Start treatment during menses and adjust dose based on response.

Moderate to severe endometriosis: 400 mg orally per day, 2 or 3 times daily for 3 to 9 months. Start treatment during menses and adjust dose based on response.

Hereditary angioedema: Start 200 to 300 mg orally 2 to 3 times daily, decreasing the dose by 50% every 1 to 3 months. If an attack occurs during treatment, practitioners may increase the dose to 200 mg/d.

Fibrocystic breast disease (off-label): 50 to 200 mg orally twice daily. Start treatment during menses and adjust dose based on response.

Special Patient Populations

Hepatic impairment: Danazol is contraindicated in patients with marked hepatic impairment.

Renal impairment: In marked renal impairment, danazol is contraindicated.

Pregnant patients: Danazol is contraindicated in pregnancy due to androgenic effects on the female fetus based on human data. Clinicians should obtain a negative pregnancy test immediately before initiating treatment, and female patients should avoid pregnancy with a non-hormonal birth control method during treatment.

Breastfeeding considerations: No studies have adequately examined infant risk when using danazol while breastfeeding. Clinicians should weigh the potential benefits against possible risks before prescribing this drug to breastfeeding women, but the general recommendation is breastfeeding while taking danazol is contraindicated.[13] Theoretically, danazol could reduce milk production based on decreased prolactin levels.

Pediatric patients: Danazol is not indicated for pediatric patients

Older patients: Studies on the relationship between age and the effects of danazol have not been performed on patients older than 65. However, no specific problems have been documented with older patients taking the medication. 

Adverse Effects

As a synthetic steroid, danazol has many adverse effects in line with other androgens, making its adverse effects broad and systemic. The most commonly reported adverse effects of danazol include weight gain, gastrointestinal symptoms including bloating, nausea, vomiting, gastroenteritis, elevated liver function tests, joint pain, muscle spasms, lethargy, headache, and depression.[4] Other than these, gynecologic adverse effects such as intermenstrual bleeding, breast atrophy, flushes, and androgenic adverse effects such as hirsutism, decreased breast size, acne, hair loss, oily skin, oily hair, menstrual irregularities, and hoarseness, adverse effects due to weak mineralocorticoid activity such as swelling and edema have also been reported.[14][4]

Elevated blood pressure can also occur and remains an area that merits further investigation, along with its effects on adrenal activity.[14] The androgenic adverse effects have been shown to resolve after discontinuation of danazol. Danazol is also known to cause decreased plasma clearance of carbamazepine, with the elimination half-life increasing from 11 hours to 24.3 hours; carbamazepine dosing should be adjusted if co-administered with danazol.[15] 

Thromboembolism, thrombotic and thrombophlebitic events (eg, sagittal sinus thrombosis, stroke), pseudotumor cerebri (benign intracranial hypertension), peliosis hepatitis, benign hepatic adenoma have been reported with danazol use. Elevated concentrations of hepatic enzymes (eg, alkaline phosphatase, AST, ALT) and 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; its concurrent use with statins has been reported to cause rhabdomyolysis.[16][17][18]

Contraindications

Danazol is contraindicated in pregnancy due to its ability to cause virilization in female fetuses. Research has revealed that female fetuses exposed to danazol after 8 weeks of gestation were more likely to experience virilization, which followed the pattern of clitoromegaly, fused labia, and fused urogenital sinus formation.[19] Surgery is usually, but not always, required for correction of virilization. Virilization can occur at doses as low as 200 mg.[19] 

Being an androgen, danazol should also be avoided in androgen-dependent tumors, eg, prostate cancer. Danazol also induces the ALA synthase enzyme and porphyrin metabolism. Therefore, it 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 adverse effect profile than other drugs used to treat similar conditions; its use still requires monitoring. Danazol can cause liver damage, especially with concomitant use of glucocorticoids.[20] This combination is used in patients with ITP; liver function tests should be monitored routinely to detect liver damage. A CBC can also be considered. Danazol decreases the clearance of carbamazepine. Thus, the carbamazepine dose should be adjusted accordingly, and blood levels should be monitored in patients receiving carbamazepine therapy being co-administered with danazol to avoid various adverse effects of carbamazepine.[15] 

Toxicity

Toxicity discussion generally revolves around the virilizing effects of danazol in females. Symptoms of overdose may include yellowing of the skin and eyes, abdominal pain, and dark urine. There is no antidote for danazol.[21]

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 due to its androgenic nature.[22] Moreover, there is clear evidence that the drug does not cause any long-term hematological problems, even for as long as 4 decades of use, which speaks to the drug's safety profile.[23] 

There is also evidence of its efficacy in acquired amegakaryocytic thrombocytopenic purpura, immune thrombocytopenia purpura, and chronic lymphocytic leukemia, where it is shown to induce apoptosis in leukemic cells.[5][12] Danazol is an inexpensive and readily available drug with a relatively safer adverse effect profile than conventional steroids. The drug has multiple implications in terms of hematological diseases. Clinicians should consider this drug 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. Danazol is still helpful for treatment-resistant varieties of endometriosis, as well as gynecological problems, including heavy menstrual bleeding.[4] Danazol can be a valuable agent in female patients with hematological and gynecological conditions, 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 older patients and those with diabetes, most of whom are already prescribed statin drugs for their conditions. The interprofessional healthcare team, including physicians, advanced practice practitioners, nursing staff, and pharmacists, should watch for drug interactions and combined toxicity. They should work collaboratively, engage in open communication, and closely monitor their medications to save the patient from liver damage and increase adherence, thereby improving therapeutic outcomes while minimizing adverse events.