Pharmacology of Danazol: a synthetic steroid

Introduction

Danazol is a synthetic steroid derived from ethisterone (a modified testosterone) and is known for its antigonadotropic and anti-estrogenic activities. It was initially approved by the U.S. FDA for the treatment of endometriosis, although its use has been largely superseded by gonadotropin-releasing hormone (GnRH) agonists. Besides endometriosis, Danazol is utilized for managing fibrocystic breast disease, hereditary angioedema, and in certain cases, refractory immune thrombocytopenia​1​.

Mechanism of Action

Danazol exerts its effects by several mechanisms:

  1. Gonadotropin Inhibition: By suppressing the pituitary-ovarian axis, possibly via inhibiting pituitary gonadotropin output, Danazol reduces the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to decreased ovarian estrogen production.
  2. Steroidogenesis Inhibition: Danazol might directly inhibit ovarian steroidogenesis and bind to androgen, progesterone, and glucocorticoid receptors, thereby modulating hormonal balance.
  3. Binding to Hormone-Binding Globulins: By binding to sex-hormone-binding globulin and corticosteroid-binding globulin, Danazol affects the metabolic clearance rate of progesterone.
  4. Immunomodulatory Effects: The drug alters the immune response by decreasing concentrations of certain immunoglobulins and autoantibodies, which could be beneficial in conditions like endometriosis.
  5. Anti-estrogenic Activities: It induces inactivity and atrophy in both normal and ectopic endometrial tissues, resulting in anovulation and associated amenorrhea in endometriosis treatment.
  6. Correction of Biochemical Deficiency in Hereditary Angioedema: Danazol elevates serum concentrations of the deficient C1 esterase inhibitor, thus correcting the biochemical deficiency seen in hereditary angioedema​1​.

Pharmacokinetics

  • Absorption: Danazol is well absorbed in the gastrointestinal tract.
  • Distribution: The distribution dynamics of Danazol are yet to be fully elucidated.
  • Metabolism: Danazol undergoes hepatic metabolism.
  • Excretion: Primarily excreted in the urine​2​.

Therapeutic Uses

Danazol is employed for several indications including:

  1. Endometriosis: Treatment of endometriosis to alleviate associated symptoms.
  2. Fibrocystic Breast Disease: Symptomatic treatment of severe pain and tenderness associated with benign fibrocystic breasts in patients unresponsive to simple measures.
  3. Hereditary Angioedema: Prophylactic treatment for all types of hereditary angioedema in both males and females.
  4. Refractory Immune Thrombocytopenia: In some cases, Danazol might be used for the management of refractory immune thrombocytopenia​1​.

Recent Updates

  • An animal study published in 2023 highlighted that Danazol could increase the oral bioavailability of midazolam by inactivating hepatic and intestinal CYP3A in rats​3​.
  • A Phase 2 clinical trial is recruiting patients to compare low-dose Baricitinib plus Danazol versus Danazol alone for patients with steroid-resistant/relapse immune thrombocytopenia​4​.

Adverse Effects

The most common adverse effects include weight gain, acne, edema, flushing, sweating, androgenic effects such as hirsutism and deepening of the voice, and menstrual irregularities. Serious adverse effects encompass hepatic dysfunction and a potential risk for thromboembolic events​2​.

Drug Interactions

Danazol can interact with anticoagulants, insulin or oral diabetes medication, and other hormonal treatments including hormone replacement therapy and hormonal contraceptives.

Conclusion

Danazol, with its multi-faceted pharmacological profile, serves as a crucial therapeutic option for various hormone-related and immunological conditions. Despite being overshadowed by newer agents, understanding its pharmacology is pivotal for rational clinical use.

The information is compiled from various sources including DrugBank, NCBI, TandFOnline, Synapse, Drugs.com, and Medicine.com among others1,​ 2, 3,​​ ​​4,5, ​​6, ​​7, ​​8, ​​9, ​​​​10, 11​​​​.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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