Pharmacology of Danazol: a synthetic steroid

Introduction and Chemical Nature

Danazol is a synthetic isoxazole derivative of 17α-ethinyl testosterone. It was developed for its unique endocrine properties and mild androgenic activity, making it useful in various gynecological and hematological conditions. Structurally, its modifications confer the ability to suppress gonadotropin secretion and interact with multiple steroid receptors.

Mechanism of Action

Danazol exerts a multifaceted mechanism:

1. Suppression of Gonadotropin Secretion:
   • Inhibits hypothalamic-pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via negative feedback. This leads to reduced ovarian estrogen synthesis and, in males, a decrease in testicular androgen production.
2. Direct Inhibition of Steroidogenesis:
   • Inhibits ovarian, testicular, and adrenal steroidogenesis by interfering with various enzymes, including aromatase and others—thus further decreasing estrogen and androgen production.
3. Binding to Steroid Receptors:
   • Binds to androgen, progesterone, glucocorticoid, and (less so) estrogen receptors; partial agonist and antagonist actions.
   • Reduces hepatic synthesis of sex hormone-binding globulin (SHBG), increasing bioavailable testosterone and estradiol.
4. Immunomodulatory effects:
   • In hereditary angioedema, danazol increases hepatic synthesis of C1 esterase inhibitor, raising serum C4 and C2 complement levels.

Pharmacokinetics

Clinical Indications

Dosing: Usual adult doses: 200–800 mg/d in divided or twice-daily dosing (lower doses for angioedema prophylaxis).

Adverse Effects

Contraindications:

• Pregnancy (teratogenic, virilization)
• Severe hepatic, renal, or cardiac dysfunction
• Known, suspected androgen-dependent tumors
• Porphyria

Drug Interactions

• CYP3A4 inhibitors or inducers may affect danazol metabolism.
• Warfarin, cyclosporine, statins: May increase toxicity due to shared metabolic pathways or plasma protein binding.
• May potentiate effects of insulin and oral hypoglycemic agents.

Clinical Pearls

• Danazol’s value in endometriosis and hereditary angioedema is established, but adverse effects (esp. androgenic, hepatic, and dyslipidemic) limit long-term use.
• Newer agents (GnRH analogs, aromatase inhibitors, and progestins for endometriosis; C1-INH, lanadelumab for angioedema) are preferred due to improved safety.
• Monitoring: LFTs, lipids, blood counts, and routine clinical assessment is mandatory for all patients on danazol.

References

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill; 2022.
2. StatPearls. Danazol [Internet]. 2024 Feb 27.
3. Donaldson VH. Danazol: endocrine pharmacology and therapeutic applications. Ann Intern Med. 1989;111(6):403–412.
4. Danazol—DrugBank. Updated Sep 2015.
5. RxList. Danazol (Danocrine): Side Effects, Uses, Dosage, and More. 2023.
6. Danocrine® US FDA label. Revised 2011.