Mechanism of Action of Danazol

Introduction

Danazol is a synthetic isoxazole derivative of 17-α-ethinyl testosterone with antigonadotropic, antiestrogenic, and weak androgenic properties. It is primarily used in the management of endometriosis, fibrocystic breast disease, hereditary angioedema, and certain gynecologic disorders. Danazol is a high-yield drug in pharmacology, gynecology, and endocrinology examinations because of its hypothalamic–pituitary axis suppression and unique hormonal effects.

Mechanism of Action (Step-wise)

Danazol exerts its therapeutic effects by suppressing gonadotropin secretion and altering sex hormone dynamics.

Step-wise mechanism:

1. Hypothalamic–Pituitary Axis Suppression
   Danazol acts centrally to inhibit the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus.
2. Reduced Gonadotropin Secretion
   Suppression of GnRH leads to decreased secretion of:
   • Luteinizing hormone (LH)
   • Follicle-stimulating hormone (FSH)
3. Inhibition of Ovarian Steroidogenesis
   Reduced LH and FSH levels result in decreased ovarian production of estrogen and progesterone.
4. Direct Inhibition of Steroidogenic Enzymes
   Danazol directly inhibits enzymes involved in steroid hormone synthesis in the ovary and adrenal glands.
5. Antiestrogenic Effect
   Lower estrogen levels lead to endometrial atrophy and suppression of ectopic endometrial tissue growth.
6. Weak Androgenic Activity
   Danazol binds weakly to androgen receptors, contributing to its therapeutic and adverse effects.
7. Increase in Complement C1 Esterase Inhibitor
   In hereditary angioedema, danazol increases hepatic synthesis of C1 esterase inhibitor, preventing bradykinin-mediated edema.

Pharmacokinetics

• Absorption: Well absorbed orally
• Bioavailability: High
• Distribution: Widely distributed; high protein binding
• Metabolism: Extensive hepatic metabolism
• Elimination: Fecal and renal excretion of metabolites
• Half-life: Approximately 15–18 hours

Danazol should be used cautiously in patients with hepatic dysfunction.

Clinical Uses

Danazol is used in hormone-dependent and complement-mediated disorders:

• Endometriosis
• Fibrocystic breast disease
• Hereditary angioedema (prophylaxis)
• Menorrhagia (selected cases)
• Precocious puberty (rare use)

Its use has declined due to androgenic adverse effects and availability of safer alternatives.

Adverse Effects

Adverse effects are largely related to androgenic and metabolic actions:

• Androgenic effects:
  • Weight gain
  • Acne
  • Hirsutism
  • Voice deepening
• Menstrual disturbances:
  • Amenorrhea
  • Irregular bleeding
• Metabolic:
  • Dyslipidemia (↓ HDL, ↑ LDL)
• Hepatic:
  • Elevated liver enzymes
  • Rare hepatotoxicity
• Others:
  • Hot flashes
  • Mood changes

Danazol is contraindicated in pregnancy due to risk of virilization of the fetus.

Comparative Analysis (must include a table + explanation)

Comparison of Drugs Used in Endometriosis

Explanation:
Danazol effectively suppresses estrogen production but is limited by androgenic side effects. GnRH agonists are more commonly used today despite hypoestrogenic effects, while progestins provide a safer long-term option.

MCQs (10–15)

1. Danazol primarily suppresses the release of:
   a) Prolactin
   b) Cortisol
   c) LH and FSH
   d) Thyroxine

Answer: c) LH and FSH

2. Danazol is chemically related to:
   a) Estrogen
   b) Progesterone
   c) Testosterone
   d) Cortisol

Answer: c) Testosterone

3. Danazol is most commonly used in the treatment of:
   a) Polycystic ovary syndrome
   b) Endometriosis
   c) Breast cancer
   d) Ovarian cancer

Answer: b) Endometriosis

4. The antiestrogenic effect of danazol is due to:
   a) Estrogen receptor blockade
   b) Decreased estrogen synthesis
   c) Increased estrogen metabolism
   d) Aromatase inhibition

Answer: b) Decreased estrogen synthesis

5. Danazol is beneficial in hereditary angioedema because it:
   a) Blocks histamine
   b) Inhibits mast cells
   c) Increases C1 esterase inhibitor
   d) Blocks bradykinin receptors

Answer: c) Increases C1 esterase inhibitor

6. A major adverse effect of danazol is:
   a) Osteoporosis
   b) Androgenic effects
   c) QT prolongation
   d) Agranulocytosis

Answer: b) Androgenic effects

7. Danazol reduces estrogen levels by inhibiting:
   a) Aromatase only
   b) Ovarian steroidogenesis
   c) Estrogen receptors
   d) Estrogen transport proteins

Answer: b) Ovarian steroidogenesis

8. Danazol is contraindicated in:
   a) Endometriosis
   b) Pregnancy
   c) Fibrocystic breast disease
   d) Hereditary angioedema

Answer: b) Pregnancy

9. Danazol decreases menstrual bleeding by causing:
   a) Endometrial proliferation
   b) Endometrial atrophy
   c) Ovulation induction
   d) Cervical dilation

Answer: b) Endometrial atrophy

10. Which lipid change is seen with danazol therapy?
    a) ↑ HDL
    b) ↓ LDL
    c) ↓ HDL
    d) ↓ Triglycerides

Answer: c) ↓ HDL

FAQs (minimum 5)

1. What is the primary mechanism of danazol?
   Suppression of LH and FSH leading to reduced estrogen production.
2. Why is danazol effective in endometriosis?
   It induces a hypoestrogenic state causing endometrial atrophy.
3. Does danazol have androgenic effects?
   Yes, due to its weak androgen receptor activity.
4. Why is danazol used in hereditary angioedema?
   It increases synthesis of C1 esterase inhibitor.
5. Is danazol commonly used today?
   Its use has declined due to side effects and availability of safer alternatives.
6. Can danazol cause liver toxicity?
   Yes, liver function monitoring is recommended.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

Download