Danazol and Gestrinone

The antiprogestogen danazol inhibits secretion of pituitary gonadotrophins. It also has androgenic, anti-oestrogenic, and antiprogestogenic activity, and usually causes amenorrhoea. It is only licensed for use in women who have not responded to other treatments.

The antiprogestogen gestrinone has similar actions to danazol, but has a longer half-life, allowing twice weekly instead of daily dosing.

Danazol combines androgenic activity with antioestrogenic and antiprogestogenic activity. It is licensed for the treatment of:

• Endometriosis:
  • Current treatment regimes are limited to 6 months because of significant metabolic side effects.¹
  • Progestogens and antiprogestogens were compared with other hormonal therapies in a Cochrane review of their efficacy for the relief of pain associated with endometriosis.²
  • There is a general lack of data and none of the studies included enough women to reach any firm conclusions. The authors concluded that treatment with antiprogestogens (or continuous progestogens) is likely to be effective.
  • Alternatives for longer-term management of symptoms include add-back therapy with GnRH analogues, combined oral contraceptives or progestins.
  • A danazol-loaded intrauterine device (IUD) has been trialled in a small number of patients with dysmenorrhea, dyspareunia, and pelvic pain significantly decreased after the first month, and a persistent effect during the 6 months of IUD insertion.³ Further work will show efficacy and adverse systemic effects in the longer term.
• Benign fibrocystic breast disease - pain and tenderness relief where other measures have proved unsatisfactory:
  • One RCT found that danazol reduced cyclical breast pain after 12 months compared with placebo, but it increased adverse effects (weight gain, deepening of the voice, menorrhagia, and muscle cramps).⁴
  • It found no significant difference in pain relief between danazol and tamoxifen.
  • Once a response has been achieved, adverse effects (which limit the usefulness of the drug) can be avoided by reducing the dose of danazol to 100 mg daily and confining treatment to the 2 weeks preceding menstruation.
• It may also be effective in the long-term management of hereditary angioedema, although this is an unlicensed indication.⁵
• It has been shown to treat aplastic anaemia refractory to immunosuppressive therapy (IST) and those who relapsed after IST.⁶ It is particularly effective in female patients.

Gestrinone has general actions similar to those of danazol and is indicated for the treatment of endometriosis.

Cautions

• Cardiac, hepatic, or renal impairment - avoid if severe
• Elderly
• Polycythaemia
• Epilepsy
• Diabetes mellitus
• Hypertension
• Migraine
• Lipoprotein disorder
• History of thrombosis or thromboembolic disease
• Withdraw if virilisation occurs, as this may be irreversible on continued use

NB: Non-hormonal contraceptive methods should be used, if appropriate.

Contraindications

It is poorly tolerated because of androgenic adverse effects of:

• Weight gain
• Hirsutism
• Acne, oily skin
• Mood changes
• Anxiety
• Changes in libido
• Occasionally deepening of the voice (which may be irreversible^2,7)
• It does not reduce bone mineral density, as its anabolic effects counteract the effect of lowered oestrogen levels^8,9
• Skin reactions including rashes, photosensitivity and exfoliative dermatitis
• Leucopenia, thrombocytopenia, eosinophilia, reversible erythrocytosis or polycythaemia reported
• Musculo-skeletal spasm, joint pain and swelling
• Temporary alteration in lipoproteins and other metabolic changes, insulin resistance
• Rarely cholestatic jaundice, pancreatitis, peliosis hepatis and benign hepatic adenomata
• Epigastric and pleuritic pain
• Menstrual disturbances
• Vaginal dryness and irritation

Gestrinone is better tolerated because it is less androgenic.¹⁰