The immunologic effects of danazol were studied in women with endometriosis and adenomyosis and include a decrease in serum immunoglobulins, a decrease in serum C3, a rise in serum C4 levels, decreased serum levels of autoantibodies against various phospholipid antigens, and decreased serum levels of CA125 during treatment (218,230–234,394,395). Danazol inhibits peripheral blood lymphocyte proliferation in cultures activated by T-cell mitogens but does not affect macrophage-dependent T-lymphocyte activation of B lymphocytes (396). Danazol inhibits IL-1 and TNF production by monocytes in a dose-dependent manner and suppresses macrophage-and monocyte-mediated cytotoxicity of susceptible target cells in women with mild endometriosis (397,398). These immunologic findings may be important in the remission of endometriosis with danazol treatment and may offer an explanation of the effect of danazol in the treatment of a number of autoimmune diseases, including hereditary angioedema, autoimmune hemolytic anemia, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura (399–403). Doses of 800 mg per day are used frequently in North America, whereas 600 mg per day is prescribed in Europe and Australia. It appears that the absence of menstruation is a better indicator of response than drug dose. A practical strategy for the use of danazol is to start treatment with 400 mg daily (200 mg twice a day) and increase the dose, if necessary, to achieve amenorrhea and relieve symptoms (393).
In a systematic review to determine the effectiveness of danazol compared to placebo or no treatment in the treatment of the symptoms and signs, other than infertility, of endometriosis in women of reproductive age, five randomized trials were included in which danazol (alone or as adjunctive therapy to surgery) was compared to placebo or no therapy (404). Treatment with danazol (including adjunctive to surgical therapy) was effective in relieving painful symptoms related to endometriosis when compared to placebo (404). Laparoscopic scores improved with danazol treatment (including as adjunctive therapy) when compared with either placebo or no treatment (404). Side effects were more commonly reported in those patients receiving danazol than for placebo (404).
The significant adverse side effects of danazol are related to its androgenic and hypoestrogenic properties. The most common side effects include weight gain, ﬂuid retention, acne, oily skin, hirsutism, hot ﬂashes, atrophic vaginitis, reduced breast size, reduced libido, fatigue, nausea, muscle cramps, and emotional instability. Deepening of the voice is another potential side effect that is nonreversible. Danazol can cause increased cholesterol and low-density lipoprotein levels and decreased high-density lipoproteins levels, but it is unlikely that these short-term effects are clinically important. Danazol is contraindicated in patients with liver disease because it is largely metabolized in the liver and may cause hepatocellular damage. Danazol is contraindicated in patients with hypertension, congestive heart failure, or impaired renal function because it can cause ﬂuid retention. The use of danazol is contraindicated in pregnancy because of its androgenic effects on the fetus.
Because of the many side effects of oral danazol, alternative routes of administration were studied. In an uncontrolled pilot study, local danazol treatment using a vaginal danazol ring (1,500 mg) was effective for pain relief in deeply infiltrative endometriosis. This treatment did not cause the classic danazol side effects or detectable serum danazol levels, and it allowed ovulation and conception to occur (405).