than 0.5 mg every evening should be avoided to prevent the risk of adrenal suppression and severe side effects that resemble Cushing syndrome. To avoid oversuppression of the pituitary– adrenal axis, morning serum cortisol levels should be monitored intermittently (maintain at >2 μg/dL). Reduction in hair growth rate was reported, and significant improvement in acne associated with adrenal hyperandrogenism (108).
Ketoconazole Ketoconazole inhibits the key steroidogenic cytochromes. Administered at a low dose (200 mg per day), it can significantly reduce the levels of androstenedione, testosterone, and calculated free testosterone (109). It is rarely used for the chronic inhibition of androgen production in women with hyperandrogenism because of the serious risk of adrenocortical suppression and development of adrenal crisis (15).
Spironolactone Spironolactone is a specific antagonist of aldosterone, which competitively binds to the aldosterone receptors in the distal tubular region of the kidney. It is an effective potassium-sparing diuretic that originally was used to treat hypertension. The effectiveness of spironolactone in the treatment of hirsutism is based on the following mechanisms: 1.
Competitive inhibition of DHT at the intracellular receptor level (22).
2.
Suppression of testosterone biosynthesis by a decrease in the CYP enzymes (110).
3.
Increase in androgen catabolism (with increased peripheral conversion of testosterone to estrone).
4.
Inhibition of skin 5α-reductase activity (22).
Although total and free testosterone levels are reduced significantly in patients with both PCOS and idiopathic hirsutism (hyperandrogenism with regular menses) after treatment with spironolactone, total and free testosterone levels in patients with PCOS remain higher than those with idiopathic hirsutism (hyperandrogenism with regular menses) (111). In both groups, SHBG levels are unaltered. The reduction in circulating androgen levels observed within a few days of spironolactone treatment partially accounts for the progressive regression of hirsutism.
At least a modest improvement in hirsutism can be anticipated in 70% to 80% of women using at least 100 mg of spironolactone per day for 6 months (112). Spironolactone reduces the daily linear growth rate of sexual hair, hair shaft diameters, and daily hair volume production (113). Combination therapy with spironolactone and oral contraceptives seems effective via their differing but synergistic activities (15,114).
The most common dose is 50 to 100 mg twice daily. Women treated with 200 mg per day show a greater reduction in hair shaft diameter than women receiving 100 mg per day (115). Maximal inhibition of hirsutism is noted between 3 and 6 months but continues for 12 months. Electrolysis can be recommended 9 to 12 months after the initiation of spironolactone for permanent hair removal.
The most common side effect of spironolactone is menstrual irregularity (usually metrorrhagia), which may occur in over 50% of patients with a dosage of 200 mg per day (115). Normal menses may resume with reduction of the dosage. Infrequently, other side effects such as mastodynia, urticaria, or scalp hair loss may occur. Nausea and fatigue can occur with high doses (112). Because spironolactone can increase serum potassium levels, its use is not recommended in patients with renal insufficiency or hyperkalemia. Periodic monitoring of potassium and creatinine levels is suggested.