Return of normal menses in amenorrheic patients is reported in up to 60% of cases (111). Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus.
Cyproterone Acetate Cyproterone acetate is a synthetic progestin derived from 17-OHP, which has potent antiandrogenic properties. The primary mechanism of cyproterone acetate is competitive inhibition of testosterone and DHT at the level of the androgen receptor (116). This agent induces hepatic enzymes and may increase the metabolic clearance rate of plasma androgens (117).
A European formulation of ethinyl estradiol with cyproterone acetate significantly reduces plasma testosterone and androstenedione levels, suppresses gonadotropins, and increases SHBG levels (118). Cyproterone acetate shows mild glucocorticoid activity (and may reduce DHEAS levels) (116,119). Administered in a reverse sequential regimen (cyproterone acetate 100 mg per day on days 5 to 15, and ethinyl estradiol 30 to 50 mg per day on cycle days 5 to 26), this cyclic schedule allows regular menstrual bleeding, provides excellent contraception, and is effective in the treatment of even severe hirsutism and acne (120).
Side effects of cyproterone acetate include fatigue, weight gain, decreased libido, irregular bleeding, nausea, and headaches. These symptoms occur less often when ethinyl estradiol is added. Cyproterone acetate administration is associated with liver tumors in beagles and is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States.
Flutamide Flutamide, a pure nonsteroidal antiandrogen, is approved for treatment of advanced prostate cancer. Its mechanism of action is inhibition of nuclear binding of androgens in target tissues. Although it has a weaker affinity to the androgen receptor than spironolactone or cyproterone acetate, larger doses (250 mg given two or three times daily) may compensate for the reduced potency. Flutamide is a weak inhibitor of testosterone biosynthesis.
In a single, 3-month study of ﬂutamide alone, most patients demonstrated significant improvement in hirsutism with no change in androgen levels (121). Significant improvement in hirsutism with a significant drop in androstenedione, DHT, LH, and FSH levels was observed in an 8-month follow-up of ﬂutamide and low-dose OCs in women who did not respond to OCs alone (122). The side effects of ﬂutamide treatment combined with a low-dose OC included dry skin, hot ﬂashes, increased appetite, headaches, fatigue, nausea, dizziness, decreased libido, liver toxicity, and breast tenderness (123).