Long-Term Efficacy and Tolerability of Flutamide Combined with Oral Contraception in Moderate to Severe Hirsutism: A 12-Month, Double-Blind, Parallel Clinical Trial

Abstract

Flutamide at 125 mg daily during 12 months was the minimum effective dose to diminish hirsutism in patients with polycystic ovary syndrome or with idiopathic hirsutism.

Retrospective observational study on the effects and tolerability of flutamide in a large population of patients with various kinds of hirsutism over a 15-year period

“…The limited utility of the fT assay (due to its low sensitivity) did not impugn the results. The evident decrease in serum androgen levels was in agreement with ours and other previous reports (6,18,19,21,22,25,31,32,34,(36)(37)(38), and in disagreement with others (16,23,27,29,30) using different doses of Flu and smaller sizes of the subject sample enrolled. Hence, although Flu is considered a pure anti-androgen, the main action of which is attributed to its peripheral antiandrogenic properties, our data also confirm a direct inhibitory effect on androgen secretion, resulting from a blockade of the steroidogenic enzymes of androgen biosynthesis in both ovarian thecal and adrenal corticoreticular cells, as has been reported already (18,21,24).…”

“…This strengthens the opinion that this inhibitory action is so strong that it minimizes any further beneficial effect on androgen secretion due to the oestroprogestogen supplementation, such as a reduction in the free, biologically active testosterone fraction resulting from the OC-induced increase in SHBG levels. In fact, whilst SHBG levels did not alter during Flu treatment, they increased markedly when Flu was used along with an OC, confirming previous results (16,20,37). Concerning gonadotrophins, Flu has no effect on FSH and LH, and also on PRL, confirming the lack of a central anti-gonadotrophic activity, as has been reported already (14,15).…”

“…A slight decrease has been observed in progesterone levels during Flu treatment according to Cesur et al (17), but this is in contrast with others (19,21). The marked decrease observed in 17-hydroxyprogesterone levels supports the inhibitory action of Flu on the 17a-hydroxylase activity, confirming ours and other studies (6,32,37). Otherwise, the marked decrease observed in FSH, LH, E 2 , E 1 , progesterone and 17-hydroxyprogesterone levels in patients treated with Flu and OCs depends on the well-known inhibitory effect exerted by the OCs on hypothalamic-pituitary-gonadal axis.…”

“…Furthermore, considering that the efficacy of the lowFlu doses (62.5-125 mg) in hirsutism is practically similar to that reported with higher daily doses (375-750 mg) (30,37), the ideal treatment for hirsutism seems to be, after an adequate period of attack therapy with 250 mg, with doses tending to be slowly reduced in the course of the time according to clinical results, so as to result in long-term therapy using the minimum effective dose and to have prolonged and almost definitive outcome. Our observations are in agreement with those of Azziz (1), who underlined that treatments for hirsutism should be continued for at least 2 years to achieve the maximum effect with a subsequent progressive reduction in the dose of antiandrogen employed, and with those of Rittmaster (48), who asserted that these medical therapies will often need to be continued indefinitely.…”

“…Fatal and non-fatal hepatotoxicity associated with the use of Flu has been reported in male prostate cancer (46) and in female hirsutism (47). Considering that flutamide hepatotoxicity appears to be dose dependent (27,30,35,37), the use of very low doses of flutamide (62.5-125 mg/day) seems appropriate to treat hirsutism, so as to almost completely eliminate adverse events caused by the drug. In fact, a tendency to use lower doses of flutamide in the course of time both as monotherapy in the treatment of hirsutism (29,38) and as polytherapy in association with insulin sensitizers in the treatment of PCOS and related metabolic disorders (35) has been accomplished.…”