Flutamide is a non-steroidal antiandrogen that is devoid of other hormonal activity. It most likely acts after converting to 2-hydroxyflutamide, which is a potent competitive inhibitor of dihydrotestosterone (DHT) binding to the androgen receptor. Flutamide is currently approved for the treatment of prostate cancer in combination with luteinizing hormone-releasing hormone (LHRH), wherein Flutamide is thought to inhibit the action of testosterone on cancer cells by blocking the receptor sites that testosterone uses in the cells.
Testosterone – Androgen 
DHT Dihydrotestosterone – Androgen
Metabolism of flutamide
Flutamide is rapidly absorbed, reaching maximum plasma levels after 4 to 6 hours. The drug is rapidly metabolized to at least 10 plasma metabolites. Of these, 2-hydroxy-flutamide is in all probability, responsible for its biologic activity. Flutamide and its metabolites are excreted mainly in the urine. At least 16 percent systemic absorption was seen with the application of 5 mg of a topical preparation of Flutamide in 50 percent propylene glycol and 50 percent ethano1. The rate of metabolism is slower with topical use of Flutamide. However, the same metabolites are present in urine and plasma after oral and topical doses.
Indications
Flutamide is useful in inhibiting the action of adrenal androgens in castrated men or those receiving GnRH blockage. (Gonadotropin-releasing hormone or GnRH stimulates the pituitary gland to release luteinizing hormone-releasing hormones and drugs known as GnRH antagonists, block this action). Flutamide can also be used in situations in which LH production is not under predominant control by androgen, such as in women. Flutamide is indicated for prostate cancer, and has been used in conjunction with oral contraceptive pills for treating hirsutism.
Flutamide’s antiandrogen activity and its affinities for the androgen receptor in various androgen-sensitive tissues make it worth investigating its role in androgen-mediated responses like androgenetic alopecia. As Flutamide is potent enough to have a feminizing effect in men, its use is limited to treating female pattern hair loss. Anti-androgen therapy may prevent the degeneration of further follicles into vellus-hair production, but is unlikely to restore terminal hair production in previously effected follicles.
Mechanism of action for flutamide
In animal studies, Flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. In mature rat studies, Flutamide was shown to cause regression of androgen target tissues such as the prostate and seminal vesicles by blocking the inhibitory feedback of testosterone on luteinizing hormone (LH) production, which results in a profound increase in their plasma concentrations.
Adult men treated with 750 mg per day Flutamide showed similar effects. The predominant pituitary effect appears to be enhancement of the frequency of pulses of LH secretion. The drug may be effective in vitro as an antiandrogen; in vivo, however, the rise in plasma testosterone levels may limit its antiandrogenic effects.
Flutamide, or most likely 2-hydroxy-flutamide, inhibits the tissue uptake and retention of testosterone and also the formation of the nuclear steroid-androgen receptor complex. Antiandrogens without a steroidal structure may inhibit the negative feedback of the gonadal steroids so that more gonadotropins are released by the pituitary and more testosterone and estradiol are produced by the gonads. These nonsteroidal antiandrogens, then, require a concomitant antigonadotropin to prevent an increase in androgen load, which could neutralize their inherent antiandrogen effect. Flutamide inhibits the negative feedback of gonadal steroids at the hypothalamic-pituitary leve1. It decreases the cytochrome P450 content in the testicular microsomal fraction in male rats and inhibits rat testicular microsomal 17 to 20-hydroxylase and 17 to 20 lyase activity- this may be how it suppresses androgen biosynthesis.
Dosage of flutamide
Flutamide is available with a prescription under the brand name Eulexin. Other brand or generic formulations may also be available. Doses of Flutamide for metastatic prostatic carcinoma are 250 mg three times daily, but in the treatment of hirsutism, doses of 125 mg twice a day have been found to be effective. Topical Flutamide can be used in androgenetic alopecia.
Side Effects of flutamide
Side effects of oral Flutamide are primarily gastrointestinal, mainly diarrhea. A high incidence of dry skin (58 percent) has also been reported. An important side effect to be cautious about in oral administration is hepatotoxicity, including progressive liver failure, which limits the usefulness of the drug in androgenetic alopecia. Evidence of hepatic injury includes elevated serum transaminase (liver enzyme) levels, jaundice, hepatic encephalopathy, and death related to acute hepatic failure. Serum transaminase levels should be measured prior to starting treatment with Flutamide. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, like nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms or jaundice.
Flutamide should not be given to pregnant women or women desiring to become pregnant. If the drug crosses the placenta, it would be expected to produce male pseudohermaphroditism, similar to cyproterone acetate. Therefore Flutamide should be combined with an oral contraceptive pill in women of child-bearing potential to avoid the risk of pregnancy.
Clinical trials with flutamide
There are incidental reports of improvement of female pattern hair loss in women with hirsutism treated with Flutamide.
- 17of 18 women with hirsutism treated with combination therapy of Flutamide 250 mg twice daily and an oral contraceptive pill had a rapid and marked reduction in their hirsutism score. Amongst these, one woman with pattern hair loss showed remarkable improvement.
- At least one study has shown decreased testosterone levels in women with idiopathic hirsutism treated with 125 mg Flutamide three times a day and a leveling of the rhythmic changes in serum androgen receptor concentration with the menstrual cycle.
- Ross reports a recent comparative study in hyper-androgenic pre-menopausal women with female pattern hair loss treated with Flutamide (250 mg per day), Cyproterone acetate, or finasteride showed that Flutamide alone was successful in producing a small but definite reduction in hair loss.
Further studies are needed to evaluate the efficacy of Flutamide as a topical agent in treating androgenetic alopecia.