Hepatotoxicity with flutamide

23 08 2012

To the Editor:

We read with great interest the article by Bruni et al. published in Fertility and Sterility (1). The article describes the hepatotoxicity with flutamide on hyperandrogenic young females. Bruni et al. found hypertransaminasemia in 19 patients during the first year of treatment.

Flutamide is an oral, non-steroidal antiandrogen drug primarily used to treat prostate cancer and excess androgen levels in hyperandrogenic women. Side effects of this drug include diarrhea, gynecomastia, muscle cramps, hematological alterations, and hepatotoxicity (2).

Drug-related hepatotoxicity is defined as an alanine aminotransferase (ALT) level of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of the normal range (3). In the study of Bruni et al., the cutoff levels of ALT and aspartate aminotransferase (AST) were determined by 40 U/L and hepatotoxicity was considered to be at least 2.5- to 3-fold higher in hypertransaminasemia. According to the definition of hepatotoxicity, in Table 3, which detailed patients with increasing levels of circulating AST/ALT, three patients have drug-related hepatotoxicity (patients 7, 17, and 18). Furthermore, in two patients (patients 17 and 18) hepatotoxicity may be associated with estroprogestagen oral contraceptives. On these grounds, hepatotoxicity with flutamide is seen in one patient (patient 7), and hepatotoxicity-based analysis might have influenced the outcomes of this study.

Hypertransaminasemia was considered hepatotoxicity with flutamide in 19 patients in Table 4. Elevations in serum enzyme levels (ALT, AST) were taken as indicators of liver injury, whereas ALT might increase more than thrice the upper limit of the normal range to define drug-related hepatotoxicity. Also, it is important to know the alkaline phosphatase and total/conjugated bilirubin level to recognize the pattern of liver injury. That issue has not been clarified.

Taken together, mild hypertransaminasemia usually can be detected in flutamide users. But, hepatotoxicity associated with low- and ultralow-dose flutamide is actually rare.

Fatih Karaahmet, M.D. and Kutlu Kurt, M.D.
Department of Gastroenterology, Dışkapı Yıldırım Beyazıt Educational and Research Hospital
Ankara, Turkey


1. Bruni V, Peruzzi E, Dei M, Nannini S, Seravalli V, Sisti G, et al. Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females. Fertil Steril, In Press, DOI: 10.1016/j.fertnstert.2012.06.018.

2. Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature. Ann Hepatol. 2011;10:93-8.

3. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.08.045

The authors respond:

We appreciate the interest in our experience about hepatotoxicity with low- and ultralow-dose flutamide in hyperandrogenic young females (1).

Concerning drug-induced hepatotoxicity, some different definitions are currently available according to the age of investigated subjects, biochemical marker used, and increasing trend with time.

Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually used to define liver involvement, with a revealing value ranging from 50% over the upper limit of the normal range to 10-fold higher than normal level according to different authors (2, 3). Also, the value of cutoff limit for AST/ALT normality varies, and, in previous studies with flutamide, ranges from 32 U/L to 38 U/L and from 32 U/L to 55 U/L, respectively, for basal circulating AST and ALT (3, 4).

In our study, combining previous definitions, we used 40 U/L as the cutoff limit both for basal circulating AST and ALT. The value revealing hepatotoxicity was considered to be at least 2.5- to 3-fold higher in moderate hypertransaminasemia and 10-fold higher in severe hypertransaminasemia, whereas all the other increases above the normal cutoff limit were defined as mild.

Considering that flutamide is used off-label for hirsutism in Italy, and several cases of severe hepatotoxicity and fatal liver complications while using flutamide in young females have been described previously (5), the treatment was administered with the utmost caution in our patients. According to our policy, treatment was immediately suspended in subjects with increased AST/ALT above-normal value, since treatment for predominantly aesthetic purposes is not supposed to be justified when an initial alteration in liver function is demonstrated. Considering this aspect, the trend in AST/ALT values when continuing the treatment can’t be foreseen and further increases cannot be fully excluded.

We are aware that methodological differences among available studies may influence comparison of results, but we believe that our observation represents a significant contribution to the scientific literature since various degrees of hypertransaminasemia with low- and ultralow-dose flutamide have been described for the first time. However, as stated in our manuscript, presented data must be proved in larger study populations, and flutamide remains a cornerstone of treatment for hyperandrogenism.

Finally, concerning the possible association of hypertransaminasemia with the use of third-generation oral contraceptives (OCs) (as used in our experience), we believe it is a rare but possible event. Our statistical analysis according to the findings observed by others (3) excluded this association. However, OCs are often chosen by young females taking flutamide, when contraception during the treatment is recommended, so this bias affects most available retrospective clinical studies.

In conclusion, the points raised are interesting and highlight the importance of using similar methods when performing clinical studies so that the results can be appropriately interpreted and reproduced. However, we do not believe these points substantially alter the present value of our data and conclusion. Again, larger prospective clinical trials will answer most of the questions.

Thank you for the opportunity to respond to these issues.

Vincenzina Bruni, M.D., Elena Peruzzi, M.D., Metella Dei, M.D., Sara Nannini, M.D.,
Viola Seravalli, M.D., Giovanni Sisti, M.D., Massimiliano Fambrini, M.D.
Department of Science for Woman and Child Health
University of Florence
Florence, Italy


1. Bruni V, Peruzzi E, Dei M, Nannini S, Seravalli V, Sisti G, et al. Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females. Fertil Steril, In Press, DOI: 10.1016/j.fertnstert.2012.06.018.

2. Kew MC. Serum aminotransferase concentration as evidence of hepatocellular damage. Lancet 2000;355:591-2.

3. Paradisi R, Venturoli S. 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. Eur J Endocrinol 2010;163:139-47.

4. Ibáñez L, Jaramillo A, Ferrer A, de Zegher F. Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women. Hum Reprod 2005;20:1833-6.

5. Osculati A, Castiglioni C. Fatal liver complications with flutamide. Lancet 2006;367:1140-1.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.08.046




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