Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.
BACKGROUND
Flutamide is a pure non-steroidal anti-androgen that may be hepatotoxic, when given in high-dose (750 mg/d). Low- to ultralow-doses (250-62.5 mg/day) have been recently explored in patients with Polycystic Ovary Syndrome (PCOS), and these lower doses were found to confer benefit on multiple PCOS markers. There is a need for evidence on the potential hepatotoxicity of low- and ultralow-dose flutamide therapy.


METHODS
We assessed circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of hepatotoxicity in a total of 190 hyperandrogenic girls and young women receiving low- or ultralow-dose flutamide because of established (n = 150) or incipient (n = 40) PCOS without obesity. Assessments were performed before start of flutamide, after 3 months, and subsequently at least twice yearly.


RESULTS
AST and ALT results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment, which was after a mean time of 19 months on low- or ultralow-dose flutamide (range 3-54 months). None of the AST or ALT levels at any time during flutamide treatment was > or = 45 U/L.


CONCLUSIONS
We found no evidence for hepatotoxicity in 190 hyperandrogenic girls or young women receiving low- or ultralow-dose flutamide for up to 54 months. These results may represent a first step in a long process whereby the status of low- and ultralow-dose flutamide may gradually evolve from 'absence of evidence on toxicity' towards 'evidence of absence of hepatic toxicity'. Ultralow-dose flutamide may become a key component within future therapies for hyperandrogenic states in girls and young women.
Ibáñez
Lourdes
L
Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. libanez@hsjdbcn.org
Jaramillo
Adriana
A
Ferrer
Angela
A
de Zegher
Francis
F
D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D005485:Flutamide / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D017588:Hyperandrogenism / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology
D000726:Androgen Antagonists; D015415:Biomarkers; D005485:Flutamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase