1 Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Passeig de sant Joan de Déu, 2 08950 Esplugues, Barcelona, Spain and 2 Department of Pediatrics, University of Leuven, Leuven, Belgium
3 To whom correspondence should be addressed. Email: libanez{at}hsjdbcn.org
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Abstract |
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Key words: androgen/androgen receptor/flutamide/hepatotoxicity/PCOS
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Introduction |
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In an attempt to maintain flutamide's anti-androgen action, while avoiding its hepatotoxicity, the ultralow-dose of 62.5 mg/day has been recently explored in women with hirsutism (Muderris et al., 2000) and in adolescents and women with hyperinsulinemic hyperandrogenisma variant of Polycystic Ovary Syndrome (PCOS) (Ibáñez and de Zegher, 2003a
, 2004
, 2005
; Ibáñez et al., 2004a
). The key finding in the latter studies was that the addition of ultralow-dose flutamide to a combination of metformin plus an oral contraceptive (OC) confers additive benefit on multiple PCOS markers, including LDL-cholesterol, interleukin-6, adiponectin, abdominal and total fat, and lean mass, while there was no evidence of hepatotoxicity (Ibáñez et al., 2004a
). The treatment duration in those reports, however, was limited to 39 months. Before more widespread use of flutamide in ultralow-dose might be envisaged for hyperandrogenic girls and women, there is a need for longer-term data on potential hepatotoxicity. In each of our low-dose flutamide studies in young patients with PCOS (Ibáñez and de Zegher, 2003a
,b
, 2004
, 2005
; Ibañez et al., 2000
, 2002
, 2003
, 2004a
), we screened on a regular basis for hepatotoxicity. Here, we report our results on the hepatotoxicity of flutamide, when given for up to 36 months in ultralow-dose and for up to 54 months in total.
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Study population and methods |
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All patients received flutamide within a series of randomized intervention studies that consecutively explored the efficacy of ever lower doses. Flutamide was given either in monotherapy or in a combination therapy with an insulin sensitizer (metformin, 8501275 mg/day) and/or an estro-progestagen OC that contained gestodene or drospirenone (Ibañez et al., 2000, 2002
, 2003
, 2004a
,b
; Ibáñez and de Zegher, 2003a
,b
, 2004
, 2005
). In these studies, the higher flutamide doses were 125 mg/day or 250 mg/day, and the low-dose was 62.5 mg/day. All patients initially receiving a higher study dose were post-study switched to the low-dose; all patients first receiving the low-dose, remained on the same low-dose.
Each of the consecutive study populations have previously been reported in detail (Ibañez et al., 2000, 2002
, 2003
, 2004a
,b
; Ibáñez and de Zegher, 2003a
,b
, 2004
, 2005
). In summary, the common inclusion criteria were: (1) post-menarcheal status; (2) hyperinsulinemia on a standard 2-h oral glucose tolerance test (oGTT), defined as peak serum insulin levels >150 µU/mL and/or mean serum insulin >84 µU/mL (Ibáñez et al., 1997
; Vidal-Puig and Moller, 1997
), and an excessive 17-hydroxy-progesterone (17-OHP) response (>160 ng/dL) to GnRH agonist (leuprolide acetate, Abbott, Madrid, Spain, 500 µg s.c.) (Ibáñez and de Zegher, 2005
); (3) BMI < 26 kg/m2.
In addition, girls with incipient PCOS (age, mean ± SEM, 12.9 ± 0.2 years) combined a history of a birthweight below 1.5 SD for gestational age (corresponding to a birthweight below 2.7 kg in term Catalan girls) with a history of precocious pubarche [presence of pubic hair before the age of 8 years (Ibáñez et al., 2001
)]; this combination is known to confer a high risk for progression to full-spectrum PCOS in adolescence (Ibáñez et al., 2001
, 2004b
).
In addition, adolescents and women with established PCOS (age, 16.4 ± 0.2 years) presented: hirsutism; amenorrhea (no menses for >3 months) or oligomenorrhea (inter-menstrual phase of >45 day); and hyperandrogenemia (elevated serum androstenedione, total testosterone, or free androgen index [testosterone x 100/sex hormone binding globulin (SHBG)]) (Ibáñez et al., 1997).
None of the subjects presented clinical evidence for thyroid dysfunction, Cushing syndrome or hyperprolactinemia; glucose intolerance (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997); a family or personal history of diabetes mellitus; late-onset congenital adrenal hyperplasia (New et al., 1983
; Sakkal-Alkaddour et al., 1996
); anemia or serum electrolyte anomalies; none used medication known to affect gonadal or adrenal function, or carbohydratelipid metabolism.
All studies were conducted in Barcelona; none was supported by pharmaceutical industry. All studies were approved by the Institutional Review Board of Sant Joan University Hospital; informed consent was obtained from parents or young women and assent from minors.
Markers of hepatotoxicity
In line with previous studies on flutamide hepatotoxicity (Gómez et al., 1992; Wysowski et al., 1993
; Wysowski and Fourcroy, 1996
; Venturoli et al., 2001
; Thole et al., 2004
), we used the circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers. Assessments were performed before start of flutamide treatment, after 3 months, and subsequently at least twice yearly. Circulating AST and ALT were assessed by an automatic system (Architect c8000, Abbott, Wiesbaden, Germany), intra- and inter-assay coefficients of variation (CV) being
2%. The upper references of normality for circulating AST and ALT are, respectively, 38 U/L and 55 U/L, while the lower limits suggestive of hepatotoxicity are thought to be at least three-fold higher (Gómez et al., 1992
; Wysowski et al., 1993
; Wysowski and Fourcroy, 1996
; Venturoli et al., 2001
; Thole et al., 2004
). Results are expressed as mean ± SD; minimum and/or maximum values are also provided.
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Results |
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Discussion |
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Acknowledgements |
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References |
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Submitted on February 11, 2005; resubmitted on February 23, 2005; accepted on March 3, 2005.