Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women

Lourdes Ibáñez1,3, Adriana Jaramillo1, Angela Ferrer1 and Francis de Zegher2

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


    Abstract
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
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 ≥45 U/L. CONCLUSION: 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.

Key words: androgen/androgen receptor/flutamide/hepatotoxicity/PCOS


    Introduction
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
Flutamide is a pure non-steroidal anti-androgen (Singh et al., 2000Go). So far, flutamide has been mainly used for the treatment of prostate cancer (Labrie et al., 1988Go). When flutamide is given in a dose range 750–1500 mg/day, hepatotoxicity is a rare but potentially fatal side-effect, usually occurring within 3 months after initiation of flutamide therapy for prostate cancer or hirsutism (Gómez et al., 1992Go; Wallace et al., 1993Go; Wysowski et al., 1993Go; Wysowski and Fourcroy, 1996Go; Andrade et al., 1999Go; Thole et al., 2004Go). Minor hepatotoxicity has been documented with doses as low as 250–375 mg/day (Venturoli et al., 2001Go; Thole et al., 2004Go).

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., 2000Go) and in adolescents and women with hyperinsulinemic hyperandrogenism—a variant of Polycystic Ovary Syndrome (PCOS) (Ibáñez and de Zegher, 2003aGo, 2004Go, 2005Go; Ibáñez et al., 2004aGo). 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., 2004aGo). The treatment duration in those reports, however, was limited to 3–9 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, 2003aGo,bGo, 2004Go, 2005Go; Ibañez et al., 2000Go, 2002Go, 2003Go, 2004aGo), 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.


    Study population and methods
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
Study population and ethics
We analysed liver function results from a total of 190 girls and young women with established (n=150) or incipient (n=40) PCOS, the latter being defined as a condition in which girls already present the endocrine-metabolic abnormalities of PCOS, but do not present hirsutism (Ferriman–Gallwey score <8) or menstrual disturbances yet (Ferriman and Gallwey, 1961Go; Ibáñez et al., 2004bGo).

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, 850–1275 mg/day) and/or an estro-progestagen OC that contained gestodene or drospirenone (Ibañez et al., 2000Go, 2002Go, 2003Go, 2004aGo,bGo; Ibáñez and de Zegher, 2003aGo,bGo, 2004Go, 2005Go). 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., 2000Go, 2002Go, 2003Go, 2004aGo,bGo; Ibáñez and de Zegher, 2003aGo,bGo, 2004Go, 2005Go). 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., 1997Go; Vidal-Puig and Moller, 1997Go), 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, 2005Go); (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., 2001Go)]; this combination is known to confer a high risk for progression to full-spectrum PCOS in adolescence (Ibáñez et al., 2001Go, 2004bGo).

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., 1997Go).

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, 1997Go); a family or personal history of diabetes mellitus; late-onset congenital adrenal hyperplasia (New et al., 1983Go; Sakkal-Alkaddour et al., 1996Go); anemia or serum electrolyte anomalies; none used medication known to affect gonadal or adrenal function, or carbohydrate–lipid 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., 1992Go; Wysowski et al., 1993Go; Wysowski and Fourcroy, 1996Go; Venturoli et al., 2001Go; Thole et al., 2004Go), 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., 1992Go; Wysowski et al., 1993Go; Wysowski and Fourcroy, 1996Go; Venturoli et al., 2001Go; Thole et al., 2004Go). Results are expressed as mean ± SD; minimum and/or maximum values are also provided.


    Results
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
Table I summarizes the screening results for flutamide hepatotoxicity, as judged by circulating AST and ALT. The results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment. None of the AST or ALT levels during flutamide treatment was ≥45 U/L. Thus, there was no evidence for hepatotoxicity in any of the 190 hyperandrogenic girls or young women on low- or ultralow-dose flutamide over a longer term, up to 54 months.


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Table I. Results of repeated screening for flutamide (Flu) hepatotoxicity in hyperandrogenic girls, adolescents and young women (n=190), who received one and/or a lower Flu dose within a context of intervention studies that consecutively explored the efficacy of decreasing Flu doses

 

    Discussion
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
The label of hepatotoxicity, rightfully conferred upon high-dose flutamide, has—in the absence of evidence to the contrary—been silently extended to low-dose flutamide. The present findings not only indicate that baseline transaminase results tend to be negative in young and non-obese patients with hyperandrogenism, but also constitute a first body of reassuring evidence on the (lack of) hepatotoxicity of low-dose flutamide; these data, however, do not allow us to exclude the possibility that ultralow-dose flutamide may still prove to be hepatotoxic in rare cases. Our screening results rather represent a first step in a long process whereby the status of ultralow-dose flutamide may gradually evolve from ‘absence of evidence’ on toxicity towards ‘evidence of absence’ of hepatic toxicity. Until there is more consensus about the latter status, we recommend that transaminase monitoring be maintained in hyperandrogenic girls and women, who receive ultralow-dose flutamide, for example, as an effective adjuvans within a combination that also includes an insulin-sensitizer and an OC (Ibáñez and de Zegher, 2004Go, 2005Go; Ibáñez et al., 2004aGo). If the efficacy–safety profile of ultralow-dose flutamide is corroborated in larger studies and other ethnic populations, then ultralow-dose flutamide may become a key component in future therapies for hyperandrogenic states in girls and young women.


    Acknowledgements
 Top
 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
Supported by the Social Security Research Fund, Health Institute Carlos III, Spain (PI/021013). FdZ is a Clinical Research Investigator of the Fund for Scientific Research, Flanders, Belgium.


    References
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 Abstract
 Introduction
 Study population and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on February 11, 2005; resubmitted on February 23, 2005; accepted on March 3, 2005.