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Special Features: William Rosner, Richard J. Auchus, Ricardo Azziz, Patrick M. Sluss, and Hershel Raff Utility, Limitations, and Pitfalls in Measuring Testosterone: An Endocrine Society Position Statement J Clin Endocrinol Metab 2007; 92: 405-413 [Abstract] [Full text] [PDF]

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Spurious increases in serum testosterone concentrations related to phenylbutazone therapy

Bernard Uzzan, Dominique Dumont-Fischer, Najiba Lahlou, Helene Bihan, Marie-Christophe Boissier, Jean-Claude Alvarez, Gérard-Yves Perret, Régis Cohen   (15 February 2007)

Spurious increases in serum testosterone concentrations related to phenylbutazone therapy 15 February 2007
Bernard Uzzan, MD Avicenne hospital, APHP, Dominique Dumont-Fischer, Najiba Lahlou, Helene Bihan, Marie-Christophe Boissier, Jean-Claude Alvarez, Gérard-Yves Perret, Régis Cohen Send letter to journal: Re: Spurious increases in serum testosterone concentrations related to phenylbutazone therapy bernard.uzzan{at}avc.aphp.fr Bernard Uzzan, et al.	In their article concerning the pitfalls in measuring testosterone, Rosner et al. (1) did not mention spurious elevations caused by phenylbutazone (PBZ), first described in this journal by Giltay et al (2), with a radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA) in five patients, including four males. We report four additional observations of this drug- hormone analytical interaction in other assays (DSL RIA, Webster, USA and BRAHMS TRACE on KRYPTOR, Berlin, Germany). A 46 year old man had been receiving PBZ (300-500 mg daily) and sulfasalazine for 10 years for a HLA-B27 positive ankylosing spondylitis. He had normal gonadal function and denied androgens intake. His serum testosterone was first reported to be 154 nmol/l in October 2000 (DSL RIA assay; normal: 9.4-37 nmol/l); his free testosterone level (DSL RIA) was 347 pmol/l(normal: 45-114 pmol/l), and his LH and FSH were slightly elevated. Cerebral and abdominal CT scans were normal. This high testosterone was confirmed twice in 2001 with the same assay, and on September 2005 using TRACE method (53 nmol/l; normal: 6.5-24 nmol/l). On January 2006, 24 days after PBZ was stopped, his serum testosterone was reported to be normal (15.8 nmol/l by TRACE). Fifteen days after reintroduction of PBZ, his testosterone was again reportedly low, 46 nmol/l. Two other patients without hyperandrogenism had high serum testosterone while on PBZ: 38.7 nmol/l (TRACE) in a 30-year-old man 7 days after initiation of PBZ, and 21.5 nmol/l (TRACE; N: 1.5-2.94 nmol/l) with a near-normal free testosterone in a 35-year-old woman. Serum PBZ and oxyphenbutazone levels were within therapeutic range, as determined by liquid chromatography coupled with tandem mass spectrometry. As Giltay et al. (2) did, we confirmed the spurious elevation of total testosterone by its normalization after stopping PBZ, positive re-challenge, and normalization after serum extraction by diethylether. In addition, testosterone levels were normal by tandem mass spectrometry in all cases. At variance with the studies of Giltay et al. (2), the measured testosterone increased by 250% after addition of PBZ to generate an eight-fold range of concentrations around therapeutic levels to the serum from three male healthy volunteers, whereas the measured testosterone concentration did not change after addition of therapeutic concentrations of oxyphenbutazone, the main PBZ metabolite. Recently, we identified a fourth consecutive case of marked elevation of serum total testosterone (20.7 nmol/l) 17 days after initiation of PBZ (400 mg/d) in a 68-year-old woman. Many patients with ankylosing spondylitis are still treated with PBZ, so physicians should be aware of this interaction, possibly due to a common epitope shared by testosterone and phenylbutazone, but not oxyphenbutazone, with antibodies used to perform several testosterone assays. Alternatively, this phenomenon could be due to interference of PBZ with the testosterone tracer. References 1. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H 2007 Position Statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society Position Statement. J Clin Endocrinol Metab 92:405-413 2. Giltay EJ, Popp-Snijders C, van Denderen JC, van Schaardenburg D, Gooren LJG, Dijkmans BAC 2000 Phenylbutazone can spuriously elevate unextracted testosterone assay results in patients with ankylosing spondylitis. J Clin Endocrinol Metab 85:4923-4924