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Department of Endocrinology St. Luke’s-Roosevelt Hospital Center New York, New York 10019
Address correspondence to: William Rosner, M.D., Department of Endocrinology, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, New York 10019.
To the editor:
Perusing the November 2000 issue of JCE&M, I noted an article in which one of the outcome measures was serum free testosterone (1). The method used to measure serum free testosterone, a direct RIA that purports to, but does not, measure the free testosterone concentration is one whose use I decried in a letter to the editor published more than 3 yr ago (2). Not long after, Vermeulen et al. (3) published a side-by-side experimental comparison of methods for determining the concentration of free testosterone in serum. Those experiments conclusively show that the direct RIA of free testosterone is seriously inaccurate, underestimating its concentration by many-fold. To my knowledge, there are no data that contradict these conclusions. Hence, I was surprised to find that the direct assay method not only was still being used for investigative purposes, but also was being published in what is among the foremost endocrine journals in the world.
To see how pervasive this situation was, I undertook to examine the frequency with which those publishing in the journal were using this methodology.
Methods. I conducted a full text, online search, of the JCE&M (January 1998-November 2000) using the term "free testosterone." Then, I evaluated each retrieved citation containing the term and ascertained whether it revealed the use of a direct RIA for free testosterone, an alternate method for measuring free testosterone, or was not applicable (e.g. free testosterone mentioned in an editorial, a comment, a discussion, a bibliography, etc.). In addition to the foregoing, there were a number of publications in which no reference was given.
Results. A total of 116 citations were retrieved: 49 were not applicable; 11 contained no reference for the method cited; 24 used a method other than direct RIA; and 32 used the direct RIA. Of the 116 citations, 67 were suitable to address the question at hand. Thus, 48% (32 of 67) of the applicable papers used a seriously inaccurate method for estimating free testosterone and, almost as serious, 16% (11 of 67) cited no method at all.
Why would anyone choose to use this methodology? Perhaps the answer can be found in the technical bulletins of one of the companies that manufacture and sell kits that use this method. The relevant citations reveal that kits made by two companies, Diagnostic Products and Diagnostic Systems Laboratories, Inc. (DSL), account for almost all the inappropriate measurements of free testosterone in papers published in the journal during the period in question. A DSL technical bulletin (http://www. dslabs.com/techlit/4900tb2.doc) advertises: "Historically, free testosterone levels were determined by a method known as equilibrium dialysis. ... The method is cumbersome, time-consuming, and equipment intensive." Conversely, we are told, the DSL direct method is simple and rapid. The only difficulty is that "the equilibrium dialysis method gave values approximately 4 times higher than did the DSL kit." As if to compensate for the inexcusable inaccuracy, the technical bulletin and accompanying X-Y plot of RIA vs. equilibrium dialysis makes the point that the correlation coefficient is 0.92. Even this is deceiving. The points at the upper end of the DSL method are the major contributors to the fitted line. Visual examination of the plot indicates that a line through the lower points (17 of 21 points below the fitted line and 2 points above it) would have a substantially different slope than that indicated by the published fitted line. Thus, in addition to being inaccurate, this observation indicates that, compared with equilibrium dialysis, the assay is not linear. Yet, the kit remains on the market because it is easy to use.
Almost one half of the publications dealing with free testosterone, in the period under consideration, used an inaccurate assay for its measurement. Even if the (somewhat more time-consuming) procedure of equilibrium dialysis were the only alternative, the literature of science ought not to use a method so grossly inaccurate when better ones exist. We all know that there are numerous assays for hormones in serum that are method specific. However, I know of no other that has been demonstrated to be so egregiously incorrect. The journal might choose to return manuscripts that use it without further evaluation to discourage its use.
Received November 29, 2000.
References
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