Abstract
The respondents 1 address the most topical and controversial area covered in our review. 2 The critical issues are: what benefits and what risks arise from testosterone treatment of ageing hypogonadal men, which in turn depends on substantive diagnosis?
Already important new information has appeared since this review was accepted for publication, notably two papers and an accompanying editorial in the same issue of the New England Journal of Medicine. The first paper reports adverse events in a small, randomized double-blind trial designed to assess the effect of testosterone treatment in older men with limitations in mobility and moderately low testosterone levels, which led to the trial being discontinued early. This was largely because of a major increase in a variety of cardiovascular events. 3 The authors recognize the limitations of their small study, which was prematurely halted and in which there were significant differences between the treated and placebo groups. These findings contrast with many other studies, most of which, however, are of low to medium quality and imprecisely related to clinical outcome. 4 This unresolved situation is reminiscent of the situation regarding hormone replacement therapy use in menopausal women, which led to the Women's Health Initiative studies – and requires the same response: adequately powered, randomized, double-blind trials. 5,6
To use age-related values, as the respondents suggest, may be intuitively appropriate and certainly would reduce the demand, hence cost of treatment for older men, but may not be correct, nor the financial incentive the prime concern. Moreover, these are presently not available. The tremendous variability in accuracy and precision of current testosterone assays militates against the creation of valid ranges. Germane to this is the second of the two back-to-back papers, which reports a study aimed at identifying reliably late-onset hypogonadism in middle-aged and elderly men from eight European centres. 7 The authors conclude that use of testosterone therapy should be limited to men with a combination of at least three sexual symptoms, associated with a total testosterone concentration of less than 11 nmol/L and a free testosterone level of less than 220 pmol/L. It should be emphasized that the free testosterone concentration was obtained by a formula using measurements of total testosterone and sex hormone binding globulin, 8 rather than so-called direct measurements – especially using analogue methods that have been shown to be unreliable. 9
The bottom line in all of this is how can the will and the funding be achieved to perform properly the trials that are so badly needed? Meanwhile all recommendations will be provisional, pragmatic and liable to change.
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