Commentary: Guideline for male testosterone therapy: a regulatory perspective.

Testosterone products are approved by the U.S. Food and Drug Administration (FDA) as replacement therapy for men with classical androgen deficiency (i.e. men with very low serum testosterone concentrations generally associated with specific medical disorders). We refer to this condition as classical hypogonadism. Many prescribers, however, advocate administration of testosterone to older men with an array of signs and symptoms, many of which may be related to normal aging, and a “low” serum testosterone concentration based on normative values for young men. For the purposes of this editorial, we refer to this condition by its most popularly accepted name, andropause (1). In 2002, the National Institute of Aging and the National Cancer Institute tasked the Institute of Medicine (IOM) to conduct a review of the current state of knowledge of the potential risks and benefits of testosterone therapy in older men and to make research recommendations regarding clinical trials (2). The IOM’s report was published in 2004 and concluded in its executive summary that “As the FDA-approved treatment for male hypogonadism, testosterone therapy has been found to be effective in ameliorating a number of symptoms in markedly hypogonadal males. Researchers have carefully explored the benefits of testosterone therapy in this population. However, there have been fewer studies, particularly placebo-controlled randomized trials, in the population of middle aged or older men who do not meet all the clinical diagnostic criteria for hypogonadism but who may have testosterone levels in the low range for young adult males and show one or more symptoms that are common to both aging and hypogonadism.” The IOM further concluded that “assessments of risks and benefits have been limited and uncertainties remain about the value of this therapy in older men.” In the June 2006 issue of this Journal, The Endocrine Society published its Clinical Practice Guideline on testosterone therapy in adult men (Clinical Guideline) (3). The authors appear to acknowledge the difference between classical hypogonadism in adult men and andropause because they address these distinct populations in separate sections of the Clinical Guideline. The authors recommend (section 2.3 of the Clinical Guideline) against a general clinical policy of offering testosterone therapy to all older men with low testosterone levels. This important statement, however, could be easily overlooked in the context of the overall document. The message of this statement also does not appear to be included in either the abstract or Patient Guide,* which are more likely to be read by providers and patients, respectively. In addition, the statement does not recommend against treating older men with low testosterone and symptoms of aging. The Clinical Guideline and its associated Patient Guide, we believe, obscure the distinction between classical hypogonadism and andropause and imply that the practice of treating men with andropause is efficacious and safe based on high-quality evidence. We agree with the authors’ assessments that the evidence regarding the strategies for diagnosis, treatment, and monitoring of older adult men with androgen deficiency syndromes is primarily supported by “very low quality evidence” (the lowest category on a four-level evidence grading scale). Notably, none of the evidence reviewed by the authors for the Clinical Guideline qualified as “high” or even “moderate quality.” It is, therefore, of great concern that The Endocrine Society offers primarily “strong recommendations” (and “suggestions”) regarding strategies for diagnosis, treatment, and monitoring of adult men who are undergoing testosterone therapy. The Clinical Guideline is described as an “evidence-based” document. This is defined as being based on strength of evidence rather than expert opinion (4). It does not appear, however, that the authors adhered to the method they selected to create the Clinical Guideline, the GRADE system (5). In this system, “recommendations should be formulated to reflect their strength—that is, the extent to which one can be confident that adherence will do more good than harm.” The GRADE working group further recommended, “in some instances it may not be appropriate to make a recommendation . . . when this is due to lack of good quality evidence . . . ” In cases of inadequate evidence, the working group recommended, as did the IOM, that specific additional research should be conducted. The abstract portion of the Clinical Guideline, which we believe is the portion most likely to be read and followed by treating physicians, is of greater concern. In this section, there is no mention at all of the poor quality of evidence that is the basis for the recommendations. Further, there are statements in the abstract that are modifications (and, thereby, potentially misleading) of recommendations in the body of the * Editor’s Note: The Patient Guide was not written by the Clinical Practice Guideline expert panel or peer-reviewed by The Journal of Clinical Endocrinology & Metabolism.