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Division of Reproductive and Urologic Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993-0002
Address all correspondence and requests for reprints to: Daniel A. Shames, U.S. Food and Drug Administration Division of Reproductive and Urologic Products, 10903 New Hampshire Avenue, White Oak Building #22, Silver Spring, Maryland 20993-0002. E-mail: daniel.shames{at}fda.hhs.gov.
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, 1 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 report. For example, the abstract states, "we recommend testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength and bone mineral density." This statement is a modification of the specific recommendation made in section 2.1 of the body of the Clinical Guideline, which addresses classical hypogonadism. In the abstract, the word "classical," which precedes the words "androgen deficiency" in the body of the Clinical Guideline, does not appear. Because this is the only treatment recommendation in the abstract, we suspect that many treating physicians will conclude that this specific recommendation pertains to men with andropause rather than those with classical hypogonadism. Indeed, this is the inference that the editors of the Urology Times made when they inserted this recommendation verbatim (which was described as "New Clinical Practice Guidelines" from The Endocrine Society) into an article that explored the treatment controversies of andropause (6).
The Patient Guide 1 that appears in the same issue of the Journal is also of concern. The guide contains a confusing mix of statements, recommendations, and suggestions extracted from both the classical hypogonadism and andropause sections of the Clinical Guidelines (7). Again, the distinctions between the two populations are blurred in this document. In addition, the Patient Guide appears to be targeted to the andropause population. This is made evident by a picture of an older man on the first page and the assertion that androgen deficiencies are characterized by "symptoms similar to menopause in women." Most unsettling are the misleading assurances that "the panel developed ‘recommendations’ based on high quality studies or ‘suggestions’ based on studies that were less carefully carried out."
The Patient Guide explicitly cautions about muscle discomfort, skin, and gum irritation related to testosterone delivery methods. The Patient Guide, however, fails to include any clear warnings to patients regarding the more serious adverse outcomes that could result from testosterone therapy, such as prostate cancer or cardiovascular events. The section on monitoring prostate-specific antigen, digital rectal examination, and hematocrit may lead patients and their physicians to infer that monitoring obviates concerns about prostate cancer or other serious adverse outcomes, despite the fact that the authors of the Clinical Guideline have concluded that evidence for the effectiveness of monitoring strategies is very poor.
As public health officials, we applaud the last paragraph of the Patient Guide that encourages a healthy lifestyle, including good nutrition, not smoking, and maintenance of appropriate body weight.
We support the right of individual physicians to treat patients based on their own knowledge or advice from known experts in the field. However, patients should be able to choose therapies based on accurate and evidence-based medical information and consultation with well-informed health-care providers. Clinical guidelines and patient guides should be based on solid clinical evidence and must convey this information clearly and accurately to physicians and patients.
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Received November 29, 2006.
Accepted December 18, 2006.
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This article has been cited by other articles:
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  G. D. Braunstein The Endocrine Society Clinical Practice Guideline and The North American Menopause Society Position Statement on Androgen Therapy in Women: Another One of Yogi's Forks J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4091 - 4093. [Full Text] [PDF]
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