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COMMENTARY |
Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Manchester M13 9WL, United Kingdom
Address all correspondence and requests for reprints to: Frederick C.W. Wu, Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Manchester M13 9WL, United Kingdom. E-mail: Frederick.wu{at}manchester.ac.uk.
Why are we suddenly assailed with a plethora of guidelines for testosterone (T) therapy in androgen deficiency (1, 2, 3), a condition that has been managed with relative success and apparent patient satisfaction for nearly seven decades?
Prescriptions for T in the United States have increased by 400% since 1999 (4), mainly in middle-aged men. Interestingly, this trend has not been duplicated in Europe [Intercontinental Marketing Services (IMS) Health Inc., New York, unpublished data] or Australasia (5). Has there been an epidemic of male hypogonadism in North America, or does this reflect a substantial shift in approach to the diagnosis and treatment of androgen deficiency?
The age-related decline in T (6) in an increasing elderly male population is the likely drive behind this trend, fueled by a number of factors specific to the United States. These include direct-to-patient pharmaceutical advertising, ready availability of reimbursement by health-care providers, willingness of patients to pay for prescriptions, prevalence of an antiageing ethos, and, most importantly, clinicians’ attitude in accepting perceived novel therapeutic opportunities. The use of T in men with chronic illnesses is still underappreciated and is unlikely to have contributed substantially to the prescribing increase.
The latest of these practice guidelines from The Endocrine Society, like others before, are ostensibly targeted at all forms of T deficiency. However, it’s not difficult to see that the real target of these guidelines is the T decline associated with ageing, thereby implicating a proportion of older men (numerically a huge potential patient population) without pituitary-gonadal disease as likely hypogonadal candidates for T treatment. Thus, by being considered together with classical prepubertal and post-pubertal hypogonadism, the age-related physiological decline in T has been conceived as a new syndrome of late-onset hypogonadism, given instant credibility by association and promulgated by proxy. The guideline therefore, intentionally or unintentionally, endorses the existence of a condition or syndrome on no evidence of high quality. In doing so, this commentator believes that a number of fundamental issues have been overlooked by the panel.
Patients (usually of a younger age) with classical hypogonadism and ageing men with borderline low T are distinct clinical entities with divergent pathophysiology. Classical hypogonadism is caused by identifiable and irreversible pathologies leading to unequivocally low T levels whose clinical consequences predictably and safely respond to replacement therapy. T in ageing men declines to the borderline low range; this is a variable phenomenon, associated with obesity, co-morbidity, and medication use, and is potentially reversible and preventable. Causal relationships between symptoms/signs and T levels in older men are unproven, while the natural history and health outcomes of lower T are unknown. The clinical efficacy and risks of T intervention are unclear. Therefore, no convincing evidence currently exists to confirm that an androgen deficiency state pertains to aging men. Thus, to consider the age-related hypotestosteronemia as a form of late-onset hypogonadism and to recommend that the diagnosis and treatment are the same as for classical androgen deficiency is a gross oversimplification that may have potentially grave consequences for patients and providers. Guidelines should be based on evidence obtained from the relevant population to which they apply and not extrapolated from other sources through expediency.
The Guideline emphasized that the diagnosis of androgen deficiency should be made only in men with characteristic symptoms and signs of androgen deficiency and unequivocally low T levels. However, the clinical features of androgen deficiency are nonspecific and based largely on empirical experience in severely androgen deficient younger patients with T levels in the low pathological range. The diagnosis of classical hypogonadism is corroborated by identifiable underlying etiologies, e.g. pituitary tumor, hypogonadostropic hypogonadism or Klinefelter’s syndrome. Unfortunately, this well-practiced diagnostic approach is frequently found wanting when dealing with the age-related decline of T in elderly men who are prone to have a significant background of non-hormone-related complaints. It remains unclear which and how many symptoms can best establish the diagnosis of androgen deficiency in ageing men. Furthermore, we do not know the threshold(s) T level below which clinical features and adverse consequences of androgen deficiency occur, and the use of arbitrary thresholds are not supported by evidence. It is not surprising that the panelists were unable to agree on specific total or free T levels below which T treatment should be offered. The range of symptoms, their dose-response relationships to T levels, and the impact of age are currently being investigated in the European Male Ageing Study. Preliminary data suggest that sexual and physical symptoms are more informative than psychological ones, while the T thresholds and dose responses varied with age and individual symptoms (7). This kind of population-based epidemiological data are required to establish meaningful population-based reference ranges and provide numerical boundaries of T levels to define eugonadism at different ages (8). Diagnostic algorithms based on a combination of validated signs and symptoms and population-based T reference limits, investigated in randomized controlled trials, would then provide a rational basis for partitioning men into androgen-deficient and androgen-replete categories.
Increased vigilance of potential side effects of T treatment with action plans for managing raised hematocrit and prostate-specific antigen are helpful, but only if applied appropriately. The Guideline recommended a catch-all standardized monitoring plan, which clearly valued older men being started on T treatment for the first time, despite the evidence that the probability of adverse effects in young hypogonadal patients is very low (9). Is it appropriate to carry out prostate examinations in a young hypogonadal patient with Kallmann’s syndrome before and 3 months after starting T replacement? This is another example of confusing the uncertainties surrounding ageing men with hypogonadal patients and a case of the tail wagging the dog.
The Endocrine Society Clinical Practice Guideline on androgen replacement therapy is timely and apposite. However, it is noteworthy that the quality of evidence on which recommendations are based was universally of very low or low quality. These efforts also illustrate a lack of conceptual clarity through the failure to differentiate pathological hypogonadism from the age-related hypotestosteronemia. The readiness to recommend T treatment, albeit a qualified one, to symptomatic older men without clearly defined lower limits of T or evidence of efficacy is surprising to say the least.
The diagnosis of androgen deficiency in adult men is currently threatening to expand beyond the classical but numerically small horizon of pathological hypogonadism to encompass a broader range of conditions with a potentially huge number of new candidates for T treatment. This is a double-edged sword. On the one side, there is the considerable pull of opportunistic practice motivated by commercial forces. On the other, the push for a more rigorous evidence-based approach to diagnosis, case detection, and clinical decision-making presents a golden opportunity to improve overall management of androgen deficiency and widen the benefits of T. If The Endocrine Society and other international opinion leaders adhere to a rigorous evidence-based approach, even though the evidence will take some years to accumulate, they will eventually ensure that an increasing number of men will benefit appropriately from safe and effective androgen treatment. In the meantime, it is important to heed some of the advice of these guidelines, which counsel the careful clinical assessment of individual symptomatic men together with repeated analyses of morning total T levels using reliable assays with validated reference ranges (10). It is also fitting to close a commentary on clinical practice guidelines by reminding ourselves of the even greater potential and cost-effectiveness of prevention, which can only be fully exploited if we exercise patience and await the key data from noninterventional observational studies.
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Received December 18, 2006.
Accepted December 18, 2006.
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  S. A. Hall, G. R. Esche, A. B. Araujo, T. G. Travison, R. V. Clark, R. E. Williams, and J. B. McKinlay Correlates of Low Testosterone and Symptomatic Androgen Deficiency in a Population-Based Sample J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3870 - 3877. [Abstract] [Full Text] [PDF]
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