Testosterone deficiency syndrome: An overview with emphasis on the diagnostic conundrum, "Beyond the Abstract," by Alvaro Morales, MD, CM, FRCS, FACS

BERKELEY, CA (UroToday.com) - The debate on the appropriateness of the diagnostic approach to testosterone deficiency syndrome (TDS) is significant. However, of more immediate concern to urologists is the controversy on the safety of testosterone therapy (TT). While concern about the consequences of TT in prostate health have abated somewhat due to new reassuring information,[1] the specter of detrimental cardiovascular effects was raised by 3 recent publications. Although there are numerous reports on beneficial effects of TT on the cardiovascular system, they need to be weighed against these new contrary studies. Such opinions are important not only because of their provenance but also because of the quality and impact of the journals publishing them. However, while all have flaws, they received considerable (uncritical) attention in the medical and lay media.

The first study[2] showed increased cardiovascular adverse events (CVAEs) in elderly men (mean age: 74±5) with serious mobility problems on TRT. In addition to the subjects’ physical limitations and the fact that the study was not designed to assess CVAEs, many of the participants reached supra-physiological T values during T therapy, a bad idea according to the Endocrine Society Guideline.[3] There was a distinct increased proportion of CVAEs in those reaching T levels > 1000 ng/dl. (34.6 nmol/L), a lesser increase in those with levels between 500 to 1000ng/dl. (17.3 – 34.6 nmol/L), and even fewer among subjects with levels ≤ 500 ng/dl. Furthermore, in the T group, “as compared with the placebo group there was a significant increase in hemoglobin and hematocrit”. The large TIMERISK study in younger and healthier men convincingly showed that borderline polycythemia is associated with increased risk of CV mortality.[4] Little wonder the study had to be stopped.

The second study[] is more problematic. The accompanying editorial[6] pointed to some of its weaknesses comprising: a. its retrospective nature with linkage of results of a single T determination with pharmacy data, b. the “frustratingly little information… whether TRT was appropriately prescribed”, and c. “the generalizability of the results to the broader population.” But there are other, such as an explanation as to why did the numerous and heterogeneous participating physicians were prompted to measure T in these men, and an absence of details about the laboratory methodologies used for measurement of T. There is a want of specifics as to why the same physicians decided to treat some patients, but not others, and the particulars of the treatments used. In addition, there is the dearth of important patient information inherent to most retrospective evaluations, including the significance of the considerable number of men who never renew their prescriptions, together with the fact that the subjects were already at high risk of heart attacks and strokes, as 80% had documented coronary artery disease. The extensive and sophisticated statistical methodology employed does not eliminate the inherent bias of the study or the follow up, which is too short for current standards. The mean duration of treatment was just over 1 year, and 82.4% filled more than one prescription, but there is no information as to how many thereafter. Most worrisome is the absence of hematology data.

The most recent study[7] is the result of mining information from employees, dependents, and retirees from a commercial claims and encounters database. CVAEs for those receiving TT or phosphodiesterase-5 inhibitors (PDE5Is) were compared. This allowed the analysis of colossal numbers of subjects on TT or PDE5Is: > 55,000 and > 167,000, respectively. It was concluded that, “in older men and younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.” Unfortunately, the study suffers from limitations similar to the ones raised for the Vigen, et al. report.[5] In addition, it is silent as to exclusions in the PDE5I cohort due to the use of nitrates (although the use of “vasodilators” is listed as a covariate), again there is no hematological information, and, most importantly, details of the pharmacological preparations used, dosage, and during-treatment serum T levels are not provided.

Despite their flaws, the 3 papers shouldn’t be dismissed, but rather, evaluated judiciously and thoughtfully, together with the ones showing positive cardiovascular effects of TRT.

References:

  1. Morales A. The effect of Testosterone Administration to Men with Prostate Cancer is Unpredictable: A word of caution and suggestions for a Registry. Brit J Urol Int 107:1369-73, 2011.
  2. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;362:109-122.
  3. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010;95:2536-2559.
  4. Kunnas T, Solakivi T, Huuskonen K et al. Hematocrit and the risk of coronary heart disease and mortality in the TIMERIK study, a 28 year follow-up. Prev Med 2009;49:45-47.
  5. Vigen R, O’Donell CI, Barón AE, Grunwalg GK, Maddox TM et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836.
  6. Cappola AR. Testosterone therapy and risk of cardiovascular disease. JAMA 2013;310:1805-1806.
  7. Finkle WD, Greenland S, Ridgeway GK, Adams JL,Frassco MA et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS1, 2014,9:1/e85805.

Written by:
Alvaro Morales, MD, CM, FRCS, FACS as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Queen's University, Kingston, Ontario, Canada

Testosterone deficiency syndrome: An overview with emphasis on the diagnostic conundrum - Abstract

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