Adverse Events Associated with Testosterone Administration miocardial infarction

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					Adverse Events Associated with Testosterone Administration

N Engl J Med 2010; 363:1865-1867November 4, 2010 (

      To the Editor:

      In their study involving elderly men with impaired mobility, Basaria et al. (July 8 issue)1 found that men
      who received testosterone treatment, as compared with those who received placebo, had a higher rate of
      cardiovascular adverse events. Apart from the reasons discussed by the authors, this observation may
      also be a consequence of a higher degree of physical activity among the men receiving testosterone
      supplementation. In line with this hypothesis, limited physical vigor has been associated with total
      testosterone levels below 13 nmol per liter, a threshold crossed by the intervention.2 The beneficial
      effects of long-term physical activity notwithstanding, a body of evidence suggests that short-term
      physical exertion can precipitate myocardial infarction, sudden death, stroke, and acute left ventricular
      dysfunction.3,4 The authors found that the men in the intervention group had improved muscle
      performance and physical function after 6 months, but unfortunately the authors do not report about
      possible changes in the level of physical activity over the course of the study period. This information
      would be valuable, since the reported data do not preclude the possibility that the risk of adverse events
      associated with testosterone supplementation in elderly men can be reduced by the avoidance of sudden
      and inadequate physical exertion.

      Cornelia Weikert, M.D., M.P.H.
      Tobias Pischon, M.D., M.P.H.
      German Institute of Human Nutrition, Potsdam-Rehbruecke Nuthetal, Germany

      Steffen Weikert, M.D., M.P.H.
      Charité University Medicine Berlin, Berlin, Germany
      weikert@dife. de (
      No potential conflict of interest relevant to this letter was reported.
      4 References (

         1. 1

             Basaria S , Coviello AD , Travison TG , et al. Adverse events associated with
             testosterone administration. N Engl J Med 2010;363:109-122
             Full Text | Web of Science | Medline

         2. 2

             Wu FC , Tajar A , Beynon JM , et al. Identification of late-onset hypogonadism in
             middle-aged and elderly men. N Engl J Med 2010;363:123-135
             Full Text | Web of Science | Medline
   3. 3

       Mittleman MA , Maclure M , Tofler GH , Sherwood JB , Goldberg RJ , Muller JE .
       Triggering of acute myocardial infarction by heavy physical exertion: protection against
       triggering by regular exertion. N Engl J Med 1993;329:1677-1683
       Full Text | Web of Science | Medline

   4. 4

       Thompson PD , Franklin BA , Balady GJ , et al. Exercise and acute cardiovascular
       events: placing the risks into perspective: a scientific statement from the American
       Heart Association Council on Nutrition, Physical Activity, and Metabolism and the
       Council on Clinical Cardiology. Circulation 2007;115:2358-2368
       CrossRef | Web of Science | Medline

To the Editor:

In the Testosterone in Older Men with Mobility Limitations (TOM) trial, Basaria et al. found that
testosterone supplementation is not without risks and should be carried out with prudence. However, the
authors did not determine the level of the hormonal defect by measuring luteinizing and follicle-
stimulating hormones before treatment. This is relevant in clinical practice, since treatment of secondary
hypogonadism is often directed at the underlying cause, rather than at replacement of the deficient
hormone downstream.
Second, many people would be surprised at the doses that were used in the study — doses that were
higher than those recommended by the manufacturer as starting doses1 — and at the relatively high
upper threshold for testosterone level of 1000 ng per deciliter (34.7 nmol per liter) in older patients.
Indeed, the Endocrine Society recommends a goal of 400 to 500 ng per deciliter (13.9 to 17.4 nmol per
liter) in these patients.2 Levels were not rechecked until week 24; actual levels were not available during
the intervention period for 24% of the patients randomly assigned to testosterone gel. Therefore it is
likely that a reason for the high rate of adverse events was inadvertent oversupplementation. Indeed,
among patients for whom data are available, there is a suggestion that cardiovascular-related events
were correlated with increasing testosterone levels.
Teck Kim Khoo, M.D.
Iowa Diabetes and Endocrinology Center, Des Moines, IA
tkhoo@mercydesmoines. org
No potential conflict of interest relevant to this letter was reported.
2 References

   1. 1

       Testim. Malvern, PA: Auxilium Pharmaceuticals, 2009 (package insert).
   2. 2

       Bhasin S , Cunningham GR , Hayes FJ , et al. Testosterone therapy in adult men with
       androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin
       Endocrinol Metab 2006;91:1995-2010[Erratum, J Clin Endocrinol Metab 2006;91:2688.]
       CrossRef | Web of Science | Medline

To the Editor:

The increased risk of cardiovascular adverse events after the use of a testosterone gel in men, reported
by Basaria et al., may have been the result of an induced increase in plasma estrogen. Because
testosterone is converted to estradiol (via aromatase), testosterone administration in men causes not only
a rise in plasma testosterone but also a dose-dependent rise in plasma estradiol levels.1 Estrogen
administration in men has been shown to induce myocardial infarction and thromboembolism,2 and
hyperestrogenemia in men has been reported to be associated with the thrombosis of myocardial
On the basis of sex, age, and low testosterone levels, the participants in the study by Basaria et al. would
be expected to have atherosclerosis.4 The superimposition of a rise of approximately 40% in estradiol,1
resulting from a more than doubling of the testosterone level, might account for the atherosclerosis-
related events reported. If so, these events might be prevented by the administration of an aromatase
inhibitor, which would lower estradiol levels while raising the testosterone level.5
Gerald B. Phillips, M.D.
Columbia University College of Physicians and Surgeons, New York, NY
gbp1@columbia. edu
No potential conflict of interest relevant to this letter was reported.
5 References

   1. 1

       Lakshman KM , Kaplan B , Travison TG , et al. The effects of injected testosterone dose
       and age on the conversion of testosterone to estradiol and dihydrotestosterone in young
       and older men. J Clin Endocrinol Metab 2010;95:3955-3964
       CrossRef | Web of Science | Medline

   2. 2

       The Coronary Drug Project: initial findings leading to modifications of its research
       protocol. JAMA 1970;214:1303-1313
       CrossRef | Web of Science
   3. 3

       Phillips GB , Pinkernell BH , Jing T-Y . The association of hyperestrogenemia with
       coronary thrombosis in men. Arterioscler Thromb Vasc Biol 1996;16:1383-1387
       Web of Science | Medline

   4. 4

       Phillips GB , Pinkernell BH , Jing T-Y . The association of hypotestosteronemia with
       coronary artery disease in men. Arterioscler Thromb 1994;14:701-706

   5. 5

       Leder BZ , Rohrer JL , Rubin SD , Gallo J , Longcope C . Effects of aromatase inhibition
       in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol
       Metab 2004;89:1174-1180
       CrossRef | Web of Science | Medline

To the Editor:

Before the availability of recombinant human erythropoietin, androgens were used to stimulate
erythropoiesis in patients with chronic kidney disease.1 Given the evidence of an association between
raising hemoglobin levels with the use of erythropoietin-stimulating agents and an increase in the risk of
adverse cardiovascular events in patients with chronic kidney disease,2,3 did the risk of cardiovascular-
related adverse events among men in the article by Basaria et al. remain elevated in the testosterone
group after adjustment for hemoglobin or hematocrit levels?
Matt Hall, M.B.
Leicester General Hospital, Leicester, United Kingdom
drmatthall@hotmail. com
No potential conflict of interest relevant to this letter was reported.
3 References

   1. 1

       Solomon LR , Hendler ED . Prospective controlled study of androgen therapy in the
       anemia of chronic renal disease: effects on iron kinetics. Acta Haematol 1988;79:12-19
       CrossRef | Web of Science | Medline
   2. 2

       Singh AK , Szczech L , Tang KL , et al. Correction of anemia with epoetin alfa in chronic
       kidney disease. N Engl J Med 2006;355:2085-2098
       Full Text | Web of Science | Medline

   3. 3

       Pfeffer MA , Burdmann EA , Chen CY , et al. A trial of darbepoetin alfa in type 2
       diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032
       Full Text | Web of Science | Medline

Author/Editor Response

Weikert and colleagues suggest that increased physical exertion during the period of testosterone
therapy may have precipitated cardiovascular events. The physical activity data are being analyzed;
however, a preliminary analysis revealed no significant difference in moderate or intense physical
activity levels between the two groups.
In response to Khoo: In the TOM trial, we recruited men with age-related decline in testosterone levels
and excluded those with known diseases of the testes and the pituitary. Previous reports have suggested
that the likelihood of a sellar lesion is very low in middle-aged and older men whose testosterone levels
are higher than 100 ng per deciliter (3.5 nmol per liter).1,2 Therefore, we recruited men whose total
testosterone level was between 100 ng per deciliter and 350 ng per deciliter (12.1 nmol per liter).
As discussed in the manuscript, the testosterone dose used in the TOM trial was higher than the typical
starting dose of testosterone gel used in clinical practice and in some previous trials but was not
dissimilar from the dose of testosterone esters used in clinical practice or the testosterone doses used in
other trials (Table 4 in the Supplementary Appendix, available with the full text of the article at The mean testosterone concentrations in the testosterone group of the TOM trial during the
intervention period were in the middle of the normal range for young men — higher than those in some
testosterone trials but not significantly different from levels reported in other trials (Table 4 in the
Supplementary Appendix).
Phillips suggests that an increase in estradiol levels in the testosterone group might have contributed to
the increase in cardiovascular events observed in this group. High estradiol levels in men have been
associated with coronary thrombosis, elevated risk of stroke,3,4 and inflammation.5 We agree that
increases in estradiol levels associated with testosterone administration may affect inflammation,
coagulation, and platelet aggregation. The estradiol levels are being analyzed.
In response to Hall: Although the increase in hemoglobin and hematocrit levels was greater in men
assigned to the testosterone group of the study than in those assigned to the placebo group, the increased
risk of cardiovascular-related adverse events persisted even after adjustment for hematocrit levels during
the treatment period.
Shehzad Basaria, M.D.
Thomas W. Storer, Ph.D.
Shalender Bhasin, M.D.
Boston University School of Medicine, Boston, MA
bhasin@bu. edu
Since publication of their article, the authors
Dr Hasnain Patel
Vice Chairman IBCMT
President ISSMTCT