Dr. Ron’s Research Review – May 15, 2013

© 2013

This week’s research review focuses on the adverse effects of testosterone use.

In 2010, a study on testosterone use in older men (65 years of age or older, mean 74) was halted. During the course of the study, the testosterone gel (100 mg in 10g gel daily for 6 months) group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. (Basaria, Coviello et al. 2010)

A greater proportion of men in the testosterone group than in the placebo group reported that they had received a diagnosis of hyperlipidemia or were taking a statin.

In the second set of analyses, the 104 (50%) participants who had self- reported cardiovascular, peripheral vascular, or cerebrovascular disease, congestive heart failure (CHF), and arrhythmias at baseline were excluded.

Of the remaining 105 subjects, nine men receiving testosterone had cardiovascular-related events as compared to two men receiving placebo gel (OR 5.8 (95%CI 1.2, 28), p=0.03); that is, results were essentially unchanged. Three men in the testosterone group had MedDRA cardiac events and two had atherosclerotic events – all in the testosterone group vs zero each in the placebo group.

The cardiovascular-related events included: an acute coronary syndrome (coronary artery obstruction), two myocardial infarctions, and one death by suspected myocardial infarction.

Several comments were brought up in the correspondence.

A new definition of late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) and a free testosterone level of less than 220 pmol per liter (64 pg per milliliter). (Wu, Tajar et al. 2010)

Men receiving testosterone supplementation often exhibit a higher degree of physical activity. Short-term physical exertion can precipitate myocardial infarction, sudden death, stroke, and acute left ventricular dysfunction. (Weikert, Pischon et al. 2010)

Doses that were higher than those recommended by the manufacturer as starting doses, and an upper threshold almost twice the level recommended by the Endocrine Society: 1000 ng per deciliter vs 4-500. (Khoo 2010)

More than doubling of the testosterone level results in a superimposition of a rise of approximately 40% in estradiol, which might account for the atherosclerosis-related events reported. If so, these events might be prevented by the administration of an aromatase inhibitor. (Phillips 2010)

A 2010 meta-analysis found the adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. (Fernandez-Balsells, Murad et al. 2010)

A 2007 meta-analysis weakly supported the inference that testosterone use in men is not associated with important cardiovascular effects. (Haddad, Kennedy et al. 2007)

A meta-analysis in 2005 found that testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of hematocrit >50% than was placebo; hematocrit increase was the most frequent adverse event associated with testosterone replacement. (Calof, Singh et al. 2005)

Dr. Ron


Articles

Adverse Events Associated with Testosterone Administration

             (Basaria, Coviello et al. 2010) Download

BACKGROUND: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS: Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS: A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.) Copyright 2010 Massachusetts Medical Society.


Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials

            (Calof, Singh et al. 2005) Download

BACKGROUND: We performed a meta-analysis of randomized clinical trials to determine the risks of adverse events associated with testosterone replacement in older men. METHODS: The MEDLINE database was searched from 1966 to April 2004, using testosterone as the indexing term; limits included human, male, > or =45 years old, and randomized controlled trial. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men > or =45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. Odds ratios (ORs) were pooled using a random effects model, assuming heterogeneous results across studies, and were weighted for sample size. RESULTS: In the 19 studies that met eligibility criteria, 651 men were treated with testosterone and 433 with placebo. The combined rate of all prostate events was significantly greater in testosterone-treated men than in placebo-treated men (OR = 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of prostate cancer, prostate-specific antigen (PSA) >4 ng/ml, and prostate biopsies were numerically higher in the testosterone group than in the placebo group, although differences between the groups were not individually statistically significant. Testosterone-treated men were nearly four times as likely to have hematocrit >50% as placebo-treated men (OR = 3.69, 95% CI, 1.82-7.51). The frequency of cardiovascular events, sleep apnea or death was not significantly different between the two groups. CONCLUSIONS: Testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of hematocrit >50% than was placebo; hematocrit increase was the most frequent adverse event associated with testosterone replacement. These data reaffirm the need to monitor hematocrit, PSA, and digital examination of the prostate during testosterone replacement in older men.


Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis

            (Fernandez-Balsells, Murad et al. 2010) Download

CONTEXT: The risks of testosterone therapy in men remain poorly understood. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. STUDY SELECTION: Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. DATA EXTRACTION: Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. DATA SYNTHESIS: The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. CONCLUSIONS: The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.


Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.

            (Haddad, Kennedy et al. 2007) Download

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized trials that assessed the effect of testosterone use on cardiovascular events and risk factors in men with different degrees of androgen deficiency. METHODS: Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The database search was performed again in March 2005. We also reviewed reference lists from included studies and content expert files. Eligible studies were randomized trials that compared any formulation of commercially available testosterone with placebo and that assessed cardiovascular risk factors (lipid fractions, blood pressure, blood glucose), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, angina or claudication, revascularization, stroke), and cardiovascular surrogate end points (ie, laboratory tests indicative of cardiac or vascular disease). Using a standardized data extraction form, we collected data on participants, testosterone administration, and outcome measures. We assessed study quality with attention to allocation concealment, blinding, and loss to follow-up. RESULTS: The 30 trials included 1642 men, 808 of whom were treated with testosterone. Overall, the trials had limited reporting of methodological features that prevent biased results (only 6 trials reported allocation concealment), enrolled few patients, and were of brief duration (only 4 trials followed up patients for > 1 year). The median loss to follow-up across all 30 trials was 9%. Testosterone use in men with low testosterone levels led to inconsequential changes in blood pressure and glycemia and in all lipid fractions (total cholesterol: odds ratio [OR], -0.22; 95% confidence interval [CI], -0.71 to 0.27; high-density lipoprotein cholesterol: OR, -0.04; 95% CI, -0.39 to 0.30; low-density lipoprotein cholesterol: OR, 0.06; 95% CI, -0.30 to 0.42; and triglycerides: OR, -0.27; 95% CI, -0.61 to 0.08); results were similar in patients with low-normal to normal testosterone levels. The OR between testosterone use and any cardiovascular event pooled across trials that reported these events (n = 6) was 1.82 (95% CI, 0.78 to 4.23). Several trials failed to report data on measured outcomes. For reasons we could not explain statistically, the results were inconsistent across trials. CONCLUSION: Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects. Patients and clinicians need large randomized trials of men at risk for cardiovascular disease to better inform the safety of long-term testosterone use.


Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis

            (Ruige, Mahmoud et al. 2010) Download

Context The literature provides no clear answer as to whether low endogenous testosterone increases risk of cardiovascular disease (CVD) in healthy men. Objective Our purpose was to estimate the predictive value of testosterone for CVD and to identify study features explaining conflicting results. Data Sources Articles were identified by a Medline and Embase search and citation tracking. Study Selection Eligible were prospective population-based cohort and nested case-control studies of testosterone and atherosclerosis, stroke, myocardial infarction, ischaemic heart disease, death from coronary heart disease or mortality. Data extraction Two independent researchers re-expressed associations of testosterone and CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of testosterone for CVD. Results and Conclusions 19 potentially eligible articles were identified. Overall, a weak independent association was found with an estimated summary RR of 0.89 for a change of one standard deviation in total testosterone level (95% CI 0.83 to 0.96). Age of study population and year of publication modified the relationship between testosterone and CVD. The estimated summary RR was 1.01 (0.95 to 1.08) for studies of men younger than 70 years of age, and 0.84 (0.76 to 0.92) for studies including men over 70 years of age. The latter studies showed a particular pronounced association if published after 1 January 2007. Results were largely confirmed by separate analyses of free- and bioavailable testosterone. The systematic review displayed no association between endogenous testosterone and risk for CVD in middle-aged men. In elderly men, testosterone may weakly protect against CVD. Alternatively, low testosterone may indicate a poor general health.


References

Basaria, S., A. D. Coviello, et al. (2010). "Adverse Events Associated with Testosterone Administration." N Engl J Med. [PMID: 20592293]

Calof, O. M., A. B. Singh, et al. (2005). "Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials." J Gerontol A Biol Sci Med Sci 60(11): 1451-7. [PMID: 16339333]

Fernandez-Balsells, M. M., M. H. Murad, et al. (2010). "Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis." J Clin Endocrinol Metab 95(6): 2560-75. [PMID: 20525906]

Haddad, R. M., C. C. Kennedy, et al. (2007). "Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials." Mayo Clin Proc 82(1): 29-39. [PMID: 17285783]

Khoo, T. K. (2010). "Adverse events associated with testosterone administration." N Engl J Med 363(19): 1865-6; author reply 1866-7. [PMID: 21047235]

Phillips, G. B. (2010). "Adverse events associated with testosterone administration." N Engl J Med 363(19): 1866; author reply 1866-7. [PMID: 21047234]

Ruige, J. B., A. M. Mahmoud, et al. (2010). "Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis." Heart. [PMID: 21177660]

Weikert, C., T. Pischon, et al. (2010). "Adverse events associated with testosterone administration." N Engl J Med 363(19): 1865; author reply 1866-7. [PMID: 21047236]

Wu, F. C., A. Tajar, et al. (2010). "Identification of late-onset hypogonadism in middle-aged and elderly men." N Engl J Med 363(2): 123-35. [PMID: 20554979]