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CME

Can Testosterone Levels Influence Mortality Risk?

  • Authors: News Author: Lisa Nainggolan
    CME Author: Laurie Barclay, MD
  • CME Released: 12/10/2013
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 12/10/2014
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Target Audience and Goal Statement

This article is intended for primary care clinicians, geriatricians, cardiologists, and other specialists who care for older men in whom testosterone therapy may be considered.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe the associations of testosterone, dihydrotestosterone, and estradiol levels with all-cause mortality in older men.
  2. Describe the associations of testosterone, dihydrotestosterone, and estradiol levels with ischemic heart disease mortality in older men.


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Author(s)

  • Lisa Nainggolan

    Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. Previously, she was science editor of Scrip World Pharmaceutical News, covering news about research and development in the pharmaceutical industry, and a consultant editor of Scrip Magazine. Graduating in physiology from Sheffield University, UK, she began her career as a poisons information specialist at Guy's Hospital before becoming a medical journalist in 1995. She can be reached at [email protected]

    Disclosures

    Disclosure: Lisa Nainggolan has disclosed no relevant financial relationships.

Editor(s)

  • Amy Nadel

    Disclosures

    Disclosure: Amy Nadel has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Yullee C. Chui

    Program Manager, Medscape, LLC

    Disclosures

    Disclosure: Yullee C. Chui has disclosed no relevant financial relationships.


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CME

Can Testosterone Levels Influence Mortality Risk?

Authors: News Author: Lisa Nainggolan CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 12/10/2013

Valid for credit through: 12/10/2014

processing....

Clinical Context

Testosterone levels decrease with increasing age. In aging men, lower testosterone levels have been associated with increased mortality risk.

The associations of testosterone metabolites, namely dihydrotestosterone (DHT) and estradiol (E2), with mortality have not been well studied. The goal of this study by Yeap and colleagues was to examine associations of testosterone, DHT, and E2 with all-cause mortality and ischemic heart disease (IHD) mortality in older men.

Study Synopsis and Perspective

A new study in older men, published online November 20 in the Journal of Clinical Endocrinology & Metabolism, has shown that those with testosterone levels in the mid-range had the lowest rates of death from any cause.

This U-shaped association of testosterone with mortality differs from that seen in prior research, said lead author Bu Beng Yeap, MBBS, FRACP, PhD, from the University of Western Australia, Perth.

"There was no benefit of having a high-normal testosterone level. Therefore, an optimal rather than a high testosterone level predicts [best] survival," Dr. Yeap told Medscape Medical News.

Trying to untangle all of this information on testosterone and its metabolites is difficult because different studies have provided conflicting results, particularly with regard to testosterone replacement therapy, Dr. Yeap conceded. Whereas some research has suggested lower mortality risk in men treated with testosterone as opposed to control participants, others have found the opposite.

There is particular concern about the use of testosterone replacement therapy in older men with comorbidities. A study published November 6 in the Journal of the American Medical Association, for example, found a 30% higher risk for adverse cardiovascular events, including death, in a Veterans Administration cohort of men with multiple comorbidities undergoing coronary angiography treated with testosterone, compared with those who did not receive it (JAMA. 2013;310:1829-1836). Also, a National Institutes of Health study of testosterone supplementation in older men was terminated early in 2010 as a result of an excess of cardiovascular events in the treatment group.

Asked to comment on the new findings, Richard Quinton, MBBChir, MD, FRCP, an endocrinologist from Newcastle University, United Kingdom, told Medscape Medical News: "A clue emerges from this study that indicates peak survival associated with the 50 to 75 serum testosterone centile, greater than that of men in the highest centiles. Serum T [testosterone] levels in the various unsuccessful testosterone-intervention studies would have been pushed well into (and indeed frequently above) this highest centile range.

"If serum T is a biomarker for health, why is having the very highest levels not quite as good as having mid-high levels? This may reflect the ability of testosterone to induce erythrocytosis, which in older men can predispose to vascular thrombosis," he postulated.

"A similar signal emerges from men and women on renal-replacement therapy receiving erythropoietin [EPO] therapy; although EPO is a great treatment for fatigue resulting from anemia of end-stage renal disease, boosting erythrocytosis too much increases adverse cardiovascular outcomes. Aiming for mid-range serum T levels is sensible, but in fact the top priority in monitoring testosterone-replacement therapy is: 'Don't let the hematocrit rise!' "

Clarifying Testosterone Link With Outcomes Will Help Inform Trials

The conflicting results with regard to the risks and benefits of testosterone replacement therapy are of great concern, given that the market for testosterone treatment is increasing exponentially, with many older men taking it without a clearly established indication. This is especially true in the United States, where direct-to-consumer advertising is driving the demand, as well as campaigns targeted at physicians by companies marketing testosterone. The phenomenon has also been observed elsewhere (eg, the United Kingdom, due to online access to such commercials).

"There have been no randomized trials of testosterone therapy with the prespecified end points of cardiovascular events or mortality, and such necessarily large studies would pose major logistic challenges," Dr. Yeap and colleagues observe in their paper.

However, clarifying associations of testosterone with health outcomes independently of conventional risk factors for ill health will help in the design of interventions to properly ascertain the benefits and risks of testosterone therapy, they note.

Hence, in this current study, they analyzed the mortality rate in a group of 3690 community-dwelling men 70 to 89 years old in Western Australia. They divided the men into 4 groups based on their endogenous testosterone levels.

Plasma total testosterone, DHT — a metabolite of testosterone — and E2 levels were assayed using liquid chromatography tandem mass spectrometry in early-morning samples collected from 2001-2004. Deaths to December 2010 were ascertained by data linkage.

U-Shaped Curve for Testosterone and Death in Older Men

There were 974 deaths (26.4%), including 325 from IHD. Men who died had lower mean baseline levels of testosterone (12.8 vs 13.2 nmol/L; P = .013), DHT (1.4 vs 1.5 nmol/L; P = .002), and E2 (71.6 vs 74.0 pmol/L, P = .022).

After adjustment for other risk factors — including age, overweight, and other confounding factors including education, smoking, body mass index, waist-to-hip ratio, hypertension, dyslipidemia, diabetes, creatinine, and prevalent cardiovascular disease and cancer — testosterone and DHT were associated with all-cause mortality.

Cumulative mortality rate was highest in those with total testosterone levels in the lowest quartile, with the second-highest rate seen in men with testosterone levels in the highest quartile. Those with testosterone levels in the middle 2 quartiles at baseline had the lowest incidence of death from any cause (testosterone quartile Q2 vs Q1, adjusted hazard ratio [HR], 0.82 [P = .033]; Q3 vs Q1, HR, 0.78 [P = .010]; and Q4 vs Q1, HR 0.86 [P = .126]).

Interestingly, higher levels of DHT were associated with lower mortality from IHD (Q3 vs Q1, HR 0.58 [P = .002]; Q4 vs Q1, HR 0.69 [P = .026]).

"Ours is the first study that I am aware of that demonstrates conclusively that higher DHT level is associated with lower ischemic heart disease mortality. DHT may be an important biomarker for ischemic heart disease in older men," Dr. Yeap noted.

E2 was not associated with either all-cause or IHD mortality.

"Older men who had testosterone in the middle range survived longer than their counterparts who had either low or high levels of the hormone," Dr. Yeap reiterated. "Having the right amount of testosterone and higher levels of DHT might indicate these men are in better health overall, or it could help them maintain good health as they grow older," he speculated.

Treat to Mid-Normal Levels, Rather Than High End?

But "in view of the controversy over possible adverse effects of testosterone therapy, particularly in older men who have limited mobility or comorbidities, the benefits vs risks of testosterone should be carefully considered," Dr. Yeap stressed.

"We need rigorous randomized clinical trials to test whether testosterone supplementation in men with low-normal as opposed to unequivocally low levels would improve health outcomes. Pending such studies, we should adhere to existing consensus guidelines when considering testosterone therapy in men."

Testosterone therapy should "be considered [only] in men who have symptoms and signs of androgen deficiency and who have been found to have unequivocally low levels of testosterone measured early in the morning using an accurate assay and confirmed at least once," he told Medscape Medical News. This is consistent with guidance from professional organizations — for example, those of the US Endocrine Society, he noted.

And "in older men, we should consider treating to mid-normal levels of testosterone rather than raising testosterone levels to the high end of the reference range," he concluded.

The authors and Dr. Quinton have reported no relevant financial relationships.

J Clin Endocrinol Metab. Published online November 20, 2013. Abstract

Study Highlights

  • From 2001-2004, the investigators collected early-morning samples from 3690 community-dwelling men 70 to 89 years old living in Perth, Western Australia.
  • Using liquid chromatography tandem mass spectrometry, they measured plasma total testosterone, DHT, and E2 levels.
  • Data linkage allowed determination of deaths to December 2010.
  • Of 974 deaths (26.4% of the sample), 325 were from IHD.
  • Compared with men who survived, men who died had lower baseline levels of testosterone (12.8 ± 5.1 vs 13.2 ± 4.8 nmol/L; P = .013), DHT (1.4 ± 0.7 vs 1.5 ± 0.7 nmol/L; P = .002), and E2 (71.6 ± 29.3 vs 74.0 ± 29.0 pmol/L; P = .022).
  • Testosterone and DHT levels were associated with all-cause mortality, after allowance for other risk factors.
  • For testosterone quartile Q2 vs Q1, the adjusted HR was 0.82 for all-cause mortality (P = .033). For Q3 vs Q1, the HR was 0.78 (P = .01), but the HR for Q3 vs Q1 was not statistically significant.
  • For DHT, the adjusted HR was 0.76 for all-cause mortality (P = .003) for Q3 vs Q1, but the HR for Q4 vs Q1 was not statistically significant.
  • Higher DHT levels were associated with a lower risk for IHD mortality. For DHT quartile Q3 vs Q1, the adjusted HR was 0.58 (P = .002); for Q4 vs Q1, the HR was 0.69 (P = .026).
  • E2 level was not associated with either all-cause or IHD mortality.
  • Exclusion of low and high outliers for hormone levels and exclusion of deaths within the first year did not affect the results, which makes reverse causality less likely.
  • On the basis of these findings, the investigators concluded that optimal androgen levels are a biomarker for survival.
  • Older men with midrange levels of testosterone and DHT had the lowest death rates from any cause, whereas those with higher DHT levels had lower IHD mortality risk.
  • The authors recommend further investigations of the biological basis underlying these associations, including randomized trials of testosterone supplementation.
  • The effects of lower and higher circulating testosterone levels might explain the U-shaped association of total testosterone with all-cause mortality.
  • Reduced androgen exposure could increase mortality risk via altered body composition, lower bone strength, frailty, modulation of cardiovascular risk factors, impairment of vascular function, or effects on angiogenesis and neovascularization.
  • The observation that higher DHT levels were associated with lower IHD mortality risk but not with non-IHD mortality risk suggests a protective influence of androgens against IHD.
  • Limitations of this study include observational design precluding causal inferences, and inability to distinguish between the effects of comorbidities or their treatments.
  • In addition, there may be a "healthy survivor" effect. The study involved only a single blood sample for hormone assays, and participants were almost entirely Caucasian, limiting generalizability to men of other ethnic origins.

Clinical Implications

  • In a prospective, population-based study, older men with midrange levels of testosterone and DHT had the lowest death rates from any cause. The effects of lower and higher circulating levels of testosterone might explain the U-shaped association of total testosterone with all-cause mortality.
  • Older men with higher DHT levels had a lower risk for IHD mortality. However, E2 levels did not predict mortality. The investigators recommend further investigations of the biological basis underlying these associations.

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