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A new systematic literature review adds complexity to the controversy over testosterone’s relationship to risk for myocardial infarction, stroke, cardiovascular death, and all-cause mortality.
Last year, the TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) trial was the first randomized, placebo-controlled study designed and powered to determine whether testosterone therapy increased risk for major cardiovascular events in men (ages 45-80 years). Its conclusions provided reassurance that modest use of testosterone therapy short term does not increase CVD risk.
But other studies have had different conclusions and TRAVERSE left unanswered questions, so Bu B. Yeap, MBBS, PhD, an endocrinologist at the University of Western Australia in Crawley, and colleagues completed a literature review with 11 prospective cohort studies of community-dwelling men with sex steroid levels measured with mass spectrometry. Nine of the studies provided individual participation data (IPD); two used aggregate data, and all had at least 5 years of follow-up.
The findings were published in Annals of Internal Medicine .
Dr. Yeap’s team concluded that certain groups of men have higher risk for CVD events. In this study, men with very low testosterone, high luteinizing hormone (LH), or very low estradiol concentrations had higher all-cause mortality. Sex hormone–binding globulin (SHBG) concentration was positively associated and dihydrotestosterone (DHT) levels were nonlinearly associated with all-cause mortality and CVD mortality.
The testosterone level below which men had higher risk of death from any cause was 7.4 nmol/L (213 ng/dL), regardless of LH concentration, the researchers concluded, writing, “This adds to information on reference ranges based on distributions of testosterone in selected samples of healthy men.”
The link between higher SHBG concentrations and higher all-cause mortality “may be related to its role as the major binding protein for sex steroids in the circulation,” the authors wrote. “We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations is warranted.”
Rigorous Methodology Adds Value
Bradley D. Anawalt, MD, with the University of Washington School of Medicine in Seattle, pointed out in an accompanying editorial that the study’s findings are particularly valuable because of the team’s rigorous methodology. The team measured testosterone with the gold standard, mass spectrometry, which can also measure DHT and estradiol more accurately than widely available commercial immunoassays, which “are inaccurate for measurement of these sex steroids in men, who typically have low serum concentrations of these two metabolites of testosterone,” Dr. Anawalt said.
Also, the researchers obtained raw data from the nine IPD studies and reanalyzed the combined data, which allows for more sophisticated analysis when combining data from multiple studies, Dr. Anawalt explained.
The main finding from the Yeap et al. study, he wrote, is that high testosterone concentrations at baseline were not linked with increased deaths from CVD or from all causes “but very low serum total testosterone concentrations at baseline were.
“It is tempting to hypothesize that testosterone therapy might have cardiovascular benefits solely in patients with very low concentrations of serum total testosterone,” Dr. Anawalt wrote.
He pointed out as particularly interesting the findings for DHT and estradiol.
“The finding that a low serum estradiol concentration is associated with higher all-cause mortality adds another reason (in addition to the adverse effects on body fat and bone health) to avoid aromatase inhibitors that are commonly taken by persons who use anabolic steroids,” he wrote. “The prospect of a U-shaped curve for the relationship between serum DHT and higher cardiovascular risk warrants further study.”
The work is funded by the Government of Western Australia and Lawley Pharmaceuticals. The authors’ and editorial writer’s conflicts of interest are listed in the full study.
A new systematic literature review adds complexity to the controversy over testosterone’s relationship to risk for myocardial infarction, stroke, cardiovascular death, and all-cause mortality.
Last year, the TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) trial was the first randomized, placebo-controlled study designed and powered to determine whether testosterone therapy increased risk for major cardiovascular events in men (ages 45-80 years). Its conclusions provided reassurance that modest use of testosterone therapy short term does not increase CVD risk.
But other studies have had different conclusions and TRAVERSE left unanswered questions, so Bu B. Yeap, MBBS, PhD, an endocrinologist at the University of Western Australia in Crawley, and colleagues completed a literature review with 11 prospective cohort studies of community-dwelling men with sex steroid levels measured with mass spectrometry. Nine of the studies provided individual participation data (IPD); two used aggregate data, and all had at least 5 years of follow-up.
The findings were published in Annals of Internal Medicine .
Dr. Yeap’s team concluded that certain groups of men have higher risk for CVD events. In this study, men with very low testosterone, high luteinizing hormone (LH), or very low estradiol concentrations had higher all-cause mortality. Sex hormone–binding globulin (SHBG) concentration was positively associated and dihydrotestosterone (DHT) levels were nonlinearly associated with all-cause mortality and CVD mortality.
The testosterone level below which men had higher risk of death from any cause was 7.4 nmol/L (213 ng/dL), regardless of LH concentration, the researchers concluded, writing, “This adds to information on reference ranges based on distributions of testosterone in selected samples of healthy men.”
The link between higher SHBG concentrations and higher all-cause mortality “may be related to its role as the major binding protein for sex steroids in the circulation,” the authors wrote. “We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations is warranted.”
Rigorous Methodology Adds Value
Bradley D. Anawalt, MD, with the University of Washington School of Medicine in Seattle, pointed out in an accompanying editorial that the study’s findings are particularly valuable because of the team’s rigorous methodology. The team measured testosterone with the gold standard, mass spectrometry, which can also measure DHT and estradiol more accurately than widely available commercial immunoassays, which “are inaccurate for measurement of these sex steroids in men, who typically have low serum concentrations of these two metabolites of testosterone,” Dr. Anawalt said.
Also, the researchers obtained raw data from the nine IPD studies and reanalyzed the combined data, which allows for more sophisticated analysis when combining data from multiple studies, Dr. Anawalt explained.
The main finding from the Yeap et al. study, he wrote, is that high testosterone concentrations at baseline were not linked with increased deaths from CVD or from all causes “but very low serum total testosterone concentrations at baseline were.
“It is tempting to hypothesize that testosterone therapy might have cardiovascular benefits solely in patients with very low concentrations of serum total testosterone,” Dr. Anawalt wrote.
He pointed out as particularly interesting the findings for DHT and estradiol.
“The finding that a low serum estradiol concentration is associated with higher all-cause mortality adds another reason (in addition to the adverse effects on body fat and bone health) to avoid aromatase inhibitors that are commonly taken by persons who use anabolic steroids,” he wrote. “The prospect of a U-shaped curve for the relationship between serum DHT and higher cardiovascular risk warrants further study.”
The work is funded by the Government of Western Australia and Lawley Pharmaceuticals. The authors’ and editorial writer’s conflicts of interest are listed in the full study.
A new systematic literature review adds complexity to the controversy over testosterone’s relationship to risk for myocardial infarction, stroke, cardiovascular death, and all-cause mortality.
Last year, the TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) trial was the first randomized, placebo-controlled study designed and powered to determine whether testosterone therapy increased risk for major cardiovascular events in men (ages 45-80 years). Its conclusions provided reassurance that modest use of testosterone therapy short term does not increase CVD risk.
But other studies have had different conclusions and TRAVERSE left unanswered questions, so Bu B. Yeap, MBBS, PhD, an endocrinologist at the University of Western Australia in Crawley, and colleagues completed a literature review with 11 prospective cohort studies of community-dwelling men with sex steroid levels measured with mass spectrometry. Nine of the studies provided individual participation data (IPD); two used aggregate data, and all had at least 5 years of follow-up.
The findings were published in Annals of Internal Medicine .
Dr. Yeap’s team concluded that certain groups of men have higher risk for CVD events. In this study, men with very low testosterone, high luteinizing hormone (LH), or very low estradiol concentrations had higher all-cause mortality. Sex hormone–binding globulin (SHBG) concentration was positively associated and dihydrotestosterone (DHT) levels were nonlinearly associated with all-cause mortality and CVD mortality.
The testosterone level below which men had higher risk of death from any cause was 7.4 nmol/L (213 ng/dL), regardless of LH concentration, the researchers concluded, writing, “This adds to information on reference ranges based on distributions of testosterone in selected samples of healthy men.”
The link between higher SHBG concentrations and higher all-cause mortality “may be related to its role as the major binding protein for sex steroids in the circulation,” the authors wrote. “We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations is warranted.”
Rigorous Methodology Adds Value
Bradley D. Anawalt, MD, with the University of Washington School of Medicine in Seattle, pointed out in an accompanying editorial that the study’s findings are particularly valuable because of the team’s rigorous methodology. The team measured testosterone with the gold standard, mass spectrometry, which can also measure DHT and estradiol more accurately than widely available commercial immunoassays, which “are inaccurate for measurement of these sex steroids in men, who typically have low serum concentrations of these two metabolites of testosterone,” Dr. Anawalt said.
Also, the researchers obtained raw data from the nine IPD studies and reanalyzed the combined data, which allows for more sophisticated analysis when combining data from multiple studies, Dr. Anawalt explained.
The main finding from the Yeap et al. study, he wrote, is that high testosterone concentrations at baseline were not linked with increased deaths from CVD or from all causes “but very low serum total testosterone concentrations at baseline were.
“It is tempting to hypothesize that testosterone therapy might have cardiovascular benefits solely in patients with very low concentrations of serum total testosterone,” Dr. Anawalt wrote.
He pointed out as particularly interesting the findings for DHT and estradiol.
“The finding that a low serum estradiol concentration is associated with higher all-cause mortality adds another reason (in addition to the adverse effects on body fat and bone health) to avoid aromatase inhibitors that are commonly taken by persons who use anabolic steroids,” he wrote. “The prospect of a U-shaped curve for the relationship between serum DHT and higher cardiovascular risk warrants further study.”
The work is funded by the Government of Western Australia and Lawley Pharmaceuticals. The authors’ and editorial writer’s conflicts of interest are listed in the full study.
FROM ANNALS OF INTERNAL MEDICINE