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ESTES PARK, COLO. – The delivery route of testosterone therapy in men with hypogonadism has emerged as a new issue in the still-developing story of the therapy’s cardiovascular safety.
A retrospective cohort study of more than 544,000 men in the United States and England who initiated testosterone therapy concluded that the associated cardiovascular risk varied significantly with the dosage form prescribed.
Testosterone by injection inevitably results in pharmacologic hormone levels. Study participants who initiated testosterone injections had a significant 26% increase in the 1-year risk of the composite endpoint of myocardial infarction, unstable angina, or stroke, compared with men using testosterone gels, which generally achieve physiologic levels. The testosterone injectors also had a 34% increase in 1-year all-cause mortality and a 16% increase in all-cause hospitalizations.
In all, 27% of the men received testosterone injections, 56% gels, and 7% patches. Outcomes did not differ between men on the gels and those on testosterone patches (JAMA Intern Med. 2015 Jul 1;175[7]:1187-96).
“This study has made our VA hospital – and VAs across the country – relook at what they’re covering as far as testosterone therapy,” Dr. Margaret E. Wierman said at a conference on internal medicine sponsored by the University of Colorado.
Dr. Wierman, who wrote the editorial accompanying the JAMA study, acknowledged the inherent limitations of an epidemiologic study such as this, which can’t prove cause-and-effect. Nonetheless, the study’s strengths, including its sheer size, make it deserving of attention. And the findings raise legitimate concerns about the huge increase in testosterone prescribing in recent years in the U.S. and elsewhere, said Dr. Wierman, who is chief of endocrinology at the Denver VA Medical Center and professor of medicine, physiology and biophysics at the university (JAMA Intern Med. 2015;175[7]:1197-8).
Those concerns were brought to the fore in what she termed an “alarming” Food and Drug Administration report issued last year. The FDA determined that during 2010-2013, testosterone prescriptions in the U.S. jumped by 76% to 2.3 million annually. Disturbingly, hypogonadism was documented in only 50% of patient charts. One quarter of the men didn’t have a baseline testosterone measurement, and 21% never had a follow-up level checked after going on the hormone therapy.
“It shows there’s a lot of charlatanism out there, and a lot of abuse,” she commented.
The FDA also found that 57% of men being prescribed testosterone were also prescribed cardiac medications, suggesting they are at increased cardiovascular risk. Yet the cardiovascular safety of testosterone therapy remains an open question, with all eyes now on the 800-subject, randomized, placebo-controlled, National Institute on Aging–sponsored Testosterone Trial in Older Men, due to report results next year.
In the interim, Dr. Wierman’s take-home message on testosterone, based on her decades of work in the field, is simple: Too little is bad; it is manifest in a variety of physical, psychologic, and sexual symptoms, many of which are related to aging and aren’t sensitive or specific to hypogonadism. Too much is bad as well, posing potential risks of accelerated growth of undiagnosed prostate cancer, tissue edema in patients with cardiac, liver, or renal disease, gynecomastia, erythrocytosis, sleep apnea, stimulation of platelet aggregation, and possibly an increase in cardiovascular events.
The virtues of the middle path were recently underscored in a study of 3,690 community-dwelling Australian men ages 70-89. Over the course of up to 9 years of follow-up, death rates were lower in men in the middle quartiles for testosterone than in those with low or high levels (J Clin Endocrinol Metab. 2014 Jan;99[1]:E9-18).
“This suggests that there may be side effects of pushing testosterone up above the physiologic range, at least in some sets of men,” according to Dr. Wierman.
She fully supports the Endocrine Society’s recommendations to treat men with both signs and symptoms of hypogonadism and documented low testosterone due to a known disorder, and to target physiologic testosterone levels.
“Usually you can find out what the cause is. I want to be a hormone detective. I want to find out what the cause is because if I can reverse the cause, I’d rather have the testosterone level come up on its own,” the endocrinologist said.
Of course, the cause isn’t always reversible. For example, high-dose narcotic therapy is one of the most common causes of acquired central hypogonadism in VA hospitals.
“There are a lot of wounded young men coming back from the war who have horrible osteoporosis and metabolic syndrome who are on narcotics and can’t get off them, and who are not getting testosterone and should be on it,” she said.
There has been a major change in thinking with regard to late-onset hypogonadism, also known as andropause, a disorder that has served as the rationale for much testosterone prescribing. Fifteen years, ago based on data from the Baltimore Longitudinal Study on Aging, it was thought that up to 30% of older men have andropause; however, that conclusion was based solely on testosterone levels, with no consideration of signs and symptoms.
More recently, European investigators used an appropriately more rigorous definition of andropause: that is, a serum total testosterone level below 320 ng/mL plus at least three sexual symptoms, such as low sexual desire, poor morning erection, and erectile dysfunction. By this definition, the prevalence of andropause is much lower, a maximum of 3%-5%. And it’s influenced by advancing age, body mass index, and comorbid conditions (N Engl J Med. 2010 Jul 8;363[2]:123-35).
“The 30% prevalence figure that’s out there is just wrong,” Dr. Wierman stressed. “There may be a diagnosis of late-onset hypogonadism – it’s a diagnosis of exclusion – but it’s much lower.”
In a follow-up study, the same European researchers showed that weight loss in middle-aged and older men was associated with a proportional increase in serum testosterone and sex-hormone binding globulin, while weight gain brought a proportional drop in testosterone and SHBG (Eur J Endocrinol. 2013 Feb 20;168[3]:445-55).
Dr. Wierman said this study contains an important lesson for everyday clinical practice: In overweight older men with low-normal testosterone levels in the 200-250 ng/mL range, the primary recommendation should be diet and lifestyle modification aimed at achieving weight loss, not testosterone therapy. Successful weight loss will boost their testosterone level, improve comorbid obstructive sleep apnea, enhance their cardiovascular and metabolic fitness, and in some cases improve erectile dysfunction, although she was quick to add that low testosterone is “actually a pretty modest cause” of erectile dysfunction.
The number-one cause of erectile dysfunction is poor vascular plumbing as predicted by hypertension and hyperlipidemia. Neurogenic causes are number two and are predicted by chronic back injury, diabetes, and vitamin B12 deficiency. Hormonal causes are next, followed by performance anxiety and other psychogenic issues, and lastly iatrogenic causes involving medication side effects.
Dr. Wierman reported that she is coprincipal investigator for a clinical trial on neuroendocrine dysfunction during rehabilitation after traumatic brain injury funded by the Colorado Brain Trust. Abbvie donates the testosterone gel and placebo utilized in the study.
ESTES PARK, COLO. – The delivery route of testosterone therapy in men with hypogonadism has emerged as a new issue in the still-developing story of the therapy’s cardiovascular safety.
A retrospective cohort study of more than 544,000 men in the United States and England who initiated testosterone therapy concluded that the associated cardiovascular risk varied significantly with the dosage form prescribed.
Testosterone by injection inevitably results in pharmacologic hormone levels. Study participants who initiated testosterone injections had a significant 26% increase in the 1-year risk of the composite endpoint of myocardial infarction, unstable angina, or stroke, compared with men using testosterone gels, which generally achieve physiologic levels. The testosterone injectors also had a 34% increase in 1-year all-cause mortality and a 16% increase in all-cause hospitalizations.
In all, 27% of the men received testosterone injections, 56% gels, and 7% patches. Outcomes did not differ between men on the gels and those on testosterone patches (JAMA Intern Med. 2015 Jul 1;175[7]:1187-96).
“This study has made our VA hospital – and VAs across the country – relook at what they’re covering as far as testosterone therapy,” Dr. Margaret E. Wierman said at a conference on internal medicine sponsored by the University of Colorado.
Dr. Wierman, who wrote the editorial accompanying the JAMA study, acknowledged the inherent limitations of an epidemiologic study such as this, which can’t prove cause-and-effect. Nonetheless, the study’s strengths, including its sheer size, make it deserving of attention. And the findings raise legitimate concerns about the huge increase in testosterone prescribing in recent years in the U.S. and elsewhere, said Dr. Wierman, who is chief of endocrinology at the Denver VA Medical Center and professor of medicine, physiology and biophysics at the university (JAMA Intern Med. 2015;175[7]:1197-8).
Those concerns were brought to the fore in what she termed an “alarming” Food and Drug Administration report issued last year. The FDA determined that during 2010-2013, testosterone prescriptions in the U.S. jumped by 76% to 2.3 million annually. Disturbingly, hypogonadism was documented in only 50% of patient charts. One quarter of the men didn’t have a baseline testosterone measurement, and 21% never had a follow-up level checked after going on the hormone therapy.
“It shows there’s a lot of charlatanism out there, and a lot of abuse,” she commented.
The FDA also found that 57% of men being prescribed testosterone were also prescribed cardiac medications, suggesting they are at increased cardiovascular risk. Yet the cardiovascular safety of testosterone therapy remains an open question, with all eyes now on the 800-subject, randomized, placebo-controlled, National Institute on Aging–sponsored Testosterone Trial in Older Men, due to report results next year.
In the interim, Dr. Wierman’s take-home message on testosterone, based on her decades of work in the field, is simple: Too little is bad; it is manifest in a variety of physical, psychologic, and sexual symptoms, many of which are related to aging and aren’t sensitive or specific to hypogonadism. Too much is bad as well, posing potential risks of accelerated growth of undiagnosed prostate cancer, tissue edema in patients with cardiac, liver, or renal disease, gynecomastia, erythrocytosis, sleep apnea, stimulation of platelet aggregation, and possibly an increase in cardiovascular events.
The virtues of the middle path were recently underscored in a study of 3,690 community-dwelling Australian men ages 70-89. Over the course of up to 9 years of follow-up, death rates were lower in men in the middle quartiles for testosterone than in those with low or high levels (J Clin Endocrinol Metab. 2014 Jan;99[1]:E9-18).
“This suggests that there may be side effects of pushing testosterone up above the physiologic range, at least in some sets of men,” according to Dr. Wierman.
She fully supports the Endocrine Society’s recommendations to treat men with both signs and symptoms of hypogonadism and documented low testosterone due to a known disorder, and to target physiologic testosterone levels.
“Usually you can find out what the cause is. I want to be a hormone detective. I want to find out what the cause is because if I can reverse the cause, I’d rather have the testosterone level come up on its own,” the endocrinologist said.
Of course, the cause isn’t always reversible. For example, high-dose narcotic therapy is one of the most common causes of acquired central hypogonadism in VA hospitals.
“There are a lot of wounded young men coming back from the war who have horrible osteoporosis and metabolic syndrome who are on narcotics and can’t get off them, and who are not getting testosterone and should be on it,” she said.
There has been a major change in thinking with regard to late-onset hypogonadism, also known as andropause, a disorder that has served as the rationale for much testosterone prescribing. Fifteen years, ago based on data from the Baltimore Longitudinal Study on Aging, it was thought that up to 30% of older men have andropause; however, that conclusion was based solely on testosterone levels, with no consideration of signs and symptoms.
More recently, European investigators used an appropriately more rigorous definition of andropause: that is, a serum total testosterone level below 320 ng/mL plus at least three sexual symptoms, such as low sexual desire, poor morning erection, and erectile dysfunction. By this definition, the prevalence of andropause is much lower, a maximum of 3%-5%. And it’s influenced by advancing age, body mass index, and comorbid conditions (N Engl J Med. 2010 Jul 8;363[2]:123-35).
“The 30% prevalence figure that’s out there is just wrong,” Dr. Wierman stressed. “There may be a diagnosis of late-onset hypogonadism – it’s a diagnosis of exclusion – but it’s much lower.”
In a follow-up study, the same European researchers showed that weight loss in middle-aged and older men was associated with a proportional increase in serum testosterone and sex-hormone binding globulin, while weight gain brought a proportional drop in testosterone and SHBG (Eur J Endocrinol. 2013 Feb 20;168[3]:445-55).
Dr. Wierman said this study contains an important lesson for everyday clinical practice: In overweight older men with low-normal testosterone levels in the 200-250 ng/mL range, the primary recommendation should be diet and lifestyle modification aimed at achieving weight loss, not testosterone therapy. Successful weight loss will boost their testosterone level, improve comorbid obstructive sleep apnea, enhance their cardiovascular and metabolic fitness, and in some cases improve erectile dysfunction, although she was quick to add that low testosterone is “actually a pretty modest cause” of erectile dysfunction.
The number-one cause of erectile dysfunction is poor vascular plumbing as predicted by hypertension and hyperlipidemia. Neurogenic causes are number two and are predicted by chronic back injury, diabetes, and vitamin B12 deficiency. Hormonal causes are next, followed by performance anxiety and other psychogenic issues, and lastly iatrogenic causes involving medication side effects.
Dr. Wierman reported that she is coprincipal investigator for a clinical trial on neuroendocrine dysfunction during rehabilitation after traumatic brain injury funded by the Colorado Brain Trust. Abbvie donates the testosterone gel and placebo utilized in the study.
ESTES PARK, COLO. – The delivery route of testosterone therapy in men with hypogonadism has emerged as a new issue in the still-developing story of the therapy’s cardiovascular safety.
A retrospective cohort study of more than 544,000 men in the United States and England who initiated testosterone therapy concluded that the associated cardiovascular risk varied significantly with the dosage form prescribed.
Testosterone by injection inevitably results in pharmacologic hormone levels. Study participants who initiated testosterone injections had a significant 26% increase in the 1-year risk of the composite endpoint of myocardial infarction, unstable angina, or stroke, compared with men using testosterone gels, which generally achieve physiologic levels. The testosterone injectors also had a 34% increase in 1-year all-cause mortality and a 16% increase in all-cause hospitalizations.
In all, 27% of the men received testosterone injections, 56% gels, and 7% patches. Outcomes did not differ between men on the gels and those on testosterone patches (JAMA Intern Med. 2015 Jul 1;175[7]:1187-96).
“This study has made our VA hospital – and VAs across the country – relook at what they’re covering as far as testosterone therapy,” Dr. Margaret E. Wierman said at a conference on internal medicine sponsored by the University of Colorado.
Dr. Wierman, who wrote the editorial accompanying the JAMA study, acknowledged the inherent limitations of an epidemiologic study such as this, which can’t prove cause-and-effect. Nonetheless, the study’s strengths, including its sheer size, make it deserving of attention. And the findings raise legitimate concerns about the huge increase in testosterone prescribing in recent years in the U.S. and elsewhere, said Dr. Wierman, who is chief of endocrinology at the Denver VA Medical Center and professor of medicine, physiology and biophysics at the university (JAMA Intern Med. 2015;175[7]:1197-8).
Those concerns were brought to the fore in what she termed an “alarming” Food and Drug Administration report issued last year. The FDA determined that during 2010-2013, testosterone prescriptions in the U.S. jumped by 76% to 2.3 million annually. Disturbingly, hypogonadism was documented in only 50% of patient charts. One quarter of the men didn’t have a baseline testosterone measurement, and 21% never had a follow-up level checked after going on the hormone therapy.
“It shows there’s a lot of charlatanism out there, and a lot of abuse,” she commented.
The FDA also found that 57% of men being prescribed testosterone were also prescribed cardiac medications, suggesting they are at increased cardiovascular risk. Yet the cardiovascular safety of testosterone therapy remains an open question, with all eyes now on the 800-subject, randomized, placebo-controlled, National Institute on Aging–sponsored Testosterone Trial in Older Men, due to report results next year.
In the interim, Dr. Wierman’s take-home message on testosterone, based on her decades of work in the field, is simple: Too little is bad; it is manifest in a variety of physical, psychologic, and sexual symptoms, many of which are related to aging and aren’t sensitive or specific to hypogonadism. Too much is bad as well, posing potential risks of accelerated growth of undiagnosed prostate cancer, tissue edema in patients with cardiac, liver, or renal disease, gynecomastia, erythrocytosis, sleep apnea, stimulation of platelet aggregation, and possibly an increase in cardiovascular events.
The virtues of the middle path were recently underscored in a study of 3,690 community-dwelling Australian men ages 70-89. Over the course of up to 9 years of follow-up, death rates were lower in men in the middle quartiles for testosterone than in those with low or high levels (J Clin Endocrinol Metab. 2014 Jan;99[1]:E9-18).
“This suggests that there may be side effects of pushing testosterone up above the physiologic range, at least in some sets of men,” according to Dr. Wierman.
She fully supports the Endocrine Society’s recommendations to treat men with both signs and symptoms of hypogonadism and documented low testosterone due to a known disorder, and to target physiologic testosterone levels.
“Usually you can find out what the cause is. I want to be a hormone detective. I want to find out what the cause is because if I can reverse the cause, I’d rather have the testosterone level come up on its own,” the endocrinologist said.
Of course, the cause isn’t always reversible. For example, high-dose narcotic therapy is one of the most common causes of acquired central hypogonadism in VA hospitals.
“There are a lot of wounded young men coming back from the war who have horrible osteoporosis and metabolic syndrome who are on narcotics and can’t get off them, and who are not getting testosterone and should be on it,” she said.
There has been a major change in thinking with regard to late-onset hypogonadism, also known as andropause, a disorder that has served as the rationale for much testosterone prescribing. Fifteen years, ago based on data from the Baltimore Longitudinal Study on Aging, it was thought that up to 30% of older men have andropause; however, that conclusion was based solely on testosterone levels, with no consideration of signs and symptoms.
More recently, European investigators used an appropriately more rigorous definition of andropause: that is, a serum total testosterone level below 320 ng/mL plus at least three sexual symptoms, such as low sexual desire, poor morning erection, and erectile dysfunction. By this definition, the prevalence of andropause is much lower, a maximum of 3%-5%. And it’s influenced by advancing age, body mass index, and comorbid conditions (N Engl J Med. 2010 Jul 8;363[2]:123-35).
“The 30% prevalence figure that’s out there is just wrong,” Dr. Wierman stressed. “There may be a diagnosis of late-onset hypogonadism – it’s a diagnosis of exclusion – but it’s much lower.”
In a follow-up study, the same European researchers showed that weight loss in middle-aged and older men was associated with a proportional increase in serum testosterone and sex-hormone binding globulin, while weight gain brought a proportional drop in testosterone and SHBG (Eur J Endocrinol. 2013 Feb 20;168[3]:445-55).
Dr. Wierman said this study contains an important lesson for everyday clinical practice: In overweight older men with low-normal testosterone levels in the 200-250 ng/mL range, the primary recommendation should be diet and lifestyle modification aimed at achieving weight loss, not testosterone therapy. Successful weight loss will boost their testosterone level, improve comorbid obstructive sleep apnea, enhance their cardiovascular and metabolic fitness, and in some cases improve erectile dysfunction, although she was quick to add that low testosterone is “actually a pretty modest cause” of erectile dysfunction.
The number-one cause of erectile dysfunction is poor vascular plumbing as predicted by hypertension and hyperlipidemia. Neurogenic causes are number two and are predicted by chronic back injury, diabetes, and vitamin B12 deficiency. Hormonal causes are next, followed by performance anxiety and other psychogenic issues, and lastly iatrogenic causes involving medication side effects.
Dr. Wierman reported that she is coprincipal investigator for a clinical trial on neuroendocrine dysfunction during rehabilitation after traumatic brain injury funded by the Colorado Brain Trust. Abbvie donates the testosterone gel and placebo utilized in the study.
EXPERT ANALYSIS FROM THE ANNUAL INTERNAL MEDICINE PROGRAM
