June 30 NEJM: Adverse Events Associated with Testosterone Administration

[Michael Scally MD]

This is hot off the NEJM press. It will be out tomorrow. I want to caution any extrapolation of the findings to TRT in general. One only has to look at the study population - elderly community dwelling men. If needed, I will comment after reading the article in detail.

There are a few hints what this study might be about for the future. As we know, SARMs are being developed by GTx (GTXI) and Ligand (LGND). It is critically important to establish meaningful endpoints for FDA approval. Bhasin is a large player in the androgen field, if not the biggest. His association with LGND should not go unnoticed!

Dr. Bhasin reports receiving consulting fees and payments for travel or accommodation expenses from Novartis and GlaxoSmithKline and grant support from Solvay Pharmaceuticals, Merck, and Ligand Pharmaceuticals. Testosterone and placebo gel for the study were provided by Auxilium Pharmaceuticals, Norristown, PA.


Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med:NEJMoa1000485. NEJM -- Adverse Events Associated with Testosterone Administration

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 .)

 

[Michael Scally MD]

The negative news is busting out all over. This will spread doubts among TRT practitioners as did the earlier NEJM article. From the appearances, the pendulum is swinging back towards NO TRT except under the most strict guidelines. As I said before, being in NEJM alone will cause almost all to read and listen. IT IS VERY SIGNIFICANT THE STUDY WAS STOPPED EARLY. [Note: this is not good for Auxilium stock and probably AndroGel.]


NIH - Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men
Treatment Phase of Clinical Trial Halted
Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men, June 30, 2010 News Release - National Institutes of Health (NIH)

A clinical trial of testosterone treatment in older men, reported June 30 online in the New England Journal of Medicine, has found a higher rate of adverse cardiovascular events, such as heart attacks and elevated blood pressure, in a group of older men receiving testosterone gel compared to those receiving placebo. Due to these events, the treatment phase of the trial was stopped. The study was supported by a grant to Shalender Bhasin, M.D., at Boston Medical Center from the National Institute on Aging (NIA), part of the National Institutes of Health.

Decreased muscle strength may contribute to difficulties in mobility, such as in walking or climbing stairs, which can limit older persons’ independence. Testosterone treatment has been shown to improve muscle strength in some older men, but it is not yet known whether it would reduce mobility limitations in older men with low testosterone levels. The TOM (Testosterone in Older Men) Trial was designed to address this question. It was a randomized, double-blind, placebo-controlled clinical trial of the effects of six months of testosterone gel treatment on strength and ability to walk and climb stairs in 209 older men with low testosterone levels and mobility limitations. The testosterone gel used in this study was administered to the skin daily. The 209 men in the trial had an average age of 74 and high rates of chronic diseases such as diabetes and cardiovascular disease.

The treatment phase of the trial was stopped on Dec. 31, 2009, following a review by the study’s Data and Safety Monitoring Board (DSMB). The DSMB is an independent panel of medical and statistical experts set up from the start of the trial to check regularly for the occurrence of adverse health events in participants and to detect any possible risks from treatment. In December 2009, the board found that 23 of the 106 men who had received testosterone experienced adverse cardiovascular-related events during the study, compared to five of the 103 men who received placebo. The cardiovascular-related events included heart attack, heart rhythm disturbances and elevated blood pressure, and one death from a suspected heart attack. The DSMB weighed the severity of the adverse events in relation to the potential benefits and recommended that participants stop taking study medications and that enrollment be stopped.

As soon as the DSMB made its recommendation, the treatment phase of the trial was halted. All participants were promptly notified and asked to meet with study physicians to discuss any questions they might have. The men who experienced cardiovascular events were treated by their personal physicians for their specific conditions. No new participants will be enrolled in the study. The study team will continue to monitor the health of all participants for at least another year after stopping testosterone use to further evaluate effects of the treatment.

The report in the New England Journal of Medicine provides detailed information about the outcomes and adverse events in participants. The authors note that physicians and patients, especially older men, should consider this study’s findings on adverse effects along with other information on the risks and benefits of testosterone therapy. They also note that further research is needed to clarify the safety issues raised by this trial.

The authors caution that the ability to draw broader conclusions about the safety of testosterone therapy based on these findings is constrained by several factors, including this study’s small size and the fact that the study’s population was older and had higher rates of chronic diseases and mobility limitation than individuals in most other studies.

In addition, the trial’s eligibility criteria excluded men with severely low testosterone levels, limiting the ability to make inferences about safety in this population. The authors also note that the testosterone doses and serum levels in this trial may be higher than those usually used in clinical practice and in some previous clinical trials.

NIA is funding six other trials studying the effects of testosterone. All of the principal investigators of those trials and their DSMBs and Safety Officers have been informed of the findings in the TOM Trial. After reviewing these findings, and other evidence relating to safety of testosterone treatment, the DSMBs and Safety Officers recommended continuation of the trials, with provision of additional information to participants and additional safety precautions. NIA has reviewed these recommendations and concurs with them.

 

[Michael Scally MD]

This is from Reuters!!! Take a look at the headline. This is TROUBLE for TRT. I state the limited interpretation of the study, but do you really think most physicians read these studies in detail?


UPDATE 1-Testosterone gel linked to heart problems
UPDATE 1-Testosterone gel linked to heart problems | Reuters

5:59pm EDT

* Older men with poor mobility studied

* Side effects spur early end to test

* Treatment improves strength, muscle mass

(Adds comment from company paragraphs 11-12,16)

By Gene Emery

BOSTON, June 30 (Reuters) - Testosterone treatments may build muscle mass in older men, but they may carry a risk of heart problems in people with poor mobility, U.S. researchers said on Wednesday.

The Massachusetts study, reported online by the New England Journal of Medicine, was halted after six months because the men using a hormone gel were developing so many heart, breathing and skin problems compared to patients applying a placebo gel to their shoulders or upper arms every day.

"I think the study raises important questions about the safety of giving testosterone to older individuals," Dr. Shalender Bhasin of the Boston University School of Medicine said in a telephone interview.

Levels of testosterone, the so-called male hormone, decline with age in men. Supplementing it in healthy men can build muscle mass and strength and lower the risk of disability.

The new test was the first to assess its effectiveness in men over 65 who already had mobility problems such as difficulty walking two blocks or climbing 10 stairs.

The 209 volunteers, with an average age of 74, also tended to suffer from obesity, diabetes, high blood pressure and high cholesterol at the start of the test. "One would expect that from a frail, older population," said Bhasin.

Recipients of the testosterone gel, sold under the brand name Testim by Auxilium Pharmaceuticals (AUXL.O: Quote, Profile, Research, Stock Buzz), became better at walking up stairs and performing chest- and leg-press exercises.

But by the time the study was terminated, 23 patients in the testosterone group and five in the placebo group had experienced a bad side effect such as fainting, chest pain or heart attack. One man in the testosterone group died of a suspected heart attack.

The numbers were too small to be statistically significant and the side effects encompassed a lot of different diagnoses, which may mean that chance played a role in the results.

Yet men receiving testosterone had more serious side effects and more side effects considered to be life-threatening, the researchers said, lasting for three months after the trial ended.

"The study was designed to study mobility limitation, a common syndrome with the elderly that predicts disability, poor quality of life and mortality," Auxilium said in a statement.

"We believe these men are not representative of the typical testosterone replacement therapy population."

Bhasin was surprised by the finding.

"Testosterone is not currently approved for older men with age-related decline or mobility problems," he said. However it is approved by the U.S. Food and Drug Administration for other patients.

Doctors thinking of prescribing testosterone for their older patients should realize that the treatment may pose a serious risk, Bhasin said. "There may be safety issues that they should weigh in their decision," he said.

Testosterone causes salt and water retention and that could have been a factor, the researchers said. The National Institute on Aging, which paid for the trial, also noted that the men in the study may have been getting exceptionally high doses of testosterone. Auxilium said they were getting double to triple the recommended dose.

 

[Michael Scally MD]

When I said this means BAD NEWS for TRT, I was being serious. In less than an hour since its release, the news is spreading on some widely read news services. Their headlines say it all. [Auxilium Pharmaceuticals, Inc. is down ~5% in AH trading. This will hit other companies. I do not know how much testosterone makes up their revenue, but if it is significant, I expect the share price to be hit.]


Bloomberg News
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study - Bloomberg

Bloomberg BusinessWeek
Auxilium Testosterone Gel Linked to Heart Problems in Older Men
Auxilium Testosterone Gel Linked to Heart Problems in Older Men - BusinessWeek

Wall Street Journal
Testosterone Trial Was Halted Over Cardiovascular Events
Testosterone Trial Was Halted Over Cardiovascular Events - Health Blog - WSJ

 

[CubbieBlue]

When I said this means BAD NEWS for TRT, I was being serious. In less than an hour since its release, the news is spreading on some widely read news services. Their headlines say it all. [Auxilium Pharmaceuticals, Inc. is down ~5% in AH trading. This will hit other companies. I do not know how much testosterone makes up their revenue, but if it is significant, I expect the share price to be hit.]


Bloomberg News
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study - Bloomberg

Bloomberg BusinessWeek
Auxilium Testosterone Gel Linked to Heart Problems in Older Men
Auxilium Testosterone Gel Linked to Heart Problems in Older Men - BusinessWeek

Wall Street Journal
Testosterone Trial Was Halted Over Cardiovascular Events
Testosterone Trial Was Halted Over Cardiovascular Events - Health Blog - WSJ

Kind of neat watching this all unfold.

Mike can you explain SARMs a little bit? How do they work?

If you can include some sort of handy analogy I would appreciate it

 

[TheOldFart]

So they were trying to keep men with an average age of 74 and with high % of hypertension and diabetes and other problems at between 500 and 1000 ng/dl, giving them up to 3 tubes of Testim daily. I don't know, but in my opinion, that is sort of nuts. I wonder what the outcome might have been if they had shot for levels between 400 and 600.

The differences in strength are just amazing to me, especially since the average T level at baseline was about 240. Not good, but not as bad as some men are in their 40s.

I don't think this will have the impact that the WHI study on estrogen and progesterone had for women, but then I might be wrong because of the bad reputation that androgens have. The WHI study was on over 10,000 women of all ages and health condition and this is a small study of unhealthy men. I would hope that most doctors will see that this study has little implications for the majority of the population. Even now, most doctors think that giving estrogen to women is fine. My wife's GYN and her 2 GYN ONCs have no problem with it, except that one of the GYN ONCs won't use it for women who have had ovarian cancer. The other one uses it routinely for his cancer patients. Hopefully most doctors will think the same with testosterone for men. I think that my doctor will.

Just as in the WHI study, the news will tout the negative results in a dramatic headline that leaves out all the real data and implications. My wife immediately stopped her estradiol patch when it came out, even though her doctor didn't want her to. Then when I read the real results of the WHI study, we realized that it was a mistake for her to stop. She is much better since restarting it and both of her doctors agree.

 

[BrianSS]

This is completely irresponsible.

So they gave sedimentary elderly men, in assisted living, with chronic health problems (including heart conditions), 2 to 3 times the recommended dose of testosterone? This sounds like murder to me.

 

[TheOldFart]

Dr. Scally, what was that June 16 NEJM study that determined that only 2% of men between 40 and 80 have hypogonadism? What was their definition of hypogonadism - 250, 300, etc? I find that 2% number hard to believe.

 

[Michael Scally MD]

Dr. Scally, what was that June 16 NEJM study that determined that only 2% of men between 40 and 80 have hypogonadism? What was their definition of hypogonadism - 250, 300, etc? I find that 2% number hard to believe.

It was 320 ng/dL (adjusted for a laboratory reference range). And you are so right in pointing out that article appeared in NEJM (less than a month ago). This will impact TRT.

 

[techlogik]

This is one of the most flawed studies I could imagine.

So let's sum this up.

They take a bunch of 74yr old, fat, sedentary men with pre-existing conditions, they slap upwards of 15G/Day of Gel onto them, they don't monitor and test the E2 levels during this study...and they wonder why they had a bunch of complaints and issues?!!?

Are you kidding me? They either have a blatant and obvious bias to show that somehow a topical gel/Test HRT treatment is dangerous for other motives, or they are clearly incompetent fools who shouldn't be in the medical and research field.

If I take 10G of day of gel, and I am a terrible transdermal absorber, I am in the 800+ range on a 1000 scale. I can't imagine what 10-15G a day would do to an old, sedentary unhealthy man with other medical conditions...wait, actually I can, I would predict the same outcome they did without wasting nearly as much time and money, unless it was for a specific reason to make it look this way to begin with.

Unreal...

 

[TheOldFart]

It was 320 ng/dL (adjusted for a laboratory reference range). And you are so right in pointing out that article appeared in NEJM (less than a month ago). This will impact TRT.

OK, this was the one that we discussed 2 weeks ago. Per their definition of hypogonadism (<11 nmol/L total T or < 220 pmol/L free T and at least 3 symptoms) it was 2.1%. However, just looking at T levels alone, it was 17%, which is near the normally estimated number of 20% that I have seen in various places.

That 3 symptoms is a pile of poop. So if a guy has severe depression, ED and loss of strength and is at 320 then he is fine and doesn't need TRT. The symptoms have to be the 3 sexual ones because they concluded that "only the three sexual symptoms had a syndromic association
with decreased testosterone levels." So my severe depression that started when my ED got bad over 2 years ago and ending when my ED got good after hormone levels got better was just a coincidence. BS. Oh well, old discussion.

 

[HeadDoc]

the parallel between this and the WHI study is incredible: older patients, sicker patients, dose too high for the age group. Whe WHI study was originally intended to look at HRT for woman who could be started as their own hormone levels were declining. Instead they took older women who were post menapausal and incorrectly inferred the rest. The problem here is that many doctors never read the study and started to make treatment recommendations on the study regardless.

 

[Kwirion]

Easy to say: TRT is bad.

Why the study / trial didn't compare:
1. TRT Testosterone only
2. TRT TT with (professional) cardio training - exercises should burn excess T/E2 and increase heart health
3. TRT: TT + anti estrogens or SERMs (Nolvadex, enclomiphene)
4. TRT: 2 + 3

 

[Kwirion]

Links:

Getting older? Take anti-oestrogens with your testosterone
Animal study: running reduces effect of steroids on testes
Effect of testosterone on heart research unreliable

 

[Michael Scally MD]

the parallel between this and the WHI study is incredible: older patients, sicker patients, dose too high for the age group. Whe WHI study was originally intended to look at HRT for woman who could be started as their own hormone levels were declining. Instead they took older women who were post menapausal and incorrectly inferred the rest. The problem here is that many doctors never read the study and started to make treatment recommendations on the study regardless.

Bingo!!!

 

[TheOldFart]

This is a quote from the Bloomberg News article that Dr. Scally linked to:

"Another study published in the same journal on June 16 found that low testosterone levels in older men are less common than doctors previously thought, with only 2 percent of men from 40 to 80 suffering from hypogonadism."

That is a total misrepresentation of the findings in that NEJM article. What it said was:

"In this analysis sample, 4.1% of subjects had a total testosterone level of less than 8.0 nmol per liter, and 17.0% had a total testosterone level of less than 11 nmol per liter. If the syndrome of late-onset hypogonadism is considered to include at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter, among men for whom data were available for testosterone levels and questionnaire responses, the overall prevalence of late-onset hypogonadism in the EMAS study population would be 2.1%....."

17% were below 317 ng/dl, but there deffinition of hypogonadism was to be below that and to have at least 3 sexual symptoms. As I read it, they did not consider loss of strength, depression, etc to be valid symptoms, but perhaps I just interpreted that wrong.

 

[Michael Scally MD]

This is a quote from the Bloomberg News article that Dr. Scally linked to:

"Another study published in the same journal on June 16 found that low testosterone levels in older men are less common than doctors previously thought, with only 2 percent of men from 40 to 80 suffering from hypogonadism."

That is a total misrepresentation of the findings in that NEJM article. What it said was:

"In this analysis sample, 4.1% of subjects had a total testosterone level of less than 8.0 nmol per liter, and 17.0% had a total testosterone level of less than 11 nmol per liter. If the syndrome of late-onset hypogonadism is considered to include at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter, among men for whom data were available for testosterone levels and questionnaire responses, the overall prevalence of late-onset hypogonadism in the EMAS study population would be 2.1%....."

17% were below 317 ng/dl, but there deffinition of hypogonadism was to be below that and to have at least 3 sexual symptoms. As I read it, they did not consider loss of strength, depression, etc to be valid symptoms, but perhaps I just interpreted that wrong.

Again, Bingo! What will occur is that TRT will become less available. Most, if not the great majority, will never read the articles. I would bet that hey will read the news releases only. The NEJM is very persuasive and powerful. Do not for a moment believe this will not affect TRT. I am very diligent about literature because this is what is proven to help, but not necessarily politically correct! The sensationalism will prevail. What I wonder about is this a return of the pendulum swinging back to a very restrictive policy. Does this have roots elsewhere?

 

[Michael Scally MD]

Researchers Halt Testosterone Gel Trial After High Number Of Heart Attacks. It does not end with the NEJM. The NEJM article I alerted Meso readers was an early online publication. Now, the NYT is bringing he news to the public! The New York Times (7/6, D7, Rabin - http://www.nytimes.com/2010/07/06/health/06hormone.html?_r=1&ref=health ) reports, "A federally financed study to see if testosterone gel helps frail elderly men build muscle and strength was abruptly halted late last year after participants taking it suffered a disproportionate number of heart attacks and other serious cardiac problems, and one died of what was apparently a heart attack." The Times says that "researchers were taken aback by the high rate of adverse heart problems." The FDA "has approved it for use only in men with hypogonadism, whose sex glands produce extremely low amounts of testosterone or none at all because of an underlying disorder," yet, "off-label use has increased in recent years."

 

[Michael Scally MD]

Testosterone Gel Trial Ends After Heart Issue
http://www.nytimes.com/2010/07/06/health/06hormone.html?_r=1&ref=health

July 5, 2010
By RONI CARYN RABIN

A federally financed study to see if testosterone gel helps frail elderly men build muscle and strength was abruptly halted late last year after participants taking it suffered a disproportionate number of heart attacks and other serious cardiac problems, and one died of what was apparently a heart attack.

Ten men taking testosterone suffered serious cardiac problems, compared with only one in a control group of elderly men who were applying a fake placebo gel, according to a paper published in The New England Journal of Medicine. The journal disclosed details of the trial’s premature termination for the first time last week.

Researchers were taken aback by the high rate of adverse heart problems. Some experts called it an anomaly, and pointed to the fact that the trial’s participants were sicker than patients in earlier testosterone studies and were treated with a relatively high dose of the hormone. Still, investigators about to begin a much larger set of testosterone trials immediately modified their study protocols, developing new inclusion criteria and agreeing to additional safety monitoring steps.

“There was a great deal of consternation and deliberation,” said Dr. Shalender Bhasin, a professor at Boston University School of Medicine and the senior author on the paper about the trial. “The lesson to be learned here is that physicians and patients, especially older men who are considering testosterone therapy, should weigh these findings of adverse events in their decision making.”

Dr. Evan Hadley, director of the division of geriatrics and clinical gerontology at the National Institute on Aging, which financed the study, said it would continue to study the hormone’s effects. “It’s important to look at all the evidence about testosterone treatment,” Dr. Hadley said. “Other studies in older men haven’t seen this pattern.”

Testosterone is not approved for use in older men whose testosterone levels have declined with age. The Food and Drug Administration has approved it for use only in men with hypogonadism, whose sex glands produce extremely low amounts of testosterone or none at all because of an underlying disorder. But the use of testosterone for other purposes, known as off-label use, has increased in recent years, with many older men taking it because of a belief it can counter or reverse the effects of aging.

There is very little solid evidence from randomized clinical trials about the potential benefits of testosterone treatment for these men. There are also concerns about long-term use, like the possibility that higher hormone levels could increase the risk of prostate cancer. The new clinical trials being financed by the National Institute on Aging are an effort to fill the information gap.

Participants in the trial that was stopped prematurely, called the Testosterone in Older Men With Mobility Limitations, or TOM, were non-institutionalized men aged 65 and older who had difficulty walking two blocks or climbing 10 steps and whose serum testosterone was 100 to 350 nanograms per deciliter (the normal range is 300 to 1,200 nanograms per deciliter). The goal was to recruit 252 men, but only 209 subjects had been enrolled by the time the trial, which started in 2005, was stopped last Dec. 31. Testosterone use had the desired effect of improving the men’s muscle strength and mobility. But they also experienced a high rate of adverse effects — not just cardiovascular problems but respiratory and skin problems.

Dr. Peter J. Snyder of the University of Pennsylvania School of Medicine is leading a much larger $45 million study financed by the N.I.A. In the 12-center trial, 800 men 65 and older who have low testosterone will be randomly assigned to testosterone treatment or placebo for a year. The trial, which is actually a set of studies, will assess testosterone’s effect on physical functioning, fatigue and sexual and cognitive function. “There is even a cardiovascular trial, the hypothesis of which is that testosterone actually makes cardiac risk factors better,” said Dr. Snyder, who characterized the TOM results as an aberration.

 

[Michael Scally MD]

EDITORIAL: Bremner WJ. Testosterone Deficiency and Replacement in Older Men. N Engl J Med;363(2):189-91.

It is now clear that men have gradual declines in average serum testosterone levels as they age. These decreases begin by middle age and continue into old age.1,2 Although the decreases are substantial in many men, they are quite variable. Some men, even in old age, maintain serum testosterone levels similar to those of healthy young men.

Many of the physical and behavioral changes that occur in men as they age are similar to those that occur in younger men with hypogonadism. These changes include decreases in muscle mass, strength, bone mass, and sexual function and increases in body fat, fatigue, and depressed mood. It is therefore reasonable to ask whether testosterone deficiency could be causing some of the adverse physical and behavioral changes of aging and whether these could be improved with the administration of testosterone.

The diagnosis of testosterone deficiency in older men is complicated by the fact that many older men (more than 20% in some studies) have testosterone levels that are lower than the normal range in younger men. In addition, the clinical presentation of male hypogonadism is nonspecific and overlaps with that of other illnesses and with the aging process itself. Therefore, it is frequently unclear in caring for individual older patients whether the diagnosis of hypogonadism is appropriate and whether testosterone administration might be helpful or might instead cause adverse effects.

Two articles in this issue of the Journal address these important issues.3,4 Wu et al.3 report on a population survey of 3369 men, 40 to 79 years of age, in eight European centers. Results of the survey with respect to subjects' general, sexual, physical, and psychological health were compared with morning measurements of total and free testosterone levels in the subjects' serum. Among many symptoms surveyed, three sexual symptoms (poor morning erection, low sexual desire, and erectile dysfunction) and three general symptoms (inability to perform vigorous activity, depression, and fatigue) were associated with low testosterone levels. Further analysis showed that the presence of at least three sexual symptoms in a man with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) could be used to define late-onset hypogonadism. This conclusion was validated in a second data set in the same study. These conclusions are a valuable addition to earlier research, as well as to society guidelines,5,6 which have also proposed the combination of symptoms and low testosterone levels to establish the diagnosis of late-onset hypogonadism. The difficulty with using symptoms alone to define late-onset hypogonadism was highlighted by the finding that more than 25% of men with normal testosterone levels had similar sexual symptoms.

Among older men with testosterone deficiency, can we replace testosterone in an effective and safe manner? Many studies involving limited numbers of men have shown that the administration of testosterone results in improved muscle mass and strength, increased bone mass, and other positive effects.7 None of the studies have been of sufficient size or duration to adequately address potential risks, such as the risk of prostate disease. The study by Basaria et al.4 was designed to assess whether leg-muscle strength in older men with severe limitations in mobility was increased as a result of testosterone administration. Community-dwelling men 65 years of age or older with a testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) were randomly assigned to receive a transdermal gel containing testosterone (to achieve testosterone levels of 500 to 1000 ng per deciliter [17.4 to 34.7 nmol per liter]) or placebo. The 209 participants had a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity. During the experimental phase, the testosterone group showed greater leg and arm strength than did the placebo group but also had higher rates of cardiovascular adverse effects. The excess of cardiovascular events in the testosterone group led the data and safety monitoring board to recommend early termination of the study. Of initial concern was the fact that 10 of the 106 men receiving testosterone had adverse cardiac events, as compared with 1 of the 103 men receiving placebo. Further investigation at the request of the data and safety monitoring board showed excesses of "cardiovascular-related" events in the testosterone group. These results are surprising, since many studies with cumulative numbers of subjects greater than those reported here have not detected substantial increases in cardiovascular risk during testosterone administration (including many studies in which subjects achieved the same or higher serum testosterone levels, some for longer periods of time).8 As the authors state, there is a clear possibility that their results are due to chance.

Many readers may disagree with the decision of the data and safety monitoring board to terminate the study early. Results of studies terminated early may differ from those of larger, longer-term studies. Also, readers will speculate that the higher rates of adverse events in the testosterone group may have been due to the fact that the two groups of men had different baseline characteristics, with a higher rate of hyperlipidemia and statin use and of hypertension in the testosterone group before the experimental interventions. To me, the decision of the data and safety monitoring board seems reasonable. For whatever reason, there were higher rates of cardiovascular disease in the group of men who were receiving testosterone in this study than in their counterparts who were receiving placebo.

Although this result sounds a note of caution in general concerning testosterone administration in older men, it certainly should not deter investigators from proceeding with additional, larger studies of testosterone administration in well-characterized groups of older men to more clearly outline benefits and risks. Similarly, it should not prevent clinicians from prescribing testosterone replacement for well-established late-onset hypogonadism, although it should provide some new caution about the administration of testosterone in older men who have an extensive history of cardiovascular disease and immobility.

Ultimately, we will need large, carefully designed trials of testosterone administration, perhaps along the lines of the Women's Health Initiative. Such trials should include a sufficient number of subjects to allow the assessment of key clinical outcomes, such as bone-fracture rates, muscle strength, and avoidance of falls, and an assessment of the role of testosterone replacement in the prevention of psychiatric disease, as well as the risks for prostate, cardiovascular, and other adverse outcomes. The numbers of older men receiving testosterone are large and increasing. We owe it to our patients and their families as well as to our physician colleagues to have much better data and guidelines for the administration of this critical hormone.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

Source Information

From the Department of Medicine, University of Washington, Seattle.

References

1. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724-731.

2. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002;87:589-598.

3. Wu FCW, 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.

4. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109-122.

5. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-2559.

6. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl 2009;30:1-9.

7. Page ST, Amory JK, Bowman ED, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip, strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90:1502-1510.

8. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560-2575.