Testosterone replacement therapy has been much debated in recent months, in light of two studies linking the treatment to increased risk of all-cause mortality, myocardial infarction, and stroke, prompting an FDA investigation into TRT’s safety and widespread criticism from members of the urologic community. In this article, Ajay Nehra, MD, discusses those studies, evolving attitudes toward “low T,” and the importance of individualizing treatment.
Dr. Nehra was interviewed by Urology Times Editorial Consultant Philip M. Hanno, MD, MPH, professor of urology at the University of Pennsylvania, Philadelphia.
Testosterone replacement therapy has been much debated in recent months, in light of two studies linking the treatment to increased risk of all-cause mortality, myocardial infarction, and stroke, prompting an FDA investigation into TRT’s safety and widespread criticism from members of the urologic community. In this article, Ajay Nehra, MD, discusses those studies, evolving attitudes toward “low T,” and the importance of individualizing treatment. Dr. Nehra is professor and chair of urology and director of men’s health at Rush University Medical Center, Chicago. He serves as a consultant for Endo Pharmaceuticals. Dr. Nehra was interviewed by Urology Times Editorial Consultant Philip M. Hanno, MD, professor of urology at the University of Pennsylvania, Philadelphia.
Q: Drug makers in the United States spent $3.47 billion on advertising directly to consumers last year, no doubt increasing health care costs significantly. Sales of prescription testosterone gels generated over $2 billion in American sales last year, a number that is expected to more than double by 2017. What is your gut feeling about direct-to-consumer advertising for testosterone supplements?
A: Direct-to-consumer advertising has become the dominant pathway in addressing the expressive pharmaceutical growth in recent years. Clearly, direct-to-consumer advertising needs an assessment and probably understates the complexity of testosterone and the education that may be required.
What is most important for us to appreciate is that while patients may be informed by direct-to-consumer advertising, they need to leave the final decisions on evaluation, diagnosis, and management to the urologist, the endocrinologist, the primary care physician.
Q: Is there a disease called “low T”? Granted, I went to medical school a long time ago, but I was never taught about low T.
A: This has been an evolutionary process. Traditionally, topics such as erectile dysfunction and loss of libido were not something that men typically discussed except possibly on the golf course or among close male friends. However, there is now a defined, well-accepted entity known as low testosterone, representing testosterone levels of less than 250-300 ng/dL.
What’s clear, however, is that this condition is not just a blood serum volume; there is a constellation of signs and symptoms that play a dramatic role. Although there are changes in the gonadal status of men over the course of their lifetime, we also have to evaluate each individual patient’s adiposity, waist circumference, and central obesity. Free testosterone and SHBG levels, as well as total testosterone, are the prerequisite serum levels that should be evaluated as well.
Besides the sexual symptoms associated with low testosterone, non-sexual symptoms include decreased energy and fatigue, depression, reduced muscle mass, and an increase in body fat. Associations with high blood pressure and high cholesterol in approximately 40% of patients have been noted. While the perception is that testosterone replacement may be overused, personally, I believe it is underused and clinicians should attempt to determine while patients are ideally suited for testosterone replacement.
Q: Many experts say that pharmaceutical advertising promotes excessive and inappropriate drug use by convincing patients that they are ill or have a more serious condition than is genuinely the case. What do you think?
A: My personal bias and knowledge of direct-to-consumer advertising is that it is meant to be educational. It isn’t meant to alarm a patient. When a patient comes to see us, we need to educate them beyond what they learn from advertising. A man or his wife may assume or state that his libido is down when there may be other factors causing this, and that’s what we need to discuss with couples.
Q: Do you think testosterone should be routinely replaced in older men, and will it safely redress frequent ordinary symptoms of male aging like decreased muscle mass and libido?
A: In the arena of men’s health, there is a growing body of evidence that the hormonal milieu in the male is a reflection of testosterone. There may be a lot of other factors as well: Osteopenia, osteoporosis, fragility, decreased muscle mass, and cognition are all extremely important aspects that have been reported in the literature, both in the middle-aged and geriatric patient.
Is it worthwhile replacing every male? Absolutely not, because you have to individualize treatment after a thorough evaluation.
Q: Let’s discuss the recent safety announcement from the FDA recommending caution with regard to testosterone supplementation. The first publication that prompted the FDA to reassess the cardiovascular safety of testosterone therapy was an observational study of older men in the U.S Veteran Affairs health system published in JAMA (2013; 310:1829-36). The study suggested a 30% increased risk of stroke, heart attack, and death in the group that had been prescribed testosterone therapy compared to those who had not received it. Can you comment on this study?
A: This study has clearly raised a huge hue and cry and prompted the FDA to take a cautionary step as well.
The Vigen study, published in JAMA, was a retrospective, observational Veteran Affairs study of men with testosterone levels <300ng/dL. Primary outcomes were all-cause mortality, myocardial infarction, and ischemic stroke. Men were started on testosterone replacement 531 days following an angiogram. The patients in this study had a 20% history of MI and heart failure, and greater than 50% of patients had obstructive coronary artery disease on angiography.
Limitations of this study include it being an observational study, selection bias, timing of testosterone levels being evaluated, and most importantly, ICD-9 codes were utilized and not validated by chart review, and only a small cohort of patients (267) were available for extended follow-up. It contrasts another study for the Veteran Affairs published by Dr. Shores where a 39% reduction in mortality risk was noted following testosterone replacement. Similar results were found by Dr. Aversa’s study, so there is contradictory evidence.
I think we need to not have a knee-jerk response; we need to conduct a meta-analysis on multiple studies and/or conduct true prospective studies to find out the cause and effect relationship.
Q: A second observational study reported an increased risk of heart attack in older men as well as in younger men with pre-existing heart disease who filled a prescription for testosterone therapy (PLOS ONE 2014; 29:e85805). The study reported a twofold increase in the risk of heart attack among men aged 65 years and older in the first 90 days following the first prescription. Among younger men less than 65 years old with a pre-existing history of heart disease, the study reported a twofold to threefold increased risk of heart attack in the first 90 days following the first prescription. Can you comment on this study, and should both of these studies influence our approach to giving our patients testosterone supplementation?
A: Does it have merit? There are a number of factors that we need to evaluate critically. First of all, it’s an observational study, it’s retrospective. Second, the authors did not evaluate these patients and thus get a substantive idea of their extent of coronary artery disease. In fact, the difference between the patients who underwent T replacement was not significant; you basically went from 3.48 to 4.78 per thousand years of nonfatal myocardial infarction prevalence, and if we extrapolate that out, those are low numbers.
Another fallacy in this particular study is that the authors looked at the time of prescription refill replacement, which traditionally is 90 days. As you and I both know, T replacement is 30 days, traditionally.
This again attests to the importance of evaluating patients individually. If you have a BMI of 32, you probably have latent or early-onset diabetes, hypertension, and either undiagnosed or prevalent coronary artery disease. One needs to weigh these risks individually. I wouldn’t blindly start these patients on T replacement.
I would individualize and assess these patients comprehensively. There’s data from Dr. Aversa, looking at carotid media thickness, that shows there was no change and possibly some improvement as well. We truly have not understood this relationship, and we need to elaborate on this further, either through prospective studies or a composite meta-analysis.
Q: Do you agree with Dr. Abraham Morgentaler that negative media stories touting testosterone’s risks are fueled by anti-pharma sentiment, anger against aggressive marketing, and anti-sexuality?
A: I think to a certain extent Dr. Morgentaler is correct because there is a certain bias, especially when it’s the lead article in New York Times or the Wall Street Journal. I think that carries a lot of weight. Consumers read it, media outlets frequently cover it, and it’s a major concern to couples.
There is a lot of media hype, and as we learn about this process, we need to have a fair and balanced approach. An objective and pragmatic index of suspicion needs to be heightened with these individual patients as we move forward and potentially replace them or not replace them.
Q: Let’s change the subject a little. Have we closed the chapter on worrying that testosterone supplementation can increase the risk of developing prostate cancer in those without a diagnosis or causing reemergence of prostate cancer in hypogonadal men who’ve been definitively treated for prostate cancer?
A: As you know, beginning with Dr. Charles Huggins’ publication in 1941 to the current labeling and AUA guidelines, T replacement is contraindicated in men who have a known diagnosis or a pre-existing diagnosis of prostate cancer. However, there have been a large number of studies that are starting to show that that may not be the case. We probably will be hearing about some of this data this year, particularly from Dr. Ian Thompson’s database on the Prostate Cancer Prevention Trial.
Q: On the positive side, can you comment on the Swedish prospective registry study that found that long-term treatment with testosterone in hypogonadal men is associated with progressive weight loss and a significant decrease in parameters of the metabolic syndrome?
A: I agree with this study, which was presented at the European Association of Urology annual congress, in that T replacement does a lot of things; there’s more energy, there’s more drive, there are changes in central obesity patterns. It’s very well documented. More important, it enhances the patient from the overall male health perspective, and as I mentioned, there are positive changes in carotid media thickness.
Q: Can you discuss the T Trial and when we may get more definitive answers about the risks and benefits of testosterone supplementation?
A: As you know, a Princeton IV Consensus Conference is tentatively scheduled for late November or early December of 2014. A multispecialty, multidisciplinary consensus panel will evaluate all the studies critically, just as Princeton I, II, and III were conducted.
Q: Is there anything you’d like to add?
A: I think we all know that aging is a huge concern in men and women both. T replacement is not meant to be anti-aging but is a pharmacologic agent that we need to utilize appropriately and not abuse.UT
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