Men too often receive T for ‘soft’ indications

July 29, 2014

To gain an endocrinologist’s perspective on current issues in testosterone therapy and hypogonadism, Urology Times interviewed Rebecca Z. Sokol MD, MPH, professor of obstetrics and gynecology and medicine at the Keck School of Medicine of the University of Southern California, Los Angeles.

 

Rebecca Z. Sokol, MD, MPHTo gain an endocrinologist’s perspective on current issues in

One of the recent issues concerning testosterone therapy is an assertion that it is being overprescribed. What is your opinion on this?

I am concerned that testosterone is being overprescribed. It’s reflected in our statistics. In the United States, testosterone prescriptions have more than doubled in the last 6 years. The most recent statistic I was able to find was from 2011: 5.6 million prescriptions, and that doesn’t include all the Internet sites that sell testosterone without a prescription. You would not believe how easy it is to get testosterone compounds online.

Related - Data fail to support concerns over T therapy, CV risk

Canadian authors estimate that there’s been an increase in the use of testosterone of 300% between 1997 and 2012. I would also point out that the most recent estimate of sales of testosterone, which is from 2011, is $1.6 billion.

 

Is there a possibility that those prescriptions are warranted?

I try to be open minded about this. More men probably need prescriptions for testosterone than we realized 25 years ago. Do I think as many men taking testosterone actually need the testosterone they’re taking? I highly doubt that.

 

You’ve been quoted as saying that you’re concerned about “the rampant use of testosterone replacement therapy for very soft indications.” Can you elaborate?

When I talk about men with “soft” indications, I’m referring to guys who are fatigued, a little depressed, having a bit of a middle-age crisis, and just not feeling their usual, perky self. I think those men are probably prescribed testosterone often but do not truly have a low testosterone level. The Androgen Deficiency in the Aging Male (ADAM) questionnaire was devised to uncover the symptoms of hypogonadism. But fatigue, poor sense of well-being, and even diminished libido can be associated with a number of different things.

 

Next: What Dr. Sokol considers to be low serum testosterone

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What serum testosterone level do you consider to be low?

I go by <250-300 ng/dL, measured in the morning on repeated testing, with associated signs and symptoms of low T. The Endocrine Society guidelines recommend using the lower limit of normal range for healthy young men measured by an assay that you know is a reliable assay, which is a really important point. Unfortunately, most physicians are not going to investigate the quality of the assays that are being used.

 

What are the appropriate indications for TRT?

If a man has true hypogonadism, meaning he has a disease that is documented to cause low testosterone, the diagnosis is very obvious. He will often have no libido and have erections sometimes but not always. He may have gynecomastia and smaller testes. He does not have male pattern baldness. He doesn’t shave normally and has diminished hair on his entire body. A subset of men who have never had adequate levels of T will present with eunichoid proportions. Those men are pretty clear candidates. You check their hormone levels and they have low testosterone.

Other men have what I refer to as a secondary adult-onset hypogonadism, meaning they have normal development and are now presenting with what they think is low testosterone production. They tend to have more of a female body habitus. There is a little shifting of where the fat is in their body, and some men will develop gynecomastia. They may or may not notice a change in the frequency with which they shave. They will have signs of decreased libido and decreased ability to obtain and maintain an erection. Many of these men will indeed have low testosterone levels, but others will not.

Some of these guys are quite depressed, but it’s a two-edged sword. I’ve seen patients who have been treated with antidepressants for 10 years for severe depression and never had their testosterone measured, and their problem is that they have low testosterone. And I’ve seen men who have been put on testosterone for depression because they and their doctors think the problem is low testosterone when in reality they have not been evaluated for depression and do much better on antidepressants.

 

How do you evaluate these men before writing a prescription?

A careful history is very important, especially for men who come in with decreased libido or potency. You have to ask if those problems are just with their current, long-term partner or with all partners. Is it true with masturbation or not true with masturbation?

You also have to make sure they’re not taking certain drugs. I have recently seen men who are addicted to opiates. Some have been heroin abusers who are now on Naloxone. Others abuse codeine compounds, often as a result of severe back injuries. We know that opiates suppress the gonadotropins, and that drops your testosterone. It’s really important to ask the hard questions.

The physical examination should include the items I mentioned above, as well as poor muscle development and strength. I measure LH, FSH, and testosterone levels. Depending on the patient’s presentation, I might order estradiol, prolactin, SHBG, and/or free T levels. If T is low, I order a bone densitometry to assess bone mineralization. I often check a semen analysis.

 

Next: How large is the population of men who should be treated?

 

 

Based on the indications you listed, how large is the population of men who should be treated? And how large is the population of men that is currently being treated?

Those are tough questions to answer. In Europe, surveys estimate that 2% to 3% of men over 65 have low testosterone. The United States estimates it to be somewhere between 6% and 12%, depending on the investigator. But I don’t know how accurate that is.

It’s hard to tell in the United States how many men are actually treated because, in addition to prescriptions written by physicians, people are getting testosterone off the Internet. In Canada, they estimate that 11 men out of every 1,000 are using testosterone and in the U.S. 2.9%, but that’s probably an underestimation.

 

Can you give an example of the type of male patient who may ask about receiving a testosterone prescription but doesn’t warrant it?

I can give you three common types of patients. One is the older guy in a relationship with a younger woman who comes in and asks for testosterone because he thinks it’s going to improve their sex life. That’s really common. The second is the middle-aged man, 50-55 years old, who feels that he’s not happy, doesn’t think his sex life is as good as it used to be, and sees the ads on TV touting testosterone as the fountain of youth. The most troublesome one is the older high school athlete who says he’s just not as strong as his father or cousins and suggests that he has a hereditary form of low T, but in reality he just wants an edge for athletics.

Unless they have truly low testosterone, I would not treat any of these patients.

 

There’s a new concern that testosterone therapy may raise men’s risk of heart attack and other cardiovascular events, and two recently published studies led to the FDA’s decision to investigate the cardiovascular safety of testosterone. How concerned are you that testosterone therapy raises men’s risk for cardiac events?

It’s important to know there are three other important articles about this. One was the study published in the New England Journal of Medicine (2010; 363:109-22). That study was stopped because the men receiving testosterone, who were receiving pretty high doses and were chronically ill, had too many cardiovascular adverse effects. Another study by Matsumoto and colleagues (J Clin Endocrinol Metab 2012; 97:2050-8) looked at a VA population, like the one in the recent JAMA study (2013; 310:1829-36), and found that testosterone improved the cardiovascular prognosis. The third is a meta-analysis that came out last year (BMC Med 2013; 11:108), in which the authors found an increased incidence of cardiovascular events with testosterone when they looked at all the studies that were controlled.

There are a lot of criticisms of the JAMA article, and I think that’s because the epidemiologists are looking at data retrospectively whereas urologists and endocrinologists are trying to look at it prospectively. Those are two very different ways of looking at the data and may account for the differences in outcomes.

I think we have enough data to suggest that men who are over 65 years old who are chronically ill-with chronic pulmonary disease or a history of cardiovascular disease, for example-shouldn’t be treated unless their testosterones are so low that it’s compromising their life.

The question is then, what do you do about the guy who is over 65 years old with some signs and some symptoms, who is not truly hypogonadal, has a testosterone of 285 ng/dL, and doesn’t have a history of cardiovascular disease? I think those are the ones we have to be on the alert for possible adverse events. We need to tell them these studies have been published, quoting both the ones that say it’s helpful and the ones that say it’s harmful, of which there are more. Then have the patient and the doctor come to a conclusion about whether or not they warrant having a therapeutic attempt. Each individual man needs to be treated as an individual, not just given a knee-reflex trial to see if it will make him feel better.

My greater concern is for men who are between the ages of 50 and 65 who are taking testosterone because their T levels are at the lower levels of normal. Except for men whom we have prescribed testosterone replacement because they have a bona fide disease from childhood and cannot make testosterone, we have no clue what the long-term side effects of 30 years of testosterone replacement are going to be. I’m most concerned about those men because they’re the ones talking their well-meaning doctor into giving them some testosterone because they think they need a boost.

 

Next: Awaiting the results of the Testosterone Trial

 

 

Do you think additional studies are needed on the safety and efficacy of testosterone therapy?

The National Institutes of Health is funding a very large prospective, placebo-controlled trial known as the Testosterone Trial, which includes a number of centers, all of which are run by outstanding andrologists. I hope that study is going to answer many of questions about testosterone therapy in men over age 65. We’re all waiting for those results, which should be coming out in 2015.

 

What is your take-home message for urologists and other clinicians?

I think it’s important to be absolutely certain that the testosterone replacement is indicated. And if it is prescribed, it’s important for the patient to be advised about the studies regarding cardiovascular disease and other potential complications, and to start therapy on a trial basis. Have the patient come back after the first month and then at the end of 3 months and then make a decision about whether or not he should continue with the testosterone. For the patient, my caveat is, buyer beware.

I also recommend that doctors read the JAMA Internal Medicine articles that were published in August 2013 by Schwartz and Woloshin, Baillargeon et al, and Braun, which discuss the marketing of testosterone. They are very eye opening and important articles for people to think about.UT

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