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“Low T”: The triumph of marketing over science

A man on TV is selling me a miracle cure that will keep me young forever. It’s called Androgel…for treating something called Low T, a pharmaceutical company–recognized condition affecting millions of men with low testosterone, previously known as getting older.

The Colbert Report, December 2012

 

And now for something completely different…sort of.

After writing so much about the latest developments in the ongoing saga of the cancer doctor who is not an oncologist and not a legitimate cancer researcher, plus a rumination on what’s up with President Obama’s nominee for Surgeon General and our favorite form of unscientific medicine, so-called complementary and alternative medicine (CAM), also known as “integrative medicine,” I thought it was time for a change of pace. I wasn’t sure what I was going to write about as Sunday rolled around, but fortunately, as sometimes happens, the New York Times dropped a topic right in my lap, so to speak, both figuratively and literally. It comes in the form of a long article on something that directly concerns men of a certain age, which unfortunately happens to mean men of my age and older. I’m referring to what pharmaceutical company advertising campaigns have dubbed “low T,” short for low testosterone. It’s not clear how the term “low T” originated but Dr. Abraham Morgentaler, founder of Men’s Health Boston, claims to have coined the term when his patients were embarrassed by their difficulty pronouncing the word “testosterone.” Other sources report that it was Solvay Pharmaceuticals that coined the phrase. It doesn’t really matter where the term “low T” came from. The term has stuck, even though the more “correct” medical term would be hypogonadism, as in a man’s testes not working.

The NYT article appears, very appropriately, not in the Health section of the paper, but rather in the Business section. Indeed, if you believe the hucksters and manufacturers of testosterone replacement therapy, pretty much every man over the age of 40 or 50 is prone to a devastating lack of testosterone that must be replaced, preferably by products provided by big pharma like AndroGel. Indeed, the NYT article, written by Natasha Singer, is entitled ‘Selling That New-Man Feeling,’ and she makes a very good case that selling is what it’s really all about, more so than science-based medicine. Since we haven’t addressed the issue of “low T” in over three years, this NYT article seemed to me like the perfect excuse to revisit the topic, looking at how pharmaceutical companies and doctors sell the concept and whether or not there has been any new evidence to guide us in the last three years.

Apparently, 70 year old men should be as virile as 20 year olds

Three years ago, both Peter Lipson and Harriet Hall wrote about the phenomenon that’s been sweeping the men’s health world over the last five years or so of diagnosing and treating “low T.” Peter acknowledged that “low T” can be a real phenomenon but pointed out that it generally only affects small numbers of men. Harriet quite rightly pointed out that testosterone, contrary to the way it’s being marketed, is not an anti-aging panacea. None of this is to say that legitimate diagnoses of low testosterone shouldn’t be treated, but questions proliferate. How low is really “too low”? What are the goals of treatment? Do low or low-normal testosterone levels actually cause the symptoms being attributed to them? For instance, if you wander over to the AndroGel site and look at the sorts of symptoms being attributed to “low T,” you’ll find:

Signs and symptoms of Low Testosterone may include:

  • Fatigue or decreased energy
  • Reduced sex drive (libido)
  • Sexual dysfunction (weak erections, fewer erections)
  • Depressed mood
  • Increased body fat
  • Reduced muscle mass and strength
  • Decreased bone strength
  • Loss of body hair (less frequent shaving)
  • Hot flashes, sweats

There’s then a test, which takes the form of a series of questions:

  1. Do you have a decrease in libido (sex drive)?
  2. Do you have a lack of energy?
  3. Do you have a decrease in strength and/or endurance?
  4. Have you lost height?
  5. Have you noticed a decrease in your enjoyment of life?
  6. Are you sad and/or grumpy?
  7. Are your erections less strong?
  8. Have you noticed a recent deterioration in your ability to play sports?
  9. Are you falling asleep after dinner?
  10. Has there been a recent deterioration in your work performance?

Just for yucks, I took the quiz, and this is what I got back:

LowT

Yes, it turns out that AbbVie, the drug maker behind AndroGel, is very concerned that I might have “low T” and really thinks that I should get myself checked out. I think I’ll probably pass, given the origin of this questionnaire, which is known by the acronym ADAM, which stands for the Androgen Deficiency in Aging Males test:

More than a decade ago, a Dutch pharmaceutical company, Organon BioSciences, asked Dr. Morley to devise a screening questionnaire covering symptoms common to older men with low testosterone. The way Dr. Morley recalls the drugmaker’s instructions, “they said, ‘Don’t make it too long and make it somewhat sexy.’ ”

In return, he says, Organon gave $40,000 to his university for research into the effects of testosterone on muscle. Along the way, Dr. Morley’s quiz acquired an official name that emphasized its intended audience was older men: the Androgen Deficiency in Aging Males, or ADAM, test.

That test has become standard fare on brand-name drug sites like androgel.com and on informational sites like AbbVie’s IsItLowT.com — where the ADAM test has been re-branded as the “ ‘Is It Low T?’ Quiz.” If the questions drive many men to identify themselves as low-T sufferers and visit their doctors seeking remedies, well, that is their purpose.

Indeed, it is, which is why I failed it. Particularly amusing is the section where it asks if you’re falling asleep after dinner. A particularly pithy quote was included from Dr. Adriane J. Fugh-Berman, an associate professor at Georgetown University Medical Center in Washington and director of Pharmed Out, who quipped, “Depends how long after dinner. We all do eventually. It’s called sleep.” Also, I would add, if it’s a particularly carb-rich dinner, I might indeed doze off not long after. Clearly many of us who will be partaking in a mere few days of our yearly Thanksgiving feasts suffer from low T!

It turns out that these “low T” advertisements take advantage of a loophole in the law. The FDA and Federal Trade Commission carefully monitor pharmaceutical company advertising. In particular, the FDA looks out for drug companies that advertise “off-label” uses for their drugs; i.e., uses for which the drug is not FDA-approved. As we’ve discussed from time to time here at SBM, off-label prescribing is a common and often accepted practice that is not necessarily outside the purview of science-based medicine, given that FDA approval can lag behind the evidence for a new indication for a drug. However, pharmaceutical companies are not permitted to promote such uses. After all, if they could market drugs for off-label uses, then why bother going to the trouble of doing all those expensive and pesky clinical trials to gain approval for new indications?

There is one sort of advertising campaign, however, that the FDA doesn’t really regulate. You can look at it as a similar end run around FDA regulations used by supplement manufacturers when they make vague “structure-function” claims. In this case, the end-run is known as “unbranded” promotions or “disease-awareness” campaigns. These are promotions that do not advocate the use of a specific brand of a drug and/or promote “awareness” of a condition:

The Food and Drug Administration closely regulates advertisements for brand-name prescription drugs, but does not generally regulate unbranded campaigns. That two-track system, says John Mack, an analyst who runs a blog called Pharma Marketing, has enabled companies to position low T as a malady with such amorphous symptoms — listlessness, increased body fat and moodiness — that it can be seen to afflict nearly all men, at least once in a while. Drug makers also promote low-T screening quizzes directly to consumers, Mr. Mack says, in an effort to prompt men to seek testosterone prescriptions from their doctors.

For this sort of campaign:

Earlier this year, Medical Marketing & Media, a trade magazine, named two AbbVie executives as “the all-star large pharma marketing team of the year” for promotions of AndroGel and unbranded efforts to advance low T.

“It didn’t hurt that baby boomers have proven less than shy about availing themselves of any product that they believe will increase their quality of life,” an article in the magazine said. The article lauded AbbVie’s DriveForFive.com, an unbranded site that encourages men to have regular checkups and to ask their doctors about five tests, among them tests for cholesterol and blood pressure — and testosterone.

Mr. Freundel of AbbVie described the effort as “a national disease-awareness initiative aimed at encouraging men to take a more proactive approach to their health.” The F.D.A., he added, encourages companies to develop such initiatives “because they serve an important role by enhancing awareness of health conditions.”

Described in Medical Marketing & Media thusly:

AbbVie took a taboo topic and, via a cagey media-and-marketing presence, rendered it less wince-inducing among its target audience. It did so at a time when a number of critics voiced their concerns that the marketing and use of testosterone-boosting products had gotten ahead of the science.

Notice how blatant MMM is in trumpeting this as a triumph of advertising over science. AbbVie overcame all those nasty doctors trying to tell people that there’s no good science to indicate that all these millions of men need testosterone replacement therapy. I guess AbbVie showed them! Indeed, this marketing campaign, coupled with other, similar campaigns by other testosterone manufacturers and physicians specializing in men’s health, testosterone prescribing is way, way up. Indeed, a recent study in the Medical Journal of Australia concluded:

In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000–2011, especially over the last half of the period. The increased testosterone prescribing appears to be primarily for older men and driven by clinical guidelines that endorse testosterone prescribing for age-related functional androgen deficiency (andropause). By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products.

In the U.S., monthly use per 1,000 population increased nearly ten-fold between 2000 and 2011; in Canada, the increase in usage was nearly 40-fold, even though it started at about the same rate in 2000. It is truly astounding how much the use of testosterone supplementation has increased in developed countries. It’s almost impossible to escape the advertising. It’s in newspapers, on television, and all over the Internet. As I’ve seen it quipped, ads for “low T” seem to be directly competing with the ads, ubiquitous since the late 1990s, for erectile dysfunction drugs. One wonders when “awareness” of “low T” will surpass awareness that, seemingly, older couples must sit side-by-side in separate bathtubs before getting it on, as anyone who’s seen a Cialis ad knows.

But I digress. Let’s take a look at “low T” and what the scientific evidence, rather than the marketing hype, says about it.

Low T, high T, fitting testosterone to a T

The Is It Low T? website claims that “millions” of men in the US suffer from “low T.” Perusing the various ads and promotional materials, one will soon see an estimate of 13 million men in the US over the age of 45 suffering from “low T.” This estimate is sometimes attributed to the American Diabetes Association, but if you look at the link to a page about low testosterone on the ADA website it says nothing about the prevalence of this condition, other than that it is “common.” As Jim Laidler pointed out in the comments of Harriet’s post on the topic, according to the US Census Bureau, there are over 53 million men over age 45 in the US as of 2010. This would mean that nearly a quarter of men over 45 have “low T.” It’s a figure that seems rather high and difficult to believe.

Part of the problem is that as is the case with estrogen levels in women, testosterone levels in men begin decreasing after the age of 30. The topic was reviewed well in the New England Journal of Medicine nine years ago, so this is not new information. Contrary to the abrupt and rapid decrease in sex hormone levels that occurs in women when they enter menopause, in men testosterone levels decrease more slowly, with the serum total testosterone concentration decreasing from a mean of about 600 ng/dL (20.8 nmol/L) at 30 years of age to a mean of about 400 ng/dL (13.9 nmol/L) at 80 years, although, the review noted, the range is wide at all ages. However, the “normal” range for serum testosterone levels varies with age, decreasing as a man ages. In younger men, the low end of the normal range is generally considered to be around 300 ng/dL, and that is often the level recommended as the cut-off by the “low T” websites.

Testosterone levels also vary considerably in that they can be affected by illness and medications such as opiates and glucocorticoids. They also can vary significantly due to circadian and circannual variations, episodic secretion, and measurement variations. In the circadian variation, peak levels are noted in the morning, although this variation is less in older men. Indeed, even with this blunting of the circadian variation of testosterone levels, a significant proportion of men over 65 with low testosterone levels in an afternoon blood draw will have normal levels in a morning blood draw. Depending on the specific male sex hormone, the various standard deviations imply that a clinician can expect to see a difference exceeding 18% to 28% about half the time when two measurements are made on the same man and a difference exceeding 27% to 54% a quarter of the time. Also, 15% of healthy young men will have a testosterone level below the normal range in any 24 hour period. That is why the Endocrine Society, in its clinical practice guideline for Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes, emphasizes that “day-to-day variations in serum testosterone concentrations were found to be sufficiently large that single testosterone measurements were inadequate to characterize an individual’s levels, and at least two testosterone measurements were needed to diagnose androgen deficiency with greater confidence.”

Funny, then, that a recent study (the same study that found skyrocketing rates of androgen replacement prescribing) also found that among all new androgen users from 2001 to 2011, only 74.72% had had their testosterone level measured in the year prior to starting to take androgen replacement. That means slightly over one quarter of men started on testosterone had never been shown to have low testosterone levels! Given this result, one wonders how careful a workup was done before prescribing testosterone replacement. After all, there are multiple forms of hypogonadism, primary and secondary. Primary hypogonadism is due to failure of the testes to make adequate testosterone, while secondary hypogonadism is due to a problem in the hypothalamus or pituitary gland, the parts of the brain that signal the testes to produce testosterone. The hypothalamus produces gonadotropin releasing hormone, which signals the pituitary gland to make the follicle-stimulating hormone (FSH) and luteinizing hormone. Luteinizing hormone then signals the testes to produce testosterone. Either type of hypogonadism may be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection, and there are specific workups and tests that need to be done to differentiate between the two, as detailed in the Endocrine Society’s guidelines.

For these men, most likely, testosterone was prescribed for some of those vague symptoms that the “Low T” websites promote as being due to low testosterone levels or to make a man “feel younger.” These are the sorts of symptoms that are relieved by testosterone in testimonials, like this one by former pro football player Daryl “Moose” Johnston, whose complaints were mainly:

I was feeling more tired than usual and I noticed that I was having trouble keeping up with my regular activities. These signs were pretty subtle at first, but it didn’t take long until they started to get in the way of things I loved to do, like exercising. As an athlete and someone who has been active my entire life, I knew something wasn’t right. That’s when I decided to see my doctor.

There’s a term for symptoms like that: Getting old. Yes, it sucks, particularly if you used to be a professional athlete and your identity is heavily invested in being physically fit and active. It often hits athletes hard when they realize that they can’t keep up with young men anymore. But how does one distinguish symptoms that are really due to “low T” from the normal changes that men (and women) experience as they get older? I’m experiencing these sorts of things, even though I was never an athlete and never particularly physically active. I highly doubt it’s due to “low T.” It’s probably because I’m getting older and, frankly, because my lifestyle and diet aren’t the greatest.

All of this brings me to asking whether there is anything to the claims that replenishing low or borderline-low testosterone levels will correct many of the symptoms for which testosterone replacement therapy is prescribed. In considering this question, it is useful to frame it as a series of four questions asked by Peter Lipson three years ago:

  1. Is there a plausible connection between testosterone levels and certain symptoms?
  2. What is a normal testosterone level?
  3. Are there specific symptoms that correlate with lower levels?
  4. Does replacement therapy correct these symptoms?

I’ve already discussed #2 in detail. Question #1 would suggest that, at the very minimum, symptoms of sexual dysfunction, such as decreased libido, infertility, and erectile dysfunction, could be plausible consequences of low testosterone levels. After all, testosterone is the primary male sex hormone. Besides libido, fertility, and sexual function, testosterone also influences energy and stamina, mood, cognitive functioning, bone density, red blood cell production, and maintenance of secondary sexual characteristics.

However, such symptoms can be caused by many things. Depression and medication side effects, for instance, can result in decreased libido. Atherosclerotic vascular disease can result in erectile dysfunction due to decreased blood flow, as can damage to the nerves controlling erection. A number of studies have looked at the symptoms attributed to low testosterone with mixed results, such that it is not unreasonable to characterize the clinical importance of age-related decreases in testosterone as controversial. For example, a recent study of middle-aged and elderly men found that only poor morning erection, low sexual desire and erectile dysfunction were associated with low testosterone levels. Other symptoms, such as decreased vigorous activity, difficulty walking more than one kilometer, fatigue, and loss of energy, all symptoms frequently attributed to “low T,” correlated poorly with testosterone levels. So the answer to #3 really only includes primarily symptoms of decreased libido and erectile dysfunction.

There are other clinical problems that have been attributed to low testosterone, but it is hard to determine whether they are causative or a consequence of the conditions associated with low testosterone. For example, metabolic syndrome has been associated with low testosterone levels. Although testosterone levels were associated with metabolic syndrome, this relationship appeared to be associated with lipid categories, hs-CRP, BMI, and insulin resistance levels and did not appear to be an independent marker for metabolic syndrome. Similarly, a recent review of the literature concluded that low testosterone is associated with depressive disorders but that “there is insufficient evidence to conclude that low testosterone level routinely leads to major depressive disorder in men,” while another recent review concluded that “men with COPD [chronic obstructive pulmonary disease] have clinically relevant lower than normal TT levels” but that “insufficient evidence from short-term studies in predominately male COPD patients suggests that testosterone therapy improves exercise capacity outcomes, namely peak muscle strength and peak workload.”

One of the strongest claims made by advocates of treating “low T” is that low testosterone levels are associated with cardiovascular diseases, such as atherosclerosis, hypertension, and myocardial infarction. A “hot off the presses” review from Belgian researchers based on the literature from 1970 to 2013 concluded:

On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore “normal concentrations” have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials.

Also hot off the press, however, is a cohort study published JAMA from the University of Texas Southwestern involving 8,709 men with low testosterone undergoing coronary angiography in the VA medical system, of whom 1,223 started testosterone therapy after a median of 531 days post-angiography. The investigators found that testosterone replacement therapy was associated increased risk of mortality, MI, or ischemic stroke. The effect sizes weren’t huge, but the results were consistent with an earlier small randomized, placebo-controlled trial of testosterone replacement therapy in men 65 or older with limitations of mobility had to be stopped because of a higher number of adverse events in the testosterone group.

There’s no doubt that for men with true hypogonadism, testosterone replacement therapy can have definite therapeutic effects, as both Peter Lipson and Harriet Hall have described, but that’s not what we’re talking about here. Moreover, testosterone replacement has known adverse effects, including sleep apnea, elevated red blood cell count, heart disease, acne, benign prostatic hypertrophy, breast enlargement, reduced sperm production, and shrinkage of testicles. It might also have unknown adverse effects over the long term, as some of the studies cited above show. At the very least, it is not the panacea that it’s advertised as.

Low T: When science meets marketing, marketing wins

The best summary of the controversy over “low T” that I’ve seen appeared in JAMA in August. It was written by Lisa M. Schwartz and Steven Woloshin and entitled Low “T” as in “Template” How to Sell Disease. Schwartz describes that template in terms of three strategies:

  • Lower the bar. By this, Schwartz means to broaden the criteria for a “disease” beyond what was previously accepted, evidence or no evidence. In other words, “lower the bar” for diagnosing that disease, so that more people need “treatment.”
  • Raise the stakes. This involves increasing the claims for the harm that comes from not treating the new condition and the benefits of treating the condition. Schwartz writes: “It is one thing to tell men that Low T can make them grumpy; it is another to say that it can kill them. Messages raising the stakes about Low T have appeared regularly in scientific meeting reports and journal articles7 and often make their way into the news (“Low testosterone could kill you,” according to ABC News).”
  • Spin the evidence. This one is self-explanatory. As Schwartz puts it: “Testosterone therapy results in only small improvements in lean body mass and body fat, libido, and sexual satisfaction, and has inconsistent (or no) effect on weight, depression, and lower extremity strength. Whether these effects are big enough to matter to patients is unknown. Nor is it known whether they are big enough to outweigh the harms of testosterone therapy, i.e., polycythemia that may increase thromboembolic events, edema, serious hepatotoxic effects, gynecomastia, worsening of sleep apnea, prostate enlargement, and rise in prostate-specific antigen level (and potential increased risk of prostate cancer).”

All of these things are going on with respect to testosterone replacement therapy. There is a paucity of evidence that “low T” is the problem that it is advertised to be and even less evidence that testosterone replacement therapy corrects the problems attributed to “low T.” Before pharmaceutical companies launch big money campaigns to make millions of men “aware” of low T, they should be required to do what they have to do before introducing a new drug for a new indication: the appropriate large-scale randomized trials to demonstrate that testosterone therapy for otherwise-healthy aging men whose testosterone levels are below the normal range for young men does more good than harm. Right now, we don’t have that evidence, and we’re not likely to get it from pharmaceutical companies.

Posted in: Clinical Trials, Diagnostic tests & procedures, Pharmaceuticals, Science and the Media

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