I’m skeptical about … testosterone therapy.

“Is it low T?” or just another scam to separate you from your money? The “T,” in this case, stands for testosterone, the male hormone that is responsible for making men, well … men. Sales of this hormone tripled between 2001-2011, thanks largely to an aggressive ad campaign targeting middle-aged men seeking a cure-all for whatever ails them. The natural aging process is associated with decreased libido, diminished sexual performance, loss of muscle mass, decreased strength, and mood swings—all things that testosterone is said to cure. Testosterone levels have been inversely associated with heart disease, stroke, diabetes, obesity, depression, dementia, and all-cause mortality. And this makes a certain amount of sense. For instance, low testosterone is associated with increased abdominal fat stores, a known risk factor for insulin resistance and diabetes. But association is not causation. Does low testosterone lead to abdominal obesity, or does a couch-potato life lead to low testosterone? I’m not surprised that men with lots of health problems have low testosterone levels, but it’s a big stretch to think that supplementing this hormone will cure any of them. There is good evidence that the real culprit for low testosterone is inactivity. One of the best ways to boost levels is through high intensity interval training. This also happens to be one of the best ways to combat obesity. I believe we should be peddling exercise, not AndroGel.

Until recently, supplementing testosterone was difficult, requiring weekly trips to the clinic for injections. It’s a lot easier now that the hormone is available in patch, gel, and buccal preparations. The ads would have you believe that vitality is as close as the nearest drugstore. Given the ease of gel administration combined with healthy doses of direct-to-consumer advertising, it’s no wonder that sales have skyrocketed, projected to reach a cool $4 billion in 2017. But this is not to say that certain specific populations won’t benefit from therapy. Those with hypogonadism related to endocrine disorders certainly warrant treatment, but the market here is small. This post is directed toward the much larger market of middle-aged men seeking a hormone cure for aging.

 

J. Fam. Practice 2016; 65 (12): 864.

J. Fam. Practice 2016; 65 (12): 864.

 

By way of reference, male testosterone levels typically range from 230-1000 ng/dL, with peak levels occurring in late adolescence and declining by roughly 1.6% per year after age 30. In the blood, testosterone exists in 3 different forms: biologically active, free testosterone (2-3%); bioavailable, protein-bound testosterone (approximately 50%); and non-bioavailable, testosterone bound to sex hormone binding globulin (approximately 45%). As men age, the proportion of non-bioavailable, protein-bound testosterone increases, meaning that even if the total testosterone level remains constant, there is still less of the stuff available to exert androgen effects. Levels also vary diurnally so testing should be done before 11 a.m., during the time testosterone peaks. At least 2 measurements of less than 280 ng/dL are required for the diagnosis of “low T,” the prevalence of which varies by age. While 12-38% of men over age 45 test low, this range increases to 30-50% by age 70. But that doesn’t mean everyone with low testosterone should be treated. Since the symptoms of “low T” are multifactorial and overlap considerably with those of normal aging, only men with testosterone levels less than 280 ng/dL and symptoms should be considered for treatment. If the testosterone level is greater than 350 ng/dL then “low T” is unlikely to be the source of symptoms. Look instead for another culprit, like diabetes, vascular disease, depression, or medication side-effects.

 

(www.precisionnutrition.com/all-about-testosterone)

(www.precisionnutrition.com/all-about-testosterone)

 

Most medical societies recommend supplementation to achieve levels equal to the mid-range for men less than 40-years of age (450-500 ng/dL), but this number is completely pulled out of a hat. There is no data to support the notion that a 75-year old man requires testosterone levels of someone half his age to achieve vitality. On the flip side, too much testosterone is clearly harmful, resulting in shrunken testicles, acne, baldness, aggression, and an increased risk of blood clots, stroke, congestive heart failure, and cardiovascular disease. Just take a look at some of the ex-NFL players from the 70s and 80s if you want to see the deleterious, long-term effects of steroid abuse.

The data on cardiovascular disease and testosterone are conflicting, some studies showing benefit, others showing harm. The FDA issued a warning in 2015, after 2 studies reported increases in cardiovascular events associated with TRT (testosterone replacement therapy), noting that: “The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone.” The most interesting thing to note about the controversy is that the degree of benefit or harm reported with TRT has little to do with testosterone levels and everything to do with who funded the study. A meta-analysis of 27 trials looking at TRT and cardiovascular disease found that, on-average, drug company-sponsored trials reported a 10% reduced risk of adverse events, while non-sponsored trials showed just the opposite, reporting more than twice as many cardiovascular events in TRT patients. And you thought science was pure.

A second warning, specifically targeting athletes and body-builders, was issued by the FDA in 2016 requiring that testosterone and androgen manufacturers include a list of the adverse health effects associated with steroid abuse on all package inserts. With inconclusive data on both efficacy and safety, the NIH (National Institutes of Health) and NIA (National Institute on Aging) subsidized a series of interrelated trials, known collectively as the “T-Trials,” to determine the efficacy of testosterone when administered to symptomatic men with age-related androgen deficiency. Investigators enrolled a total of 790 symptomatic men aged 65 or older with low serum testosterone (less than 275-300 ng/dL) to receive either a placebo or a testosterone containing gel for 1 year. Participants were enrolled in one or more trials to examine the effects of supplementation on 7 different parameters: bone density, anemia, cognition, cardiovascular disease, physical function, vitality, and sexual function. The results of these trials are now available.

 

AndroGel (the active ingredient used in the "T Trials" sponsored by the NIH and AbbVie Pharmaceuticals)

AndroGel (the active ingredient used in the “T Trials” sponsored by the NIH, NIA, and AbbVie pharmaceuticals)

 

TRT demonstrated moderate improvements in bone density as measured by quantitative CT scanning, but the trial’s duration was too short to determine whether this will translate into meaningful patient outcomes like a reduction in falls and fractures. So, too, TRT improved red blood cell counts in patients with anemia, and also resulted in modest increases in the counts of non-anemic patients, a few of whom developed polycythemia (a disorder of increased blood viscosity from too many red blood cells, predisposing to stroke). The number of participants suffering a stroke over the course of the trial was the same in the treatment group and the placebo group (5 of 394 in both). No conclusions can be drawn regarding the long-term stroke risk associated with therapy.

TRT had no meaningful effect on cognition as measured in the trial. Treated patients performed no better than untreated patients on tests of visual or reading memory retention. Vitality was measured via a 13-question survey, each question graded 0-4, based on answers to questions like: “I feel fatigued,” “I feel weak all over,” and “I have trouble finishing things.” On this survey, TRT did not improve outcomes. So much for the vitality claims of the testosterone pushers. If you want more “get-up-and-go,” maybe try a double-shot espresso instead.

As regards to cardiovascular health, TRT resulted in an increase in the amount of plaque deposited along the walls of coronary arteries as measured by specialized CT scanning. And, since we know that the degree of plaque clogging these arteries constitutes a major risk factor for heart attack, these results indicate the potential for harm. It’s important to note that none of the “T Trials” were designed to measure safety. They were, instead, designed to determine efficacy; does the hormone work on real patients in the community? Furthermore, the results of this trial are hard to interpret in light of several observational trials supporting a cardioprotective role for TRT, including those of a trial published earlier this year that found a moderate reduction in cardiac events like heart attack, worsening chest pain, or sudden death in men treated for at least a year with TRT. Unfortunately, observational trials can only show associations—it takes a randomized controlled trial to show cause and effect. The question of cardiovascular safety remains unanswered.

 

Chemical structure of testosterone.

Chemical structure of testosterone.

 

How about physical function? Can testosterone make you stronger, thinner, and more agile? This trial didn’t answer those questions, but TRT didn’t have any meaningful effect on the physical performance of deconditioned, elderly men when measured on a 6-minute walk test. Granted that they weren’t a very fit cohort going in—to be eligible required a gait speed of less than 1.2 meters/sec (equating to a 22.4 minute/mile pace). These results are not translatable to highly conditioned athletes where uber-supplementation enhances performance (at a cost), but they do suggest that, at recommended doses, the benefit on physical performance for the average Joe is likely to be minimal.

That leaves the big question: Does testosterone improve sexual function? Being a stud is important, which is why Donald Trump proudly held up his hands during the last election cycle, even releasing his testosterone level to the public (441 ng/dL). Men wanting an improved sex life constitute the overwhelming majority of those requesting treatment. The “T trials” examined 3 components of sexual function: activity, desire, and erectile function. The results were underwhelming. Based on the answers to a series of pre-validated questions, participants related slight improvements in sexual activity (+0.58 on a 0-12 scoring system), sexual desire (+2.93 on a 0-30 scoring system), and erectile function (+2.64 on a 0-33 scoring system). Of note: the improvement in erectile function was less than that achieved with drugs like Cialis and Viagra. At the end of the trial, more of the men in the treatment group reported improvement in sexual desire than in the placebo group. Testosterone works to improve sexual function, but not very well. Unfortunately, there wasn’t a third arm involving exercise. Physical fitness is likely the single most important factor when it comes to sexual desire and erectile function. Want to boost testosterone and improve your sex drive? Try exercising with your partner and showering together afterward. As most women will tell you, a hard man is good to find.

Lastly, a note on my own experience with supplements. A decade ago, at age 48, I was a highly-competitive skater on the in-line marathon circuit struggling to make the podium at national races, mostly due to a lack of top-end speed during the final sprint. I knew from talking to other athletes that supplements alone wouldn’t necessarily make me faster, but they would almost certainly allow me to work harder, longer, and with less recovery time. And maybe that would land me a place on the podium. So, I went to one of those high-priced anti-aging/wellness centers catering to middle-aged men looking to boost their mojo and underwent an executive physical that included a battery of neurocognitive tests, an EKG, a body fat analysis, bone density assessment, and a host of lab tests including a testosterone panel. Since I was there for performance enhancement, I wasn’t surprised when the doctor recommended a course of hGH (human growth hormone) in addition to a bevy of vitamin and nutrition supplements, but I was most definitely surprised when he recommended a testosterone stimulant because my level (at 881 ng/dL) already had me at the very top of my age group. Despite this, he thought I could push it a bit higher still: “If you want to perform like a 20-year old, you need the testosterone of a 20-year old.”  In the end, I declined all supplements, but my point is that if you go to one of these clinics looking for testosterone you’ll get it. That’s how they make their money. Even worse, nearly a quarter of the 11 million men receiving androgen prescriptions haven’t had their testosterone levels screened within the past year. Now, that’s discouraging. Caveat emptor.

 

References:

  1. Roger Stanworth and Hugh Jones, “Testosterone for the Aging Male; Current Evidence and Recommended Practice,” Clin Interventions in Aging 2008; 3 (1): 25-44.
  2. Lin Xu et al., “Testosterone Therapy and Cardiovascular Events Among Men: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Trials,” BMC Med 2013; 11: 108-19.
  3. “FDA Drug Safety Communication: FDA Cautions about Using Testosterone Products for Low Testosterone Due to Aging,” US Food and Drug Administration, Safety Announcement, March 3, 2015, www.fda.gov/Drugs/DrugSafety/ucm436259.htm.
  4. Peter Snyder et al., “The Testosterone Trials: Seven Coordinated Trials of Testosterone Treatment in Elderly Men,” Clin Trials 2014; 11: 362-75.
  5. Peter Snyder et al., “Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men with Low Testosterone: A Controlled Clinical Trial,” JAMA Int Med 2017;177 (4): 471-79.
  6. Cindy Roy et al., “Association of Testosterone Levels with Anemia in Older Men: A Controlled Clinical Trial,” JAMA Int Med 2017; 177 (4): 480-90.
  7. Susan Resnick et al., “Testosterone Treatment and Cognitive Function in Older Men with Low Testosterone and Age-Associated Memory Impairment,” JAMA 2017; 317 (7): 717-27.
  8. Matthew Budoff et al., “Testosterone Treatment and Coronary Artery Plaque Volume in Older Men with Low Testosterone,” JAMA 2017; 317 (7): 708-16.
  9. Craig Cheetham et al., “Association of Testosterone Replacement with Cardiovascular Outcomes Among Men with Androgen Deficiency,” JAMA Int Med 2017; 177 (4): 491-99.
  10. Peter Snyder et al., “Effects of Testosterone Treatment in Older Men,” NEJM 2016; 374 (7): 611-24.
  11. Samantha Huo et al., “Treatment of Men for ‘Low Testosterone’: A Systematic Review,” PLoS One 2016; 11 (9): e0162480.
  12. Andrew Hoover and Jeffrey Kirchner, “Does Your Patient Really Need Testosterone Replacement?” J Fam Practice 2016; 65 (12): 864-75.

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