It's controversial territory, the whole "Low T" arena, and will likely long remain so. But at least some serious data points are beginning to emerge in the form of the Testosterone Trials: a major set of government-funded, double-blind, placebo-controlled studies just published in the New England Journal of Medicine.
The seven linked trials examined the benefits of a year of testosterone gel (vs. placebo gel) in more than 700 men over age 65. It found those benefits to be "moderate," and mainly for sexual function. Not vitality. Not much for physical functions like walking. A bit for mood. Overall, the Mighty T of the infomercial world is looking more like the modest T.
I spoke with Harvard Medical School's Prof. Shalender Bhasin, director of the Research Program in Men’s Health: Aging and Metabolism at Brigham and Women’s Hospital and one of the lead researchers on the Testosterone Trials. Our conversation, lightly edited:
How would you sum up these findings?
The main finding of the Testosterone Trials was that testosterone treatment of older men with low testosterone levels has certain benefits, but the size of the benefits was modest. Testosterone improved all aspects of sexual function: It improved sexual activity, sexual desire, erections. Again, the magnitude of the effect was small, much smaller than the effect from previously approved medications for erectile dysfunction such as Viagra and Cialis.
The benefits on physical function and vitality were unclear. There was no improvement in vitality and there was a small improvement in walking ability whose clinical meaningfulness is not clear at the present time. And there was some improvement in mood. The trial was mostly an efficacy trial, so the long-term safety of testosterone still remains unclear. We need larger studies to address the issue of long-term safety, so that the risk-benefit ratio can be appropriately evaluated.
I must say that given all the buzz around testosterone, and the advertisements, the efficacy seems to be kind of underwhelming, doesn't it?
Yes, the conversation around testosterone's benefits and risks has been very schizophrenic. A lot of the discussion is conflated because people confuse hypogonadism — due to known diseases of the testis, pituitary and the hypothalamus — with age-related decline in testosterone concentrations.
Testosterone is currently approved by the FDA for treatment of hypogonadism in men due to known diseases of the testis, pituitary and hypothalamus, but neither the long-term risks nor benefits of testosterone were known prior to the Testosterone Trials. There have been many small studies but none adequately powered to determine the effects in older men who had low testosterone levels for no discernible reason other than age, and who also had symptoms. So this is a landmark set of trials in that these trials were adequately powered for efficacy, they recruited men who had clearly low testosterone concentrations and who had symptoms.
What do those symptoms tend to be?
To enroll in one of the three major testosterone trials, the participants had to have either sexual symptoms — low libido; physical symptoms — difficulty in walking and low gait speed; and low vitality or fatigue.
How do you imagine these new data playing out in the doctor's office?
I think there are a couple of things that are clear, which doctors can use in their conversations with patients who are seeking testosterone therapy.
From this trial, and from a previous trial which we published last June, in which we included men with no symptoms and normal testosterone concentration, it’s clear that testosterone does not improve sexual function in men who have normal testosterone concentrations.
The second point is that in men who have low libido and low testosterone levels, testosterone improves sexual function modestly.
The third point is that there are two aspects of the clinical decision to consider in choosing a treatment: The potential benefits of the treatment, and then the potential benefits of the treatment in relation to the potential risks. This set of testosterone trials were designed to determine efficacy; they were not statistically powered to determine long-term risks, particularly cardiovascular and prostate risks. So I think the risk-benefit ration still remains unclear, in need of much larger and longer trials.
And though the results are mixed, there is a real suggestion of possible cardiovascular and prostate risks — even though they're unclear, right?
Those are potential risks, but we don't know whether they are real risks, whether testosterone increases the risk of prostate cancer or of cardiovascular events. And so that's an important part of the clinical decision-making for which we do not have definitive data from this trial or any other trial.
So with these trials, patients are hearing about the benefits before they're hearing about the risks. It seems a little fraught with peril, doesn't it?
You’re exactly right: The results need to be viewed in the context of the fact that these were efficacy trials, they were not designed to establish long-term safety. And, in addition, the treatment effects were modest.
So the doctor says to the patient, we see some moderate benefits, and the risks are unknown, so therefore, caution?
I think it's appropriate for doctors to consider these results in weighing the decision to treat or not treat. In older individuals who are experiencing distressing sexual symptoms and have consistently low testosterone concentrations, these results provide the basis for a conversation for prescribing testosterone with the admonition that the potential improvements in sexual function may be modest and that the long term risks remain unknown.
Some people draw potential parallels with Hormone Replacement Therapy in women. How do you see that?
That parallel has some historical resonance, in that the estrogen use peaked just before the major randomized trials were being published. And then, after the Women's Health Initiative trial was published, estrogen sales plummeted. And now, estrogen sales have recovered quite a bit. We have come to an understanding that estrogen therapy is useful in a subset of women, but that it should be used in a time-limited manner, in a specific subset of women who are having vasomotor or other symptoms. We have a better understanding of the risks and benefits.
For testosterone, this is the first adequately powered set of efficacy trials, which now provide a context for the potential benefits, so this will be part of the conversation between doctors and men who seek treatment for age-related symptoms. But these trials were not designed to address the long term safety issue. So we still need larger trials, but the landmark Testosterone Trials have certainly advanced the field very substantially.
And there will be more trials soon to assess the risks better?
Those are needed. Of course, getting funding for such large trials is not easy. So it’s unlikely we’ll have data in the next year or two, but I think, given the need for such large-scale safety trials in light of the widespread and growing off-label use of testosterone in middle-aged and older men, such trials will be conducted. But it will be many years — at least six, seven, eight years — before we see data from these new large safety trials.