Dr. Kaye's Response to the New England Journal of Medicine article on Testosterone Administration

A recent report in the New England Journal of Medicine by Dr. Basaria, et. al stated that the TOM (testosterone in older men with mobility limitations) study was discontinued recently due to an increased occurrence of adverse cardiac events in the group receiving testosterone compared to the placebo group (those not receiving testosterone). The study protocol involved applying between 50mg/day to 150mg/day to the skin of elderly men over the age of 65. The product used was a brand named product, Testim. The study was ended prematurely due to the following results in the treatment group of 106 patients: 4 acute coronary events, 1 death from assumed MI, 5 episodes of peripheral edema, 2 episodes of CHF, 2 episodes of syncope (loss of consciousness), 3 abnormal EKG results, 1 stroke, 3 patients with elevated blood pressure. This compared to the following in the 103 patients in the placebo group: 1 episode of syncope, 1 elevated blood pressure, 2 episodes of arrhythmia. Clearly, on first review, this pattern raises some concern, that at least in elderly men with significant concurrent medical illness, topical testosterone may not be appropriate.

 

If we look at the makeup of the study populations, however, we see something interesting: The testosterone group had a worse cardiovascular status at the out set of the study than did the placebo group. The testosterone group had 53% with known preexisting cardiovascular disease vs. 47% in the placebo, 85% with elevated blood pressure vs. 78% in the placebo, 85% in the testosterone group were being treated with antihypertensive drugs vs. 73% in the placebo, 62% of the testosterone group required statin therapy vs. 47% of the placebo group. Clearly the populations were not equivalent with respect to cardiovascular illness. Interestingly, the C-reactive protein was not reported in either group; it is an important indicator of cardiac risk for MI and is an indicator of inflammation, an underlying mechanism of acute coronary events. In addition, the numbers of adverse events were small compared to the total number of participants making it hard to conclude that this was not an effect of chance.

 

The authors state in the article that the interpretation of adverse events in the study is limited by several factors: " The generalizability of our data about the safety of testosterone therapy is limited by several factors. First, cardiovascular events were not a planned primary or secondary outcome, and therefore, a structured evaluation of cardiovascular events was not performed, a factor that may have influenced the ascertainment of events. Most of the cardiovascular-related events were verified from medical records or by direct examination. Second, the sample, although larger than those in most previous trials, was small, and the number of adverse events was small. The results of individual small trials may not be confirmed in large trials,28 and trials that have been stopped early tend to overestimate treatment differences. Third, the clinical characteristics of our study population differ from those of most other populations in which testosterone therapy has been administered in a clinical setting or as part of a clinical trial. Men who were younger than 65 years of age and men with severe hypogonadism were excluded from the trial. Participants had substantial limitations in mobility and a high prevalence of chronic conditions, including preexisting heart disease, obesity, diabetes, and hypertension. Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility."

 

Given the diverse types of events and the lack of a clear unifying underlying mechanism for all of the events, it is hard to attribute the adverse events to the use of testosterone, particularly when the study populations were different, the absolute numbers of adverse events were small, and the patients were quite ill to start with.

 

On the other hand, the benefit of the men receiving testosterone was evident in the dramatically increased strength noted in several measures. No mention was made of other reported benefits of testosterone due to the small size of the study and incomplete duration of the study. I have treated scores of men in my practice who are suffering from andropause, the premature or age-related decrease in serum testosterone levels which are accompanied by fatigue, obesity, loss of muscle mass, depression and anxiety, loss of mental focus and concentration, glucose intolerance, osteoporosis, loss of libido, and erectile dysfunction; I have not noted any increased rate of adverse cardiovascular events among them after treatment. I would note, however that my patients are generally not as ill as those in this study. My clinical experience is that my patients improve their body composition by decreasing body fat and increasing the amount of muscle, have improvement in mental focus and memory, and an improvement in their blood sugar indicators such as HbA1c, insulin levels, 2 hour glucose tolerance, and fasting blood sugar and their libido and erectile dysfunction improve as well. These effects are all reported in the literature.

 

In my practice, I monitor testosterone differently depending on the route of administration. I rarely use transdermal creams as I find them less effective than subcutaneous implants. However, I have found salivary testosterone levels or whole blood testosterone levels to be more useful than serum levels when testosterone is delivered transdermally. Unfortunately, the typical hospital labs do not offer this type of testing; I send my samples to reference laboratories to determine these measurements. It is thought that testosterone administered transdermally is not carried in the serum so much as on the red blood cell lipid membrtanes, leading to a falsely low reading when using serum testing which does not monitor the levels on the RBCs. In fact, when looking at whole blood testosterone, one finds the "missing" testosterone. It is therefore possible that these patients were overdosed because of the investigator's reliance on serum rather than whole blood or saliva tests and, given their frail condition, that they were unable to handle the effects of this relative overdose compared to younger men. In my experience, giving as little as 10-25mg/day of transdermal testosterone causes a restoration to normal of salivary and whole blood testosterone levels and appropriately reduces LH, an indicator of adequate replacement. In most of my patients, I prefer to use subcutaneous implants of testosterone. This is a method of replacement that has been used by physicians for over 50 years and, in my experience, releases testosterone more slowly and evenly into the bloodstream than does an injection or a gel, more perfectly reproducing the normal function of the testes. In my practice, men who receive testosterone via this route do not experience the elevation of red blood count or the mood swings noted with injection and have a better outcome with respect to libido and sexual function than with the transdermal creams. In testosterone replacement, in my experience, the route of administration is important. Gel administration is not equivalent to implants or injection. In women's studies, it has now been noted that the risks of administering estrogens varies depending on whether the drugs are given transdermally or orally. I suspect the same may be true in men with respect to testosterone delivery methods.

 

The bottom line in terms of this study is that it is difficult to draw any conclusions given the differences in the populations of men, the underlying levels of illness in both groups, the small numbers and varying types of complications, the incomplete period of follow-up, and lack of a single underlying biological mechanism explaining the types of adverse events noted. In light of the study findings, I would still be somewhat concerned with respect to administering testosterone gels to elderly men with significant comorbidity and cardiovascular illness. In cases where this is done, I would recommend closer observation and monitoring with whole blood or saliva levels of testosterone and by following LH to individualize treatment. It is my opinion that the benefits in terms of increased strength, protection from osteoporosis and fall injuries, improvement in mental functioning, and improvement in glucose metabolism that result from the use of testosterone may still warrant it's use in this population until larger and better studies are performed to more clearly determine the actual risks and benefits in this population. As with any medication, one must know in advance what the goal is that one expects to achieve before using the drug and monitor carefully to determine if the goal is being met and if any adverse reactions are developing. I do not recommend the ad hoc use of testosterone or any other medicine in a population such as in this study, rather it should be targeted to achieve certain defined endpoints and monitored carefully by appropriate laboratory and clinical measures.