Testosterone replacement has been a controversial issue, despite a large number of physicians who prescribe it, FDA approval of products for mass marketing, and a number of advocates that see it as an anti-aging and performance enhancing drug for aging men. The science behind is has been surprisingly slow. In an era where inequities in health care are often argued by race or sex, this seems to be one where the science at least lags far behind what is known for women. Expert opinion about testosterone replacement has changed very little over the years, despite much popular literature about how this has occurred for years in Europe and there is widespread benefit for physical and emotional well being of men as they age. From a clinical perspective, psychiatrists are seeing more and more middle-aged men on testosterone replacement. This treatment modality has significant implications for any medical treatment provided by psychiatrists as well as associated comorbidity. From a psychiatric perspective it is also important to determine if the testosterone use is more than indicated, is associated with increasing muscle mass and body image changes, and if it occurring in the context of unreasonable expectations like preserving youth , reversing the effects of aging, or athletic performance enhancement.
In the most recent study of men 65 years of age and older the authors examined the effects of treatment with testosterone gel for a period of one year (1). The total number of subjects was 790 out of a total of 51,085 men who were screened. In order to qualify for the trial testosterone level had to be sufficiently low (less than 275 ng/dl) on one of two samples and that eliminated 85% of all of the screened men. The trial was designed to look at physical function, sexual function, and vitality. The treatment resulted in testosterone levels that were in the mid-normal range for 19 to 40 year old men. Despite considerable medical comorbidity in the recruited patients there were clear cutoffs for medical comorbidity. Those cutoffs included a history of prostate cancer or risk of prostate cancer on the Prostate Cancer Risk Calculator, other conditions known to cause hypogonadism, medications known to effect the concentration of testosterone, high cardiovascular and severe depression (PHQ-9 score >20). The overall results showed that there was moderate benefit on sexual functioning and some benefit with mood and depressive symptoms but no effect on physical functioning or vitality. A look at these measurements is instructive.
Physical Function was assessed using the 6 minute walk. Recent normative data has been established for various age cohorts using subjects from several countries. That data establishes normative curves for age cohort stratified by sex. The six-minute walk distance (6MWD) ranged from 559 +/- 80 meters in 60-69 year old men to 514 +/- 71 meters in 70-80 year old men. On two trials subjects usually walked on average 12 meter farther on the second trial. In the present study, the criterion for a positive effects from testosterone was a walking distance increase of 50 meters. When compared with controls, the testosterone treated men had significantly more men increasing the distance walked by 50 meters, the percentage of men exceeding this measure, the change from baseline, and the percentage of men with higher scores on the physical function domain test (PF-10) from the Medical Outcomes Study 36-Item Short Form Instrument (SF-36). One of the concerns I had reading this methodology is the use of testosterone for physical performance enhancement. Is it effective without using a training program? Were the subjects in this study advised to extend their walking distances or speed? Without it I am skeptical that it would have much of an effect.
Vitality was determined by measures on the FACIT-Fatigue score as the primary outcome measure. Interestingly FACIT stands for Functional Assessment of Cancer Treatment and their web page links to an extensive list of modified rating scales. I could not tell if the rating scale had been validated in normal 65 year old men without a cancer diagnosis. No significant differences were noted between testosterone treated men and controls. On secondary measures testosterone treated men were more likely to report higher energy at the end of the trial, but that measure was unspecified and may have been a line item in the SF-36.
Sexual Function was measured primarily by question 4 of the Psychosexual Daily Questionnaire. This item is a 12 item yes-no checklist of male sexual behaviors, thoughts, and fantasies. Greater testosterone levels achieved in treatment correlated with higher testosterone levels. A secondary measure - the Derogatis Interview for Sexual Functioning in Men-II (DISF-M-II) also documented increased sexual desire and it was also used as a screen for participants in the Sexual Function arm of the trial. The sexual function measures do appear to be more straightforward, but they are all self report measures over considerable time frames.
One of the most interesting aspects of this trial was an analysis of the side effects. One of the main concerns in treating men with testosterone is the risk of prostate cancer that is sensitive to testosterone levels. I have had personal communication with physicians who were treating patients with testosterone who developed widely metastatic prostate cancer. The significant adverse effects in this trial were all summarized in a table. There were 394 placebo treated men compared with 394 testosterone treated men. The events were summarized according to prostate-specific antigen (PSA) level increases, diagnoses of prostate cancer, elevations of hemoglobin, myocardial infarction, stroke, all cause cardiovascular death, death and hospitalization. Although there were a greater number of PSA elevations in the testosterone treated men, there was only 1 case of prostate cancer (compared to 0 in the controls) during the year of study and 2 cases of prostate cancer in the testosterone group and one in the placebo group in the subsequent year of the study.
The rationale for this study was try to to add to the results of previous trials that showed inconsistent results of testosterone replacement on muscle mass, body fat, sexual function, energy level, and physical function. It is disappointing to read through all of these details and find out that there was not much of an effect and that the methodology in the 21st century is so weak. The only good news that I can find in the article is that it is relatively safe to replace testosterone in 65 year old men who are rigorously screened for hypogonadism and prostate cancer risk. Although selection bias for a project like this is certainly a consideration, I asked myself whether men self-selected for replacement by low testosterone ads would be rejected at the 85% level by their physicians. Of course the researchers here point out that the risk over the long run can only be determined by larger trials or (my opinion) post marketing surveillance. But post marketing surveillance as suggested by the FDA is really a blunt instrument compared with any type of organized pharmacosurveillance or screening all new cases of prostate cancer on a particular electronic health record for testosterone prescriptions. At some level, I wonder if the research questions would have been answered more completely by trials focused solely on each groups, but there were a very large number of investigators. Many of the investigators have the appearance of conflict of interest through affiliations with pharmaceutical companies and many do not.
The results of this study are consistent with what clinical psychiatrists see in their practice. It is not uncommon to see men taking supraphysiological doses of testosterone and not wanting to reduce those doses. It is common to see men on testosterone who stop taking it because there is no clear efficacy and/or because they are concerned that the women and girls in their life will accidentally come into contact with testosterone. But let's face it - this is really not about hypoandrogenism. That is not what is fueling the debate. I am not an advocate of aging gracefully and accepting what happens. I think if you have been dieting and exercising through the first 65 years of life it would be useful if medical science could provide something to help you maintain an active lifestyle and prevent the kind of morbidity that slows you down, leads to deconditioning and the host of metabolic factors that hasten aging and death. Preventing that pathway of physical deterioration depends on maintaining attitude, muscle, joints, and bone. This is another paper documenting that there is no clear solution to that array of problems.
It is unfortunate that medicine does not have a scientific solution at this point - even after hearing all of the unscientific hype about testosterone and growth hormone for the past 30 years.
George Dawson, MD, DLFAPA
1: Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016 Feb 18;374(7):611-24. doi: 10.1056/NEJMoa1506119. PubMed PMID: 26886521.
2: Casanova C, Celli BR, Barria P, Casas A, Cote C, de Torres JP, Jardim J, LopezMV, Marin JM, Montes de Oca M, Pinto-Plata V, Aguirre-Jaime A; Six Minute Walk Distance Project (ALAT). The 6-min walk distance in healthy subjects: reference standards from seven countries. Eur Respir J. 2011 Jan;37(1):150-6. PubMed PMID: 20525717.
The two minute NEJM video summarizing this trial can be found at this link. Interestingly the video attributes sexual function, vitality, and physical function to testosterone decrease with age and yet full replacement to the point where it is equivalent to levels in much younger men does nothing for physical function or vitality.