The difficult journey to find peace and happiness as a man ages (The Conclusion)
Could a low testosterone level actually be the cause?
In my last article titled, the difficult journey to find peace and happiness as a man ages, I discussed the fact that actual cause of melancholia, low libido, and a lack of overall well-being may be due to low testosterone levels. The medical term for low testosterone is hypogonadism. I discussed the clinical features of hypogonadism, how the diagnosis is made, and who should consider testosterone replacement therapy. In this article, I want to talk about the risks and benefits of testosterone therapy.
First, let’s discuss the data about the benefits of testosterone replacement. The multicenter TTrials were a coordinated set of seven placebo-controlled clinical trials to test the one-year efficacy of testosterone on sexual function, physical function, vitality, cognitive function, anemia, bone density, and cardiovascular risk factors in older men with symptoms of hypogonadism and consistently low testosterone. Hypogonadism in a male refers to a decrease in one or both of the two major functions of the testes: sperm production or testosterone production. Men over age 65 years (n = 788) with low serum testosterone (<275 ng/dL) early in the morning on two occasions and symptoms and objective evidence of sexual dysfunction, physical dysfunction, and/or reduced vitality were assigned to receive testosterone or placebo gel with balancing by minimization for one year and participated in one or more of three main trials (the sexual function [n = 470], physical function [n = 390], and vitality [n = 474] trials). Over 51,000 men were screened to enroll the 790 men who met inclusion criteria (only 1.5 percent of those screened). The median pretreatment testosterone concentration was 232 ng/dL. After one year of testosterone gel therapy, average serum testosterone concentrations increased into the mid-normal range (approximately 500 ng/dL) for men ages 19 to 40 years. The following results were reported:
Sexual function–Testosterone therapy was associated with a moderate improvement in sexual function, including sexual activity, sexual desire (libido), and, to a lesser extent, erectile function.
Physical function–There was no significant difference between the testosterone- versus placebo-treated groups in walking distance on a six-minute walk test in the 390 men who were enrolled in the physical function trial, but testosterone did improve walking distance when all 788 men were included.
Vitality-Did not differ in testosterone- versus placebo-treated men enrolled in the vitality trial but testosterone improved vitality [energy] slightly when subjects from all three main trials were included. However, men receiving testosterone reported better mood and lower severity of depressive symptoms when compared with placebo.
Cognitive function-After 6 and 12 months, there were no differences in changes from baseline in testosterone- and placebo-treated men in test scores for memory and other cognitive functions (delayed paragraph recall, visual memory, executive function, or spatial ability), but testosterone improved executive function when all subjects from all three main trials were included.
What were the significant adverse events in the TTrials?
Erythrocytosis–More men in the testosterone group experienced erythrocytosis (hemoglobin ≥17.5 g/dL). Although erythrocytosis is noted to increase blood viscosity and thrombosis(clotting), the incidence of major adverse cardiovascular events (stroke and heart attack) and other adverse events was otherwise similar with testosterone and placebo in the TTrials.
Effects on the Prostate-Only 2.5 percent of men experienced an increase above baseline of ≥3.4 ng/mL, A confirmed PSA >4.0 ng/mL occurred in 1.9 percent of men on testosterone and 0.3 percent on placebo.
Coronary artery plaque-Although there was an increase in noncalcified plaque volume in a subset of 170 men, there was no increased risk of heart attacks compared with placebo. Remember, that as we age, we all have progressive atherosclerosis to some degree. Unless a lesion is causing a decrease in blood blood flow to a heart artery, a negligible increase in plaque volume measured by CT coronary angiogram is meaningless to me. (And that is coming from a board-certified cardiac surgeon).
The TTrials, in short, demonstrated that testosterone treatment of symptomatic older men with unequivocally low testosterone levels is efficacious in improving sexual function, walking, mood, depressive symptoms, anemia, and bone density, all to modest degrees. Testosterone treatment, however, did not improve vitality or cognitive function and was associated with an increase in noncalcified coronary artery plaque volume. Although testosterone treatment was not associated with increased risks of clinical cardiac events or prostate cancer, a much larger and longer trial would be needed to assess these risks with greater certainty.
There are theoretical and other reasons to think that testosterone treatment of older men with low testosterone might exacerbate certain diseases. For example, the prostate gland is testosterone dependent, so it is reasonable to wonder if raising the serum testosterone concentration will increase the risk of prostate cancer or benign prostatic hyperplasia (enlarged prostate gland). Erythropoiesis (red blood cell production) is also testosterone dependent, so raising the testosterone level, especially to supraphysiologic levels, can cause erythrocytosis. Some epidemiologic studies have shown a larger number of cardiovascular events in men treated with testosterone, but others have not. The potential significance of this adverse effect is that in the Framingham Heart Study, men who were in the highest quintile (46 to 70 percent) with regard to hematocrit had greater overall mortality and cardiovascular mortality than those in the middle two quintiles.
Prostate cancer is partly testosterone dependent. This dependency is illustrated by the current practice of treating men who have metastatic and locally advanced prostate cancer by lowering their serum testosterone concentrations with drugs that decrease testosterone synthesis and/or its action. In the few clinical trials of testosterone in older men, few cases of prostate cancer occurred. In a 2010 meta-analysis of 51 randomized trials of testosterone therapy in men designed to look at the primary endpoints of mortality, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis, testosterone treatment was not associated with increased incidence of prostate cancer, need for prostate biopsy, or other prostate outcomes when compared with the placebo/nonintervention group. My own personal opinion is that I would not be comfortable taking testosterone if I was currently being treated for prostate cancer non-operatively no matter what. That includes “watchful waiting”. The only possible exception would be if I had a radical prostatectomy for early stage cancer, an adequate amount of time had elapsed post-operatively such that I had normal PSA levels on multiple occasions, and I was extremely symptomatic from hypogonadism with a low testosterone level. If all those criteria were met, I would have a discussion with my urologic oncologist about using topical transdermal testosterone replacement.
For further guidance or medical advocacy, please go to PaladinMDs because “it’s like having a doctor in the family.”
Great article
Probably a great majority of men aren’t aware of this
It is life changing