A testosterone molecule
Symptoms of low testosterone
A July 2010 article in the NEJM by Wu et al. found that the only symptoms that clearly correlate to low testosterone levels are poor morning erection, low sexual desire, and erectile dysfunction. But the websites promoting testosterone treatment provide a whole laundry list of symptoms that they say could be caused by low testosterone levels, including fatigue, weakness, depression, mood problems, irritability, infertility, reduction of pubic hair, sweating, memory loss, sleep disturbances, low self-confidence, lack of motivation, aches and pains, diminished mental aggressiveness, decreased stamina, and many more. They imply that if you have any of these symptoms, you should be at least tested and probably treated.
Normal testosterone values vary from 270-1070 ng/dl; the definition of “normal” varies slightly according to different experts. Levels decrease with age, but that is a normal physiologic process, not a disease requiring treatment. There is no reason to think a 70-year-old man should have the testosterone level of a 20-year-old. Low-T doctors say if your level is normal but in the lower end of the normal range, you may have symptoms and benefit from replacement. That claim is not supported by scientific evidence. They suggest a trial of treatment for anyone with suspicious symptoms, to see if they improve. That is not a good idea. It amounts to an uncontrolled experiment; it would be confounded by placebo responses, misattribution of spontaneous improvements and regression to the mean, and would provide the doctor with an excuse to keep prescribing testosterone long-term for patients who may not need it. They also claim that low testosterone causes a higher risk of diabetes, osteoporosis, and cardiovascular disease. That’s a misleading claim apparently based on the risk of those diseases in infertile men and the fact that men with low sperm counts are more likely to be diagnosed with hypogonadism.
The TTrials, part 1
I wrote about testosterone again in 2016 when the first results from the TTrials were released. The TTrials were a coordinated set of double-blind, placebo-controlled trials lasting one year, carried out at 12 sites on men over the age of 65 whose testosterone levels were below the normal range for men 19-40 years of age. Low testosterone was not very prevalent; they had to screen 51,085 men to find 790 who had sufficiently low testosterone levels and met the other criteria for enrollment. There were seven separate trials. For each trial, patients were randomized and treated with either Androgel or a placebo gel. Results for three of the seven trials were released in 2016.
Sexual Function Trial required self-reported decreased libido. Results: modest improvements in sexual function that tended to wane after several months and were not as robust as the effects of Viagra.
Physical Function Trial required self-reported difficulty walking or climbing stairs and a gait speed of less than 1.2 m per second on the 6-minute walk test. Results: small gains in physical performance.
Vitality Trial required self-reported low vitality and a score of less than 40 on the Functional Assessment of Chronic Illness scale (FACT). Results: overall vitality was no better with Androgel than with placebo.
In short, some modest benefits with questionable clinical significance.
The TTrials, part 2
In February 2017, the results of the other four trials were released.
Bone Trial, on 189 men, found that testosterone improved bone density and estimated bone strength.
Anemia Trial found that testosterone significantly improved hemoglobin concentrations in 54% of 62 patients with unexplained anemia and 52% of 64 patients with anemia of known cause.
Cardiovascular Trial found that testosterone increased coronary artery noncalcified plaque volume and narrowed coronary arteries in 73 men using Androgel compared to 65 in the placebo group.
Cognition Trial found no effect on memory or cognitive function in 493 patients with age-associated memory impairment.
What do these findings really tell us?
The clinical significance of the positive findings is not clear. No major cardiovascular events occurred during the study and there was no reduction in the incidence of fractures, but the trials only lasted a year. The number of subjects in some of the trials was small. Longer, larger trials will be needed to confirm findings. Other studies have reached different conclusions: for instance, a retrospective cohort study found an association of testosterone prescriptions with a reduced risk of cardiovascular events in men over the age of 40 with testosterone levels lower than 300ng/dL.
Side effects of testosterone treatment
Testosterone is not harmless. It can contribute to sleep apnea, cause acne, stimulate benign prostatic growth and prostate cancer, enlarge breasts, cause male pattern baldness, reduce sperm production, shrink testicles, and increase the risk of a blood clot. A long list of other side effects can be found here. And some studies have found that it increases the rate of cardiovascular events.
The dangers are not limited to the patient. The gel can be transferred from the patient’s body to others by simple contact, affecting children, women, and pets. There have been reports of early puberty and aggressiveness in children, increases in acne and body hair and menstrual irregularity in women, and severe hormonal effects in pets.
Conclusion: Still no easy answers
The new studies don’t really change the overall equation, although they add to the information doctors can give patients. Testosterone supplementation has both benefits and risks, and the decision to prescribe it should be carefully considered for each individual. The Endocrine Society has published clinical practice guidelines for the treatment of androgen deficiency, stressing caution in making the diagnosis, but these guidelines have not been updated since 2010. As with so much in medicine, it’s complicated. But one thing is clear: testosterone supplementation is not an anti-aging panacea.