Testosterone Replacement Therapy – why is it so controversial?
For reasons that are not readily apparent, there appears to be a conservative political movement that opposes the use of testosterone in older men. This was clearly demonstrated by the report of the Institute of Medicine, which felt that testosterone is not yet ready for prime time and that there is still a need for studies to prove its efficacy 1. Along the same lines, the guidelines of the Endocrine Society on testosterone use in older men seem to be ultra-cautious 2 . But fortunately, there are also other, more liberal guidelines and recommendations 3-5.

Probably no other medical issue has been bombarded by the influx of “expert” views from all walks of life; from endocrinologists and psychiatrists to urological surgeons and gerontologists, from the lay press to the regulatory agencies and from the pharmaceutical to the entertainment industries. The dismal result of all this free-for all cacophony of opinions is a great deal of confusion, erroneous information and significant detriment to patients and physicians alike.

Let’s take an in-depth look at the reasons for the negative attitudes to male testosterone replacement therapy (I will cover post-menopausal testosterone replacement in an upcoming article), and the hard scientific data that refutes it…

Unsubstantiated Claim 1:

There Is Insufficient Evidence That Testosterone Is Beneficial in Older Men
Data:

Numerous placebo-controlled studies have demonstrated salutary effects testosterone therapy in older men 6-11. Testosterone therapy clearly improves sexual function (both libido, erectile and ejaculatory function) in older men 12. In addition, testosterone supplementation in borderline hypo-gonadal men increases muscle mass 13-17, decreases fat mass 14, 15, 17, and improves strength 8, 13, 16, 17. There are also data showing that testosterone replacement in older men increases bone mineral density 18, 19 (and thereby and counteracts osteoporosis), improves cognition (in both Alzheimer and non-demented elderly) 20-22 and mood 16, 20, 23, and also alleviates depression 24.

Recent studies have also shown that testosterone therapy significantly improves not only symptoms of androgen deficiency (including erectile dysfunction), but also metabolic and control (lowering of blood glucose and glycated hemoglobin (HbA1c) (from 10.4 to 8.6%) 25, while decreasing abdominal obesity 25. These beneficial effects were seen without any adverse effects on blood pressure or hematological, biochemical and lipid parameters 25. Testosterone gel also has been shown to reverse the metabolic syndrome and improve glycemic control in men with sub-normal plasma testosterone 26. The improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity seen is these studies show that testosterone therapy contributes to an overall reduction in cardiovascular risk.

It is strange that treatment of testosterone deficiency caused by classical diseases affecting the hypothalamus, pituitary, and/or testes has been accepted for decades although there were no large multicenter trials, but that that treatment of testosterone deficiency caused by aging is taboo despite overwhelming scientific data showing significant benefits. It appears that physicians and regulatory agencies are much more comfortable treating older men with questionable drugs that pose more harm than benefit in terms of both quality of life, cancer and mortality 27-47, than using testosterone, a drug that not only improves important symptoms and risk factors, but also can reverse sarcopenia and frailty 48-54 which has well-documented detrimental effects on well-being, physical independence, morbidity and mortality. This is a poster-child example of “eminence” based medicine trumping evidence-based medicine.

Unsubstantiated Claim 2:
Testosterone Increases Prostate Cancer
Data:

The most prominent concern regarding testosterone treatment is its effect on prostate health. For decades, the concept that testosterone is “bad for the prostate” has gone unchallenged. Even though prostate-specific antigen (PSA) levels increase in response to testosterone supplementation 55, 56, recent research shows that the longstanding fear of stimulating prostate cancer with testosterone supplementation is without scientific basis 57-59.
Mechanistic studies have shown that the development and growth of prostate cancer are much more complex than simply an excess of lack of androgens: nonsteroidal hormones (e.g., insulin, leptin, glucocorticoids and growth hormone), genetic susceptibility, inflammation and environmental factors appear to be significant contributors 60. Further, there are a number of puzzling situations. For instance, prostate cancer cell lines that requires initial stimulation by androgens to grow is eventually suppressed by them 60. More evidence for the not so clear-cut relation between testosterone and prostate cancer lies in the fact that prostate cancer occurs in older men at a time when testosterone levels have already declined to low levels 61. In addition, there is no prospective evidence that testosterone is correlated with the development of prostate cancer 62, and retrospective studies have failed to demonstrate an increase in prostate cancer in men treated with testosterone 63.

Unsubstantiated Claim 3:
Testosterone increases cardiovascular disease risk

Another debate centers on the putative increased cardiovascular risk of testosterone therapy. While it is true that supra-physiological doses of testosterone, such as those administered by athletes, doe increase several risk factors for cardiovascular disease and cardiac events 64-66, this is not the case when testosterone therapy is used to restore low age-related testosterone levels to the normal range 59. To counter this, the anti-testosterone maffia often points to a study that was stopped before completion because much more adverse cardiovascular events were measured in the treatment group 67. However, the adverse cardiovascular events in this study could be explained by the pre-study high prevalence of cardiovascular risk factors within the study participants.
The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit (volume percentage (%) of red blood cells in blood) 59, 68, and a small decrease in HDL (the “good” cholesterol) 59, 69. However, elderly men with low testosterone tend to have a low hematocrit and also frequently present with anemia (hemoglobin deficiency) 70, so this side-effect can actually be a good thing. And the hematocrit-induced increase in blood viscosity can be alleviated with fish oil 71, while the decrease in HDL can be counteracted by carbohydrate restriction 72 and/or niacin (vitamin B3, the most effective way for increasing HDL) 73, 74, and a moderately increased physical activity 75-78. It should be noted that the small HDL reduction is primarily observed with intramuscular testosterone injections 69, and not with transdermal gel preparations 79.

To the contrary, it is well documented that low testosterone levels actually increase cardiovascular disease risk 80, 81. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in cardiovascular health. Observational studies show that blood testosterone levels are consistently lower among men with cardiovascular disease 80, 81, suggesting a preventive role for testosterone therapy.

In middle-aged and older men, lower testosterone levels are associated with insulin resistance, metabolic syndrome and diabetes, and related conditions that predispose to cardiovascular disease 82. Lower testosterone levels predict cardiovascular events, such as stroke and transient ischaemic attack, in older men and are associated with higher cardiovascular and overall mortality 82. Randomized trials have even shown that testosterone supplementation in men with existing coronary artery disease can be protective against heart attack (myocardial ischaemia) 82.

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