Testosterone Replacement Therapy (TRT)

BY JEFFREY TURNER, MD


Testosterone (T) preparations have been available for more than 70 years.  In 2013, over 2.2 million Americans were prescribed testosterone.  Interestingly enough, about 1 in 4 men prescribed testosterone do not have a baseline testosterone level drawn as primary care physicians may write the prescription without ordering a blood test first.  In a study of 63,000 men from the Truven Health Marketscan Commercial and Medicare Supplemental Insurance database between 2010 and 2012, 71% of men had their testosterone level checked once, 40% twice, and 29% had no measurement at baseline.  Physicians need to do a better job following men on testosterone replacement. Is testosterone replacement therapy really all that good for anything aside from rejuvenation and virility? 

Let’s break this down to risks and benefits below:

Risks of Prostate Cancer

The most universal risk which has been the controversy of much discussion is the association with prostate cancer.  Clinicians remain concerned that Testosterone Replacement Therapy (TRT) can cause or stimulate prostate carcinogenesis and therefore they are reluctant to prescribe it for the aging male who has a higher risk of prostate cancer.  In the 1940s, Huggins and Hodges discovered the association of testosterone with prostate cancer by demonstrating that castration causes the disease to regress. The reality is that TRT may stimulate the growth of existing prostate cancer cells, but it will not cause cancer to form.  As the general male population grows, so does the risk for prostate cancer--patients should be closely evaluated with digital rectal examinations, PSA checks and prostate imaging such as color Doppler ultrasound.

Risk of Prostate Enlargement

Another controversial topic is the assumption that supplemental testosterone leads to a prostate growth, benign prostate hypertrophy, which leads to worse quality of life due to worsening urinary symptoms.  It has long been assumed that high T levels induce prostate overgrowth, but most studies failed to find the correlation between circulating T levels and BPH.  It has been hypothesized that dihydrotestosterone (DHT) could be more responsible for prostate growth than T.  There have been a number of studies evaluating TRT in hypo-gonadal men with BPH.  The results have suggested that there is actually a trend toward an improvement in urinary symptoms.

Risk of High Red Counts—Polycythemia or Erythrocytosis

Erythrocytosis is the increase in red blood cell mass production which can be the result of testosterone replacement therapy.  This is the most frequent adverse effect associated with TRT.  Recent trials have demonstrated that men on TRT have a 4 times higher chance of having high red blood cell counts.  Some reports have implicated excessively high red blood cell levels with an increased risk for heart attack or stroke. We commonly recommend patients remain on a baby aspirin daily and monitor their blood counts. Some patients may benefit by donating a unit of blood if the levels are too high.

Risk of Obstructive Sleep Apnea

Frequently reported in various literature is the association of worsening sleep apnea symptoms for men on testosterone replacement.  There has been only one randomized control trial to date that addresses this association and it showed that obese men with severe sleep apnea may worsen their oxygenation with TRT at relatively high doses.  This study evaluated injection formulations of testosterone. So far transdermal formulations have not been similarly implicated.

Risk of Infertility

Testosterone replacement leads to inhibition of the pituitary gland located at the base of the brain which can potentially suppress the production of sperm.  Hence, cases of TRT-induced male infertility have been reported. This impact appears to be transient and disappears once TRT is stopped.

Improved Sexual Function

A decreased libido and/or potency remains one of the most common reasons that men desire testosterone replacement.  TRT can certainly improve sexual function in those who have erectile dysfunction primarily due to a low level of testosterone.  Patients need to recognize that there are a series of other reasons for being impotent that are unrelated to low levels of testosterone which must also be investigated as well before concluding that TRT will be the optimal corrective measure.

Improved Cardiovascular Effects

The association of TRT with heart attacks has been very controversial. We must not forget that men with low T levels are at higher risk for poor health due to being more frail and susceptible to other medical issues including obesity and diabetes. As a result, they become more prone to adverse cardiovascular outcomes.  Four out of five of the most recent meta-analyses demonstrated neither a protective or harmful effect of TRT on cardiovascular events. In men with heart failure, it has been demonstrated that low T levels are an independent risk factor for worse outcomes.  Studies also demonstrated that men with heart failure who supplemented with testosterone had a better exercise capacity, oxygen levels, and less fatigue.

Improved Metabolic Effects

Large scale data exists to document the association of low T and worsening blood sugar levels along with a higher chance of developing diabetes. TRT can improve body composition and help to reduce fat which can lead to better control of diabetes.

Reversal of Osteoporosis

Lower testosterone levels are associated with a higher risk of bone fractures and worsening bone health.  TRT has been demonstrated to have a positive effect on bone mineral density.

Improvement in Chronic Kidney Disease

Low T is very common (approximately 50%) in men undergoing dialysis for end stage renal disease. Reduced T levels have in men on hemodialysis have been tied to higher rates of all-cause cardiovascular mortality.   Studies suggest that TRT may improve the levels of a hormone called erythropoeitin (EPO). This hormone stimulates improved production of red blood cells which in turn increases levels of red blood cell mass, energy, stamina, and overall well-being.

Conclusion

It is clear to see that testosterone replacement offers a multitude of benefits which span past merely increasing one’s libido or potency.  The bottom line remains that patients on testosterone supplementation must have close follow-up including both clinical and laboratory evaluation to ensure they are gaining benefit and not placing themselves at increased risk from potential adverse effects.  Physicians must clearly discuss the risks and benefits of supplementation along with employing routine monitoring of PSA, testosterone levels, blood counts, digital rectal examination, and color Doppler ultrasound.