Testosterone Replacement Therapy

Risks of Cardiovascular Disease and Prostate Cancer

Testosterone Replacement Therapy (TRT) has been used to treat secondary effects of hypogonadism including decreased libido, decreased energy level, depressed mood, impairment in cognition, and reduced muscle mass (Warburton 2015). Recent reports in the scientific and the press have suggested that TRT may increase risk of cardiovascular disease and prostate cancer (Corona 2015, 2017).

In a 2015 report, the Food and Drug Administration (FDA) warned that prescribing testosterone medications is approved only for men who have low testosterone levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection). In this report, the FDA mentioned that the benefits and safety of TRT have not been established for the treatment of low testosterone levels due to aging, even if symptoms seem to be related to low testosterone levels. (Corona 2015)

More recent analyse has revealed that when age-related hypogonadism is properly diagnosed and testosterone therapy is correctly performed no cardiovascular and prostate risk have been documented (Corona 2015, 2017). In fact TRT has shown to provide many health and quality of life benefits for those who have low testosterone levels (Corona 2015).

However, there remains controversy on what level of testosterone constitutes low levels and if marginally low, yet 'normal' levels should be treated. Interestingly the reference ranges provided with blood test values are a 2 standard deviations from the medium, encompassing 95% of the population.

Concern regarding the effect of testosterone on prostate cancer tumor promotion and progression has led to reservations in prescribing TRT to individuals with a history of the disease. The historical basis for this concern dates back to a 1941 case study on a castrated patient who was given testosterone therapy and later developed prostate cancer. It turns out that low testosterone throughout many years promotes the development of prostatic intraepithelial neoplasia. In this primed precancerous state, testosterone therapy appears to increase risk of prostate cancer. However, when testosterone therapy is introduced soon after it is detected, it offers protection from prostate cancer. This is because the prostate gland has a saturation point where it only accepts normal blood levels of testosterone. Beyond this amount, testosterone does not affect the prostate. (Warburton 2015)

Earlier epidemiological studies suggested testosterone therapy may increase risk of cardiovascular disease. This resulted in petitioning for warning labels on testosterone preparations. Later studies relieved these studies statistical analysis and experimental methods were flawed. In fact, later epidemiological studies have reviewed that those receiving testosterone therapy had a 39% to 50% decrease in mortality (Corona 2015). Other studies show that testosterone has a protective effect on the heart (Corona 2015, Cheetham 2017).

Interestingly, there appears to be a clear dose-response relationship between testosterone levels and all-cause mortality and cardiovascular risks in both young and older men. In fact, the threshold for increased mortality appears to be near total testosterone cutoffs for the highest age-category-specific tertiles. Furthermore, low testosterone may play an early, causal role in chronic disease processes. (Peterson 2018)

Testosterone therapy also improves cholesterol and glucose levels and reducing body fat and increasing lean muscle mass. At least some of this effect had been attributed to the approximately 10% of testosterone that aromatizes to estradiol. In fact, estradiol keeps arteries supple, maintains nitrix oxide (acts as a vasodilator), and helps prevent arteriosclerosis in addition to other health benefits. (Corona 2015)

Meta-analyzed data does not support a causal role between TRT and adverse cardiovascular events or prostate risks. This is particular true when hypogonadism is properly diagnosed and TRT is properly performed. (Corona 2015, 2017)

Elevated hematocrit represents the most common adverse event related to TRT. Therefore it is important to monitor hematocrit regularly in patients undergoing TRT in order to avoid potentially serious adverse events. (Corona 2015)


Cheetham TC, An J, Jacobsen SJ, Niu F, Sidney S, Quesenberry CP, VanDenEeden SK (2017). Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med. 177(4): 491-499.

Corona G, Rastrelli G, Maseroli E, Sforza A, Maggi M (2015). Testosterone Replacement Therapy and Cardiovascular Risk: A Review. World J Mens Health. 33(3): 130-142.

Corona G, Sforza A, and Maggi M (2017) Testosterone Replacement Therapy: Long-Term Safety and Efficacy. World J Mens Health. 35(2): 65–76.

Peterson MD, Belakovskiy A, McGrath R, Yarrow J (2018). Scientific Reports. 8(5887).

Warburton D, Hobaugh C, Wang G, Lin H, Wang R (2015). Testosterone replacement therapy and the risk of prostate cancer. Asian Journal of Andrology, 878–881; doi: 10.4103/1008-682X.150841.

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