Testosterone Replacement Therapy and the Risk of Prostate Cancer. Is There a Link?

A. Barqawi; E. D. Crawford


Int J Impot Res. 2006;18(4):323-328. 

In This Article

Abstract and Introduction


Substantial evidence supports the value of testosterone replacement therapy (TRT) in improving quality of life in men with proven aging male syndrome (AMS). Benefits of TRT include improved bone mineral density, reduced fracture risk, increased muscle mass, and improved mood, sense of well being, and libido, among others. There is currently a heated debate about the theoretical association between TRT and the initiation, progression, and aggressiveness of prostate cancer; however, this link has not been uniformly studied, and any results have been contradictory and nonconclusive. Although no clear evidence links TRT to prostate cancer, the possibility of increasing the risk of a clinical manifestation of a latent pre-existing malignancy can influence the decision about TRT use. Current recommendations are to exclude prostate cancer before initiating TRT in men over age 40 and to closely monitor men in the first year of testosterone replacement, followed by observation in subsequent years.


Prostate cancer is a common disease that affects many men in the sixth and seventh decade of life. Historically, the development, differentiation, and maintenance of the prostate gland has been shown to be closely linked to the bioavailability of testosterone and other related sex hormones.[1] Although the association between testosterone and cancer cell transformation in the prostate is well established, the mechanisms of this link and the role of androgen receptor (AR) transformation are less well described. It is postulated that these effects are mainly mediated via the activation of ARs by the ligand: testosterone from androstenedione in Leydig cells and dihydrotestosterone (DHT) by 5α-reductases from testosterone. However, these steroidal functions involve complex interactions of many other growth factors with different receptors affecting various cell types in the prostate. For example, the exact contribution of androgen-induced signaling via the AR to the carcinogenic transformation remains unknown. Several transgenic prostate cancer mice have demonstrated an oncogenic potential for ARs, implicating a mutation or hormone perturbation at the level of the AR as facilitating a malignant transformation in the prostate.[2] There has been heated debate about the trigger for such transformation. In addition, the effect of testosterone levels on the complex interaction with other growth factors, including the steroid hormones estrogen and DHT, remains a mystery.[3] Recent research partially indicates an indirect link between mutations of the AR gene and the initiation, amplification, and overexpression of prostate cancer.[2] Regardless of the complexity and lack of full understanding of these mechanisms, there is a growing demand for testosterone replacement therapy (TRT) in men with symptoms suggestive of aging male syndrome (AMS), also known as late-onset hypogonadism (LOH). This is due in part to the recognition that many symptoms associated with aging, are similar to those characteristic of AMS, and well-publicized data have recently suggested a potential benefit of TRT on the overall quality of life in these men.[4,5] However, these benefits are offset by the potential side effects of TRT, which may include, the exacerbation of existing prostatic disease, hematological and cardiovascular events, plus possible negative effects on male reproduction. Perhaps the single greatest concern associated with TRT is the possibility that it may significantly increase the risk of developing prostate cancer or may contribute to the progression of the disease. This review focuses on the potential link between the use of TRT and the risk of prostate cancer, as reported in the literature.


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