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It is estimated that more than one third of men over age 45 suffer from hypogonadism (defined as a total testosterone level below 300 ng/ml). Perhaps even more disturbing to health care providers invested in men’s health is the fact that only 4%-5% of these men are receiving treatment for the condition.1
While hypogonadism may have a negative effect on quality of life and overall health, the unspoken question of how testosterone replacement may affect men who have been or will be diagnosed with prostate cancer (PCa) looms in the background. The objective of this review is to better define the role that testosterone plays in the diagnosis, prognosis, and growth of PCa and to review the current status of treatment for hypogonadism in the PCa patient.
Testosterone is a critical hormone in the regulation of metabolic, sexual, and developmental functions. It not only facilitates the development of secondary sex characteristics such as deeper voice and male hair growth patterns, but also fuels bone growth and lean muscle mass development.
It has been postulated to play a role in cognition as well, and research has begun to associate testosterone with brain development, concentration, and possibly memory.2 Symptomatic hypogonadism can dramatically decrease the quality of a man’s life by decreasing libido, affecting erectile function, precipitating hot flashes and gynecomastia, as well as causing fatigue and depression and other metabolic and cognitive derangements.3,4,5,6
Despite the health benefits men reap from testosterone, there continues to be understandable concern regarding the safety of testosterone replacement therapy (TRT) given the role the hormone plays in advanced PCa. The sordid past of testosterone began in 1941 when Charles Huggins demonstrated that metastatic PCa was activated by androgens and inhibited by their absence.7 In spite of the advances medicine has made since that time, it is still androgen deprivation that continues to provide men with advanced PCa the relief they seek from pain and other associated morbidities by promoting regression of metastatic disease.
Health care providers must question whether TRT does more harm than good for men who have definitively treated PCa who also suffer from hypogonadism. New theories regarding the biology of testosterone are continually evolving and informing the discussion. Morgentaler and Traish have introduced the hypothesis of the “saturation model” to explain seemingly disparate roles of testosterone in men’s overall health with respect to PCa.
They suggest that testosterone relies on an androgen receptor (AR) to exert biologic effects on PCa, and because of a finite number of ARs, it is possible to saturate the receptors. Any increase in testosterone above this level of saturation will not result in greater biologic effects. This model explains the exquisite sensitivity of advanced PCa to even small amounts of testosterone and provides a rationale for why castrate levels of testosterone are effective for androgen deprivation while increasing levels of testosterone above castrate levels seem to have a negligible effect on PCa growth.8 This theory also suggests that TRT in hypogonadal men will not exponentially fuel a smoldering cancer.
Given the surge of men diagnosed with PCa in the post-PSA era combined with the increasing incidence of men diagnosed with hypogonadism, the debate regarding the role of TRT is more salient than ever. Current guidelines clearly state that androgens are contraindicated in patients with known PCa.9 The evidence to support this position, however, is controversial.