Revisiting Testosterone and Prostate Cancer
By: Dan Sperling, MD
Each year in the U.S. over half a million men are diagnosed with Testosterone Deficiency Syndrome (TDS). For the most part, the onset of this occurs between the ages of 50 to 70. The symptoms of TDS include diminished sexual desire and performance, depressed mood, low energy or fatigue, reduced muscle mass, and diminished mental function. Diagnosis of TDS occurs through a blood test, as levels of total testosterone and free testosterone can only be confirmed in this manner. The remedy for TDS is testosterone replacement therapy, or TRT. However, for men at risk of prostate cancer (PCa), or men already diagnosed and/or treated for this disease, TRT has traditionally been discouraged.
The reason for withholding TRT from PCa patients was due to a long-held belief that was first articulated in 1941. The Nobel Prize winning work of Huggins and Hodges, in which they demonstrated that castrating men with metastatic PCa caused the disease to regress, led to the conclusion that prostate cancer is “fueled” by testosterone, similar to throwing kerosene on a fire. For decades since then, the standard of care for men with advanced prostate cancer has been to treat them either with hormone ablation (chemical castration) or removal of the testes (surgical castration). Needless to say, most of these patients experienced diminished quality of life as the symptoms of TDS hit. Today, this protocol is increasingly controversial.
A consistent spokesperson for the view that testosterone is not the culprit it’s made out to be is Abraham Morgentaler, MD, a Harvard urologist. Morgentaler’s first clue that something was amiss with the Huggins model came when he began biopsies on men with low blood testosterone (low T) to rule out PCa before putting them on TRT. To his surprise, he found that the 15% of low T patients who had PCa was virtually identical to that of men with normal T levels. In 2004, reviewing international literature, he found no evidence that men with high T levels had any greater risk of PCa. He asked himself how depriving metastatic PCa patients of testosterone would result in an observable setback for the disease. After delving into all published literature on the subject, he concluded that male hormones do affect prostate tissue, but that there is an absolute limit on the impact of testosterone based on the mechanism of androgen receptors in the prostate.
In 2007, published his saturation model which was consistent with the temporary regression of PCa during early androgen deprivation but which also called into scrutiny the belief that testosterone played a causal role in the disease. Since then, numerous studies by Morgentaler and others make a compelling case that administering TRT to PCa patients who are diagnosed with low T does not drive their disease. Three years ago, the Journal of Urology published a study showing that administering testosterone therapy to untreated prostate cancer patients who were low in testosterone had no growth effect on their cancer.[i] A group from Baylor College of Medicine recently published how TRT is being administered with increasing confidence to PCa patients with low T based on further research that affirms Morgentaler’s saturation model.[ii]
Contemporary publications offer compelling evidence to back up the good news about the safety and effectiveness of TRT for PCa patients. A July 2014 article in the respected British Journal of Urology International reported the effects of long-acting testosterone injections on 20 PCa patients who had been treated with brachytherapy (radioactive seed implants).[iii] They were not all low-risk patients; three had Gleason 3+4 and one had Gleason 4+4. Patients were followed for an average of 31 months, and there were no cases of rising PSA, disease progression, or recurrence. Summarizing this “new era” that demythologizes the poor clinical reputation of testosterone use, authors Khera et al state:
The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulate PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism [diagnosed TDS].[iv]
Finally, some researchers report the evidence that low levels of testosterone appear to be correlated with higher levels of aggression once prostate cancer develops. This would suggest a potential advantage of treating PCa patients who have diminishing testosterone levels with TRT as a measure of protection against aggressive disease. Morgentaler wrote an editorial in the journal Cancer in which he stated, “After seven decades of circumstantial evidence pointing us in the wrong direction, perhaps it is time to consider the once unthinkable – conducting a testosterone therapy trial of sufficient size and duration to determine whether normalization of serum testosterone in older men many reduce the risk of prostate cancer, particularly high-risk prostate cancer.”[v]
Such research can direct clinicians in prescribing TRT for PCa patients who have had a focal treatment and who also have less quality of life due to ebbing testosterone levels as they age.
[i] Morgentaler A, Lipshultz LI, Bennett R et al. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011 Apr;185(4):1256-60.
[ii] Kovac JR, Pan MM, Lipshultz LI, Lamb DJ. Current state of practice regarding testosterone supplementation therapy in men with prostate cancer. Steroids. 2014 Nov;89C:27-32. doi: 10.1016/j.steroids.2014.07.004. Epub 2014 Jul 27.
[iii] Balbontin FG, Moreno SA, Bley E, Chacon R et al. Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. BJU Int. 2014 Jul;114(1):125-30.
[iv] Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Cur Urol. 2014;65:115-123.
[v] Morgentaler, A. Turning conventional wisdom upside-down. Cancer. 2011 Sep 1;117(17):3885-8.