For decades, medical science has incorrectly theorized and functioned under the idea that testosterone replacement therapy (TRT – treatments for low testosterone) increases one’s risk of cancer, and more specifically prostate cancer.  Several researchers, spearheaded by the work of Doctor Abraham Morgentaler, MD, FACS, have demonstrated this theory to be incorrect.  Furthermore, said researchers have clearly shown the opposite correlation (relationship) to be true, namely that low testosterone levels increase the risk of prostate cancer.  This truth has been especially visible with aging men.  However, as with most paradigm shifts (broad changes in thinking), the conversion in thought has been a slow one.

Background on Low Testosterone Treatment and Prostate Cancer

Until recently, the past few years, it was generally believed that testosterone replacement therapy led to some degree of increased risk of prostate cancer.  During that time TRT represented a seemingly unfair trade off of short-term sexual and physical rewards for a greater chance of developing cancer.  This belief has been proven false, and slowly but surely medical opinion has begun to shift in light of solid evidence that testosterone replacement therapy is safe for the prostate.

Actually, the origin of how this fear originally came about was quite valid and involved a couple of Nobel Prize winners, several medical breakthroughs, and a critical mystery that took nearly 65 years to solve.  Nevertheless, the relationship of prostate cancer to testosterone has undergone a significant reevaluation.  The foundation for this myth began with the work of urologist Charles B. Huggins at the University of Chicago where Huggins expressed interest in the medical condition called benign enlargement of the prostate, which he later called benign prostatic hyperplasia (BPH) – a condition that causes frequent and urgent urination and which may occasionally cause a complete blockage of the urine passageway.  On a side note, the celebrated American forefather, politician, inventor, and scientist Benjamin Franklin was reported to have suffered from BPH, and is actually credited with inventing a catheter-like tube which he inserted up through his urethra (urinary canal) to relieve the obstruction.  Around the turn of the twentieth century there were reports that castration (the removal of the testicles) had been successful in the treatment of men with severe obstruction from BPH, and it was at this time that Huggins began experimenting on the effects of castration on BPH in dogs, the only other species besides human beings known to naturally develop prostate problems on a regular basis.  Although he was successful in shrinking dog prostates with castration, Huggins’ additional observations proved far much more groundbreaking.

In short, he found cancerous prostates in a number of his castrated dogs, and noticed that when their prostates were removed, the dogs had no further evidence of the cancerous-appearing (as described in the original Huggins research literature) areas.  By this time, it was a rather well known fact that the key effect of castration was to reduce testosterone levels in the bloodstream.  Huggins, applying what he’d learned from his dog studies, took a group of men all of whom had prostate cancer (which had already spread to their bones) and lowered their testosterone levels through the administration of estrogen or by via castration.  Based on his early preliminary work, Huggins and his coworkers concluded that reducing testosterone levels caused prostate cancer to shrink, and that raising testosterone levels caused “enhanced growth” of prostate cancer.  Later on, in 1966 Huggins was awarded the Nobel Prize for his work showing that prostate cancer shrank or grew depending on testosterone levels.  Until recently, this early research regarding prostate cancer and testosterone had not been seriously questioned.  Ironically, the shift in medicine’s understanding of the relationship between testosterone and prostate cancer has even led to a growing concern that low testosterone (rather than increasing it through TRT) puts one at risk for prostate cancer.

A Change in Understanding Low Testosterone Treatment and Prostate Cancer

According to Dr. Morgentaler, by the time he began practicing in the early 80’s the prevailing theories were so ingrained that he and his fellow residents learned to repeat the comments of their instructors to their patients.  Their common examples when discussing this was that the relationship of testosterone to prostate cancer was like “pouring gasoline on a fire” or providing “food for a hungry tumor”, and he says that these phrases are still in use throughout the medical world today.  However, it was his groundbreaking discovery as the numbers of low testosterone possessing men whom he’d biopsied (tested for cancer) who tested positive for cancer continued to climb.  Although Dr. Morgentaler’s findings were counter to what had always been believed, and even though many ignored his research, most experts just didn’t know what to make of such clearly staggering study results.  By 1996, the 14% cancer rate previously reported by Dr. Morgentaler and his staff was several times greater in men with normal PSA (4.0 ng/mL or less).  Numerous studies had reported biopsy results in men with normal PSA with cancer rates of 0 percent or 2 percent, with the highest value reported being 4.5 percent.

Next came a bunch of studies that pushed the truth even further out of the proverbial bag.  Scientists found that men with low testosterone did not seem to be protected against developing cancer as had been previously thought.  This coupled with the other extreme, the finding that men at high risk for prostate cancer did not seem to suffer any dramatic “explosion” of cancer when treated for a year with testosterone therapy changed everything.  Studies broke out all over the place, and it was discovered that the natural progression of prostate cancer, it never (or very rarely) occurred in men who were in their twenties when testosterone levels are at their lifetime peak.  Even autopsy studies have shown that a significant percentage of these young men already harbor microscopic prostate cancers.  Instead, prostate cancer becomes increasingly common as men age, when testosterone levels have declined.

By 2004 there were fifteen longitudinal studies examining the relationship of hormones and prostate cancer.  Since 2004, there have been approximately a half-dozen more.  Not one has shown any direct relationship between the level of total testosterone in a man’s blood and the subsequent likelihood that he will develop prostate cancer.  Specifically, average total testosterone levels were not higher in the cancer group compared to men without cancer, and men with the highest testosterone levels were at no greater risk for later developing prostate cancer than men with the lowest testosterone levels.

What is rapidly becoming accepted as a new truth, that TRT does not cause prostate cancer and that low testosterone increases one’s risk of prostate cancer, has been supported by the studies from an incredible number of researchers working on the same topic from various angles some of which include:

• Agarwal PK, Oefelein MG. Testosterone replacement testosterone therapy after primary treatment for prostate cancer. J Urol. 2005 Feb;173(2):533-6.
• Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J Androl. 2003;24:299-311.
• Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. 1995;27(1):25-31.
• Gann PH, Hennekens CH, Ma J, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88(16): 1118-26.
• Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol. 2000;163: 824-7.
• Hsing AW. Hormones and prostate cancer: what’s next? Epidemiologic Rev. 2001;23(1):42-58.
• Huggins CB, Stevens RB, Hodges CV. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209.
• Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004 Sep;172(3):920-2.
• Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296:2351-61.
• Morgentaler A, Bruning CO, III, DeWolf WC. Incidence of occult prostate cancer among men with low total or free serum testosterone. JAMA. 1996;276:1904-6.
• Morgentaler A. Testosterone replacement therapy and prostate risks: where’s the beef? Can J Urol. 2006;13:S40-3.
• Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treatment Options Oncol. 2006;7:363-9.
• Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen of 4.0 ng/ml or less. Urology. 2006;68:1263-7.
• Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin N Am. 2007;34:555-63.
• Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol. 2003;170:2348-51.
• Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res. 2006;18:201-5.Shabsigh R. Testosterone therapy in erectile dysfunction. Aging Male. 2004;7:312-8. 

Prostate Cancer Treatment Followed by Low Testosterone Treatment

The use of TRT in men following treatment for prostate cancer usually coincides with one of the three primary prostate cancer treatments:  radical prostatectomy (RP); external beam radiation therapy (EBRT); and brachytherapy (BT).  Many physicians, clinicians, and investigators still contend that a history of prostate cancer should be considered an absolute TRT contraindication – something (as a symptom or condition) that makes a particular treatment or procedure inadvisable.  Some testosterone products contain package inserts that state that testosterone is contraindicated in men who have a history of prostate cancer and/or in men suspected of having prostate cancer, and many urologists are hesitant to prescribe TRT in patients who have had RP.

Several different studies have evaluated this concern by investigating TRT use in men after RP, the majority of which seem to show that TRT improves the symptoms of hypogonadism and increases circulating testosterone levels without any suggestion of an increased risk of recurrence or persistence of prostate cancer.  Such studies include: Agarwal and Oefelein’s ‘Testosterone replacement therapy after primary treatment for prostate cancer’ from the Journal of Urology in 2005; Kaufman and Graydon’s ‘Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men’ from the Journal of Urology 2004; and M. Khera, et al’s ‘Testosterone replacement therapy following radical prostatectomy’ in the Journal of Sexual Medicine in 2009.  Approximately one and half percent (1.4%) of the 74 subjects reported in these studies had biochemical recurrence of prostate cancer.  This singular patient had a Gleason score of 8, a known risk factor for biochemical recurrence after what is called ‘definitive therapy’ – a specific treatment for the resolution of prostate cancer such as radical prostatectomy, external beam radiation therapy, or brachytherapy.  In patients with a high risk of recurrence, androgen deprivation has been previously demonstrated to improve survival rates such as in the 2010 Journal Clinical Oncology study by PW Kantoff, et al entitled, ‘Overall survival analysis of a phase ii randomized controlled trial of a poxviral-based psa-targeted immunotherapy in metastatic castration-resistant prostate cancer’.  Numerous no less substantial studies with a smaller number of subjects have been conducted on men receiving TRT after definitive therapy with either BT or EBRT such as the 2007 study in Cancer by MF Sarosdy entitled, ‘Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy’, and the 2009 British Journal of Urology study by Morales and Black entitled, ‘Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: Preliminary observations’, respectively.  In both of these studies researchers Morales and Black came to the same conclusion, namely that TRT was a safe follow up to the respective definitive prostate cancer treatments.  No recent and carefully designed studies, indicate a clear relationship between testosterone replacement and a higher risk of incident prostate cancer, thus there is no substantial evidence currently linking increased prostate cancer risk to short-term testosterone replacement in the treatment of hypogonadism.