The search for the male fountain of youth dates back to 1849 through the experiments of Arnold Berthold where he castrated roosters, and subsequently implanting the testes back to the animals where he noticed physiologic and behavioral changes connected to a substance secreted by the testes. Later on in France, Dr. Charles E. Brown-Séquard, a Harvard professor, presented on his experience injecting himself with testicular extracts derived from dogs and guinea pigs causing an increase in physical strength, mental abilities, and appetite. Finally, Adolf Butenandt and Leopold Ruzicka were awarded the Nobel Prize in Chemistry in synthesizing the testicular hormone named Testosterone (T). (1)
Currently, T therapy is a $2 billion industry as men seek for longevity and vitality. (2) The concern, of course, is when is T therapy a problem? More specifically, does T fuel prostate cancer?
The Relationship between Testosterone and Prostate Cancer (CaP)
Until less than ten years ago it was believed that high endogenous Testosterone (T) led to an increased risk of prostate cancer (CaP) – and treating prostate cancer patients with exogenous T was heretical. In the middle of the 20th century, it was thought that T is the fuel that lit up malignancies in the prostate.
The stark connection that T propelled prostate cancer began in the early 1940’s with Dr. Charles Huggins, a Chicago University urologist and a noble prize winner for his work in demonstrating that prostate cancer growth is dependent on the serum T level. He and his research team observed that dogs with enlarged prostates, or clinically known as benign prostatic hyperplasia (BPH) had their gland shrink after being castrated by surgical removal of the testicles. Huggins and his research team further noticed that when suspicious, cancerous cells appeared in the canine prostates, not only did the prostate shrink after castration but so did suspicious malignant lesions.
The logical sequence for Dr. Huggins is to study the castrating effect in men who had advanced prostate cancer. These men either had their testicles removed or were given estrogen while having the anti-androgenic treatment effects measured by serum acid phosphatase. Huggins and his coworkers showed that acid phosphatase dropped substantially within days of lowering T in men with prostate cancer, therefore, concluding that high T enhanced prostate cancer growth and reducing T eliminated it. (3)
Finally, there was a viable treatment for prostate cancer in Androgen Deprivation Therapy, it was thought, a disease with almost no cure at the time. From that point forward, lowering T to negligible levels was the standard treatment for prostate malignancies and it is still used today for advanced cases.
Is Testosterone Really the Fuel for Prostate Cancer (CaP)
In test tubes, testosterone demonstrates an increase in prostate cancer in numerous cancer cell lines but apoptosis (programmed cancer cell death) once androgens are removed. (4) A similar response is found in rat studies: androgens promote tumor progression until androgens are withdrawn – then causing regression of prostate tumor cells. (5)
A meta-analysis of three prospective studies controlling for testosterone, estradiol, Sex Hormone Binding Globulin (SHBG), age and body mass index (BMI) demonstrated an increase in CaP for men in the highest levels of serum testosterone but no association with DHT or estradiol. (6)
So far, you’d think that T is a huge no – no for CaP but when one looks at more recent and robust studies the exact opposite might be true.
A meta-analysis called the Endogenous Hormones and Prostate Cancer Collaborative Group included 3886 men diagnosed with CaP and 6438 controls. The results demonstrated no direct association between endogenous serum androgens and the development of prostate cancer. (7)
Another, well-designed human clinical trial looked at 3255 men in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial, also known as the REDUCE trial. Prostate biopsies done at 2 and 4 years revealed (After prostate biopsies at 2 to 4 years men), no relationship between testosterone or dihydrotestosterone (DHT) levels and prostate cancer risk. (8)
Here is the crux of the story; not only is there no causal relationship with high endogenous T and CaP but low T may cause the disease.
One such clinical trial demonstrated a high incidence rate of aggressive, more deadly type of CaP among men with low T defined as >7.6nmo/l (220ng/d). (9)
Similarly, a group of Chinese men, 110 total, showed greater high-grade CaP (higher Gleason score) in men with low T. (10)
Beyond analyzing staging with Gleason grade on biopsy, a high-risk disease has been was associated with low T after prostatectomy.
For example, in 673 men undergoing prostatectomy had their morning T levels taken with surgical pathology outcomes and observed a significant risk of advanced disease that included seminal vesicle invasion in severely hypogonadal men. (11)
Can Men be Treated with Testosterone after Prostate Cancer (CaP) Diagnosis?
Until recently, the idea of treating hypogonadal men with T after CaP diagnosis was even more dissentient. However, during the 21st century, significant advances have been made in this arena where the appropriate CaP patient can too improve their quality of life with T therapy without major risk.
Medicare data (SEER) looking at 1181 men who received T therapy after a diagnosis with CaP demonstrated no cancer-specific or overall mortality from increasing T levels exogenously. (13)
Another study reported no increase in CaP recurrence in 103 men treated with T therapy after cancer-related prostatectomy, although an overall increase in serum PSA was revealed over 36 months. (14) Finally, investigators evaluated CaP progression and biochemical recurrence in patients after undergoing multiple treatments including radiation therapy, radical prostatectomy, or cryotherapy, as well as those on an active surveillance (AS) regimen. All patients had a slight increase in serum PSA levels; however, not all men experienced biochemical recurrence or progression. Interestingly, no progression of disease in the AS group was observed on subsequent biopsy samples, and no biochemical recurrence occurred in men who received radical prostatectomy, which shows that despite exposure to exogenous testosterone, no pathological progression had taken place on subsequent biopsy sampling. Also, men in the radiotherapy group had a biochemical recurrence rate of 6%, but whether this recurrence was natural disease behavior or an effect of therapy is unclear: the authors cite a 23% biochemical recurrence rate in patients who received radiotherapy in the largest known (15).
My Take on the Testosterone / Prostate Cancer (CaP) Connection
Carefully treating selected hypogonadal men with T therapy is a viable approach in those experiencing associated symptoms that include: low energy, low libido and lack of luster along with low serum T levels, without fear of stimulating prostate cancer growth or progression. Close monitoring of men on T therapy is crucial to the patient’s success, especially after prostate cancer diagnosis. For example, one study saw an increase in CaP progression in patients with extremely high serum T levels after exogenous treatment. (16) Lastly, an explanation of why the prostate grows and PSA elevates in a high T natural environment is explained by Abraham Morgentaler, MD who has been pivotal in debunking long-held theories suggesting testosterone treatment could lead to the promotion of prostate cancer. Dr. Morgantaler argues that a “saturation model” accounts for the critical observation that prostate tissue is exquisitely sensitive to changes in serum testosterone at low concentrations, but becomes indifferent to these changes at higher levels. Exposure to increasing concentrations of androgens causes prostate tissue growth, but this growth rate plateaus when the concentration reaches a limit. In other words, there is a threshold (saturation point) beyond which there is no further ability to induce androgen-driven changes in prostate tissue growth. (17) Thus, this offers an explanation why dramatic PSA changes are noted when serum testosterone is manipulated into or out of the castration range, but minimal PSA changes occur when high testosterone doses are administered to normal men.
- Morales A.: The long and tortuous history of the discovery of testosterone and its clinical application. J Sex Med 2013; 10: pp. 1178-1183
- Von Drehle, David; “Manopause; Aging, Insecurity and the $2 billion industry.” Time Magazine, August 18, 2014.
- Huggins C, Hodges CV; Studies on prostatic cancer: I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941.J Urol. 2002 Jul; 168(1):9-12.
- Schwab T., Stewart T., Lehr J., Pienta K., Rhim J., Macoska J. (2000) Phenotypic characterization of immortalized normal and primary tumor-derived human prostate epithelial cell cultures. Prostate 44: 164–171.
- Ahmad I., Sansom O., Leung H. (2008) Advances in mouse models of prostate cancer. Expert Rev Mol Med 10: e16.
- Shaneyfelt T., Husein R., Bubley G., Mantzoros C. (2000) Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol 18: 847.
- Roddam A.W., Allen N.E., Appleby P., et al: Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008; 100: pp. 170-183
- Muller R., Gerber L., Moreira D., Andriole G., Castro-Santamaria R., Freedland S. (2012) Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol 62: 757–764.
- Lane B., Stephenson A., Magi-Galluzzi C., Lakin M., Klein E. (2008) Low testosterone and risk of biochemical recurrence and poorly differentiated prostate cancer at radical prostatectomy. Urology 72: 1240–1245.
- Dai B., Qu Y., Kong Y., Ye D., Yao X., Zhang S., et al. (2012) Low pretreatment serum total testosterone is associated with a high incidence of Gleason score 8–10 disease in prostatectomy specimens: data from ethnic Chinese patients with localized prostate cancer. BJU Int 110: E667–E672.
- Salonia A., Gallina A., Briganti A., Abdollah F., Suardi N., Capitanio U., et al. (2010) Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy. Cancer 117: 3953–3962.
- Massengill J., Sun L., Moul J., Wu H., Mcleod D., Amling C., et al. (2003) Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 169: 1670–1675.
- Kaplan A., Trinh Q., Sun M., Carter S., Nguyen P., Shih Y., et al. (2014) Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. J Sex Med 11: 1063–1070.
- Pastuszak A., Pearlman A., Lai W., Godoy G., Sathyamoorthy K., Liu J., et al. (2013) Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol 190: 639–644.
- Ory, J. et al. Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. J. Urol. http://dx.doi.org.ezproxy.med.nyu.edu/10.1016/j.juro.2016.04.069 (2016).
- Leibowitz R., Dorff T., Tucker S., Symanowski J., Vogelzang N. (2010) Testosterone replacement in prostate cancer survivors with hypogonadal symptoms. BJU Int 105: 1397–1401.
- Morgentaler A., and Traish A.M.: Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009; 55