The Evidence as it Now Stands
For over sixty-five years, there has been a fear that testosterone therapy will cause new prostate cancers to arise or hidden ones to grow. Although no large-scale studies have yet been performed to provide a definitive verdict on the safety of testosterone therapy, it is quite remarkable to discover that the long-standing fear about testosterone and prostate cancer has little scientific support. The old concepts, taken as gospel, do not stand up to critical examination. I believe the best summary about the risk of prostate cancer from testosterone therapy, based on published evidence at the time this book is written, is as follows:
Low blood levels of testosterone do not protect against prostate cancer and, indeed, may increase the risk.
High blood levels of testosterone do not increase the risk of prostate cancer.
Treatment with testosterone does not increase the risk of prostate cancer, even among men who are already at high risk for it.
In men who do have metastatic prostate cancer and who have been given treatment that drops their blood levels of testosterone to near zero, starting treatment with testosterone (or stopping treatment that has lowered their testosterone to near zero) might increase the risk that residual cancer will again start to grow.
Prostate cancer with infiltration into bladder, lymph nodes, and urethra.
One of the most important and reassuring studies regarding testosterone and prostate cancer was an article published in the Journal of the National Cancer Institute in 2008, in which the authors of eighteen separate studies from around the world pooled their data regarding the likelihood of developing prostate cancer based on concentrations of various hormones, including testosterone. This enormous study included more than 3,000 men with prostate cancer and more than 6,000 men without prostate cancer, who served as controls in the study. No relationship was found between prostate cancer and any of the hormones studied, including total testosterone, free testosterone, or other minor androgens. In an accompanying editorial, Dr. Carpenter and colleagues from the University of North Carolina School of Public Health suggest scientists finally move beyond the long-believed but unsupported view that high testosterone is a risk for prostate cancer.
More and more physicians are coming around to recognize that testosterone therapy is not a true risk for prostate cancer, but it can take many years to alter established beliefs. Donít be surprised if your own doctor still raises this issue with you if you are considering testosterone therapy. If he objects to treating you for that reason, you should refer him to the article above, or one of the other review articles listed in the References at the back of this book. Even better, have him read this chapter!
Q. Iím fifty-three years old and Iíve been on testosterone therapy for two years, with good results. However, my father was diagnosed with prostate cancer at age seventy-five. Does this mean I need to stop testosterone?
A. There is a familial form of prostate cancer, but only in families in which prostate cancer occurs at age sixty-five or younger. Even in those families where a family member develops cancer at a young age, this does not necessarily mean that every other male in the family will develop cancer. Men with a family history of prostate cancer should be sure to have a yearly PSA and prostate exam. There is no need to discontinue testosterone treatment.
Q. My physician started me on testosterone, but I never had a prostate biopsy. I am sixty-four years old. Was this a mistake?
A. Because there is no evidence that testosterone treatment increases the risk of prostate cancer, it is fine to begin therapy as long as your PSA and DRE are normal. My own practice is to recommend prostate biopsy in men with low testosterone because our published data indicate there is an increased risk that cancer is already present in men with low testosterone, but this is by no means a standard recommendation yet among physicians.
Q. Why do you prostate biopsies on men with low testosterone if you donít feel that testosterone treatment will make a hidden cancer grow?
A. Because so many men with prostate cancer will not die from it, even without treatment, there is a fair amount of controversy over how aggressive to be in making the diagnosis. My perspective is that it is worth knowing the diagnosis, whether or not one chooses to be treated immediately. And because low testosterone seems to represent a small but definite increased risk, I feel that biopsy in men over fifty with low testosterone is worthwhile.
Q. A man in my bowling league was started on testosterone treatment and then developed prostate cancer one year later. Doesnít that show that testosterone is risky for prostate cancer?
A. If the wife of this man had switched to a new type of laundry detergent before the cancer was diagnosed, would we assume the cancer was caused by the detergent? Of course not. But we are predisposed to believe that testosterone therapy causes prostate cancer, so it is easy to hear a story like this and assume that testosterone therapy caused the cancer. Prostate cancer and testosterone therapy are both common in the United States, and both tend to occur in the same age range, so there will always be stories of men developing cancer some time after beginning testosterone therapy. If testosterone really made prostate cancers grow, then we should see high rates of cancer among men who start testosterone therapy. But we donít. Itís false logic.
Q. Isnít it true that all men would eventually get prostate cancer if they lived long enough? If so, why does it even matter if testosterone were to increase the risk of something that is inevitable anyway?
A. Men do get prostate cancer at an increasingly high rate as they age. And it is true that most men diagnosed with prostate cancer would never have a momentís trouble from it, even if it were left untreated, because most of these cancers grow so slowly that other medical conditions eventually become more troublesome. Yet for those with more aggressive forms of prostate cancer, the danger is very real. The challenge is to identify men at risk, because even high-grade prostate cancer is curable when caught early.
Q. It took more than thirty years for scientists to learn that hormones were dangerous for women and caused breast cancer. Isnít it possible weíll eventually find out the same is true for testosterone and prostate cancer?
Abraham Morgentaler, MD
A. The fear that hormone therapy is dangerous in women is currently being reevaluated, and it appears to not be as dangerous as was originally proclaimed. More to the point, it is critical to understand that men are not women and that testosterone is not estrogen. Anyone, particularly a scientist, must always allow for the possibility that new information will one day change current views. But after so much research over so many decades, there is little reason to believe that testosterone therapy poses a major risk for prostate cancer. As a medical student once said to me, ďIf testosterone is really so dangerous for prostate cancer, why is it so hard to show it?Ē
Abraham Morgentaler, MD, is an associate clinical professor of urology at Harvard Medical School, and is the founder of Menís Health Boston, a center focusing on sexual and reproductive health for men. He is the author of a number of popular books including The Male Body and The Viagra Myth.
Excerpted with permission from Testosterone for Life: Your Sex Drive, , Energy and Overall Health by Abraham Morgentaler, MD, FACS. Published by McGraw-Hill.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
Agarwal PK, Oefelein MG. Testosterone replacemen testosterone therapy after primary treatment for prostate cancer. J Urol. 2005 Feb;173(2):533-6.
Araujo AB, Kupelian V, Page ST, et al. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007;167:1252-60.
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.
Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997;82:407-13.
Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-81.
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.
Cherrier MM, Craft S, Matsumoto AH. Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. J Androl. 2003;24:568-76.
Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation- testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3469-78.
English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Circulation. 2000;102(16):1906-11.
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.
Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol. 2005 Feb;173(2):341.
Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metabol. 2001;86(2):724-31.
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: whatís 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.
Hwang TI, Chen HE, Tsai TF, Lin YC. Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone. Int J Impot Res. 2006;18:400-4.
Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004 Sep;172(3):920-2.
Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in non-obese men. J Clin Endocrinol Metab. 2006;91:843-50.
Lazarou S, Morgentaler A. Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. Curr Urol Rep. 2005;6:476-81.
Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide Variability in Laboratory Reference Values for Serum Testosterone. J Sex Med. 2006;3:1085-9.
Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod. 1999;61:1012-6.
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.
McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. Br J Urol. 2003;91:69-74.
Morgentaler A. The Viagra Myth: The Surprising Impact on Love and Relationships. San Francisco, CA: Jossey-Bass/Wiley, 2003.
Morgentaler A, Crews D. Role of the anterior hypothalamus-preoptic area in the regulation of reproductive behavior in the lizard, Anolis carolinensis: Implantation studies. Horm Behav. 1978;11:61.
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. Male Impotence. Lancet. 1999;354:1713-8.
Morgentaler A. Testosterone and the prostate: is there really a problem? Contemporary Urol. 2006;18:26-33.
Morgentaler A. Testosterone replacement therapy and prostate risks: whereís 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. Testosterone and Prostate Cancer: An Historical Perspective On A Modern Myth. Eur Urol. 2006;50:935-9.
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 and sexual function. Med Clin N Am. 2006;90:S32-4.
Morgentaler A. Cultural Biases and Scientific Squabbles: The Challenges to Acceptance of Testosterone Therapy As A Mainstream Medical Treatment. Aging Male. 2007;10:1-2.
Morgentaler A. Guideline for Male Testosterone Therapy: A Clinicianís Perspective. J Clin Endocrinol Metab. 2007;92:416-7.
Morgentaler A. Testosterone Deficiency and Prostate Cancer: Emerging Recognition of an Important and Troubling Relationship. Eur Urol. 2007;52:623-5.
Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin N Am. 2007;34:555-63.
Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, LH and FSH in healthy older men. Metabolism. 1997;46(4):410-3.
Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol. 2005;48:1-4.
Oh JY, Barrett-Connor E, We**** NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002;25:55-60.
Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:105-11.
Rhoden EL, Estrada C, Levine L, Morgentaler A. The value of pituitary magnetic resonance imaging in men with hypogonadism. =J Urol. 2003;170:795-8.
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. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res. 2004;16:95-7.
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.
Shores MM, Moceri VM, Gruenwals DA, et al. low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc. 2004;52:2077-81.
Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660-5.Tenover JL. Testosterone replacement therapy in older adult men. Int J Androl. 1999 Oct;22(5):300-6.
Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency. J Androl. 2005;26:242-8.
Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666-72.
The Institute of Medicine Report. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press, 2004.
Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Endocrinol Metab. 2000;85(8):2839-53.
Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med. 2001;111(4): 261-8.
Zvara P, Sioufi R, Schipper HM, Begin LR, Brock GB. Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model. Int J Impot Res. 1995;7:209-19.