Advertisement

Testosterone and Prostate Cancer: An Historical Perspective on a Modern Myth

      Abstract

      Objectives

      To review the historical origins and current evidence for the belief that testosterone (T) causes prostate cancer (pCA) growth.

      Methods

      Review of the historical literature regarding T administration and pCA, as well as more recent studies investigating the relationship of T and pCA.

      Results

      In 1941 Huggins and Hodges reported that marked reductions in T by castration or estrogen treatment caused metastatic pCA to regress, and administration of exogenous T caused pCA to grow. Remarkably, this latter conclusion was based on results from only one patient. Multiple subsequent reports revealed no pCA progression with T administration, and some men even experienced subjective improvement, such as resolution of bone pain. More recent data have shown no apparent increase in pCA rates in clinical trials of T supplementation in normal men or men at increased risk for pCA, no relationship of pCA risk with serum T levels in multiple longitudinal studies, and no reduced risk of pCA in men with low T. The apparent paradox in which castration causes pCA to regress yet higher T fails to cause pCA to grow is resolved by a saturation model, in which maximal stimulation of pCA is reached at relatively low levels of T.

      Conclusions

      This historical perspective reveals that there is not now—nor has there ever been—a scientific basis for the belief that T causes pCA to grow. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship of T and pCA that may be clinically and scientifically rewarding.

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to European Urology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Huggins C.
        • Hodges C.V.
        Studies on prostatic cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate.
        Cancer Res. 1941; 1: 293-297
      1. Kolata G. Male hormone therapy popular but untested. NY Times 2002.

      2. Physician’s desk reference.
        Thomson PDR, Montvale, NJ2005 (p. 3245)
        • Rhoden E.L.
        • Morgentaler A.
        Risks of testosterone-replacement therapy and recommendations for monitoring.
        N Engl J Med. 2004; 350: 482-492
        • Bhasin S.
        • Singh A.B.
        • Mac R.P.
        • Carter B.
        • Lee M.I.
        • Cunningham G.R.
        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
        • Barqawi A.B.
        • Crawford E.D.
        Testosterone replacement therapy and the risk of prostate cancer: a perspective view.
        Int J Impot Res. 2005; 17: 462-463
      3. Liverman C.T. Blazer D.G. Institute of Medicine report on: testosterone and aging. National Academies Press, Washington, DC2004
        • Sakr W.A.
        • Grignon D.J.
        • Crissman J.D.
        • et al.
        High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy study of 249 cases.
        In Vivo. 1994; 8: 439-443
        • Huggins C.
        Endocrine-induced regression of cancers.
        Cancer Res. 1967; 27: 1925-1930
        • Fowler J.E.
        • Whitmore Jr., W.F.
        The response of metastatic adenocarcinoma of the prostate to exogenous testosterone.
        J Urol. 1981; 126: 372-375
        • Brendler H.
        • Chase W.E.
        • Scott W.W.
        Prostatic cancer: further investigations of hormonal relationships.
        Arch Surg. 1950; 61: 433-440
        • Prout G.R.
        • Brewer W.R.
        Response of men with advanced prostatic carcinoma to exogenous administration of testosterone.
        Cancer. 1967; 20: 1871-1878
        • Pearson O.H.
        Discussion of Dr. Huggins’ paper “control of cancers of man by endocrinological methods”.
        Cancer Res. 1957; 17: 473-479
        • Bubley G.J.
        Is the flare phenomenon clinically significant?.
        Urology. 2001; 58: 5-9
        • Kuhn J.M.
        • Billebaud T.
        • Navratil H.
        • et al.
        Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (Buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (Nilutamide).
        N Engl J Med. 1989; 321: 413-418
        • Tomera K.
        • Gleason D.
        • Gittelman M.
        • et al.
        The gonadotropin-releasing hormone antagonist Abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.
        J Urol. 2001; 16: 1585-1589
        • Freeland S.J.
        • Partin A.W.
        Prostate-specific antigen: update 2006.
        Urology. 2006; 67: 458-460
        • Hsing A.W.
        Hormones and prostate cancer: what’s next?.
        Epidemiol Rev. 2001; 23: 42-58
        • Parsons J.K.
        • Carter H.B.
        • Platz E.A.
        • Wright E.J.
        • Landis P.
        • Metter E.J.
        Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy.
        Cancer Epidemiol Biomarkers Prev. 2005; 14: 2257-2260
        • Statin P.
        • Lumme S.
        • Tenkanen L.
        • et al.
        High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study.
        Int J Cancer. 2004; 108: 418-424
        • Chen C.
        • Weiss N.S.
        • Stanczyk F.Z.
        • et al.
        Endogenous sex hormones and prostate cancer risk: a case-control study nested within the Carotene and Retinol Efficacy Trial.
        Cancer Epidemiol Biomarkers Prev. 2003; 12: 1410-1416
        • Platz E.A.
        • Leitzmann M.F.
        • Rifai N.
        • et al.
        Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era.
        Cancer Epidemiol Biomarkers Prev. 2005; 14: 1262-1269
        • Barrett-Connor E.
        • Garland C.
        • McPhillips J.B.
        • Khaw K.T.
        • Wingard D.L.
        A prospective, population-based study of androstenedione, estrogens, and prostatic cancer.
        Cancer Res. 1990; 50: 169-173
        • Gann P.H.
        • Hennekens C.H.
        • Ma J.
        • Longcope C.
        • Stampfer M.J.
        Prospective study of sex hormone levels and risk of prostate cancer.
        J Natl Cancer Inst. 1996; 88: 1118-1126
        • Morgentaler A.
        • Bruning III, C.O.
        • DeWolf W.C.
        Incidence of occult prostate cancer among men with low total or free serum testosterone.
        JAMA. 1996; 276: 1904-1906
        • Thompson I.M.
        • Pauler D.K.
        • Goodman P.J.
        • et al.
        Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4 ng per milliliter.
        N Eng J Med. 2004; 350: 2239-2246
        • Lefkowitz G.K.
        • Taneja S.S.
        • Brown J.
        • Melamed J.
        • Lepor H.
        Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels.
        J Urol. 2002; 168: 1415-1418
        • Rhoden E.L.
        • 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: 2348-2351
        • Bhasin S.
        • Woodhouse L.
        • Casaburi R.
        • et al.
        Testosterone dose-response relationships in healthy young men.
        Am J Physiol Endocrinol Metab. 2001; 281: E1172-E1181
        • Cooper C.S.
        • Perry P.J.
        • Sparks A.E.T.
        • MacIndoe J.H.
        • Yates W.R.
        • Williams R.D.
        Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men.
        J Urol. 1998; 159: 441-443
        • Behre H.M.
        • Bohmeyer J.
        • Nieschlag E.
        Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls.
        Clin Endocrinol. 1994; 40: 341-349
        • Hoffman M.
        • DeWolf W.C.
        • Morgentaler A.
        Is low serum free testosterone a marker for high grade prostate cancer?.
        J Urol. 2000; 163: 824-827
        • Massengill J.C.
        • Sun L.
        • Moul J.W.
        • et al.
        Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy.
        J Urol. 2003; 169: 1670-1675
        • Ribeiro M.
        • Ruff P.
        • Falkson G.
        Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer.
        Am J Clin Oncol. 1997; 20: 605-608
        • Prehn R.T.
        On the prevention and therapy of prostate cancer by androgen administration.
        Cancer Res. 1999; 59: 4161-4164
        • Algarte-Genin M.
        • Cussenot O.
        • Costa P.
        Prevention of prostate cancer by androgens: experimental paradox or clinical reality.
        Eur Urol. 2004; 46: 285-295