There has been an increase in the number of individuals seeking testosterone (T) replacement treatment (TRT) due to a decrease in their blood T levels. Prostate cancer (PCa) is also an important issue in the same age group. However, we, urologists, are anxious about PCa development after T treatment. This is because it has been assumed that T may cause PCa or exacerbate insidious PCa which is already present. In this paper, recent developments regarding the relationship between serum levels of sex hormone and prostate tissue, the causal relationship between T and development of PCa, the effect of TRT on the group of patients who are at high risk of developing PCa, the suitability of TRT for patients who have already been diagnosed with PCa, and the effect of TRT on serum prostate-specific antigen level are analyzed. 1. Introduction According to the Bureau of Census of the United States, the population of men over the age of 65 that is 35 millions in year 2000 will reach 40, 54.6, and 70 millions by years 2010, 2020, and 2030, respectively [1, 2]. According to another study conducted in Germany, it is estimated that 1/3 of the population will be over 60 years and that 11% will be over 80 years of age by year 2050 [3]. Serum testosterone (T) level in men has been shown to be decreased significantly with aging in both cross-sectional and longitudinal studies [4–7]. Therefore, the number of patients needing T replacement treatment (TRT) due to a decrease in their T levels secondary to aging is increasing. Despite the accumulating knowledge on the effects of T, many still continue to carry a suspicion on the use of T. Until recently, regarding prostate cancer (PCa), TRT has been indisputably considered as adding fuel to the flames or feeding a hungry tumor [8]. It was scared that TRT will cause PCa or flare up occult PCa which stemmed from the studies of Huggins and Hodges in 1941 [9]. According to their work, PCa regressed when serum T levels had been reduced and progressed when exogenous T had been given. However, there has been no clear evidence reported since then that men receiving or with high T levels have had an increased risk of developing PCa [8, 10]. On the contrary, in a large prospective study investigating the correlation between high levels of circulating T and risk of PCa, higher levels were found to be related to reduced risk of PCa [11]. Additionally, there have been several contemporary reports stating that decreased serum T levels can be a marker for occult PCa [12]. PCa has a much more aggressive course regardless of disease stage in
References
[1]
W. He, M. Sengupta, V. A. Velkoff, K. A. DeBarros, and U. S. Census Bureau, Current Population Reports, U.S. Government Printing Office, Washington, DC, USA, 2005.
[2]
C. G. Roehrborn, “Current medical therapies for men with lower urinary tract symptoms and benign prostatic hyperplasia: achievements and limitations,” Review Urology, vol. 10, no. 1, pp. 14–25, 2008.
[3]
G. Schreiber and M. Ziemer, “The aging male—diagnosis and therapy of late-onset hypogonadism,” Journal der Deutschen Dermatologischen Gesellschaft, vol. 6, no. 4, pp. 273–279, 2008.
[4]
A. Gray, H. A. Feldman, J. B. McKinlay, and C. Longcope, “Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study,” Journal of Clinical Endocrinology and Metabolism, vol. 73, no. 5, pp. 1016–1025, 1991.
[5]
S. M. Harman, E. J. Metter, J. D. Tobin, J. Pearson, and M. R. Blackman, “Longitudinal effects of aging on serum total and free testosterone levels in healthy men,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 724–731, 2001.
[6]
A. B. Araujo, G. R. Esche, V. Kupelian et al., “Prevalence of symptomatic androgen deficiency in men,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 11, pp. 4241–4247, 2007.
[7]
F. C. W. Wu, A. Tajar, S. R. Pye et al., “Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European male aging study,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 7, pp. 2737–2745, 2008.
[8]
A. Morgentaler, “Testosterone replacement therapy and prostate cancer,” Urologic Clinics of North America, vol. 34, no. 4, pp. 555–563, 2007.
[9]
C. Huggins and C. V. Hodges, “Studies on PCa I. The effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate,” Cancer Research, vol. 1, no. 4, pp. 293–297, 1941.
[10]
M. Khera, “Androgen replacement therapy after prostate cancer treatment,” Current Urology Reports, vol. 11, no. 6, pp. 393–399, 2010.
[11]
P. Stattin, S. Lumme, L. Tenkanen et al., “High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study,” International Journal of Cancer, vol. 108, no. 3, pp. 418–424, 2004.
[12]
A. Morgentaler, C. O. Bruning III, and W. C. DeWolf, “Occult prostate cancer in men with low serum testosterone levels,” Journal of the American Medical Association, vol. 276, no. 23, pp. 1904–1906, 1996.
[13]
M. A. Hoffman, W. C. DeWolf, and A. Morgentaler, “Is low serum free testosterone a marker for high grade prostate cancer?” Journal of Urology, vol. 163, no. 3, pp. 824–827, 2000.
[14]
J. C. Massengill, L. Sun, J. W. Moul et al., “Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy,” Journal of Urology, vol. 169, no. 5, pp. 1670–1675, 2003.
[15]
M. Ribeiro, P. Ruff, and G. Falkson, “Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer,” American Journal of Clinical Oncology, vol. 20, no. 6, pp. 605–608, 1997.
[16]
S. S. Chen, K.-K. Chen, A. T. L. Lin, Y.-H. Chang, H. H. Wu, and L. S. Chang, “The correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis,” BJU International, vol. 89, no. 7, pp. 710–713, 2002.
[17]
S. Yamamoto, J. Yonese, S. Kawakami et al., “Preoperative Serum Testosterone Level as an Independent Predictor of Treatment Failure following Radical Prostatectomy{A figure is presented},” European Urology, vol. 52, no. 3, pp. 696–701, 2007.
[18]
L. Mearini, E. Costantini, A. Zucchi et al., “Testosterone levels in benign prostatic hypertrophy and prostate cancer,” Urologia Internationalis, vol. 80, no. 2, pp. 134–140, 2008.
[19]
P. J. Snyder, H. Peachey, J. A. Berlin et al., “Effects of testosterone replacement in hypogonadal men,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 8, pp. 2670–2677, 2000.
[20]
C. Wang, G. Cunningham, A. Dobs et al., “Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 5, pp. 2085–2098, 2004.
[21]
A. T. Guay and J. Jacobson, “The relationship between testosterone levels, the metabolic syndrome (by two criteria), and insulin resistance in a population of men with organic erectile dysfunction,” Journal of Sexual Medicine, vol. 4, no. 4, pp. 1046–1055, 2007.
[22]
A. Morales, A. M. Black, and L. E. Emerson, “Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations,” BJU International, vol. 103, no. 1, pp. 62–64, 2009.
[23]
C. Wang, E. Nieschlag, R. Swerdloff et al., “Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations,” European Urology, vol. 55, no. 1, pp. 121–130, 2009.
[24]
S. M. Ho, D. Damassa, P. W. Kwan, H. S. Seto, and I. Leav, “Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated Noble rats,” Journal of Andrology, vol. 6, no. 5, pp. 279–290, 1985.
[25]
A. M. Traish, D. F. Williams, N. D. Hoffman, and H. H. Wotiz, “Validation of the exchange assay for the measurement of androgen receptors in human and dog prostates,” Progress in Clinical and Biological Research, vol. 262, pp. 145–160, 1988.
[26]
L. S. Marks, N. A. Mazer, E. Mostaghel et al., “Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial,” Journal of the American Medical Association, vol. 296, no. 19, pp. 2351–2361, 2006.
[27]
P. H. Gann, C. H. Hennekens, J. Ma, C. Longcope, and M. J. Stampfer, “Prospective study of sex hormone levels and risk of prostate cancer,” Journal of the National Cancer Institute, vol. 88, no. 16, pp. 1118–1126, 1996.
[28]
J. K. Parsons, H. B. Carter, E. A. Platz, E. J. Wright, P. Landis, and E. J. Metter, “Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 9, pp. 2257–2260, 2005.
[29]
A. Morgentaler and E. L. Rhoden, “Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less,” Urology, vol. 68, no. 6, pp. 1263–1267, 2006.
[30]
I. M. Thompson, D. K. Pauler, P. J. Goodman et al., “Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter,” The New England Journal of Medicine, vol. 350, no. 22, pp. 2239–2321, 2004.
[31]
A. W. Roddam, N. E. Allen, P. Appleby, and T. J. Key, “Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies,” Journal of the National Cancer Institute, vol. 100, no. 3, pp. 170–183, 2008.
[32]
K. R. Loughlin and J. P. Richie, “Prostate cancer after exogenous testosterone treatment for impotence,” Journal of Urology, vol. 157, no. 5, article 1845, 1997.
[33]
F. D. Gaylis, D. W. Lin, J. M. Ignatoff, C. L. Amling, R. F. Tutrone, and D. J. Cosgrove, “Prostate cancer in men using testosterone supplementation,” Journal of Urology, vol. 174, no. 2, pp. 534–538, 2005.
[34]
L. J. G. Gooren, “A ten-year safety study of the oral androgen testosterone undecanoate,” Journal of Andrology, vol. 15, no. 3, pp. 212–215, 1994.
[35]
C. S. Cooper, J. H. MacIndoe, P. J. Perry, W. R. Yates, and R. D. Williams, “The effect of exogenous testosterone on total and free prostate specific antigen levels in healthy young men,” The Journal of Urology, vol. 156, no. 2, pp. 438–442, 1996.
[36]
A. T. Guay, J. B. Perez, W. A. Fitaihi, and M. Vereb, “Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer,” Endocrine Practice, vol. 6, no. 2, pp. 132–138, 2000.
[37]
R. E. Gerstenbluth, P. N. Maniam, E. W. Corty, and A. D. Seftel, “Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement,” Journal of Andrology, vol. 23, no. 6, pp. 922–926, 2002.
[38]
E. L. Rhoden and A. Morgentaler, “Risks of testosterone-replacement therapy and recommendations for monitoring,” The New England Journal of Medicine, vol. 350, no. 5, pp. 482–492, 2004.
[39]
O. M. Calof, A. B. Singh, M. L. Lee et al., “Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials,” Journals of Gerontology A, vol. 60, no. 11, pp. 1451–1457, 2005.
[40]
D. McLaren, D. R. Siemens, J. Izard, A. Black, and A. Morales, “Clinical practice experience with testosterone treatment in men with testosterone deficiency syndrome,” BJU International, vol. 102, no. 9, pp. 1142–1146, 2008.
[41]
R. Shabsigh, E. D. Crawford, A. Nehra, and K. M. Slawin, “Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review,” International Journal of Impotence Research, vol. 21, no. 1, pp. 9–23, 2009.
[42]
M. R. Feneley and M. Carruthers, “Is testosterone treatment good for the prostate? Study of safety during long-term treatment,” The Journal of Sexual Medicine, vol. 9, no. 8, pp. 2138–2149, 2012.
[43]
H. Isbarn, J. H. Pinthus, L. S. Marks et al., “Testosterone and prostate cancer: revisiting old paradigms,” European Urology, vol. 56, no. 1, pp. 48–56, 2009.
[44]
E. L. Rhoden and A. Morgentaler, “Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia,” Journal of Urology, vol. 170, no. 6, pp. 2348–2351, 2003.
[45]
G. K. Lefkowitz, S. S. Taneja, J. Brown, J. Melamed, and H. Lepor, “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,” Journal of Urology, vol. 168, no. 4, pp. 1415–1418, 2002.
[46]
A. Morgentaler, “Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer,” Journal of Sexual Medicine, vol. 6, no. 2, pp. 574–577, 2009.
[47]
A. Morgentaler, L. I. Lipshultz, R. Bennett, M. Sweeney, D. Avila Jr., and M. Khera, “Testosterone therapy in men with untreated prostate cancer,” Journal of Urology, vol. 185, no. 4, pp. 1256–1260, 2011.
[48]
A. Morales, “Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry,” BJU International, vol. 107, no. 9, pp. 1369–1373, 2011.
[49]
S. Bhasin, G. R. Cunningham, F. J. Hayes et al., “Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2536–2559, 2010.
[50]
J. M. Kaufman and R. J. Graydon, “Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men,” Journal of Urology, vol. 172, no. 3, pp. 920–922, 2004.
[51]
P. K. Agarwal and M. G. Oefelein, “Testosterone replacement therapy after primary treatment for prostate cancer,” Journal of Urology, vol. 173, no. 2, pp. 533–536, 2005.
[52]
J. Mulhall, L. Goldenberg, J. Narus, G. Gotto, R. Tal, and O. Nabulsi, “Outcomes of testosterone supplementation in hypogonadal men following radical prostatectomy,” The Journal of Urology, vol. 179, no. 4, pp. 426–427, 2008.
[53]
M. Khera, E. D. Grober, B. Najari et al., “Testosterone replacement therapy following radical prostatectomy,” Journal of Sexual Medicine, vol. 6, no. 4, pp. 1165–1170, 2009.
[54]
H. Isbarn, M. Fisch, H. Huland, M. Graefen, and F. Sommer, “Testosterone treatment after radical prostatectomy for pathologically organ-confined prostate cancer: results from a multiinstitutional study,” The Journal of Urology, vol. 183, no. 4, pp. 576–577, 2010.
[55]
A. W. Pastuszak, A. M. Pearlman, W. S. Lai et al., “Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy,” The Journal of Urology, vol. 190, no. 2, pp. 639–644, 2013.
[56]
R. L. Leibowitz, T. B. Dorff, S. Tucker, J. Symanowski, and N. J. Vogelzang, “Testosterone replacement in prostate cancer survivors with hypogonadal symptoms,” BJU International, vol. 105, no. 10, pp. 1397–1401, 2010.
[57]
M. F. Sarosdy, “Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy,” Cancer, vol. 109, no. 3, pp. 536–541, 2007.
[58]
H. H. Davila, C. N. Arison, M. K. Hall, R. Salup, J. L. Lockhart, and R. E. Carrion, “Analysis of the PSA response after testosterone supplementation in patients who have previously received management for their localized prostate cancer,” The Journal of Urology, Supplement, vol. 179, 428, abstract 1247, 2008.
[59]
A. W. Pastuszak, A. M. Pearlman, G. Godoy, B. J. Miles, L. I. Lipshultz, and M. Khera, “Testosterone replacement therapy in the setting of prostate cancer treated with radiation,” International Journal of Impotence Research, vol. 25, no. 1, pp. 24–28, 2013.
[60]
G. Dohle, S. Arver, C. Bettocchi, et al., “Members of the EAU guidelines office. guidelines on male hypogonadism,” in Proceedings of the 27th EAU Annual Congress, EAU Guidelines, Paris, France, 2012.
[61]
A. Morgentaler and A. M. Traish, “Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth,” European Urology, vol. 55, no. 2, pp. 310–321, 2009.
[62]
C. S. Cooper, P. J. Perry, A. E. T. Sparks, J. H. MacIndoe, W. R. Yates, and R. D. Williams, “Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men,” Journal of Urology, vol. 159, no. 2, pp. 441–443, 1998.
[63]
S. Bhasin, T. W. Storer, N. Berman et al., “The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men,” The New England Journal of Medicine, vol. 335, no. 1, pp. 1–7, 1996.
[64]
M. Ramsay and P. Schlegel, AUA Updates Series Vol 29, Lesson 32, 2010.
[65]
K. L. Greene, P. C. Albertsen, R. J. Babaian et al., “Prostate specific antigen best practice statement: 2009 update,” Journal of Urology, vol. 182, no. 5, pp. 2232–2241, 2009.
