- Email: [email protected]
Reply from Authors re: Andrea Salonia. Androgens and Prostate Cancer: We Are Still (Almost) Completely Ignorant. Eur Urol 2014;65:690–1
EUROPEAN UROLOGY 65 (2014) 690–692
Another issue to ponder is that Gershman and coworkers [5] highlighted that their null results would suggest that reverse causation may be responsible for previous observations of adverse outcomes in men with low circulating androgens [6–8], which, however, were assayed when disease were already diagnosed. Once again, timing is important, in particular, the temporal aspect of the relationship between hormones and cells and tissues of the prostate. As adequately emphasized by Gershman and co-workers [5], considering only one single hormonal assessment inevitably neglects the true endocrine biology of prostate tissue, which is dependent on the exposure time at a given concentration of sex steroid during the lifespan of the individual. This paper implies that the road is still very long—unfortunately and fortunately, at the same time! Conflicts of interest: The author has nothing to disclose.
691
[2] Endogenous Hormones and Prostate Cancer Collaborative Group. Roddam AW, Allen NE, Appleby P, Key TJ, et al. Endogenous sex hormones and prostate cancer: a col laborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170–83. [3] Imamoto T, Suzuki H, Fukasawa S, et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 2005;47:308–12. [4] Salonia A, Abdollah F, Capitanio U, et al. Circulating sex steroids and prostate cancer: introducing the time-dependency theory. World J Urol 2013;31:267–73. [5] Gershman B, Shui IM, Stampfer M, et al. Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer. Eur Urol 2014;65:683–9. [6] Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009;55:310–21. [7] San Francisco IF, Regan MM, Dewolf WC, Olumi AF. Low age adjusted free testosterone levels correlate with poorly differentiated prostate cancer. J Urol 2006;175:1341–5. [8] Rhoden EL, Riedner CL, Morgentaler A. The ratio of serum testos-
References [1] Isbarn H, Pinthus JH, Marks LS, et al. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol 2009;56:48–56.
terone to prostate specific antigen predicts prostate cancer in hypogonadal men. J Urol 2008;179:1741–5. http://dx.doi.org/10.1016/j.eururo.2013.02.041
Platinum Priority Reply from Authors re: Andrea Salonia. Androgens and Prostate Cancer: We Are Still (Almost) Completely Ignorant. Eur Urol 2014;65:690–1 Androgens and Prostate Cancer: Clinical Implications and Future Directions Boris Gershman a, Irene M. Shui b, Lorelei A. Mucci b,c,* a
Department of Urology, Massachusetts General Hospital, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; c Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA b
Androgens have been known to play an important role in prostate cancer (PCa) biology for many years, but it is now recognized that this relationship is more complex than the simple historical view that androgens stimulate cancer growth [1]. As Salonia emphasized in his editorial [2], there is much to learn regarding the exact role of androgens in the development, growth, and treatment of PCa. Androgen deprivation remains a mainstay of therapy for metastatic PCa, and a number of studies have shown an association between lower pretreatment androgen levels and higher Gleason score [3] and pathologic stage [4]. Despite these findings, epidemiologic studies have failed to show a DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2013.02.041, http://dx.doi.org/10.1016/j.eururo.2013.01.003. * Corresponding author. Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. Tel. +1 617 432 1732. E-mail address: [email protected] (L.A. Mucci).
consistent relationship between PCa incidence and sex hormone levels [5], and the current study found no association between prediagnostic circulating sex hormones and lethal PCa [6]. To reconcile the apparent inconsistencies in the literature, we must consider the timing of sex hormone exposure as well as the potential role of reverse causation, a phenomenon in which the cancer itself may influence blood levels of sex hormones. The epidemiologic studies that have failed to show an association between sex hormone levels and PCa incidence have relied largely on sex hormones assayed prior to the diagnosis of PCa [5]. In contrast, studies that noted an association between sex hormone levels and adverse prognostic markers have largely used hormone levels obtained after PCa diagnosis. This consideration is essential because evidence supports the concept of central gonadotropin suppression by PCa. Studies have noted, for instance, an increase in testosterone following radical prostatectomy, with a concomitant increase in luteinizing hormone and follicle-stimulating hormone [7,8]. Greater gonadotropin suppression by a prostate-related substance such as the glycoprotein inhibin may explain the association between low androgen levels and adverse PCa features [8]. Pretreatment hormone levels may thus reflect the biology of the PCa itself (precisely the phenomenon of reverse causation), whereas prediagnostic levels may better reflect the hormonal milieu in which the cancer develops. Under Salonia’s time-dependency theory [2], studies would ideally have information on the levels of circulating hormones throughout the lifespan of the individual to capture a wider
692
EUROPEAN UROLOGY 65 (2014) 690–692
etiologic period of exposure. One area where our study [6] still falls short is assessing the hormonal milieu in adolescence and young adulthood, which are critical developmental periods and may be relevant for PCa. Despite the implications of our null study for the role of sex hormones in the pathogenesis of PCa, there is still potential clinical utility for the use of sex hormone levels for the diagnosis and management of PCa. Testosterone levels, for example, have shown some value in the diagnosis of PCa in men with elevated prostate-specific antigen, although results have not been consistent in several studies [9]. Androgen levels also play a critical role in the management of metastatic disease. As Salonia [2] comments, we have much to learn regarding the endocrine biology of PCa. Further studies to characterize the role of sex hormones over the life course of an individual should enhance our understanding of the etiology and clinical management of this disease. Conflicts of interest: The authors have nothing to disclose.
[2] Salonia A. Androgens and prostate cancer: we are still (almost) completely ignorant. Eur Urol 2014;65:690–1. [3] Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001;47:52–8. [4] Isom-Batz G, Bianco Jr FJ, Kattan MW, Mulhall JP, Lilja H, Eastham JA. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol 2005;173:1935–7. [5] Endogenous Hormones and Prostate Cancer Collaborative Group. Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170–83. [6] Gershman B, Shui IM, Stampfer M, et al. Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer. Eur Urol 2014;65:683–9. [7] Madersbacher S, Schatzl G, Bieglmayer C, et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002;60:869–74. [8] Miller LR, Partin AW, Chan DW, et al. Influence of radical prostatectomy on serum hormone levels. J Urol 1998;160:449–53. [9] Schulman CC, Irani J, Morote J, et al. Testosterone measurement in
References
patients with prostate cancer. Eur Urol 2010;58:65–74.
[1] Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol 2008;15:472–80.
http://dx.doi.org/10.1016/j.eururo.2013.03.028
Another issue to ponder is that Gershman and coworkers [5] highlighted that their null results would suggest that reverse causation may be responsible for previous observations of adverse outcomes in men with low circulating androgens [6–8], which, however, were assayed when disease were already diagnosed. Once again, timing is important, in particular, the temporal aspect of the relationship between hormones and cells and tissues of the prostate. As adequately emphasized by Gershman and co-workers [5], considering only one single hormonal assessment inevitably neglects the true endocrine biology of prostate tissue, which is dependent on the exposure time at a given concentration of sex steroid during the lifespan of the individual. This paper implies that the road is still very long—unfortunately and fortunately, at the same time! Conflicts of interest: The author has nothing to disclose.
691
[2] Endogenous Hormones and Prostate Cancer Collaborative Group. Roddam AW, Allen NE, Appleby P, Key TJ, et al. Endogenous sex hormones and prostate cancer: a col laborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170–83. [3] Imamoto T, Suzuki H, Fukasawa S, et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 2005;47:308–12. [4] Salonia A, Abdollah F, Capitanio U, et al. Circulating sex steroids and prostate cancer: introducing the time-dependency theory. World J Urol 2013;31:267–73. [5] Gershman B, Shui IM, Stampfer M, et al. Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer. Eur Urol 2014;65:683–9. [6] Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009;55:310–21. [7] San Francisco IF, Regan MM, Dewolf WC, Olumi AF. Low age adjusted free testosterone levels correlate with poorly differentiated prostate cancer. J Urol 2006;175:1341–5. [8] Rhoden EL, Riedner CL, Morgentaler A. The ratio of serum testos-
References [1] Isbarn H, Pinthus JH, Marks LS, et al. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol 2009;56:48–56.
terone to prostate specific antigen predicts prostate cancer in hypogonadal men. J Urol 2008;179:1741–5. http://dx.doi.org/10.1016/j.eururo.2013.02.041
Platinum Priority Reply from Authors re: Andrea Salonia. Androgens and Prostate Cancer: We Are Still (Almost) Completely Ignorant. Eur Urol 2014;65:690–1 Androgens and Prostate Cancer: Clinical Implications and Future Directions Boris Gershman a, Irene M. Shui b, Lorelei A. Mucci b,c,* a
Department of Urology, Massachusetts General Hospital, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; c Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA b
Androgens have been known to play an important role in prostate cancer (PCa) biology for many years, but it is now recognized that this relationship is more complex than the simple historical view that androgens stimulate cancer growth [1]. As Salonia emphasized in his editorial [2], there is much to learn regarding the exact role of androgens in the development, growth, and treatment of PCa. Androgen deprivation remains a mainstay of therapy for metastatic PCa, and a number of studies have shown an association between lower pretreatment androgen levels and higher Gleason score [3] and pathologic stage [4]. Despite these findings, epidemiologic studies have failed to show a DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2013.02.041, http://dx.doi.org/10.1016/j.eururo.2013.01.003. * Corresponding author. Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. Tel. +1 617 432 1732. E-mail address: [email protected] (L.A. Mucci).
consistent relationship between PCa incidence and sex hormone levels [5], and the current study found no association between prediagnostic circulating sex hormones and lethal PCa [6]. To reconcile the apparent inconsistencies in the literature, we must consider the timing of sex hormone exposure as well as the potential role of reverse causation, a phenomenon in which the cancer itself may influence blood levels of sex hormones. The epidemiologic studies that have failed to show an association between sex hormone levels and PCa incidence have relied largely on sex hormones assayed prior to the diagnosis of PCa [5]. In contrast, studies that noted an association between sex hormone levels and adverse prognostic markers have largely used hormone levels obtained after PCa diagnosis. This consideration is essential because evidence supports the concept of central gonadotropin suppression by PCa. Studies have noted, for instance, an increase in testosterone following radical prostatectomy, with a concomitant increase in luteinizing hormone and follicle-stimulating hormone [7,8]. Greater gonadotropin suppression by a prostate-related substance such as the glycoprotein inhibin may explain the association between low androgen levels and adverse PCa features [8]. Pretreatment hormone levels may thus reflect the biology of the PCa itself (precisely the phenomenon of reverse causation), whereas prediagnostic levels may better reflect the hormonal milieu in which the cancer develops. Under Salonia’s time-dependency theory [2], studies would ideally have information on the levels of circulating hormones throughout the lifespan of the individual to capture a wider
692
EUROPEAN UROLOGY 65 (2014) 690–692
etiologic period of exposure. One area where our study [6] still falls short is assessing the hormonal milieu in adolescence and young adulthood, which are critical developmental periods and may be relevant for PCa. Despite the implications of our null study for the role of sex hormones in the pathogenesis of PCa, there is still potential clinical utility for the use of sex hormone levels for the diagnosis and management of PCa. Testosterone levels, for example, have shown some value in the diagnosis of PCa in men with elevated prostate-specific antigen, although results have not been consistent in several studies [9]. Androgen levels also play a critical role in the management of metastatic disease. As Salonia [2] comments, we have much to learn regarding the endocrine biology of PCa. Further studies to characterize the role of sex hormones over the life course of an individual should enhance our understanding of the etiology and clinical management of this disease. Conflicts of interest: The authors have nothing to disclose.
[2] Salonia A. Androgens and prostate cancer: we are still (almost) completely ignorant. Eur Urol 2014;65:690–1. [3] Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001;47:52–8. [4] Isom-Batz G, Bianco Jr FJ, Kattan MW, Mulhall JP, Lilja H, Eastham JA. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol 2005;173:1935–7. [5] Endogenous Hormones and Prostate Cancer Collaborative Group. Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170–83. [6] Gershman B, Shui IM, Stampfer M, et al. Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer. Eur Urol 2014;65:683–9. [7] Madersbacher S, Schatzl G, Bieglmayer C, et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002;60:869–74. [8] Miller LR, Partin AW, Chan DW, et al. Influence of radical prostatectomy on serum hormone levels. J Urol 1998;160:449–53. [9] Schulman CC, Irani J, Morote J, et al. Testosterone measurement in
References
patients with prostate cancer. Eur Urol 2010;58:65–74.
[1] Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol 2008;15:472–80.
http://dx.doi.org/10.1016/j.eururo.2013.03.028