Does TRT Induce Prostate Cancer?

Does TRT Induce Prostate Cancer? Prism VI, Bruges, Belgium 21-22November 2014 Herman Leliefeld, Urologist, Utrecht The Netherlands

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCa during TRT?

Medical literature reviewed Guidelines: Endocrine Society, 2010 ISSM Standard Committee, 2013 ISA,ISSAM,EAU,ASA, 2010 EAU, 2012 Update on TRT, Corona G, 2011 JSM Fernandez-Balsells,2010 JCEM Khera,2013 Sex Med Rev Shared opinions/slides of Frans Debruyne and Marco Marcelli

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCA during TRT?

It is in our Minds!! The prostate increases in size after the onset of puberty as testosterone levels increase. without androgen the prostate regresses (lack of a palpable prostate gland in 26 eunuchs Chinese men 41-65 years post-castration) Chinese Med J. 1987;100:271 272, does not increase in size in genetic males who have complete androgen insensitivity (Corbetta S, et al. Fertil Steril. 2011;95:1119) remains rudimentary in males with 5- reductase deficiency, indicating that DHT is the major androgen in the prostate (Imperato-McGinley J, et al. J Clin Endocrinol Metab. 1992; 75:1022-6) Increases in size in men with hypogonadism after implementation of TRT Androgen depletion has been the first line of treatment for invasive PCa since 1941

Prostate Volume in 16 Hypogonadal Men before and after Testosterone Treatment for 36 months Snyder PJ, et al. J Clin Endocrinol Metab 2000; 85:2670 P = 0.004

Consequences of Huggins paper Androgen ablation became the first line of treatment for advanced prostate cancer Because prostate cancer flare up was associated with TRT, we are still questioning whether the population of patients receiving TRT is at increased risk to develop prostate cancer

Huggins s heritage from a 1967 review article: Orchiectomy or the administration of estrogens resulted in regression of PCa whereas, in untreated prostates,testosterone enhanced the rate of growth of cancer Huggins, Cancer Res 27 ;1925-30, 1967

There is general agreement that castration causes regression of PCa But There is no prove for the second part of Huggins assertion: T causes PCa to grow!! based on only one patient

Why is the relationship between T and PCa further under great scrutiny? TRT for hypogonadism is progressivily expanding More PCa survivors with LOH ask for TRT

Why is TRT a controversial topic? Is there a risk of Developing Lower Urinary Tract Symptoms(LUTS) with TRT?

Can TRT lead up to: Increase in prostate volume? Increased risk of LUTS and BPH? Increase in PSA levels? Stimulate growth of an occult tumor?

We cannot answer these questions because: 1) to establish a link between development of a disease and certain steroid hormone levels, studies need to be prospective and should last until the disease of interest has developed; 2) circulating hormone levels vary significantly throughout the day and over the years. It is difficult to determine to what extent the level of a hormone measured once, reflects a lifetime index of hormone status; 3) the levels of circulating steroid hormones do not necessarily reflect their intraprostatic concentrations.

Prostate Volume in 16 Hypogonadal Men before and after Testosterone Treatment for 36 months Snyder PJ, et al. J Clin Endocrinol Metab 2000; 85:2670 P = 0.004

AUA Symptom Index Changes During Study Period Pearl JA et al. J Urol. 2013;190:1828-1833 n=120; Mean duration of followup therapy:692 +/- 773 days

No difference in the risk of significant increase of PSA, changes in IPSS, LUTS and composite endpoints (Fernandez-Balsells, J Clin Endocrinol Metab 95: 2560 2575, 2010) Conclusions: these data do not support causality between Pca,LUTS and TRT

Does TRT induce prostate diseases? No evidence based on available data. However for conclusive evidence adequately powered prospective studies are needed Endocrine Society Guidelines: A patient on TRT needs urological consultation if there is: PSA concentration >1.4 ng/ml in a year PSA velocity of >0.4 ng/ml yr using the PSA level after6 months TRT Abnormal RT An AUA/ IPSS prostate symptom score of >19 Bhasin S, J Clin Endocrinol Metab, June 2010, 95(6):2536 2559

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCA during TRT?

Relevant questions: It is commonly believed that PCa is an androgendependent cancer; but in that case: 1. Do high T levels contribute to the development of PCa? 2. Does high T cause rapid growth of PCa? 3. Is low T protective against development of PCa and causes it PCa to regress?

Low T is not protective while high T is not a risk factor for the development of Pca Morgentaler A, Roden EL. Urol 2006; 68:1263

Incidence and death rates per 100,000, US 2005-2009 Incidence and death rates per 100,000 population prostate cancer United States, 2005 to 2009 250 228,7 CA Cancer J Clin 2013 200 150 100 141 77,2 98,8 124,9 Incidence Deat rate 50 53,1 21,7 10 19,7 17,8 0 White African American Asian American American Indian Hispanic

ng/ml Serum testosterone levels do not differ between black and white men in a nationally representative sample of Americans (NHANES III) J Clin Endocrinol Metab 92: 2519 2525, 2007 6 5 5,1 5,24 4 3 2 1 0 NHW 0,101 0,104 NHB Testosterone (ng/ml) Free Testosterone (ng/ml)

Testosterone Concentration (ng/ml) Prostate Cancer Grade: Serum Testosterone at Diagnosis Schatzl G, et al. Prostate. 2001;47:52 4,5 4,0 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 4,3 4,1 3,7 P<0.001 2.8* n=34 n=33 n=51 n=38 Gleason Score Gleason 5 Gleason=6 Gleason=7 Gleason 8 N=156

Serum concentrations of sex hormones are not associated with the risk of prostate cancer J Natl Cancer Inst 2008;100: 170 183 Paper by Roddam 3886 men with incident prostate cancer and 6438 controls

Androgen levels and PCA What learns the literature: - 18 prospective studies: 3,886 men with PCA 6,438 controls Conclusion: no association between risk of PCA and T level Roddam,2008

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCA during TRT?

Testosteron and risk for PCA -No correlation between higher T and PCA risk -But the opposite seems more frequently: a low T is associated with a higher PCA-risk! Selph and Carson JSex Med 2013 Garcia-Gruz 2012 Porcaro 2010

Low T : a risk for prostate cancer Possible explanation: Prostate cancer exerts an inhibitory effect on Hypothalamic-Pituitary-Testicular-axis: T declines After RRP: T doubled in patients with G3! Miller, 1998 Madersbacher, 2002

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCA during TRT?

Evidence in support of an association between PCa and TRT No evidence of such correlation A trial of 6000 men randomized to receive testosterone or placebo for five years is necessary to determine if testosterone increases the incidence of prostate cancer by 30 percent

No significant effect of testosterone therapy on the incidence of prostatic cancer or the need for prostate biopsy ( Fernandez-Balsells, J Clin Endocrinol Metab 95: 2560 2575, 2010)

TRT and PCa TRT-treated men have no greater incidence of Ca prostate than non-treated men even in men at highest risk* The risk of developing prostate Ca on TRT is approx 1%, the same as non-trt treated population Rhoden E and Morgentaler A New England J Med 350: 482-492 (2004) *Travis RC et al. Serum androgens and prostate cancer. Int J Cancer 2007:121:1331-1338 *Gann PH et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88:1118-1126 *American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8(6):439-456.

Prostate cancer growth Proposed saturation model for the relation of PCa growth and serum T concentration Near castrate range Threshold beyond which T has no effect on growth of PCa Serum T levels Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am - 01-NOV-2007; 34(4): 555-63, vii

Molecular Basis for Saturation AR becomes maximally bound to androgen (saturated) at ~4 nmol/l (120 ng/dl) Morgentaler A, Traish AM Eur Urol 2009; 55: 310

Does TRT Induce Prostate Cancer? Why is it a controversial topic? Is there an association between T level and PCA-risk? What is the risk of PCA during TRT?

Does TRT Induce Prostate Cancer? Prism VI, Bruges, Belgium 21-22November 2014 Herman Leliefeld, Urologist, Utrecht The Netherlands

Fact All available evidence demonstrates a powerful effect of T on PCa growth at low T concentrations near castrate T concentrations BUT little or no effect of T on PCa growth above near castrate T concentrations

Fact Clinical evidence has demonstrated the possibility that the growth of androgen-independent prostate cancers might be reduced by the administration of androgens. Prehn RT Cancer Res 59: 4161-4164 (1999)

Saturation model: the limits of androgen-dependent growth Khera, Sex Med Rev, 2013, vol 1 Morgentaler and Traish,2009

Do patients on TRT develop PCA? Is there a stimulation of latent PCA? Is there a de novo development of PCA? Answer: no: prevalence of PCA is similar to the general population: 1,1% Rhoden,J Urol,2003 Calof, 2005

Are serum sex steroid levels correlated with an increased risk of prostate events? Significance of all studies is limited because: 1) to establish linkage between development of a disease and certain steroid hormone levels, studies need to be prospective and should last until the disease of interest has developed; 2) circulating hormone levels vary significantly throughout the day and over the years. It is difficult to determine to what extent the level of a hormone measured once, reflects a lifetime index of hormone status; 3) the levels of circulating steroid hormones do not necessarily reflect their intraprostatic concentrations.

Does TRT induce prostate diseases? No evidence based on available data. However for conclusive evidence adequately powered prospective studies are needed Endocrine Society Guidelines: A patient on TRT obtain urological consultation if there is: An increase in serum PSA concentration >1.4 ng/ml within any 12- month period of testosterone treatment. A PSA velocity of >0.4 ng/ml yr using the PSA level after 6 months of testosterone administration as the reference Detection of a prostatic abnormality on digital rectal examination. An AUA/ IPSS prostate symptom score of >19 Bhasin S, J Clin Endocrinol Metab, June 2010, 95(6):2536 2559

Low T :a risk for prostate cancer -Low T related to higher risk of PCA-progression -PSA/FT ratio: preop marker for G and T-stadium: if PSA/FT 0,40 : T3,T4 and G8 and G9! Garcia-Gruz, 2012 Porcaro,2010