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Testosterone e cancro alla prostata
The document discusses testosterone replacement therapy (TRT) and prostate cancer. It notes that while traditional views held that high testosterone led to rapid cancer growth, recent evidence challenges this. Studies found no association between endogenous hormone levels and cancer risk. The saturation model suggests maximal cancer growth occurs at relatively low testosterone levels. Accumulating evidence also links low testosterone with higher-risk cancer features. TRT studies up to 3 years found similar cancer detection rates to screening. While long-term safety data is still needed, available evidence suggests TRT may be considered for selected prostate cancer patients with symptoms of hypogonadism after obtaining informed consent.
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Testosterone e cancro alla prostata
- 1. Testosterone e cancroalla prostata: è controindicata la terapia sostitutiva con testosterone? ALESSANDRO PIZZOCARO U.O. Urologia Servizio di Andrologia Istituto Clinico Humanitas Rozzano (MI)
- 2. Lack of soundevidence that TRT actually cause prostate cancer (PCA) progression and/or recurrence in men with a history of PCA • Key points • The prostate saturation theory • The association PCA-low testosterone levels • The possible protective nature of TRT against the development of PCA Moith Khera, Scott Dept Urol, Baylor College of Medicine, Houston, TX, USA; J. Sex Med, 2013
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- 4. Traditional view 1.High T → rapid PCa growth 2. Low T → protective against PCa 3. T therapy contraindicated in men with PCa, or even suspicion of PCa
- 5. Huggins and Hodges(1941) 1.Reduction of testosterone concentration by castration or oestrogen treatment results in regression of prostate cancer 2.Exogenous testosterone results in progression of prostate cancer
- 6. Mental associations: Riskof TRT – a survey among physicians in Germany, Spain and England Gooren LJ et al. Aging Male 2007; 10: 173–81.
- 7. Meta-analysis: Pooled dataof 18 studies No. of case patients/ Hormone Fifth No. of control subjects RR (95% Cl) RR & 95% Cl 2 1 for trend P Testosterone 1 784/1302 1.00 2 761/1309 0.97 (0.85 to 1.11) 3 837/1287 1.08 (0.95 to 1.23) 0.17 .68 4 792/1281 1.03 (0.90 to 1.17) 5 712/1259 0.94 (0.82 to 1.07) Free testosterone 1 691/1181 1.00 2 684/1165 1.01 (0.88 to 1.16) 3 750/1155 1.13 (0.98 to 1.29) 2.89 .09 4 707/1162 1.09 (0.95 to 1.25) 5 718/1152 1.11 (0.96 to 1.27) DHT 1 240/298 1.00 2 192/284 0.83 (0.65 to 1.07) 3 188/282 0.82 (0.63 to 1.06) 1.19 .28 4 194/295 0.83 (0.64 to 1.08) 5 196/286 0.86 (0.66 to 1.11) 0. 5 0.7 5 1 1. 5 2. 0 3886 men with PCa and 6438 Controls serum concentrations of sex hormones were not associated with the risk of prostate cancer. Endogenous Hormones and Prostate Cancer Collaborative Group J Natl Cancer Inst 2008; 100: 170–83.
- 8. PCa prevalence increasesas testosterone levels decline 40–49 50–59 60–69 70–79 % PCa Total T Age (years)
- 9. Androgens are essentialfor normal development of the prostate • Secretory functions • Cellular differentiation • Normal proliferation
- 10. Eugonadal man Prostatevolume 19 mL PSA 0.9 ng/mL Untreated hypogonadal man Prostate volume 8 mL PSA 0.4 ng/mL
- 11. Prostate volume (mL) Prostate volume measured by transrectal ultrasonography Hypogonadal patient without therapy Normal men Age (years) 50 40 30 20 10 0 20 30 40 50 60 70 80 Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
- 12. Prostate volume (mL) Prostate volume measured by transrectal ultrasonography Hypog. pat. without therapy Hypog. pat. with therapy Normal men Age (years) 50 40 30 20 10 0 20 30 40 50 60 70 80 Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
- 13. Prostate size in334 hypogonadal men after a total of 6,596 injections of TU (maximal treatment duration 15 years) Zitzmann M and Saad F Endocrine Reviews 2010 (Abstract Book)
- 14. PSA in 334hypogonadal men after a total of 6,596 injections of TU (maximal treatment duration 15 years) Zitzmann M and Saad F Endocrine Reviews 2010 (Abstract Book)
- 15. Testosterone and theprostate Treatment with testosterone • Incidence of cancer in testosterone treatment studies up to 3 years: 1% • Risk similar to detection in screening programmes Rhoden E & Morgentaler A. New Engl J Med 2004; 350: 482–92.
- 16. Can very highdoses of testosterone induce adverse events in the prostate?
- 17. Serum testosterone andPSA in young men treated with escalating doses of testosterone Bhasin S et al. Am J Physiol Endocrinol Metab 2001; 281: e1172–81. 10 8 6 4 2 0 Serum PSA at Week 20
- 18. Serum testosterone andPSA in older men treated with escalating doses of testosterone Bhasin S et al. J Clin Endocrinol Metab 2005; 90: 678–88. 14 10 8 6 4 2 0 Serum PSA at Week 20 12
- 19. What happens withinthe prostate?
- 20. From: Effect ofTestosterone Replacement Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism: A Randomized Controlled Trial JAMA. 2006;296(19):2351-2361. doi:10.1001/jama.296.19.2351 In the testosterone replacement therapy group (n = 9), individuals whose genes were selected for study were those with the greatest percentage increase in tissue androgens when tissue was available; in the placebo group (n = 7), 3 men with large increases in tissue androgens were intentionally avoided. Date of download: 1/9/2014 Copyright © 2012 American Medical Association. All rights reserved. Figure Legend:
- 21.
- 22. Saturation model MorgentalerA & Traish AM. Eur Urol 2009; 55: 310–21. 4 nmol/L (125 ng/dl) (Near-castrate Range)
- 23. Is low testosterone a risk factor for the prostate?
- 24. Testosterone levels andGleason scores in 47 men with prostate cancer before radical prostatectomy p<0.05 Madersbacher S et al. Urology 2002; 60: 869–74.
- 25. Testosterone levels andprostate cancer cases among 345 hypogonadal men (TT <300 or FT <1.5 ng/dL) with PSA ≤4 ng/mL p=0.04 p=0.04 Morgentaler A & Rhoden EL. Urology 2006; 68: 1263–7.
- 26. Kaplan-Meier PSA failure-freesurvival curves according to preoperative testosterone levels Yamamoto S et al. Eur Urol 2007; 52: 696–701.
- 27. DHT levels andprostate cancer survival Prostate cancer-specific survival for the 65 prostate cancer patients divided into two groups with dihydrotestosterone (DHT) level above and below the median. There is a significant improved survival in the group with DHT above the median (log rank p=0.0075). Kjellman A et al. Eur Urol 2008; 53: 106–11.
- 28. Seattle-Veterans Study 1031hypogonadal men Treated n=398, age 61 yrs Shores et al JCEM 2012 baseline T=5.6 nmol/L incident PCa 1.6% Untreated n=633, age 63 yrs baseline T=6.7 nmol/L incident PCa 2.0% Log Rank p=0.029 Shores M et al. J Clin Endocrinol Metab 2012; 97:
- 29. TRT in men with prostate cancer
- 30. Testosterone Replacement TherapyFollowing the Diagnosis ofProstate Cancer: Outcomes and Utilization Trends Alan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070
- 31. Testosterone Replacement TherapyFollowing the Diagnosis ofProstate Cancer: Outcomes and Utilization Trends Alan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070 Conclusion TRT was not associated with worse overall or cancer-specific mortality nor was it associated with the use of salvage hormone therapy (ADT). Although our findings suggest TRT may be safe in the setting of prostate cancer diagnosis and treatment, confirmatory prospective studies are needed.
- 32. A New Eraof Testosterone and Prostate Cancer: From Physiology to Clinical Implications Mohit Khera , David Crawford, Alvaro Morales, Andrea Salonia, Abraham Morgentaler European Urology 65, 2014; 115–123
- 33. A New Eraof Testosterone and Prostate Cancer: From Physiology to Clinical Implications Khera M , Crawford D, Morales A, Salonia A, Morgentaler A, EUROPEAN UROLOGY 65 (2014) 115–123 The small size and limited duration of these case series make it impossible to assess the overall safety of testosterone therapy after definitive treatment for PCa, but so far, these results are reassuring. Large, randomized prospective studies will be needed to provide reliable safety information.
- 34. BPH (LUTS) and TRT
- 35. Urinary flow ratein untreated hypogonadal men (n=47), TRT – treated hypogonadal men (n=78) and matched controls (n=75) Max flow (mL/s) untreated treated controls 40 35 30 25 20 15 10 5 0 Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
- 36. TRT with intramuscularTU over 26 weeks International Prostate Symptom Score and PSA in 20 patients with pre-diagnosed LOH and LUTS p<0.00001 p<0.00001 NS Kalinchenko SY et al. Aging Male 2008; 11: 57–61.
- 37. CONCLUSIONS The long-heldbelief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations (Saturation model) Accumulating data indicate an important association between low testosterone concentrations and worrisome aspects of PCa It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism, despite the limited safety information in this population
- 38. * TRT inPCa pts *TRT only after - obtaining informed consent and - beginning with the lowest- risk individuals (such as those with undetectable PSA >1 yr following RP). Informed consent should include the information that no long-term safety data are available and there is therefore an unknown degree of risk that PCa may recur or progress. Khera M. 2014
- 39. Odds Ratio forMajor Adverse Cardiovascular Events (MACE) According to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit; MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone 100 Odds ratio for MACE Source # Trials MH-OR LL p TRT Placebo #Events # Patients #Events # Patients Placebo TS Associated diseases Elderly men 10 1,22 0,49 3,03 0,67 Men with CVD 2 2,48 0,35 17,45 0,36 Frail men 5 2,25 0,72 7,08 0,17 Men with metabolic diseases 4 0,19 0,04 0,85 0,03 Hypogonadism status Mixed population 14 1,26 0,58 2,73 0,56 TT < 12 nM 12 0,84 0,32 2,23 0,73 Type of support Drug company not supported 12 0,94 0,39 2,24 0,88 Drug company supported 14 1,07 0,51 2,24 0,86 Trial duration ≤ 12 weeks 4 1,02 0,20 5,29 0,98 >12 weeks 22 1,01 0,55 1,84 0,98 13 954 6 549 3 62 1 64 13 401 4 355 1 303 5 203 15 1066 11 865 16 829 9 476 10 437 8 332 21 1458 12 2 147 2 145 29 1746 18 1196 0.01 0.1 1 10 UL 1009 Corona G et al. Expert Opin Drug Saf, published online August 19, 2014
- 40. MACE in hypogonadism Corona G.et al, J Sex Med 2010;7:1557–1564
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Editor's Notes
- #6 hohes Testosteron = hohes PCa-Risiko / schlechter Verlauf niedriges Testosteron = niedriges PCa-Risiko / günstiger Verlauf Verhältnis von T zum PCa = Benzin ins Feuer gießen
- #8 Data on serum concentrations of sex hormones from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects
- #23 The androgen hypothesis has therefore been replaced by the saturation model [10] to accommodate the dual observations that PCa is (1) exquisitely sensitive to variations in androgens at low concentrations and (2) indifferent to variations at normal and high concentrations. The simple yet profound paradigm change is that androgens appear to have a finite ability to stimulate PCa growth. This creates opportunities for new clinical uses of testosterone therapy Indications for testosterone therapy in men include low testosterone levels in combination with signs and symptoms of testosterone deficiency, such as fatigue, erectile dysfunction, depression, decreased libido, and decreased muscle mass. Although any history of PCa has been a longstanding contraindication for testosterone therapy, there may now be circumstances where this is a reasonable therapeutic choice, as we discuss below. The saturation model explains the paradoxical observations that prostate tissue is exquisitely sensitive to changes in serum testosterone at low concentrations but becomes indifferent to changes at higher testosterone concentrations. A threshold effect occurs in which increasing androgen concentrations reach a limit (the saturation point) beyond which there is no further ability to induce androgen-driven changes in prostate tissue growth This explains why dramatic changes in PSA are notedwhen serum testosterone is manipulated into or out of the castration range, whereas minimal or absent PSA changes occurwhen supraphysiologic testosterone doses are administered to normal men. One important mechanism contributing to the saturation model is the finite ability of androgen to bind AR. Maximal androgen–AR binding (ie, saturation) occurs atfairly low androgenconcentrations inratandhumanprostate tissue, reported in human prostate in vitro at approximately 4 nmol/l (approximately 125 ng/dl). In clinical practice, the saturation point appears to be approximately 8 nmol/l or 250 ng/dl, subject to interindividual variation.
- #26 Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology 2006;68:1263–7. In a larger study of 345 men with testosterone deficiency and PSA levels <4.0 ng/ml, men with the lowest tertile of serum testosterone had double the risk of PCa compared withmenwith less severe testosterone deficiency. The cancer rate was 30% for these men with a PSA value of 2.0–4.0 ng/ml [25].
- #29 FU ergänzt PCA-> PSA
- #31 Population-based observational study of testosterone replacement therapy in men with a history of prostate cancer (149,354 subjects) Age 65 years or older, diagnosed with prostate cancer between 1991 and 2007 The cohort was divided into those that received TRT (n = 1,181) following prostate cancer diagnosis and those that did not (n = 148,173). Utilization was associated with younger age (P = 0.001) and higher education (P < 0.0001) status (Table 1). Median follow-up after prostate cancer diagnosis was 6 years (IQR 3–8) for the no TRT and 8 years (IQR 5–11) for the TRT groups (P < 0.001). RESULTS: First: TRT was not associated with increased overall or cancer-specific mortality. In fact, mortality events were significantly lower in the TRT group than in the men who did not receive TRT. The reason for lowered mortality rates among men receiving TRT is not clear Second: the use of TRT in men with prostate cancer was exceedingly low, and usage declined over time. Less than 1% of men in the cohort received testosterone therapy. The prevalence of hypogonadism ranges from 2.1 to 25% in the general population, depending on the strictness of the criteria Third: use of TRT was directly related to income and educational status and inversely related to age. Finally, TRT was not associated with later use of salvage ADT, which may be considered a proxy for clinically significant disease recurrence following treatment. Within the median follow-up of 6 years, men who underwent TRT were no more likely to be treated with salvage ADT than men not receiving TRT. Thus, by this measure, progressive disease was not associated with use of TRT in men with a history of prostate cancer.
- #34 The small size and limited duration of these case series make it impossible to assess the overall safety of testosterone therapy after definitive treatment for PCa, but so far, these results are reassuring. Large, randomized prospective studies will be needed to provide reliable safety information. We are aware of a single controlled prospective study to date following RP (Baylor College of Medicine, Clinical- Trials.gov identifier NCT00848497). One possible explanation for the lack of PCa recurrence noted in the previous studies is that these men may not have had any residual PCa cells to be stimulated by androgens. Amore provocative study, therefore, is to assess the response to testosterone therapy in men with untreated PCa. Morgentaler et al. treated 13 men on active surveillance with testosterone therapy for a median of 2.5 yr (range: 1.0–8.1) [8]. All men underwent follow-up prostate biopsies, with a mean of two sets of biopsies per patient. At initial biopsy, 12 men had Gleason score 6 and one had Gleason 7 (3 + 4). Mean serum testosterone increased from 238 to 664 ng/dl. Mean PSA and prostate volume did not change with testosterone therapy. No definite PCa progression was noted in any man, and no cancer was found in 54% of followup biopsies. These were the first results to directly assess the effect of raising testosterone in men with untreated PCa. These results inmenwith untreated PCamust be regarded cautiously given the severely limited global experience, and a report by Morales of erratic PSA responses to testosterone therapy in several men on active surveillance [45].