testosterone e cancro alla prostata
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Testosterone e cancro alla prostata: è controindicata la terapia sostitutiva con testosterone?
ALESSANDRO PIZZOCAROU.O. Urologia
Servizio di Andrologia Istituto Clinico Humanitas
Rozzano (MI)
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Lack of sound evidence 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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Is Testosterone Safe?
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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
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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
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Gooren LJ et al. Aging Male 2007; 10: 173–81.
Mental associations:
Risk of TRT – a survey among physicians in Germany, Spain and England
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Endogenous Hormones and Prostate Cancer Collaborative Group J Natl Cancer Inst 2008; 100: 170–83.
Meta-analysis: Pooled data of 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 1.002 761/1309 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 .284 194/295 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.
03886 men with PCa and 6438 Controls
serum concentrations of sex hormones were not associated with the risk of prostate cancer.
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PCa prevalence increases astestosterone levels decline
40–49 50–59 60–69 70–79
% PCa
Total T
Age (years)
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Androgens are essential for normal
development of the prostate
• Secretory functions
• Cellular differentiation
• Normal proliferation
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Eugonadal man
Prostate volume 19 mLPSA 0.9 ng/mL
Untreated
hypogonadal man
Prostate volume 8 mLPSA 0.4 ng/mL
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Pro
sta
te v
olu
me (
mL
)
Age (years)
Hypogonadal patient without therapy
Normal men
0
10
20
30
40
50
20 30 40 50 60 70 80
Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
Prostate volume measured bytransrectal ultrasonography
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Pro
sta
te v
olu
me
(m
L)
Age (years)
0
10
20
30
40
50
20 30 40 50 60 70 80
Hypog. pat. with therapyHypog. pat. without therapy Normal men
Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
Prostate volume measured bytransrectal ultrasonography
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Prostate size in 334 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)
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PSA in 334 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)
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Treatment with testosterone
• Incidence of cancer in testosterone treatmentstudies up to 3 years: 1%
• Risk similar to detection in screeningprogrammes
Testosterone and the prostate
Rhoden E & Morgentaler A. New Engl J Med 2004; 350: 482–92.
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Can very high doses of testosteroneinduce adverse events in the prostate?
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Serum testosterone and PSA in young men treated with escalating doses of testosterone
Bhasin S et al. Am J Physiol Endocrinol Metab 2001; 281: e1172–81.
0
2
4
6
8
10
Seru
m P
SA
at W
eek 2
0
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Bhasin S et al. J Clin Endocrinol Metab 2005; 90: 678–88.
Serum testosterone and PSA in older men treated with escalating doses of testosterone
0
2
4
6
8
10S
eru
m P
SA
at W
eek 2
0
12
14
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What happens within the prostate?
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Date of download: 1/9/2014Copyright © 2012 American Medical
Association. All rights reserved.
From: Effect of Testosterone 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.
Figure Legend:
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by A. Morgentaler
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Morgentaler A & Traish AM. Eur Urol 2009; 55: 310–21.
Saturation model
4 nmol/L
(125 ng/dl)
In vivo
(Near-castrate
Range)
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Is low testosteronea risk factor for the prostate?
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Testosterone levels and Gleason scores in 47 men with prostate cancer before radical prostatectomy
Madersbacher S et al. Urology 2002; 60: 869–74.
p<0.05
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Testosterone levels and prostate cancer cases
among 345 hypogonadal men(TT <300 or FT <1.5 ng/dL) with PSA ≤4 ng/mL
Morgentaler A & Rhoden EL. Urology 2006; 68: 1263–7.
p=0.04 p=0.04
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Kaplan-Meier PSA failure-free survival curves according topreoperative testosterone levels
Yamamoto S et al. Eur Urol 2007; 52: 696–701.
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Kjellman A et al. Eur Urol 2008; 53: 106–11.
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).
DHT levels and prostate cancer survival
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Shores et al JCEM 2012
Treated n=398, age 61 yrs
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
Seattle-Veterans Study
1031 hypogonadal men
Shores M et al. J Clin
Endocrinol Metab 2012; 97:
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TRT in menwith prostate cancer
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Testosterone Replacement Therapy Following the Diagnosis ofProstateCancer: Outcomes and Utilization TrendsAlan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070
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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.
Testosterone Replacement Therapy Following the Diagnosis ofProstateCancer: Outcomes and Utilization TrendsAlan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070
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A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications
Mohit Khera , David Crawford, Alvaro Morales, Andrea Salonia, Abraham MorgentalerEuropean Urology 65, 2014; 115–123
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A New Era of 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.
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BPH (LUTS)
and
TRT
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Urinary flow rate in untreated hypogonadal men (n=47),
TRT – treated hypogonadal men (n=78) and matched controls (n=75)
Max f
low
(m
L/s
)
untreated treated controls0
5
10
15
20
25
30
35
40
Behre HM et al. Clin Endocrinol 1994; 40: 341–9.
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TRT with intramuscular TU over 26 weeksInternational 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.
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CONCLUSIONS
The long-held belief 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
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*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.
*
TRT in PCa pts
Khera M. 2014
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CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit;MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone
100
Odds ratio for MACESource # 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
Odds Ratio for Major 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
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MACE in hypogonadism
Corona G.et al, J Sex Med 2010;7:1557–1564
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