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1. Testosterone e cancro alla prostata: è controindicata la
terapia sostitutiva con testosterone?
ALESSANDRO PIZZOCARO
U.O. Urologia
Servizio di Andrologia
Istituto Clinico Humanitas
Rozzano (MI)

2. 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

3. Is Testosterone Safe?

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:
Risk of TRT – a survey among physicians in
Germany, Spain and England
Gooren LJ et al. Aging Male 2007; 10: 173–81.

7. 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 1.00
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 increases as
testosterone levels decline
40–49 50–59 60–69 70–79
% PCa
Total T
Age (years)

9. Androgens are essential for normal
development of the prostate
• Secretory functions
• Cellular differentiation
• Normal proliferation

10. Eugonadal man
Prostate volume 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 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)

14. 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)

15. Testosterone and the prostate
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 high doses of testosterone
induce adverse events in the prostate?

17. 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.
10
8
6
4
2
0
Serum PSA at Week 20

18. Serum testosterone and PSA 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 within the prostate?

20. 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.
Date of download: 1/9/2014
Copyright © 2012 American Medical
Association. All rights reserved.
Figure Legend:

21. by A. Morgentaler

22. Saturation model
Morgentaler A & 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 and Gleason 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 and prostate 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-free survival curves according to
preoperative testosterone levels
Yamamoto S et al. Eur Urol 2007; 52: 696–701.

27. DHT levels and prostate 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
1031 hypogonadal 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 Therapy Following the Diagnosis ofProstate
Cancer: Outcomes and Utilization Trends
Alan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070

31. Testosterone Replacement Therapy Following 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 Era of 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 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.

34. BPH (LUTS)
and
TRT

35. Urinary flow rate in 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 intramuscular TU 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-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

38. *
TRT in PCa 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 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
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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