The role of TRT in the management of hypogonadism and TRT ... · PDF fileThe role of TRT in...
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The role of TRT in the management
of hypogonadism and TRT:
Dispelling the myths
Dr Geoff Hackett
Safety concerns over testosterone
replacement therapy (TRT)
• Concerns over the safety of testosterone may have
contributed to underuse of TRT
– Cardiovascular (CV) risk
– Prostate cancer and other prostate disorders
(e.g. BPH)
• Extensive evidence shows that neither of these safety
issues now warrants the concerns raised
Cardiovascular
0
10
20
30
40
50
60
35-44 45-54 55-64 65-74 75-84
Inci
de
nce
of
CH
D (
%)
Age (years)
Age-related incidence of CHD in the general population
through 26 years
N=5,127
Lerner DJ & Kannel WB. Am Heart J 1986;111:383–390.
Males
Females
Testosterone and cardiac risk – incidence
of coronary heart disease (CHD) higher in men
0,7
0,8
0,9
1
1,1
0 2 4 6 8 10
Cu
mu
lati
ve
su
rviv
al
Years of follow up
Testosterone 4 highest
3
2
1 lowest
N=2,314
CV mortality: adjusted survival by quartile
of total testosterone in men aged 42–78 yrs in
the EPIC-Norfolk Study 1993–2003
Khaw KT et al. Circulation 2007;116:2694–2701.
Vikan T et al. Eur J Endocrinol 2009;161:435–442.
Number of deaths from all causes by decentiles of free
testosterone
N=1,687
The Norway Tromsø-Study: androgens
and the prospective mortality risk
Corona G et al. J Sex Med 2010;7:1557–1564.
p=NS
TT 10.4 nmol/l TT 8-10.4 nmol/l TT < 8 nmol/l
p<0.05 vs. TT 10.4
p<0.0001 vs. TT 10.4
N=1,687
Follow up (years)
Pro
po
rtio
n f
ree o
f M
AC
E l
eth
ality
Proportion free of MACE lethality as a function of
baseline testosterone in a consecutive series of
1,687 ED subjects
Testosterone and coronary artery disease
(CAD)
• Bioavailable testosterone (BT) levels are significantly reduced in males with CAD
– Approximately 1 in 4 men (23.4%) with CAD have serum T levels within the clinically hypogonadal range (93.5% positive ADAM questionnaire)
• TRT improves anginal symptoms and cardiac ischaemia
• TRT improves functional capacity and NYHA class compared with placebo
– Malkin et al showed a significant correlation between the increase in BT with treatment and the increase in walking distance, with results sustained over 12 months
English et al. Eur. Heart J 2000;21:890–894; English et al. Circulation. 2000;102:1906–1911; Pugh et al. Endocrine Society Abstract
2003:p225. Malkin et al. Eur Heart J 2006;27:57–64.
Physiologic testosterone therapy (5mg T patch/d/3 months)
improves angina threshold in men with chronic stable angina –
double-blind, randomised, placebo-controlled, add-on trial
English KM et al. Circulation 2000;102:1906–1911.
Studies in men with cardiovascular
disease
250
270
290
310
330
350
370
Testosterone Placebo
Baseline Week 6 Week 14 Baseline Week 6 Week 14
p=0.0068 NS
Tim
e (
sec)
South Yorkshire Study, Pugh et al., unpublished.
23.4
52.6
10
20
30
40
50
60
Pro
po
rtio
n o
f m
en
(%
)
tT < 7.5 nmol/L and/or bT < 2.5 nmol/L tT < 12 nmol/L and/or bT < 4 nmol/L
Hypogonadism is present in a high
proportion of men with CAD
N=891
Effect of baseline BT on all-cause mortality in
men with proven CHD mean follow up 6.9 years
Malkin CJ et al. Heart 2010;96:1821–1825.
N=930
Jankowska EA et al. Circulation 2006;114:1829–1837.
Serum levels of total testosterone in men
with cardiac heart failure (CHF) by NYHA Class
Pooled odds ratios for adverse CV events
of TRT
Event Testosterone rate (per 1,000 patient-
years)
Placebo rate (per 1,000 patient-
years)
Pooled odd ratio (95% CI)
Haematocrit >50% 64.5 2.8 3.67*(0.46,2.52)
Chest pain ischaemia 7.4 8.3 0.93 (0.40;2.44)
Myocardial infarction 7.4 8.3 0.99 (0.67; 2.09
Coronary procedure, CABG
3.7 13.9
0.79
Atrial fibrillation/ arrhythmia
9.2 2.8 1.22
Cerebrovascular events 5.5 11.1 0.86
All cardiovascular events 33.2 44.3 1.14
Death 0 5.5 0.78
Calof et al. 2005, cited by Buvat J et al. J Sex Med 2010;7:1627–1656.
*Odd ratio significantly different from placebo
CABG = coronary artery bypass graft
Adverse events of testosterone therapy in adult
men: a systematic review and meta-analysis
Fernández-Balsells MM et al. J Clin Endocrinol Metab 2010;95:2560 – 2575.
Pugh PJ et al. Heart 2004;90:446–447.
100
0
200
300
400
500
600
700
800
900
Dis
tan
ce
wa
lked
(m
)
Testosterone Placebo
Baseline 12 weeks Baseline 12 weeks
p=0.001 p=0.122
Studies in men with CVD
Testosterone treatment improves exercise capacity in
men with chronic heart failure – randomised, double-
blind, placebo-controlled trial
-0,6
-0,5
-0,4
-0,3
-0,2
-0,1
-1E-15
18 wk vs. baseline 30 wk vs. baseline
Time
Testosterone Placebo
-0,2
-0,1
0
0,1
0,2
18 wk vs. baseline 30 wk vs. Baseline
Time
H
DL
ch
ole
ste
rol (m
mo
l/L
)
p=0.20
Lipids: LDL and HDL – absolute changes
L
DL
ch
ole
ste
rol (m
mo
l/L
)
p=0.07
Kalinchenko S et al. Clin Endocrinol 2010;73(5):602–612.
Inflammation: CRP and TNFα
0,9
1
1,1
1,2
1,3
Baseline 18 30
Time (weeks)
(normal range: 0)
p=0.03
0
1
2
3
4
5
Baseline 18 30
C-r
ea
cti
ve
pro
tein
(m
g/d
L)
Time (weeks)
(normal range: 0–5)
p<0.001
Testosterone Placebo
Kalinchenko S et al. Clin Endocrinol 2010;73(5):602–612.
Tu
mo
ur
ne
cro
sis
fa
cto
r α
(p
g/m
L)
Testosterone replacement could reduce
deaths in men with type 2 diabetes
N=587
Jones TH. Endocrine Abstracts 2011;25:163.
Testosterone treatment is associated with reduced
mortality in men with low serum testosterone levels
Design:
• An observational, retrospective cohort study using VA electronic medical records, from Jan 2001 through Dec 2005, of 1,031 male veterans, 40 years or older, with low tT levels (≤250 ng/dL), excluding those with a history of prostate cancer and baseline anti-androgen or TRT
Results:
• The T-treated men comprised 36% of the cohort (n=372) and were treated for an average of 13.1 12.5 (SD) months. In unadjusted analyses, treated men had a cumulative mortality of 10% compared with 21% in the untreated men (p<0.001). Effect modification was noted with age, diabetes and coronary heart disease (p<0.05 for all) with a greater mortality reduction in men aged 40–65, with diabetes, and without cardiac disease
Conclusions:
• Our data suggest that testosterone treatment in men with low testosterone levels is associated with decreased mortality, particularly in men aged 40–65 and in diabetic men
Shores et al. Endocr Rev, Vol. 32-03(MeetingAbstracts): P1–772.
Adverse events associated with
testosterone administration
• In this study, the testosterone dose applied was not in accordance with the product labelling, clearly recommending a starting dose of 50 mg testosterone (5 g Testim®). In the study, the starting dose was 100 mg testosterone (10 g Testim®). The dose of 150 mg testosterone (15 g Testim®) per day is not at all mentioned in the product labelling
• The study included patients with a high CV risk profile
• The study design does not comply with guidelines and recommendations on testosterone therapy and monitoring for hypogonadism by the medical societies
• The study was not sufficiently powered to give significance for CV events as AEs or SAEs respectively were not endpoints
• The adverse events usually occurred in men with higher testosterone levels
• There was a total low number of poorly documented events (for instance, self-reported syncope, review of medical records). These events are a mixture of different types with no clear evidence that one particular type of event is significant.
Basaria S et al. N Engl J Med 2010;363(2):109–122.
Basaria NEJM 2009: CV-related events
Basaria et al. NEJM 2010;363:109–122.
Bremner W. N Engl J Med 2010;336(2):189–191.
Editorial by William Bremner
Lower testosterone levels predict incident
stroke and transient ischaemic attack in older men
• 3,443 men at least 70 years of age in the Health In Men
Study in Western Australia:
A total testosterone level in the lowest
quartile (<11.7 nmol/l) predicted incident
stroke or TIA with a hazard ratio (HR) of 1.99
Yeap B et al. J Clin Endocrinol Metab 2009;94(7):2353–2359.
Calof OM et al. J Gerontol 2005;60A(11):4051–4057.
2,8
64,5
0
10
20
30
40
50
60
70
80
90
100
Haematocrit > 50%
8,3
13,9
11,1
7,4
3,7
5,5
0
2
4
6
8
10
12
14
16
18
20 Placebo
Testosterone
Meta-analysis of placebo-controlled testosterone trials in
middle-aged and older men: cardiovascular adverse event rates per
1,000 patient-years
Testosterone and CV risk
• It has long been believed that high levels of
testosterone may increase CV risk
• Results from >40 cross-sectional studies found NO
association between high testosterone and CVD
• In approximately half of the studies that assessed the
relationship between T and CHD found lower T levels in
CHD patients
Buvat J et al. J Sex Med 2010;7:1627–1656.
Prostate
Testosterone and prostate cancer risk
27 Comhaire FH. Eur Urol. 2000;38:655–662.
Inverse relationship between decreasing serum testosterone concentration and
the increasing prevalence of prostate cancer with age
1000
800
600
400
200
0
Relative frequency
of prostate cancer
Total Testosterone
(ng/dL)
20 30 40 50 60 70 80 90 >
Age (years)
Morgentaler A. J Urol 2009;181:972–979.
Pro
sta
te g
row
th o
r P
SA
Serum testosterone concentration
a
b
c
The saturation model
T-dependent range T-indifferent range
Pre-treatment testosterone levels predict pathological
stage in men with prostate cancer before radical
prostatectomy
30 Massengill JC et al. J Urol 2003;169:1670–1675.
330
350
pT1-T2
(organ confined)
pT3-T4
(nonorgan confined)
Te
sto
ste
ron
e (
ng
/dL
)
p=0.041
N=879
Testosterone levels and Gleason Scores in men
with prostate cancer before radical prostatectomy
Madersbacher S et al. Urol 2002;60:869–874.
2.2
4.2
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Gleason score 2–6
(n=32)
Gleason score 7–10
(n=17)
Te
sto
ste
ron
e (
ng
/mL
)
p<0.05
upper normal limit
Normal men Testosterone-
treated
hypogonadal men
Untreated
hypogonadal
men
PS
A (
µg
/l)
0
1
2
3
4
PSA in untreated hypogonadal men (n=47), testosterone-treated
hypogonadal men (n=78), and age-matched normal men (n=75)
Effects on the prostate of normalising
testosterone levels in hypogonadal men
Behre H et al. Clin Endocrinol 1994;40:341–349.
Serum PSA and testosterone flare in prostate
cancer patients treated with LHRH-analogue
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Se
rum
n
g/d
l
Days following injection
Testosterone
PSA
100
200
300
400
500
600
700
800
Do high doses of testosterone induce
adverse effects in the prostate?
Tomera K et al. J Urol 2001;16:1585–1589, In: Morgentaler A & Traish AM. Eur Urol 2009;55:310–321.
2,8
38,7
0
10
20
30
40
50
Prostate biopsies
8,3 9,2
0
10
20
Diagnosed prostate cancer
Placebo
Testosterone
Effects on the prostate of normalising
testosterone levels in hypogonadal men
Meta-analysis of placebo-controlled testosterone trials in
1,070 middle-aged and older men: prostate adverse
event rates per 1,000 patient-years
Calof OM et al. J Gerontol 2005;60A(11):4051–4057.
IPASS Nebido® – safety data (1,123 men)
• No case of prostate cancer was observed (4 prostate biopsies
documented)
• Prostate enlargement and urinary retention occurred in 1 patient
PSA = prostate-specific antigen; SD = standard deviation
PSA (ng/mL)
n Mean SD
Baseline 938 1.10 0.94
Visit 2 708 1.20 1.08
Visit 3 676 1.30 1.18
Visit 4 537 1.20 1.03
Visit 5 455 1.10 1.05
Haematocrit (%)
n Mean SD
Baseline 843 42.8 6.56
Visit 2 725 44.0 5.83
Visit 3 684 44.7 6.05
Visit 4 534 44.7 6.18
Visit 5 474 44.5 6.12
Zitzmann M et al. Men’s Health World Congress 2010.
Safety parameters: prostate
0
0,2
0,4
0,6
0,8
1
1,2
Nebido Placebo
Baseline 18 30
0
5
10
15
20
25
30
35
40
Nebido Placebo
PSA total, ng/mL
p=0.13
0.8
1.0
Prostate volume, mL
34 33.4
27.9 28.3 0.8 0.8
p=0.45
0.8
0.9
N=184
Kalinchenko S et al. Clin Endocrinol 2010;73(5):602–612.
Serum testosterone and PSA in older men treated with
escalating doses of testosterone
0
500
1000
1500
2000
2500
3000
3500
25 50 125 300 600
Seru
m T
Weekly testosterone dose (mg)
Testosterone
PSA
0
2
4
6
8
10
Seru
m P
SA
Week 2
0
12
14
Do high doses of testosterone induce
adverse effects in the prostate?
Bhasin S et al. J Clin Endocrinol Metab 2005;90:678–688.
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
100 mg/wk (n=10)
250 mg/wk (n=10)
500 mg/wk (n=10)
PS
A (
ng
/dL)
Before TT Week 16 Week 28 Week 40
11
12
13
14
100 mg/wk (n=10)
250 mg/wk (n=10)
500 mg/wk (n=11)
Pro
sta
te v
olu
me
(m
L)
Effect of exogenous testosterone on prostate volume
and PSA in healthy young men
Do high doses of testosterone induce
adverse effects in the prostate?
Cooper CS et al. J Urol1998;159(2):441–443.
Changes in PSA levels during 36 months
of Testogel® treatment
40
0
1
2
3
4
5
Month
0 6 12 18 24 30 36
Wang C et al. J Clin Endocrinol Metab 2004;89(5):2085–2098.
No significant changes in PSA with 1 year
of IM TU therapy
4
0
1
2
3
Baseline 3 months 6 months 9 months 12 months
PS
A c
on
ce
ntr
ati
on
(µ
g/L
)
Normal value: <4.0 µg/L
Median age: 64 years, range: 54–76
PSA in men with hypogonadism (n=28) presenting with ED
under treatment with TU (Nebido®)
Saad F et al. Arch Androl 2007;53:1–5.
No significant changes in PSA after 1 year of
testosterone treatment* in men with hypogonadism
*IM or transdermal
N=58
0.0
2.0
4.0
PSA
(ng/mL)
Before
After
40–60 years >60 years Injection Transdermal
Rhoden EL & Morgentaler A. Int J Imp Res 2006;18:201–205.
PSA and prostate volume during treatment with
TE/TU in men with hypogonadism*
*n=40
Mean age 41, range: 18–74 yrs
Time (Weeks)
PS
A
(µg
/L)
0.0
0.3
0.5
0.8
1.0
-3 0 3 6 9 12 15 18 21 24 27 30 0
5
10
15
20
25
0 12 30 0 12 30
Pro
sta
te v
olu
me
(m
L)
(Transrectal ultrasonography)
18.24 17.16
14.29 14.51
19.84 20.75
T-Enanthate T-Undecanoate
Time (Weeks)
Huebler D et al. Int J Impot Res 2002;4(Suppl. 4):Abstract P52.
Changes in prostate volume with long
term TU treatment (Nebido®)
Time (Weeks)
10
15
20
25
30
35
0 50 100 150 200 250 300 350
Pro
sta
te V
olu
me (
mL
)
Highest value in total observation period
Von Eckardstein S et al. Andrologia 2004;36(4):65(Abstract).
Changes in PSA levels in hypogonadal men
undergoing long-term treatment with TU (Nebido®)
Time (weeks)
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0 50 100 150 200 300 400 450 250 350
N=22
Zitzmann M et al. Endo 2005. Abstract 306.
0
0,5
1
1,5
2
Before TT After TT Change
no PIN (n=55)
PS
A (
ng
/dL
)
Results of 1 year of testosterone treatment in
hypogonadal men with prostatic
intraepithelial neoplasia (PIN)
Testosterone in patients at high risk
of PCa
Conclusions
• After 1 year of TRT:
– No increase in PSA in men with PIN is observed
– No significantly increased risk of cancer is observed in men without PIN
– Therefore, TRT is not contraindicated in men with a history of PIN
Rhoden EL & Morgentaler A. J Urol 2003;170:2348–2351.
Testosterone in patients at high risk
of PCa
Khera M et al. J Sex Med 2009;6:1165–1170.
Conclusion: TRT is effective in improving testosterone levels, without increasing PSA
values, in men with hypogonadism who have undergone radical prostatectomy (RP)
Study No of patients
Follow-up (months)
Pre-TRT PSA
(ng/dL)
Post-TRT PSA
(ng/dL)
Pre-T (ng/dL)
Post-T (ng/dL)
Agarwal and Oefelein
10 19 <0.1 <0.1 197 591
Kaufman and Graydon
7 24 <0.1 <0.1 97 434
Khera et al
57 13 <0.1 <0.1 254 459
Total 74
Urine flow in untreated hypogonadal men (n=47), testosterone-treated
hypogonadal men (n=78), and age-matched normal men (n=75)
Ma
xim
al u
rin
e f
low
(m
l/s
)
Untreated
hypogonadal men
T-treated
hypogonadal men
Normal
men
0
5
10
15
20
25
30
35
40
Testosterone and lower urinary tract
symptoms (LUTS)
Behre et al. Clin Endocrinol 1994;40:341–349.
Effects on the prostate of normalising
testosterone levels in hypogonadal men
Pro
sta
te v
olu
me
(m
l)
Age (years)
0
10
20
30
40
50
20 30 40 50 60 70 80
Normal men
Hypog. pat.
with therapy
Hypog. pat.
without therapy
Prostate volume measured by transrectal ultrasonography
Behre H et al. Clin Endocrinol 1994;40:341–349.
0
2
4
6
8
10
12
14
16
18
20
IPSS Total T
0
0,5
1
PSA
p<0.00001
p<0.00001
NS
Effect of treatment with IM testosterone undecanoate (Nebido®) for 26 weeks on IPSS and
PSA in 20 men with late-onset hypogonadism (LOH)
Testosterone and LUTS
Kalinchenko SY et al. Aging Male 2008;11(2):57–61.
Baseline
16 weeks
26 weeks
Effect of treatment with testosterone gel 50-100 mg/d (Testogel®) for 6 months in 24
men with LOH and ED on urinary function
0
2
4
6
8
10
12
14
16
18
20
IPSS Average flow (ml/s)
Baseline
6 months
500
550
600
650
Maximal bladder capacity (ml)
p=0.009 N S
p=0.006
Testosterone and LUTS
Karazindiyanoğlu S & Çayan S. Aging Male 2008;11(3):146–149.
IPS
S s
core
Bla
dder
capacity (
mL)
Effect of treatment with testosterone gel 50–100 mg/d (Testogel®) for 6
months in 24 men with LOH and ED on urinary function
0
10
20
30
40
50
60
70
80
Bladder compliance (ml/cm H2O) P detrusor at Qmax (cm H2O)
Baseline
6 months p=0.037
p=0.016
Testosterone and LUTS
Karazindiyanoğlu S & Çayan S. Aging Male 2008;11(3):146–149.
What the guidelines say about TRT and
the prostate
Wang C et al. Eur Urol 2009;55:21–130.
EAU guidelines on erectile dysfunction
2010
• 2.3. Treatment of erectile dysfunction
Hatzimouratidis, Amar, Eardley et al. Eur Urol 2010;57(5):804–814
Fact from fiction – the prostate
• There is no evidence that endogenous testosterone is
associated with prostatic diseases
• Treating testosterone deficiency normalises prostate
development so an initial increase in prostate volume
and PSA is physiologic and could be expected
• Based on the current scientific and medical evidence,
treating hypogonadism with physiologic testosterone
doses after proper diagnosis and under proper
monitoring according to the guidelines can be
considered acceptably safe
Separating the facts from the myths
• Fear of testosterone treatment being associated with an
increased risk of prostate cancer
• Current literature does not provide any evidence for a
cause-effect relationship between endogenous T or T
treatment and prostate cancer development