the role of trt in the management of hypogonadism and trt ... · pdf filethe role of trt in...

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

)


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


-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



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



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


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



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



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.



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


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


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

the role of trt in the management of hypogonadism and trt ... · pdf filethe role of trt in...

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