1. No category

Controversies in testosterone
deficiency: who is a candidate for
treatment and why?
Perspectives from Muenster,
Germany
Prof. Dr. Michael Zitzmann
Internal Medicine –
Endocrinology, Diabetology, Andrology
University of Muenster, Germany
Target organs of androgens
Testosterone levels and symptoms
434 men (age 50-86 years)
Total testosterone (nmol/l)
20
n=
74
69
15
12
10
8
0
Zitzmann et al. J Clin Endocrinol Metab 2006; 91(11): 4335-4343
Non-linearity of androgen effects
Zitzmann et al. JCEM 2006
190
434 men
> 50 years
(untreated)
Hemoglobin g/L
170
150
130
110
90
70
0
5
10
15
20
25
30
35
Total Testosterone nmol/L
40
45
50
Testosterone
Androgen - Receptor
AR co-Activators
AR co-Repressors
Transcription of target genes
Androgenic effects
CAG repeat Polymorphism of the AR gene
The CAG repeat polymorphism
in the androgen receptor (AR) gene
q11-12
p
5’
1
X - chromosome
q
2
3
4 5 6 7 8
3’
AR gene with
exons
Exon 1
Variable number of CAG triplets
NH2
COOH
Variable length of polyglutamine
stretch
Prof. Dr. M. Zitzmann Klinische Andrologie Münster
Curiculum Urologicum, Düsseldorf, 3.-4.12.2010
AR protein
Zitzmann Pharmacogenomics 2009
Modulation of androgen effects
e.g. Mhatre et al. Nature Genetics 1993 5:184–8
Beilin et al. J Mol Endocrinol 2000 25:85-96
Number of CAG repeats
37
9
Increasing
transcriptional activity
 38
Kennedy
Syndrome
Bone structure in relation to testosterone
Benito et al. J Clin Endocrinol Metab 2003 88:1497-502.
Distal Tibia
Normal
MRI-Microimaging
Hypogonadal
Bone density in Finnish Men
aged 50 to 60 years
Remes et al. 2003 Bone 32:412-420
Femur prox.
1.4
1.4
1.3
1.3
1.2
2
p = 0.02
p = 0.05
g / cm
g / cm
2
L4
1.2
1.1
1.1
1.0
1.0
(CAG) 15-17 (CAG) 22-26
(CAG) 15-17 (CAG) 22-26
Depression as
symptom of T deficiency
Picture from an Exhibition „Melancholia“ Paris/Berlin
Increased incidence of depression in hypgonadism
Shores et al Arch Gen Psychiat 2004
N = 278 men > 45 years
initially without depression
Total T > 7 nmol/L
log-rank test p=0.008,
Hazard ratio 4.2
Total T < 7 nmol/L
Time until diagnosis of depression ICD-9-CM , days
Depression in men, age > 50 years
P=0.01 T
P<0.001 CAGn
(Patient Health Questionnaire)
% With Depression
Schneider, Zitzmann et al, Am J Ger Psych 2010
<10
Total T
10 – 12
estoste
>1 2
rone nm
ol / L
9
<1
–2
19
4
AR
4
>2
n
G
CA
Suspicion of Hypogonadism
Canale et al 2005 Clin Endocrinol 63:482
Patients (n=29)
Controls (n=91)
none
Symptoms
normal
Hair pattern
normal
Prostate size
Total Testosterone
15.3 nmol/L
15.2 nmol/L
CAG repeats
24
21
p<0.001
Results of ADAM questionnaire
Liu et al. JSM 2012 epub
Modulation of androgen effects: model
Zitzmann M Nature CPU 2007, Zitzmann Pharmacogenomics 2009
Canale et al. Clin Endocrinol 2005, Zitzmann et al. JCEM 2006
short CAGn
Long CAGn
Symptom-specific
thresholds
0
5
10
15
20
25
30
35
Total Testosterone nmol / L
40
45
An
dr
og
en
ici
ty
T
S
SHBG
Total
Testosterone
CAG
Androgenreceptor
CAG-repeats
Another Problem: Obesity
PREVALENCE OF
TYPE 2 DIABETES MELLITUS, 2007
Source: IDF diabetes atlas
PREVALENCE OF
TYPE 2 DIABETES MELLITUS, 2025
Source: IDF diabetes atlas
European Male Aging Study (EMAS)
relation between age and testosterone (40-79)
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS)
Beziehung zwischen Alter, BMI und Testosteron
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
New Criteria for the
Definition of the Metabolic Syndrome
1.
Waist Circumference >94-102 cm
2.
Triglycerides > 150 mg/dl
or treatment
3.
HDL-Cholesterol < 40 mg/dl
or treatment
4.
Arterial Blood Pressure > 130 mmHg systolic
and/or > 85 mmHg diastolic
or treatment
5.
Fasting glucose > 100 mg/dl
or known Type 2 Diabetes mellitus
3 of 5 Criteria have to be met (Consensus IDF & NCEP ATP III)
Alberti et al. 2009 Circulation
“Silent killers” – components of
the metabolic syndrome
Visceral fat
tissue
+
 Dyslipidemia
 Arterial hypertension
 Insulin resistance/ type
2 diabetes
Sattar N et al. Circulation 2003; 108: 414–9.
General life expectancy and testosterone levels
858 Men (Age ≥ 40 Years; ø 60 Y.)
Cumulative Survival
1,0
0,9
0,8
Total testosterone at
2 assessments
0,7
≥ 8,7 nmol/l
(n=452)
BMI>30
kg x m-2
0,6
< 8,7 nmol/l
(n=160)
0,5
0
2
4
6
Years
Shores et al. Arch Int Med 2006; 166: 1660
8
10
BMI and BMI are not the same...
waist circumference has more to tell
189 cm, 93 kg = BMI 26
Waist circumference
Testosterone
190 cm, 94 kg = BMI 26
>
<
Waist circumference
Testosterone
Testosterone levels decrease with
increasing waist circumference
Total testosterone (nmol/L)
Men aged 25–84 years (n=1584)
p<0.001 for trend
14.7
12.7
n=
Waist circumference (cm):
Limit of lower
normal
11.0
666
536
346
<94
94–101.9
≥102
Svartberg J et al. Eur J Epidemiol 2004; 19: 657–63 (The Tromsø-Study).
Total T levels decrease with increasing number
of metabolic syndrome components
Prevalence of hypogonadism
TT <8 nmol/L
TT <10.4 nmol/L
TT <12 nmol/L
n=1491
p<0.001 for trend in
all subgroups
0
1
2
3
4–5
Number of metabolic syndrome components
Corona G et al. Int J Androl 2009
Visceral Fat
Insulin
Leptin
IL-6
Testosterone
With agreement of Rob McLachlan und Carolyn Allan, Monash University, Melbourne, Australia
Zitzmann et al. 2003 + 2005, Walsh et al. 2005, Mulligan et al. 2006
Zitzmann,
Nature Endo Reviews
2009
Testosterone
changes pathways for stem cells
Mesenchymal Stem Cells
Testosterone
Fat Cells
Singh et al. Endocrinology 2003; 144(11): 5081-5088
Smooth Muscle Cells
A pathway to endothelial dysfunction
and vascular morbidity
PDE5-Inhibitors
Endothelial
dysfunction
Lifestyle
Lack of physical activity
Overnutrition
Smoking
Stress
MetS
TDS
Type 2
diabetes
Time until the onset of the effects of testosterone substitution
Saad, Zitzmann et al. EJE 2011
lean mass
fat mass
waist circumference
1493 patients
were enrolled in 155
sites in 23 countries
worldwide
Zitzmann M et al. JSM epub.
Mean trough serum total testosterone levels
at the end of an injection interval
are within the physiological range
Mean total T (nmol/l)
40
Mean
30
ANOVA: p<0.0001
20
16,0
17,0
17,3
914
813
664
543
9,6
10
0
15,2
n=
1108
Baseline
Zitzmann M et al. JSM epub.
Injection 2
Injection 3
Injection 4
Injection 5
TU therapy improved overall level of mood
very negative/ negative
moderate
positive/ very positive
100%
Patients (%)
19
46
60
45
69
75
25
19
50%
43
33
36
0%
n=
1432
Baseline
11
6
5
5
1390
1295
1220
1140
Injection 2
Injection 3
Injection 4
Overall Chi-Square-Test: p<0.0001
Zitzmann M et al. JSM epub.
Injection 5
Waist circumference (cm)
TU therapy decreased waist circumference
100
Mean
ANOVA: p<0.0001
100
99
98
97
96
96
92
n=
1432
Baseline
Zitzmann M et al. JSM epub.
1388
Injection 2
1294
Injection 3
1215
Injection 4
1140
Injection 5
HbA1c mean change :
total study population and patients with
HbA1c >6.1% at baseline
Baseline 6.2 %
Mean change (%)
0,0
Baseline 7.9 %
-0,3%
-0,4
t-test: p=0.01
-1,1%
-0,8
t-test: p<0.0001
-1,2
n=293
Total population
Zitzmann M et al. JSM epub.
n=60
HbA1c >6.1%
at baseline
Mean Change from Baseline in HOMA/IR
Placebo
T-Gel
Placebo
T-Gel
0,6
0,4
0,2
-0
-0,2
P < 0.05
P < 0.01
-0,4
-0,6
-0,8
6 months
12 months
Improvement
Mean change from baseline in HOMA-IR
Jones TH et al. Diab Care 2012
p=0.029
Treated
n=398, age 61y
baseline T=5.6 nmol/L
incident PCA 1.6%
Untreated n=633, age 62 y
baseline T=6.6 nmol/L
incident PCA 2.0%
Shores et al JCEM 2012 epub
Obesity
Depression
´Classical´ TDS
Check testicular size
< 10 ml
Special diagnostics,
i.e./e.g.:
• Gonadotropins, free T
• Prolactin, Estradiol
• Thyroid and adrenal axes
• Stimulation-tests of pituitary
• Karyotype, (fertility status)
• Testicular ultrasound
• MRI head
Possible cooperation with an
andrologist / endocrinologist
> 10 ml
Measure total testosterone with
an assay you are familiar with
T < lower threshold + 20%:
Proceed with substitution trail
after exclusion of contraindications
Control visits every 3 months:
• Efficacy of treatment satisfying ?
• Hematocrit and PSA normal?
• Additional PDE5-inhibitor ?
Main messages
Signs of T Deficiency are multifold
Think about
• „Classical“ TDS Symptoms
• Obesity
• Depression
• Osteoporosis
• In case of normal T: there is an androgen receptor!