Testosterone and obesity · 2018-02-22 · Testosterone and obesity Prof. Dr. Michael Zitzmann...
Transcript of Testosterone and obesity · 2018-02-22 · Testosterone and obesity Prof. Dr. Michael Zitzmann...
Testosterone and obesity
ReferentProf. Dr. Michael Zitzmann
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Testosterone and obesity
Prof. Dr. Michael Zitzmann
Andrologist, Endocrinologist, Diabetologist
Sexual Medicine (FECSM)
Clinical Andrology /
Centre for Reproductive Medicine and Andrology,
University Clinics Muenster
Germany
WHO Collaborating Centre for Research in Human Reproduction
Training Centre of the European Academy of Andrology
Testosterone levels in men related to age (n=10098)
Kelsey et al. PLoS one 2014
Problem: Obesity
New EAU guideline 2015Markers
of Hypogonadism and Indications for Substitution Therapy
in case of low total T (<12.1 nmol/L) or free T (<243 pmol/L)
• Loss of Libido
• Depressive Mood
• Metabolic Disorders
http://www.uroweb.org/gls/pdf/16_Male_Hypogonadism_LR%20II.pdf
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
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)
40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
European Male Aging Study (EMAS)
relation between age and testosterone (40-79), n=3174
Corona G et al. J Sex Med 8: 2098-2105 (2011)
Prevalence of Hypogonadism in 1687 Men Presenting
to an Outpatient Andrology Unit
0
5
10
15
20
25
30
35
40
17-41 42-51 52-58 59-64 65-88
Age quintiles (years)
Pre
va
len
ce
of
Hy
po
go
na
dis
m (
%)
p<0.0001 for trend
p<0.0001 for trend
NS
BMI < 25 kg/m2 BMI 25-29.9 kg/m2 BMI 30 kg/m2
PREVALENCE OF
TYPE 2 DIABETES MELLITUS, 2025
Source: IDF diabetes atlas
LH
(U
/L)
Testosterone (nmol/L)
Hypogonadal status in 4173
ED subjects studied atthe
University of Florence
Corona et al.,
J. Sex. Med., 2014
Jul;11(7):1823-34.
LH
(U
/L)
Compensated
hypogonadism
(4.1%)
Testosterone ≤10.4 nmol/L
Primary
hypogonadism
(2.5%)
Secondary
hypogonadism
(17.3%)
LH = 9.4 U/L
Eugonadism
(76.1%)Testosterone (nmol/L)
Hypogonadal status in
4173 ED subjects
Corona et al.,
J. Sex. Med., 2014
Jul;11(7):1823-34.
Unknown
Secondary
Primary
Eugonadism
Prevalence of hypogonadism in patients seeking medical
care for ED, n=4220
69.2%
Specific medical
conditions
3.2%
17.4%
50.4% 49.6%
89.1% 10.9%
Corona & Maggi, 2015 JSM
Radio-T
Surgery/CT
Genetic
Specific medical conditions associated with
secondary hypogonadism
1,1
3,4
1,1 1,7
1,1
0,1
2,4
89.1% 10.9%
Trauma
PRL-adenomas
Empty sella DrugsUnknown
Specific medical conditions
Corona & Maggi, 2015 JSM
Unknown
Concomitant metabolic disease
Obesity, T2DM or MetS
Specific medical conditions associated with
secondary hypogonadism
71,828,2
89.1% 10.9%
Unknown
Specific medical conditions
Corona & Maggi, 2015 JSM
Men with TDS as patients in general practice
Risk factor Hypogonadism
prevalence rate
(95% CI)
Odds ratio
(95% CI)
Obesity 52.4 (47.9–56.9) 2.38 (1.93–2.93)
Diabetes
mellitus50.0 (45.5–54.5) 2.09 (1.70–2.58)
Hypertension 42.4 (39.6–45.2) 1.84 (1.53–2.22)
Hyperlipidemia 40.4 (37.6–43.3) 1.47 (1.23–1.76)
Complaints related to testosterone levels
Mulligan T et al. Int J Clin Pract 2006; 60: 762–9.
CI, confidence interval
0
8
10
12
15
20
To
tal
testo
ste
ron
e (
nm
ol/
l)Testosterone levels and symptoms
Zitzmann et al. J Clin Endocrinol Metab 2006; 91(11): 4335-4343
434 men (age 50-86 years)
69
Loss of libidoLoss of vigour
More and moreproblems
84
Overweight
DepressionSleeping disorders
Heat flushes
Erectile Dysfunction
Lacking concentrationTyp 2-Diabetes mellitus
65
67
75
n=
74
Testicular damage
Functional hypogonadismPossibly reversible
Hypothalamic /
pituitary disorder
T LH
Hormone constellations in male
hypogonadism
New Criteria for the
Definition of the Metabolic Syndrome
Alberti et al. 2009 Circulation
1. Waist Circumference >94-102 cm
2. Triglycerides > 150 mg/dl or treatment
3. HDL-Cholesterol < 40 mg/dlor treatment
4. Arterial Blood Pressure > 130 mmHg systolic and/or > 85 mmHg diastolicor treatment
5. Fasting glucose > 100 mg/dlor known Type 2 Diabetes mellitus
3 of 5 Criteria have to be met (Consensus IDF & NCEP ATP III)
Total T levels decrease with increasing
number of metabolic syndrome components
Corona G et al. Int J Androl 2009
Pre
vale
nce o
f h
yp
og
on
ad
ism
0
Number of metabolic syndrome components
1 2 3 4–5
n=1491
TT <12 nmol/LTT <10.4 nmol/LTT <8 nmol/L
p<0.001 for trend in
all subgroups
BMI and BMI are not the same...
the role of visceral fat tissue
189 cm, 93 kg = BMI 26 190 cm, 94 kg = BMI 26
Waist circumference Waist circumference
Testosterone Testosterone
><
Testosterone levels decrease with
increasing waist circumference
Waist circumference (cm):
Svartberg J et al. Eur J Epidemiol 2004; 19: 657–63 (The Tromsø-Study).
14.7
12.711.0
To
tal te
sto
ste
ron
e (
nm
ol/
L)
n= 666 536 346
<94 94–101.9 ≥102
Men aged 25–84 years (n=1584)
Limit of
lower normal
p<0.001 for trend
With agreement of Rob McLachlan und Carolyn Allan, Monash University, Melbourne, Australia
InsulinLeptinIL-6Visceral Fat
Testosterone
Zitzmann et al. 2003 + 2005, Walsh et al. 2005, Mulligan et al. 2006
Testosterone induces Myogenesis in pluripotent Stem Cells
Singh et al. Endocrinology 2003; 144(11): 5081-5088
Testosterone Concentration
0 nM 3 nM 30 nM 100 nM 300 nM
MHC+ Myogene Zellen
0 3 30 100 300
T (nM)
150
100
50
0
MH
CII
+Are
a/f
ield
(μm
2x 1
03) ** **
***
0 3 30 100 300
T (nM)
40
30
20
0
Fat
cells
/fie
ld
*****
***
10
*
Myogenic Cells Fat Cells
Myogenic Cells: ** p< 0,01; ***p< 0,001Fat Cells: *p = 0,02; **p< 0,004; ***p< 0,001
Testosterone changes pathways for stem cells
Singh et al. Endocrinology 2003; 144(11): 5081-5088
Fat Cells Smooth Muscle Cells
Mesenchymal Stem Cells
Testosterone
Visceral fat tissue
Metabolic Syndrome➢Insulin Resistence➢Arterial
hypertension➢Adiposity
Hypogonadism➢Depression➢Other psychotropic effects➢Osteoporosis➢Anemia
ConsequencesType ➢ 2 Diabetes mellitusCardiovaskular➢ DiseasesErectile➢ Dysfunction
Leptin
Insulin Cytokines
Leydig CellFunction
Hypothalamic-Pituitary-GonadalAxis / GPR54-Kisspeptin-System
Visceral Fat
+
+
+
+
+
+
-
Zitzmann M. Nat Rev Endocrinol 2009; 5: 673-681
Estradiol
The interplay of fat tissue, insulin resistance, testosterone deficiency and
VASCULAR INTEGRITY
Zitzmann Nature Endo Rev 2009
Grossmann M et al. J Clin Endocrinol Metab 96(8): 2341-2353 (2011)
Effects of Weight Loss on Testosterone Levels
Bariatric Surgery
Diet / Exercise
Meta-Analysis
Changes Testosterone related to weight change – longitudinal results
European Male Ageing Study (n=2395)
Camacho EM et al. Eur J Endocrinol 168: 445-455 (2013)
5,75
1,96
0,28
-0,33
-1,2
-1,89
-4,35
-6
-4
-2
0
2
4
6
8
lost > 15% lost 10-15% lost 5-10% within 5% gained 5-10% gained 10-
15%
gained > 15%
p<0.05
p<0.05 p<0.05 p<0.05
p<0.01Δ (nmol/l)
Rastrelli et al JCEM June 2015
Rastrelli et al JCEM June 2015
Rastrelli et al JCEM June 2015
1
3
6
9
2
457
8
1011
Months
Time-depent and symptom-specific onset of effects of testosterone substitution
Saad, Zitzmann et al. EJE 2011
Libido
Vigor
Depression
Red blood count
Obesity
Insulin sensitivity
Erectile function
Bone density
• Design: 56-week, randomised, double-blind, parallel, placebo-
controlled study conducted at a tertiary referral centre
• Subjects: 100 obese adult men (BMI ≥30 kg/m2) with a repeated
total testosterone level <12 nmol/L and median age 53 years
receiving 10 weeks of a VLED followed by 46 weeks of weight
maintenance
• Treatment: randomisation to 56 weeks of 1000 mg intramuscular
testosterone undecanoate (n=49) or matching placebo (n=51)
• Key outcome measures (pre-specified): differences in fat and
lean mass by DXA scan, and visceral fat area by CT scan
Fui MNT et al. BMC Med 14:153 (2016)
Effects of testosterone treatment on body
fat and lean mass in obese men on a hypocaloric diet:
a randomised controlled trial
*p<0.05 versus baseline within group; data are mean + 95% confidence interval
NS, not significant; VLED, very low energy diet
Fui MNT et al. BMC Med 14(1):153 (2016)
Change from Baseline in Body Composition After 10 Weeks of a
VLED and Treatment with Intramuscular Testosterone Undecanoate
or Placebo
Ch
an
ge f
rom
Bas
eli
ne i
n O
utc
om
e
Testosterone (n=49)Placebo (n=51)
p=NS
p=NS
p=NS
**
**
**
*p<0.05 versus baseline within group; data are mean + 95% confidence interval
NS, not significant
Fui MNT et al. BMC Med 14(1):153 (2016)
Change from Baseline in Body Composition After 56 Weeks of
Treatment with Intramuscular Testosterone Undecanoate or PlaceboC
han
ge f
rom
Baseli
ne i
n O
utc
om
e
Testosterone (n=49)Placebo (n=51)
p=0.04
p=0.003
p=0.002
*
*
*
*
*
*p<0.05 versus baseline within group; data are mean + 95% confidence interval
NS, not significant; VAT, visceral abdominal tissue; VLED, very low energy diet
Fui MNT et al. BMC Med 14(1):153 (2016)
Change from Baseline in Body Composition After 10 and 56 Weeks of Treatment with Intramuscular Testosterone Undecanoate or
Placebo
Testosterone (n=49)Placebo (n=51)
Ch
an
ge f
rom
Baseli
ne
in V
AT
Are
a (
mm
2)
p=NS
*
*
p=0.04
*
*
Effects of 5 years Treatment with Testosterone on Δ Total Testosterone (nmol/L) in 40
Hypogonadal Men (T<11 nmol/L) with Metabolic Syndrome (IDF criteria)
-2
-1
0
1
2
3
4
5
6
7
8
9
10
baseline 12 months 24 months 36 months 48 months 60 monthsCh
an
ge
in
To
tal
tes
tos
tero
ne
(n
mo
l/L
)
Testosterone (n=20) Control (n=20)
Francomano D et al. Urol 2013
***
***
****** ***
Effects of 5 years Treatment with Testosterone on Δ Waist Circumference
(cm) in 40 Hypogonadal Men (T<11 nmol/L) with Metabolic Syndrome (IDF)
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
baseline 12 months 24 months 36 months 48 months 60 months
Ch
an
ge
in
Wa
ist
cir
cu
mfe
ren
ce
(c
m)
Testosterone (n=20) Control (n=20)
Francomano D et al. Urol 2013
***
******
******
Effects of 5 years Treatment with Testosterone on Δ Body Weight (kg)
in 40 Hypogonadal Men (T<11 nmol/L) with Metabolic Syndrome (IDF)
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
2
baseline 12 months 24 months 36 months 48 months 60 months
Ch
an
ge
in
We
igh
t (k
g)
Testosterone (n=20) Control (n=20)
Francomano D et al. Urol 2013
***
***
***
***
***
Reduction of Waist Circumference (mean ± S.E.s) in 411 Hypogonadal Men
in Obesity Classes I, II, and III Receiving Long-Term Testosterone TreatmentW
ais
t C
ircum
fere
nce (
cm
)
90
100
11
01
20
13
01
40
15
0
Class I Class II Class III
214
214
213
207
174
161
139
86
70
150
150
146
144
126
124
100
67
56
47
47
47
45
45
43
34
28
24
BaselineYear 1
Year 2Year 3
Year 4Year 5
Year 6Year 7
Year 8
**
* * * * * *
**
* * ** * *
**
**
* * * *#
#
# p=
0.0
001
p=
0.0
027
p=
NS
p=
NS
#
#
#
#
#
p=
NS
p=
0.0
32
2
#
#
#
# p=
0.0
009
p=
NS
p=
0.0
04
3
* p<0.0001 vs. baseline; # p<0.0001 vs. previous year; all other p values indicate comparison to previouss yr.
Saad F et al. Int J Obes 40(1): 162-170 (2016)
Reduction of Body Weight (mean ± S.E.s) in 411 Hypogonadal Men
in Obesity Classes I, II, and III Receiving Long-Term Testosterone TreatmentW
eig
ht
(kg
)
80
90
10
01
10
12
01
30
14
01
50
Class I Class II Class III
214
214
213
207
174
161
139
86
70
150
150
146
144
126
124
100
67
56
47
46
47
45
45
43
34
28
24
BaselineYear 1
Year 2Year 3
Year 4Year 5
Year 6Year 7
Year 8
*
**
* **
**
*
**
**
**
*
*
*
*
*
**
* *#
#
#
p=
0.0
001
#
#
p=
0.0
074
#
#
#
#
#
p=
0.0
001
p=
0.0
115
#
#
#
#
#
p=
0.0
434
p=
0.0
160
* p<0.0001 vs. baseline; # p<0.0001 vs. previous year; all other p values indicate comparison to previouss yr.
Saad F et al. Int J Obes 40(1): 162-170 (2016)
Traish A et al. J Cardiovasc Pharmacol Therapeut 22, published online Feb 09, 2017
Baseline Characteristics, Comorbidities and Concomitant Medication in
Total and Propensity-Matched Groups
Traish A et al. J Cardiovasc Pharmacol Therapeut 22, published online Feb 09, 2017
Changes in Waist Circumference in Total Testosterone-Treated and Untreated Groups
Yellow bars show the estimated mean difference between groups, adjusted for baseline age, weight, waist
circumference, fasting glucose, lipids, blood pressure, and quality of life (measured by AMS)
Longterm treatment of hypogonadal men:
results from a 9-year-registry
• 650 patients with hypogonadism
• 266 with primary forms (age 34±12 y) including 149 Klinefelter
patients
• 196 with secondary origin (age 32±12 y)
• 188 with non-classical (“functional”) hypogonadism (age 42±11 y)
• receiving intramuscular of T undecanoate (1000 mg) for max 9 y
88,0
90,0
92,0
94,0
96,0
98,0
100,0
96,0
98,0
100,0
102,0
104,0
106,0
108,0
110,0
Body weight (kg)ANOVA p<0.0001
Waist Circumference (cm)ANOVA p<0.0001
Baseline and follow-up years
Baseline and follow-up years
Zitzmann et al AUA 2017
Longterm treatment of hypogonadal men:
results from a 9-year-registry
Zitzmann et al AUA 2017
Longterm treatment of hypogonadal men:
results from a 9-year-registry
Zitzmann et al AUA 2017
Meta-Analysis of 59 randomized controlled trials of
T substitution in hypogonadism
3029 men (treated) vs 2049 (controls)
Corona, Maggi, Zitzmann et al EJE 2016; 174(3):R99-R116
Endothelial
dysfunction
Type 2
diabetes
A pathway to endothelial dysfunction and vascular morbidity
Lifestyle
Lack of physical activity
Overnutrition
Smoking
Stress
MetS
TDS
Other
interventions
Modified after Makhsida et al. J Urol 2005; 174: 827-834