presentation

Testosterone in Sexual
Dysfunction and
Diabetes
Dr. Leighton Seal
Consultant Endocrinologist
St George’s Hospital NHS Trust
Epidemiology
ED
affects an estimated 2.3 million men in
the UK alone
ED
affects at least 1 in every 10 men
It
is estimated that the prevalence of ED will
double over the next 20 years or so
Aytac LA et al, BJU International 1999;84:50-56
Impotence Explained. A couple’s guide to Erectile Dysfunction. The Impotence Association.
The risk of ED at any Age
Probabilty (% population)
70
60
50
40
Minimal
Moderate
Severe
30
20
10
0
40
45
50
55
Age
60
65
70
Hypogonadism
Hypogonadism
testes1,2
Prevalence:
is inadequate function of the
5 men in 1000 in the UK3
–2-4 million men in the US, estimated only 5%
treated4
Diagnosis:
clinical symptoms and
biochemical tests
1. Petak SM et al. Endocrine Pract 2002;8:439-456.
2. Nieschlag E et al. Eur Urol 2005;48:1-4.
3. Handelsman DJ. Androgens. In: Male reproductive endocrinology; Ed. Mclachlan RI. Endotext.com; 2002.
4. Rhoden EL & Morgentaler A. NEJM 2004;350:482-92.
The diagnosis of
hypogonadism1,2
History Examination
Investigations
1. Petak SM et al. Endocrine Pract 2002; 8(6): 439-456.
2. Heinemann LAJ et al. The Aging Male 2001; 4: 14-22.
30
20
10
E-E Baulieu 2002 Mol Cell Endocrinol 198, (1-2) 41-49
Calculated Free Testosterone
http://www.issam.ch/freetesto.htm
R Lepage Clin Biochem 2006 39(2) 97-108
9 am Testosterone levels requiring substitution
Total T
Free T
Testosterone substitution not required
12 nmol/L*
250 pmol/L*
Consider trial of treatment if other causes
of symptoms have been excluded
8 nmol/L*
180 pmol/L*
Testosterone substitution required
* Cut-off values may have to be adjusted
according to laboratory reference values
Nieschlag et al. Eur Urol 2005, 48: 1-4.
Testosterone levels are lower
at all ages in Men with ED
Patient
Control
Testosterone (nmol/l)
30
25
20
15
10
5
0
18-35
35-55
56-70
Age Group
Janinin Int J Androl 1999 22 385-392
Incidence of Testosterone
Deficiency in ED
Nickel
1984
Maatman 1986
Johnson 1992
Buvat
1997
Bodie
2003
Govier 1996
17.5%
1.7%
1.2%
8.0%
18.7%
15.6%
14.6%
256
300
330
1022
3547
268
5467
The Physiology of
Erection
Veno-occlusive
mechanism of
erection
Effects of Castration on Central and
Peripheral Stimulation of Penile
Erection
Suzuki N et al. J Androl 28(2): 218-222 (2007)
Testosterone on the Cavernosal
Nerve Fibers in the Rat Model
Control (sham-operated)
Castrated
Castrated + testosterone
Traish A et al. Eur Urol 52: 54-70 (2007)
Effect of Castration and Androgen Substitution
on Smooth Muscle and Connective Tissue
Content in the Corpus cavernosum
Control
Castrated + Vehicle
Castrated + Testosterone
Traish A et al. Endocrinol 140(4): 1861-1868 (1999)
Testosterone Levels in human
Penis and Blood During
Different Phases of Erection
14
10
7
Becker 2001 UROLOGY 58: 435-440125–129
Pathological Changes in
Hypogonadism
Decreased
Intracavernosal Blood
Pressure
Decreased Nitric Oxide Synthesis
Apoptosis of Smooth Muscle
Decreased corporeal relaxation
Testosterone and Survival
MM Shores Arch Int Med 2006 166 1660-5
Coronary Artery Disease and
Free Testosterone
E-E Baulieu 2002 Mol Cell Endocrinol 198, (1-2) 41-49
Seasonal Changes in
Testosterone
Svartberg J et al. J Clin Endocrinol Metab 2003; 88(7): 3099–3104
Testosterone is Inversely
Related to Central Adiposity
Svartberg J et al. Eur J Epidemiol 2003; 19: 657–663
Weight Reduction Can Increase
Plasma Testosterone
Tsai 2000 Int J Obese 24 485-91
Insulin Sensitivity increases with
Plasma Testosterone and
SHBG
N Pitteloud,, et al. 2005 Diab Care. 28(7);1636,
G Corona European Urology 2006 50(3) 595-604
Incidence of Testosterone
Deficiency in ED
Nickel
1984
Maatman 1986
Johnson 1992
Buvat
1997
Bodie
2003
Govier 1996
17.5%
1.7%
1.2%
8.0%
18.7%
15.6%
14.6%
256
300
330
1022
3547
268
5467
St George’s Diabetic Men’s
Health Clinic
264
80
N=368
70
50
40
81
30
20
11
12
10
ry
H
yp
op
itu
ita
ia
yp
er
pr
ol
ac
ti n
ae
m
H
yp
og
on
ad
al
H
or
m
al
0
N
% Patients
60
Testosterone Levels are Lower in
Men with Type 2 Diabetes
Ding EL et al. JAMA 2006;295(11):1288-1299
+ Angiogram CHD
CHD
CVD
Corona EJE 2011 165 687–701
ED and Silent Ischaemic in
Diabetes
HbA1c %
T Chole (mmol/l)
HDL-C (mmol/l)
LDL-C (mmol/l)
MAU %
Smoking %
LMW Lp(a) %
ED %
CAD
7.4+1.2
5.7+1.0
1.1+0.2
3.3+1.1
45.1
59.4
69.2
No CAD
7.5+1.3
5.4+1.0
1.2+0.2
3.0+1.0
11.8
26.0
31.5
OR 14.8(CI
33.8 3.8-56.9)
4.7
Gazzaruso 2004 Circulation 100 22-6
Summary
ED is a risk factor for IHD
 It is the best indicator of high
cardiovascular risk in Diabetes
 CVS Risk Factor Intervention should be
undertaken in Patients with ED
 On average you have 3 years before the
first major Cardiovascular event

Erectile
Dysfunction
Hypogonadism
IHD
Metabolic
Syndrome
The Male Brain
Reduced testosterone in ED may
be Independent of Libido
Normals
Potent HSD
Impotent HSD
Schavi 1988 Psychosom Med 50:304-318
The threshold Testosterone
levels for Nocturnal
Erection is low
3.5-7
Penile size and erectile
response is Reduced in
hypogonadism
Hypogonadism does not impair
VES Erections
Carani Psychoneuroendocrinology 1992 17647-654
Bancroft 1983 Arch Sex Behav 1983 59-63
Number of Patients
Testosterone level at which
men perceive a reduction in
sexual function
9
8
7
6
5
4
3
2
1
0
1
2
3
4
5
6
7
8
9 10 11
Testosterone (nmol/l)
Gooren 1987 Arch Sex Behav 16 463-473
Overview of symptom-specific
concentrations of TT levels
25
Patients (n)
74
Total testosterone (nmol/l)
20
69
15
12
Loss of Libido
Loss of Vigour
p<0.001
p<0.001
Obesity
p<0.001
Feeling Depressed
Poor Sleep
Poor Concentration
Type 2 DM
10
8
5
0
84
Hot Flushes
Erectile Dysfunction
p= 0.001
p=0.004
p=0.002
p=0.001
65
67
p<0.001
p=0.003
Increasing
prevalence of
symptoms with
decreasing
testosterone
concentration
75
Zitzmann M et al. JCEM 2006;91:4335-4343
DHT has a role in Libido
Endocrine variables:
DHT (nmol/l)
Mean
(SD)
2.73 (0.72)
Univariate
Regression
Coefficients
0.81
Partial regression
Coefficients
(95%CI)
0.610
(0.052 to 1.168)
0.034
-0.009
(-0.058 to 0.040)
0.665
An increase34.01
of(8.77)
dihydrotestosterone
by
0.006
0.184
2
SD
(1.36
nmol/l)
was
associated
with
A4 (nmol/l)
11.10 (2.06)
0.221
(-0.008 to 1.376)
an increase of the weekly number0.037
of
DHEAS (µmol/l)
4.83 (1.25)
0.111
(-0.294 to 0.368)
orgasms by at least one
0.004
Testosterone (nmol/l)
Oestradiol (pmol/l)
Oestrone (pmol/l)
SHBG (µg/dl)
276.57 (81.20)
115.67 (28.74)
0.893 (0.205)
P
Value
0.060
0.685
0.004
(-0.0005 to 0.0085)
0.103
-0.0011
-0.002
(-0.016 to 0.012)
0.793
-1.024
-1.025
(-2.945 to 0.900)
0.298
Mantzoros 1995 BMJ 310 1289-1291
Oestrogen is associated with
reduced orgasmic sexual activity
Knissmann 1986 Arch Sex Behav 15 429-445
The Effects of
Testosterone
Replacement in
Hypogonadism
Morning Erections Increase
with Testosterone
Replacement
1. Rouskova D. Schering data on file 15 Jan 2002.
Testosterone Replacement
Improves ejaculations
1. Nieschlag E et al. Clin Endocrinol (1999); 51: 757-763.
Patch T 14 nmol/l
Gel 50 T 19 nmol/l
Gel 100 T 27.5 nmol/l
Copyright ©2000 The Endocrine Society
Wang, C. et al. J Clin Endocrinol Metab 2000;85:2839-2853
Erectile Response to Testosterone
in Hypogonadism
Jain J Urol 2000164, 371-375
Bancroft 1983 Arch Sex Behav 1983 59-63
Bancroft 1983 Arch Sex Behav 1983 59-63
PDE5 and Response Rates in
Complicating Conditions
Guay 2001 J Androl 22 793-797
Aversa et al Clin Endo (2003) 58, 632–8
Testosterone Improves
Effectiveness of PDE5 in
Hypogonadism
Before
(n=32)
Sildenafil (Sil)
(n=32)
Testosterone (T)
(n=32)
T+Sil (n=21)
TT (nmol/l)
7.7+3.5
9.7+ 5.5
14.5+5.7
17.4+6.2
FT (pmol/l)
178.5+66.5
196.0+94.5
364.0+140
409.5+161
IIEF-EF
12.6 + 7.5
12.0 + 8.5
14.8+6.8*
17.5+ 5.2**
Question 3
2.4 + 0.6
2.3 +0.8
3.1 + 0.7**
3.5+1.0***
Question 4
2.3 + 0.6
2.3 +0.8
2.3 + 0.6
3.6+0.9***
*
P<0.05; ** P<0.01; *** P<0.001.
IIEF-EF: Erectile function domain of IIEF.
Question 3: achieve an erection sufficient for satisfactory sexual intercourse.
Question 4: maintain an erection sufficient for satisfactory sexual intercourse.
Ti-S Hwang Int J Imp Res(2006) 18, 400–404.
% Patients with improved EF
80
70
60
Comparison of 4 vs 10 weeks on
Testosterone on PDE 5
Response
Baseline T 5.4
50
40
T 14.8
30
20
T 10.7
10
0
Group I
4 Weeks
Group II
10 weeks
A. A. Yassin 2006 Andrologia 38 61–68
IIEF in Response to
Testosterone + PDE5
20
IIEF
15
Group I
4W T + TADA
10
Group II
10W T + TADA
5
0
0
4
Time (weeks)
10
A. A. Yassin 2006 Andrologia 38 61–68
Trials Looking At Testosterone
Treatment and ED
Adverse
events
Authors
No. of subjects/
hypogonadism
Sildenafil
response at
baseline
Overall
efficacy
Aversa et al.
20/no
Failure
80%
none
Kalinchenko et al.
120/yes
Failure
70%
none
Shabsigh et al.
75/yes
Failure
70%
not evaluated
Chatterjee et al
12/yes
Not evaluated
100%
none
Shamloul et al
40/no
Failure/present
Improved
none
Greenstein et al.
49/yes
Not evaluated
63%
18% rash
Hwang et al.
32/yes
Failure
57%
none
Rosenthal et al.
24/yes
Failure
92%
1% headache
Tas et al.
23/yes
Not evaluated
34%
none
E A Greco Eur Urol 2006 50(5) 940-7
Effect on body composition
180
Leg
64
strength1
Lean body mass1
170
Weight (Kg)
Weight (Kg)
62
160
150
60
58
140
56
130
0
30
60
Treatment day
90
0
30
60
90
Treatment day
1. Wang C et al. J Clin Endocrinol Metab 2000; 85(8): 2839-2853.
Waist circumference
Results: Waist
Circumference
A
slight decrease in body weight was seen, not reaching statistical significance
Zitzmann et al. J Sex Med 2012
The Effect of Testosterone on
Glycaemic Control
HEUFELDER J Androl 30,(6) 2009 726-733
The Effect of Testosterone on
Glycaemic Control
HEUFELDER J Androl 30,(6) 2009 726-733
Results: HbA1c
HbA1c
mean change
- 0.3%
- 1.1%
Graph
taken from Poster presented at 26th EAU, Vienna, 18th – 22nd March 2011
Zitzmann et al. J Sex Med 2012
Effects Of Testosterone in Heart
Failure
Improvement
in NYHA by
1 class in
35% vs 8%
Malkin European Heart Journal (2006) 27, 57–64
Results: Change in
Metabolic Parameters
Parameter
Unit
Baseline:
Mean ± SD
Injection 5:
Mean ± SD
P (t-test)
Blood pressure
(systolic)
mm Hg
129.3 ± 14.6
127.2 ± 13.1
0.0002
Blood pressure
(diastolic)
mm Hg
79.8 ± 9.8
78.7 ± 8.9
0.016
Serum
triglycerides
mg/dL
1.8 ± 1.13
1.69 ± 0.98
<0.0001
5.09 ± 1.2
4.84 ± 1.14
<0.0001
1.22 ± 0.47
1.24 ± 0.42
0.3
3.00 ± 1.05
2.87 ± 1.01
0.0017
Serum total
cholesterol
mg/dL
Serum HDL
cholesterol
mg/dL
Serum LDL
cholesterol
mg/dL
Zitzmann et al. J Sex Med 2012
Testosterone Supplementation
in Eugonadal males
Psychosexual Stimulation scale
(extent someone allows sexual
stimulation
[lower score+ more
stimualation]
Anderson 1992 JCEM 75 1505-1507
Copyright ©2001 American Physiological Society
Bhasin, S. et al. Am J Physiol Endocrinol Metab 281: E1172-E1181 2001
Alexander 1993 Psychoneuroendo 18:91-102
Testosterone and Libido in
Women
Higher
mid cycle testosterone is associated with
 Less sexual Avoidance
More sexual Gratification
More sexual ideation
More initiation of sexual activity
Higher sexual interest and desire
Increased frequency of masturbation
Increases vasocongestive response to
stimulation
Davies et al TRENDS in Endo and Metab 12 (1) 2001
Androgens correlate with sexual
activity during the menstrual
cycle
Caruso J Sex Med 2014;11:211–221
Testosterone response to VES
Carani 1990 Psychoneuroendo 15 207-216
Janinin Int J Androl 1999 22 385-392
Summary
Structural
and functional changes in the penis
may be caused by chronically low testosterone
levels; they may in part be reversed by
testosterone treatment.
Approximately 15 % of men presenting with
erectile dysfunction have hypogonadal
testosterone levels.
Approximately 50 % of these hypogonadal men
may respond to testosterone alone as a first-line
treatment for ED.
Summary
ED
is a classical symptom of Hypogonadism
and this responds to testosterone treatment
Testosterone does not alter sexual function in
Eugonadal men
PDE5 action is inhibited in Hypogonadism and
improves when testosterone is replaced.
Successful treatment of ED can improve
plasma testosterone levels
Conclusions
ED
is intimately linked to Metabolic
Syndrome
Coexistent Testosterone Deficiency
may be the link to increased IHD
Testosterone Therapy can improve
Glycaemia control in diabetes
TRT may improve function in CHD
2nd Princeton Consensus Conference AJC 200596:313-321;85M-93M