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Mario MaggiSexual Medicine &
AndrologyUniversity of
Florence,[email protected]
Alternative managementof hypogonadism:DHEA and other
Mario MaggiSexual Medicine &
AndrologyUniversity of
Florence,[email protected]
Alternative managementof hypogonadism:DHEA and other
G. RastrelliG. Corona
at age 25 years,DHEA =0.2-0.9 μg/dL (7-31 nmol/L)DHEAS= 75-370 μg/dL (2-10 µmol/L),
Alternative managementof hypogonadism:DHEA
DHEAS= 75-370 μg/dL (2-10 µmol/L)
Cholesterol
Pregrenolone 17-hydroxypregrenolone DHEA
Progesterone 17-hydroxyprogesterone Delta-4-androstenedione
Testosterone
Dihydrotestosterone
17-
17- 17, 20
17, 20
3- 3- 3-
17-R
5--R
Estradiol
EstroneA
A 17-R
DHEASSK
DHEA has been implicated in a broad range of age-related biological abnormalities including:
-Obesity-Diabetes, insulin resistance-Osteoporosis-Sexual dysfunction-Mental disorders-Cancer-Hypertension, -Atherosclerosis-Coronary artery disease-Eating disorders
■The gamma-aminobutyric acid (GABA)-A/benzodiazepine receptor complex, via which DHEA and DHEA-S may antagonize the effects of GABA [1]■ N-methyl-D aspartate excitatory amino acid receptors, where DHEA may potentiate the effects of glutamate [2]■A nuclear hormone-type receptor called CAR, for which reduced metabolites of DHEA may be the natural ligands [3]■A cell-surface receptor in vascular endothelial cells that binds DHEA (but not DHEA-S) and is functionally coupled to G-proteins and nitric oxide synthase [4]■The sigma-1 receptor binds neurosteroids, including DHEA and DHEA-S, which have antidepressant-like effects in animal models of depression [5]
1.Sousa A, Ticku MK. Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA(A) receptor complex reveals that it may act via the picrotoxin site. J Pharmacol Exp Ther 1997; 282:827.2.Johansson T, Le Grevès P. The effect of dehydroepiandrosterone sulfate and allopregnanolone sulfate on the binding of [(3)H]ifenprodil to the N-methyl-d-aspartate receptor in rat frontal cortex membrane. J Steroid Biochem Mol Biol 2005; 94:263.3.Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 1998; 395:612.4.Liu D, Dillon JS. Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3). J Biol Chem 2002; 277:21379.5.Takebayashi M, Hayashi T, Su TP. A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry 2004; 37 Suppl 3:S208.
DHEA Mechanism of Action
Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006221.
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
PUBLISHED studiesMedline searchN=220
29 Retrieved
UNPUBLISHED StudiesN=22
SpecificSub-population N=7
Women N=9
OngoingN=4
N=0 Retrieved
Specificsub-population N=51
No results stratified for DHEAS=75
No RCT studies N=49
Women N=8
Men and women pooled results N=2
Children N=6
N=29
TOTAL N=29
No results available N=2
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Study Design
n=3369
Study Design• Longitudinal study
– Baseline survey 2003 - 2005 – Follow-up survey 2008-2009
• Random population sample of community-dwelling men stratified by age (40-79 yr)
• 8 centres in Europe, 400 subjects/country• Identical instruments, standardised methods across 8 centres
for anthropometric evaluation and heel ultrasound• Questionnaires translated into local languages• Blood samples for measurement of 18 hormones and DNA
polymorphisms • Lee et al. (Int J Androl. 2008; 31:1-14)
Principal Investigators
F WU (Coordinator, Manchester)and J Arnott (Manchester)
G Bartfai (Szeged)
F Casanueva (Santiago de Compostela)
G Forti (Florence)A Giwercman (Malmo)
I Huhtaniemi (Turku)
K Kula (Lodz)
M Punab (Tartu)
D Vanderscheuren (Leuven)
Expert AdvisorsS Boonen (Leuven)M Lean, J Lara, T Han (Glasgow)D O’Connor (Leeds) N Pendleton, G McFarlane, J Adams, E Riley (Manchester)J McKinlay (Boston)M Maggi (Florence)
Co-ordinationJ Finn, C Moseley, P Steer (Manchester)
Data AnalysisG Dunn M Lunt G Corona G RastrelliT O’Neill A TajarS Pye D Lee
Funding: Commission of the European Communities Fifth Framework Programme “Quality of Life and Management of Living Resources” Grant QLK6-CT-2001-00258
EMAS Research Team
DH
EA
S (
mol
/L)
DHEA (nmol/L)
r=0.44; p<0.0001
Relationship between circulating DHEA and DHEAS levels in European population
Rastrelli, Corona et al., 2014, unpublished
Does DHEA supplementation increaseDHEAS
levels in elderly men?
0,00
10,00
20,00
30,00
40,00
50,00
60,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
DHEAS mean differences (mol/L) 0 10 20 30 40 50 60
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Baulieu et al., 2000
Arlt et al., 2001
Jedrzejuk et al., 2003
Villareal et al., 2004
Nair et al., 2006
Villareal et al., 2006
Jankowski et al., 2008
Muhlen et al., 2008
Weiss et al., 2009
Overall
Favours Placebo Favors DHEA
30,10 7,90 52,30 0,01
12,06 7,50 16,62 0,00
17,62 11,85 23,38 0,00
8,01 6,45 9,56 0,00
7,70 5,83 9,57 0,00
21,20 18,59 23,82 0,00
8,44 7,85 9,02 0,00
9,00 4,78 13,22 0,00
7,40 6,85 7,95 0,00
5,90 4,16 7,64 0,00
6,50 5,91 7,09 0,00
8,13 7,88 8,38 0,00
9,09 8,00 10,19 0,00
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Age (years)
ng/d
l
B=-0.131±0.004; P<0.0001
Florence Lods Manchester Szeged
Leuven Malmo Santiago Tartu
p=0.002 at ANOVA
DH
EA
S (
mol
/L)
DH
EA
S (
mol
/L)
DHEA levels variations in European populationas a function of age and centres
Rastrelli, Corona et al., 2014, unpublished
Age (years)
ng/d
l
B=-0.131±0.004; P<0.0001
DH
EA
S (
mol
/L)
DHEA levels variations in European populationas a function of age and centres
+ DHEA
In RCT DHEA supplementation increases
DHEAS level of 9.09 [8-10.19] mol/L with
Doses ranging fro 25-100 mg/daily
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
r=0.05; p=0.004 r=-0.04; p=0.014 r= -0.09; p<0.00016
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
Tota
l Tes
tost
eron
e (n
mol
/L)
17 β
Est
radi
ol(p
mol
/L)
SHB
G (
nmol
/L)
Sex hormone levels according to DHEAS levels in European population
Rastrelli, Corona et al., 2014, unpublished
r=0.16; p<0.0001 r=0.08; p<0.0001
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
Free
Tes
tost
eron
e (p
mol
/L)
Free
17 β
Est
radi
ol(p
mol
/L)
r=0.04; p=0.016
I II III IVQuartiles of DHEAS
DH
T (n
mol
/L)
Sex hormone levels according to DHEAS levels in European population
Rastrelli, Corona et al., 2014, unpublished
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
Hem
oglo
bin
(g/d
L)
Prol
actin
(ng/
mL
)
I II III IVQuartiles of DHEAS
PSA
(ng/
mL
)
Sex hormone dependent parameters according to DHEAS levels in European population
B= 0.011±0.009; p=0.214 B= 0.033±0.040; p=0.402
B= 0.121±0.053; p=0.022
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT
adjusted model
+ Androgenic + Estrogenic + Androgenic
Rastrelli, Corona et al., 2014, unpublished
I II III IVQuartiles of DHEAS
SHB
G (
nmol
/L)
Sex hormone levels according to DHEAS levels in European population
I II III IVQuartiles of DHEAS
B= 0.015±0.007; p=0.022
adjusted model
B= -0.292±0.098; p=0.003
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT
Even after adjusting forconfounders and major sexsteroid levels, DHEAS isassociated with some effects:1) Androgenic (SHBG)2) Estrogenic (PRL)
Prol
actin
(ng/
mL
)
+ Estrogenic + Androgenic
Rastrelli, Corona et al., 2014, unpublished
Does DHEA supplementation increases T and 17βE2 levels in elderly men?
‐40,00
‐20,00
0,00
20,00
40,00
60,00
80,00
100,00
120,00
140,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
E2 mean differences (pmol/L) -40 -20 0 20 40 60 80 100 120 140
Favours Placebo Favors DHEA
Morales et al., 1994
Nestler et al., 1988
Flynn et al., 1999**
Flynn et al., 1999**Baulieu et al., 2000
Arlt et al., 2001
Jedrzejuk et al., 2003
Villareal et al., 2004
Martina et al., 2006Nair et al., 2006
Villareal et al., 2006
Jankowski et al., 2008
Muhlen et al., 2008
Weiss et al., 2009
Overall
9,40 -6,60 25,40 0,25
26,00 -20,46 72,46 0,273
85,81 50,32 121,30 0,000
77,94 34,86 121,02 0,000
1,67 -8,09 11,42 0,738
1,00 -6,71 8,71 0,799
2,57 -27,60 32,75 0,867
41,18 23,65 58,70 0,000
16,00 3,45 28,55 0,012
20,00 10,62 29,38 0,000
50,40 34,30 66,50 0,000
59,50 27,75 91,25 0,000
3,00 -7,58 13,58 0,578
23,16 8,81 37,52 0,002
24,76 14,14 35,39 0,000
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐15,00
‐10,00
‐5,00
0,00
5,00
10,00
15,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
TT mean differences (nmol/L) -15 -10 -5.0 0 5 10 15
Favours Placebo Favors DHEA
Morales et al., 1994Morales et al., 1998Nestler et al., 1988Reiter et al., 1998Flynn et al., 1999*Flynn et al., 1999**Baulieu et al., 2000Arlt et al., 2001Kahn et al., 2002Jedrzejuk et al., 2003Kawano et al., 2003Libè et al., 2004Villareal et al., 2004Martina et al., 2006Villareal et al., 2006Jankowski et al., 2008Muhlen et al., 2008Morales et al., 2009Weiss et al., 2009Overall
1,00 -4,32 6,32 0,710,00 -2,77 2,77 1,00
-0,40 -10,40 9,60 0,943,43 1,54 5,32 0,001,32 -1,53 4,17 0,36
-2,64 -5,17 -0,10 0,045,49 2,05 8,93 0,00
-0,50 -3,18 2,18 0,711,37 -0,95 3,69 0,251,03 -3,51 5,56 0,66
-0,12 -4,58 4,34 0,96-0,53 -7,54 6,48 0,88-0,34 -3,21 2,53 0,816,30 3,91 8,69 0,000,70 -2,86 4,26 0,70
-1,70 -3,72 0,32 0,101,50 -1,57 4,57 0,343,00 0,19 5,81 0,041,47 -2,97 5,92 0,521,20 0,00 2,42 0,05
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
DHEA: only a sex steroid precursor or indeed an effective androgen?
1. body fat composition2. glycometabolic profile3. lipid profile4. CV risk5. bone health6. quality of life7. sexual functioning8. mental disorders
body fat composition
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
BM
I Kg/
m2
Wai
st c
ircu
mfe
renc
e (c
m)
r= -0.09; p<0.0001 r= -0.154; p<0.0001
Antropometric paramenters according to DHEAS levels in European population
unadjusted model
Rastrelli, Corona et al., 2014, unpublished
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT
Antropometric paramenters according to DHEAS levels in European population
adjusted model
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
BM
I Kg/
m2
Wai
st c
ircu
mfe
renc
e (c
m)
B= -0.077±0.026; p=0.003 B= -0.214±0.071; p=0.003
Rastrelli, Corona et al., 2014, unpublished
unadjusted model
Antropometric paramenters according to DHEAS levels in European population
Fat mass markers
Rastrelli, Corona et al., 2014, unpublished
I II III IVQuartiles of DHEAS
Bic
ep sk
info
ld th
ickn
ess (
cm)
Tric
ep sk
info
ld th
ickn
ess (
cm)
I II III IVQuartiles of DHEAS
r=0.05; p=0.004 r=0.04; p=0.016
I II III IVQuartiles of DHEAS
Bic
ep sk
info
ld th
ickn
ess (
cm)
Tric
ep sk
info
ld th
ickn
ess (
cm)
adjusted model
B= -0.102±0.025; p<0.0001 B= -0.151±0.033; p<0.0001
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT
Antropometric paramenters according to DHEAS levels in European population
Fat mass markers
Rastrelli, Corona et al., 2014, unpublished
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
Arm
cir
cum
fere
nce
(cm
)
Cal
f cir
cum
fere
nce
(cm
)
r= -0.08; p<0.0001 r= 0.08; p<0.0001
unadjusted model
Antropometric paramenters according to DHEAS levels in European population
Lean mass markers
Rastrelli, Corona et al., 2014, unpublished
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
Arm
cir
cum
fere
nce
(cm
)
Cal
f cir
cum
fere
nce
(cm
)
Antropometric paramenters according to DHEAS levels in European population
Lean mass markers
B= -0.034±0.021; p=0.099 B= -0.049±0.026; p=0.060
adjusted modelAdjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT Rastrelli, Corona et al., 2014, unpublished
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites and confounders
Does DHEA supplementation improvebody fat composition in elderly men?
‐3,50
‐3,00
‐2,50
‐2,00
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
FAT mass standarized mean differences (ng/ml) -3.5 -3.0 -2.5 -2.0 -1.5 -1.0-0.5 0 0.5 1.0
Morales et al., 1994
Morales et al., 1995
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Kahn et al., 2002
Jankowski et al., 2006
Nair et al., 2006
Weiss et al., 2011
Overall
-0,04 -0,81 0,72 0,91
-1,07 -2,12 -0,02 0,04
-1,22 -2,22 -0,21 0,02
-1,46 -2,86 -0,07 0,04
-0,10 -0,72 0,52 0,74
0,08 -0,56 0,72 0,81
-0,08 -0,51 0,34 0,70
0,03 -0,47 0,53 0,91
-0,21 -0,71 0,30 0,43
-1,00 -1,60 -0,41 0,00
-0,35 -0,65 -0,05 0,02
Favours Placebo Favors DHEACorona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐10,00
‐8,00
‐6,00
‐4,00
‐2,00
0,00
2,00
4,00
6,00
8,00
10,00
Source
Lean mass standarized mean differences (ng/ml) -10 -8.0 -6.0-4.0-2.0 0 2 4 6 8 10
Favours Placebo Favors DHEA
Morales et al., 1995
Morales et al., 1998
Flynn et al., 1999 dheas*
Flynn et al., 1999 placebo**
Jankowski et al., 2006
Nair et al., 2006
Jankowski et al., 2011
Overall
1,00 0,09 1,91 0,03
0,70 -7,62 9,02 0,87
0,20 -6,00 6,40 0,95
0,00 -8,27 8,27 1,00
-0,20 -1,21 0,81 0,70
0,87 -0,02 1,76 0,06
-0,10 -0,91 0,71 0,81
0,39 -0,05 0,84 0,08
Diff. in mean LL, 95% CI UL, 95% CI p
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT decreases fat mass and does not increases leanmass.
‐3,50
‐3,00
‐2,50
‐2,00
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
FAT mass standarized mean differences (ng/ml) -3.5 -3.0 -2.5 -2.0 -1.5 -1.0-0.5 0 0.5 1.0
Morales et al., 1994
Morales et al., 1995
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Kahn et al., 2002
Jankowski et al., 2006
Nair et al., 2006
Weiss et al., 2011
Overall
-0,04 -0,81 0,72 0,91
-1,07 -2,12 -0,02 0,04
-1,22 -2,22 -0,21 0,02
-1,46 -2,86 -0,07 0,04
-0,10 -0,72 0,52 0,74
0,08 -0,56 0,72 0,81
-0,08 -0,51 0,34 0,70
0,03 -0,47 0,53 0,91
-0,21 -0,71 0,30 0,43
-1,00 -1,60 -0,41 0,00
-0,35 -0,65 -0,05 0,02
Favours Placebo Favors DHEA
ultivariate analysis fat mass after DHEA supplementation:E2 adj r= 0.478 ; p <0.0001TT adj r=-0.415; p<0.0001DHEAS adj r=0.057; p=0.246
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites
Glycometabolic profile
B= -0.003±0.010; p=0.802
I II III IVQuartiles of DHEAS
Gly
caem
ia (m
mol
/l)
I II III IVQuartiles of DHEAS
Insu
lin (m
U/L
)
B= -0.228±0.082; p=0.005
Glycometabolic parameters according to DHEAS levelsin European population
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT Rastrelli, Corona et al., 2014, unpublished
Does DHEA supplementation improve glycometabolic profile in elderly men?
Morales et al., 1994
Nusen et al., 1995
Flynn et al., 1999
Flynn et al., 1999**
Jedrzejuk et al., 2003
Nair et al., 2006
Overall
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00 Diff. in mean LL, 95% CI UL, 95% CI pSource
Glycaemia mean differences (mmol/L) -1.5 1 0.5 0 0.5 1.0
Favours Placebo Favors DHEA
-0,11 -0,88 0,66 0,78
-0,44 -1,14 0,26 0,22
0,02 -0,60 0,64 0,96
0,00 -0,64 0,64 1,00
0,04 -0,76 0,84 0,93
0,04 -0,46 0,55 0,87
-0,06 -0,32 0,21 0,67
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00
1,50 Diff. in mean LL, 95% CI UL, 95% CI pSource
Insulin mean differences (mU/L) -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5
Favours Placebo Favors DHEA
Morales et al., 1998
Flynn et al., 1999*
Flynn et al., 1999**
Jedrzejuk et al., 2003
Kawano et al., 2003
Martina et al., 2006
Nair et al., 2006
Jankowski et al., 2011
Overall
0,24 -0,26 0,74 0,35
0,00 -0,92 0,93 0,99
-0,14 -0,50 0,23 0,46
0,10 -0,18 0,38 0,48
0,00 -0,26 0,26 1,00
0,40 -0,04 0,84 0,07
-0,03 -0,14 0,08 0,58
0,00 -0,33 0,33 1,00
0,00 -0,08 0,09 0,92
-0,10 -0,51 0,31 0,63
-0,03 -0,16 0,10 0,62
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites.
2. Glycometabolic profile: no association with glycaemia, only with insulin.No improvement after DHEA-RT
I II III IVQuartiles of DHEAS
Tota
l cho
lest
erol
(mm
ol/l)
B= 0.014±0.009; p=0.143
I II III IVQuartiles of DHEAS
I II III IVQuartiles of DHEAS
HD
L ch
oles
tero
l (m
mol
/l)
B= 0.012±0.003; p<0.0001
I II III IVQuartiles of DHEAS
LD
L ch
oles
tero
l (m
mol
/l)
B= 0.006±0.009; p=0.526
I II III IVQuartiles of DHEAS
Trig
lyce
ride
s (m
mol
/l)
B= -0.017±0.008; p=0.042
Lipid parameters according to DHEAS levelsin European population
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT
I II III IVQuartiles of DHEAS
HD
L ch
oles
tero
l (m
mol
/l)
B= 0.012±0.003; p<0.0001
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTBMI
I II III IVQuartiles of DHEAS
Trig
lyce
ride
s (m
mol
/l)
B= -0.017±0.008; p=0.042
Lipid parameters according to DHEAS levelsin European population
Does DHEA supplementation improvelipid profile in elderly men?
‐2,00
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00
1,50 Diff. in mean LL, 95% CI UL, 95% CI pSource
Total cholesterol mean differences (mmol/L) -2.0 -1.5 -1.0 0.5 0 0.5 1.0 1.5
Favours Placebo Favors DHEA
Morales et al., 1994
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Jedrzejuk et al., 2003
Kawano et al., 2003
Martina et al., 2006
Jankowski et al., 2011
Overall
0,14 -0,47 0,75 0,65
-0,41 -1,42 0,60 0,43
-0,18 -1,10 0,74 0,70
-0,05 -0,60 0,50 0,86
-0,36 -0,86 0,14 0,16
0,15 -0,54 0,84 0,67
0,02 -1,02 1,06 0,97
-0,30 -0,85 0,25 0,289
0,11 -0,53 0,75 0,736
-0,11 -0,33 0,11 0,340
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Morales et al., 1994
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Jedrzejuk et al., 2003
Kawano et al., 2003
Martina et al., 2006
Nair et al., 2006
Srinivasan et al., 2010
Overall
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00
1,50 Diff. in mean LL, 95% CI UL, 95% CI pSource
LDL cholesterol mean differences (mmol/L) -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5
Favours Placebo Favors DHEA
0,18 0,03 0,33 0,02
-0,26 -1,04 0,52 0,51
-0,13 -0,85 0,59 0,72
0,03 -0,50 0,56 0,91
-0,21 -0,69 0,27 0,39
0,02 -0,64 0,68 0,95
0,21 -0,90 1,32 0,71
-0,20 -0,75 0,35 0,48
-0,12 -0,40 0,16 0,40
0,18 -0,37 0,73 0,52
0,06 -0,05 0,18 0,30
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60 Diff. in mean LL, 95% CI UL, 95% CI pSource
HDL cholesterol mean differences (mmol/L) -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
Favours Placebo Favors DHEA
Morales et al., 1994
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Jedrzejuk et al., 2003
Kawano et al., 2003
Martina et al., 2006
Nair et al., 2006
Srinivasan et al., 2010
Overall
-0,01 -0,15 0,13 0,89
0,00 -0,36 0,36 1,00
-0,11 -0,31 0,09 0,28
0,00 -0,19 0,19 1,00
-0,12 -0,38 0,14 0,37
-0,01 -0,18 0,16 0,91
-0,08 -0,69 0,53 0,80
0,10 -0,18 0,38 0,48
-0,08 -0,17 0,01 0,09
0,00 -0,04 0,04 0,96
-0,01 -0,05 0,02 0,41
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Morales et al., 1994
Morales et al., 1998
Nestler et al., 1988
Flynn et al., 1999*
Flynn et al., 1999**
Jedrzejuk et al., 2003
Kawano et al., 2003
Martina et al., 2006
Nair et al., 2006
Srinivasan et al., 2010
Overall
‐1,00
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60
0,80 Diff. in mean LL, 95% CI UL, 95% CI pSource
Triglycerides mean differences (mmol/L) -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8
Favours Placebo Favors DHEA
-0,07 -0,45 0,31 0,72
-0,08 -0,80 0,64 0,83
0,11 -0,39 0,61 0,67
-0,07 -0,46 0,32 0,73
-0,16 -0,76 0,44 0,60
0,01 -0,30 0,32 0,95
0,09 -0,44 0,62 0,74
0,00 -0,44 0,44 1,00
-0,06 -0,36 0,24 0,70
-0,10 -0,51 0,31 0,63
-0,03 -0,16 0,10 0,62
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites.
2. Glycometabolic profile: no association with glycaemia, only with insulin.No improvement after DHEA-RT.
3. Lipid profile: positive and negative relationships were found with HDLand triglycerides, however no improvement in lipid profile afterDHEA-RT.
CV and metabolic risk
B= -0.020±0.009; p=0.022
DH
EA
S (
mol
/L)
0 1 2 3 4 5# MetS Factors (AHA 2009)
DHEAS levels according to # of MetS factorsin European population
Adjusted forCentre, alcoholMass derived FT, FE2, DHT
Rastrelli, Corona et al., 2014, unpublished
B= -0.009±0.001; p<0.0001
I II III IVQuartiles of DHEAS
Est
imat
ed 1
0 yr
CV
ris
k (%
)
Estimated CV risk according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
Adjusted forCentre, alcoholMass derived FT, FE2, DHTBMI
Corona et al., 2011 Eur J Endocrinol. 165:687-701
‐4 ‐3 ‐2 ‐1 0 1 2 3 4 5 Diff. in mean LL, 95% CI UL, 95% CI pSource
DHEAS mean differences (mmol/L) -4.0 -3.0 -2.0 -1.0 0 1 2 3 4 5
Favours CVD Favors no CVD
-1,74 -3,16 -0,32 0,02
-0,1 -1,12 0,92 0,85
1,1 -0,13 2,33 0,08
-1,4 -2,28 -0,52 0,00
0 -0,96 0,96 1,00
-0,62 -1,84 0,61 0,32
0,66 -0,39 1,72 0,22
-0,7 -1,68 0,28 0,16
0,11 -0,22 0,44 0,52
-0,14 -0,65 0,38 0,61
1,5 -0,86 3,86 0,21
0,12 -0,29 0,53 0,57
-1,22 -1,56 -0,88 0,00
-0,32 -0,76 0,13 0,16
Slowinska-Srzednicka et al., 1989
Hauner et al., 1991
Hautanen et al., 1994
Price et al., 1997
English et al., 2000
Dunajska et al., 2004
Dunajska et al., 2004
Fischer et al., 2004
Kajinami et al., 2004
Debing et al., 2008
Page et al., 2008
Fallah et al., 2009
Cao et al., 2010
Overall
Corona et al., 2011 Eur J Endocrinol. 165:687-701
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites.
2. Glycometabolic profile: no association with glycaemia, only with insulin.No improvement after DHEA-RT.
3. Lipid profile: positive and negative relationships were found with HDLand triglycerides, however no improvement in lipid profile afterDHEA-RT.
4. CV and metabolic risk: DHEAS levels are negatively associated with MetSand estimated CV risk, however DHEA-RT did not ameliorateCV mortality
Bone health
No association of DHEA and DHEAS with bone structure & metabolism
Does DHEA supplementation improveBone health in elderly men?
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00
1,50Source
Lumbar BMD standarized mean differences (ng/ml) -1.5 -1.0 -0.5 0 0.5 1.0 1.5
Favours Placebo Favors DHEA
Morales et al., 1998
Jankowski et al., 2006
Nair et al., 2006
Muhlen et al., 2008
Overall
0,00 -0,92 0,92 1,00
-0,06 -0,56 0,44 0,81
0,01 -0,49 0,52 0,96
-0,06 -0,43 0,31 0,75
-0,04 -0,29 0,21 0,76
Diff. in mean LL, 95% CI UL, 95% CI p
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60
0,80
1,00
1,20Source
Neck BMD standarized mean differences (ng/ml) -0.8 -0.6 -0. 4-0.2 0 0.2 0.4 0.6 0.8 1.0 1.2 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Baulieu et al., 2000
Jankowski et al., 2006
Nair et al., 2006
Muhlen et al., 2008
Weiss et al., 2009
Overall
0,10 -0,24 0,44 0,58
0,12 -0,38 0,63 0,63
0,53 0,01 1,04 0,04
-0,01 -0,38 0,37 0,97
-0,05 -0,64 0,53 0,86
0,12 -0,08 0,31 0,24
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐1,50
‐1,00
‐0,50
0,00
0,50
1,00Source
Bone resorption markers standarized mean differences (ng/ml) -1.5 -1.0 -0.5 0 0.5 1.0 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Morales et al., 1998
Kahn et al., 2002
Muhlen et al., 2008
Weiss et al., 2009
Overall
-0,23 -1,16 0,70 0,63
0,09 -0,33 0,51 0,67
0,21 -0,17 0,58 0,28
-0,19 -0,78 0,39 0,52
0,07 -0,18 0,31 0,58
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐1,00
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60
0,80Source
Bone neoformation markers standarized mean differences (ng/ml) -1.0 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
0,00 -0,34 0,34 0,99
0,00 -0,42 0,42 0,99
0,17 -0,20 0,55 0,37
-0,33 -0,92 0,26 0,27
0,01 -0,19 0,21 0,92
Baulieu et al., 2000
Kahn et al., 2002
Kritz-Silverstein et al., 2008
Weiss et al., 2009
Overall
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites.
2. Glycometabolic profile: no association with glycaemia, only with insulin.No improvement after DHEA-RT.
3. Lipid profile: positive and negative relationships were found with HDLand triglycerides, however no improvement in lipid profile afterDHEA-RT.
4. CV and metabolic risk: DHEAS levels are negatively associated with MetSand estimated CV risk, however DHEA-RT did not ameliorateCV mortality
5. Bone health : no association after adjustment for DHEA metabolites. Nosignificant improvement after DHEA-RT
Quality of life
B= 0.418±0.050; p<0.0001
I II III IVQuartiles of DHEAS
SF36
-phy
sica
l com
pone
nt
Physical functioning according to DHEAS levelsin European population
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHT Rastrelli, Corona et al., 2014, unpublished
B= 0.146±0.054; p=0.007
I II III IVQuartiles of DHEAS
SF36
-phy
sica
l com
pone
nt
Physical functioning according to DHEAS levelsin European population
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTBMI Rastrelli, Corona et al., 2014, unpublished
Does DHEA supplementation improvequality of life in elderly men?
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60Source
SF-36 mental component standardized mean differences -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Van Niekerk et al., 2001
Nair et al., 2006
Kritz-Silverstein et al., 2008
Overall
-0,09 -0,52 0,35 0,69
-0,14 -0,65 0,37 0,59
-0,20 -0,58 0,17 0,29
-0,15 -0,40 0,10 0,23
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Van Niekerk et al., 2001
Nair et al., 2006
Kritz-Silverstein et al., 2008
Overall
‐1,00
‐0,80
‐0,60
‐0,40
‐0,20
0,00
0,20
0,40
0,60Source
SF-36 physical component standardized mean differences -1.0 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 Diff. in mean LL, 95% CI UL, 95% CI p
-0,07 -0,51 0,36 0,74
-0,41 -0,92 0,10 0,12
-0,20 -0,57 0,18 0,30
-0,21 -0,45 0,04 0,10
Favours Placebo Favors DHEACorona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Only a sex steroid or indeed an effective androgen?
1. body fat composition: DHEAS levels are inversely associated with BMIand body fat, even after adjusting for DHEA metabolites andconfounders. DHEA-RT improves fat mass… the latter disappeared afteradjusting for DHEA metabolites.
2. Glycometabolic profile: no association with glycaemia, only with insulin.No improvement after DHEA-RT.
3. Lipid profile: positive and negative relationships were found with HDLand triglycerides, however no improvement in lipid profile afterDHEA-RT.
4. CV and metabolic risk: DHEAS levels are negatively associated with MetSand estimated CV risk, however DHEA-RT did not ameliorateCV mortality
5. Bone health : no association after adjustment for DHEA metabolites. Nosignificant improvement after DHEA-RT
6. Quality of life: association with SF36 physical component score, evenafter adjusting for DHEA metabolites. No improvement after DHEA-RT.
Sexual functioning
DH
EA
S (
mol
/L)
Overall sexual functioning
B= 0.080±0.035; p=0.022
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTBMI
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
DH
EA
S (
mol
/L)
Overall sexual functioning
B= 0.018±0.010; p=0.059
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTbicep and tricep skinfold thicknessInsulinSF36-physical componentMetS AHA criteria
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
DH
EA
S (
mol
/L)
Erection changed during the last year
B= -0.010±0.005; p=0.035
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
Increased Unchanged Decreased Decreasedmoderately a lot
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTBMI
DH
EA
S (
mol
/L)
Erection changed during the last year
B= -0.009±0.005; p=0.084
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
Increased Unchanged Decreased Decreasedmoderately a lot
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTbicep and tricep skinfold thicknessInsulinSF36-physical componentMetS AHA criteria
DH
EA
S (
mol
/L)
DH
EA
S (
mol
/L)
How many times have you attempted sexual intercourse?
How often do you engage in kissing, fondling, petting, etc.?
B= 0.093±0.034; p=0.006 B= 0.065±0.023; p=0.004
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
None 1/mo 2-3/mo 1/wk 2-3/wk >3/wk None 1/mo 2-3/mo 1/wk 2-3/wk >3/wk
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTBMI
DH
EA
S (
mol
/L)
How many times have you attempted sexual intercourse?
B= 0.019±0.012; p=0.096
Sexual function according to DHEAS levelsin European population
Rastrelli, Corona et al., 2014, unpublished
None 1/mo 2-3/mo 1/wk 2-3/wk >3/wk
Adjusted forAge/centre/n°morbidities ,Smoking/alcoholMass derived FT, FE2, DHTbicep and tricep skinfold thicknessInsulinSF36-physical componentMetS AHA criteria
Does DHEA supplementation improvSexual function in elderly men?
‐15,00
‐10,00
‐5,00
0,00
5,00
10,00
15,00Source
IIEF-15 total score mean differences -15 -10 -5.0 0 5 10 15 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Kritz-Silverstein et al., 2008
Morales et al., 2009
Overall
-3,20 -11,38 4,98 0,44
0,80 -9,74 11,34 0,88
-1,70 -8,16 4,76 0,61
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐10,00
‐5,00
0,00
5,00
10,00
15,00
20,00
25,00
30,00Source
IIEF-EF score mean differences -10 -5 0 5 10 15 20 25 30 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Reiter et al., 1998
Morales et al., 2009
Overall
17,00 15,14 18,86 0,00
0,50 -4,08 5,08 0,83
8,89 -7,28 25,06 0,28
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
‐2,00
0,00
2,00
4,00
6,00
8,00
10,00Source
Desire standardized mean differences -2 0 2 4 6 8 10 Diff. in mean LL, 95% CI UL, 95% CI p
Favours Placebo Favors DHEA
Morales et al., 1994
Reiter et al., 1998
Morales et al., 2009
Overall
1,00 0,18 1,82 0,02
7,50 5,74 9,26 0,00
-0,17 -0,69 0,35 0,51
2,62 -0,36 5,61 0,08
Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26
Sexual functioning• Mild/borderline associations of DHEAS with:A. Overall sexual functioningB. Change in erectionC. # sexual intercourse
• No effect of DHEA on sexual parameters (few RCT)
Mental disorders
DH
EA
S (
mol
/L)
DHEAS and depression (BDI): metabolite- and morbidity-adjusted model
BDI total score
r=-0.099;p<0.0001
r=-0.099;p<0.0001
DHEAS and depression (BDI): unadjusted model
(0-2) (3-5) (6-9) (10-56)
BDI total score
DH
EA
S (
mol
/L)
Adjusted forAge/centre/n°morbidities,Smoking/alchool/BMIMass derived TT and E2Physical component score
B=0.006±0.008;p=0.490
DHEAS and depression (BDI): Fully adjusted model
(0-2) (3-5) (6-9) (10-56)
BDI total score
DH
EA
S (
mol
/L)
Does DHEA supplementation improvmood disorders in elderly men?
Date of download: 6/19/2013 Copyright © 2012 American Medical Association. All rights reserved.
From: Dehydroepiandrosterone Monosupplementation in Midlife-Onset Major and Minor Depression
Arch Gen Psychiatry. 2005;62(2):154-162. doi:10.1001/archpsyc.62.2.154
Men (n = 23) and women (n = 23) aged 45 to 65 years with midlife-onset major or minor depression Six weeks of DHEA administration (90 mg/d for 3 weeks and 450 mg/d for 3 weeks, vs. 6 weeks of placebo) was associated with a significant improvement in the 17-Item Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings compared with both baseline (P<.01) and 6 weeks of placebo treatment (P<.01)
Men (n = 110) and women (n = 115) aged 55 to 85 aged treated with 50 mg daily oral DHEA versus placebo for 1 year. Over time, BDI scores decreased for men (P=.006) and women (P=.02), but there were no differences between the DHEA and placebo groups over time.
DHEA: only a sex steroid or indeed an effective androgen?
In the EMAS study, after adjusting for age, life-style, metabolites, morbidities and SF-36 physical component ,
DHEAS levels are associated with:- Lower body fat mass- Higher HDL levels- Increased sexual frequency and less worry about sexual acts
Little evidence from placebo-controlled RCT that DHEA-RTmight be useful in middle-age and elderly men.
• DHEA and DHEAS are (interesting) markers of overall physical(and sexual) health
• DHEA replacement does not significantly affect any of the measured physical, psychological or sexual parameters with the exception of body composition (↓fat mass):
1. sex steroid metabolites (?)2. DHEA receptor in adipocytes (CAR?)
Lesson from meta-analysis of RCT & EMAS studyin middle-aged and elderly men