Mario Maggi Andrology University of Florence, m.maggi · PDF fileMario Maggi Sexual Medicine &...

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


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


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


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


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


r=0.05; p=0.004 r=-0.04; p=0.014 r= -0.09; p<0.00016

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


r=0.16; p<0.0001 r=0.08; p<0.0001



Free

Tes

tost

eron

e (p

mol

/L)

Free

17 β

Est

radi

ol(p

mol

/L)

r=0.04; p=0.016


DH

T (n

mol

/L)





Hem

oglo

bin

(g/d

L)

Prol

actin

(ng/

mL

)


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



SHB

G (

nmol

/L)



B= 0.015±0.007; p=0.022

adjusted model

B= -0.292±0.098; p=0.003


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


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


E2 mean differences (pmol/L) -40 -20 0 20 40 60 80 100 120 140


Morales et al., 1994



Flynn et al., 1999**Baulieu et al., 2000

Arlt et al., 2001



Martina et al., 2006Nair et al., 2006



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


‐15,00

‐10,00

‐5,00

0,00

5,00

10,00


TT mean differences (nmol/L) -15 -10 -5.0 0 5 10 15


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


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



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




adjusted model



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


unadjusted model


Fat mass markers



Bic

ep sk

info

ld th

ickn

ess (

cm)

Tric

ep sk

info

ld th

ickn

ess (

cm)


r=0.05; p=0.004 r=0.04; p=0.016


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



Fat mass markers





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


Lean mass markers




Arm

cir

cum

fere

nce

(cm

)

Cal

f cir

cum

fere

nce

(cm

)


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


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





Flynn et al., 1999*


Kahn et al., 2002


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




Flynn et al., 1999 dheas*

Flynn et al., 1999 placebo**


Nair et al., 2006


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



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


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





Flynn et al., 1999*


Kahn et al., 2002


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


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



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


Gly

caem

ia (m

mol

/l)


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?


Nusen et al., 1995

Flynn et al., 1999



Nair et al., 2006

Overall

‐1,50

‐1,00

‐0,50

0,00

0,50


Glycaemia mean differences (mmol/L) -1.5 1 0.5 0 0.5 1.0


-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


‐1,50

‐1,00

‐0,50

0,00

0,50

1,00


Insulin mean differences (mU/L) -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5



Flynn et al., 1999*



Kawano et al., 2003

Martina et al., 2006

Nair et al., 2006


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



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


Tota

l cho

lest

erol

(mm

ol/l)

B= 0.014±0.009; p=0.143



HD

L ch

oles

tero

l (m

mol

/l)

B= 0.012±0.003; p<0.0001


LD

L ch

oles

tero

l (m

mol

/l)

B= 0.006±0.009; p=0.526


Trig

lyce

ride

s (m

mol

/l)

B= -0.017±0.008; p=0.042

Lipid parameters according to DHEAS levelsin European population



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


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


Total cholesterol mean differences (mmol/L) -2.0 -1.5 -1.0 0.5 0 0.5 1.0 1.5





Flynn et al., 1999*



Kawano et al., 2003



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





Flynn et al., 1999*



Kawano et al., 2003


Nair et al., 2006

Srinivasan et al., 2010

Overall

‐1,50

‐1,00

‐0,50

0,00

0,50

1,00


LDL cholesterol mean differences (mmol/L) -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5


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


‐0,80

‐0,60

‐0,40

‐0,20

0,00

0,20

0,40


HDL cholesterol mean differences (mmol/L) -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6





Flynn et al., 1999*



Kawano et al., 2003


Nair et al., 2006


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





Flynn et al., 1999*



Kawano et al., 2003


Nair et al., 2006


Overall

‐1,00

‐0,80

‐0,60

‐0,40

‐0,20

0,00

0,20

0,40

0,60


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


-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




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


B= -0.009±0.001; p<0.0001


Est

imat

ed 1

0 yr

CV

ris

k (%

)

Estimated CV risk according to DHEAS levelsin European population


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





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




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


‐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




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


‐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



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


‐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


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


Kahn et al., 2002

Kritz-Silverstein et al., 2008

Weiss et al., 2009

Overall







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


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


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


Van Niekerk et al., 2001

Nair et al., 2006


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


Van Niekerk et al., 2001

Nair et al., 2006


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






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


Sexual function according to DHEAS levelsin European population


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



DH

EA

S (

mol

/L)

Erection changed during the last year

B= -0.010±0.005; p=0.035



Increased Unchanged Decreased Decreasedmoderately a lot


DH

EA

S (

mol

/L)

Erection changed during the last year

B= -0.009±0.005; p=0.084



Increased Unchanged Decreased Decreasedmoderately a lot


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



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


DH

EA

S (

mol

/L)

How many times have you attempted sexual intercourse?

B= 0.019±0.012; p=0.096



None 1/mo 2-3/mo 1/wk 2-3/wk >3/wk


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




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


‐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


Reiter et al., 1998


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


‐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



Reiter et al., 1998


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


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

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