Potential Beneficial Effects of DHEA in Humans

Wendy M Kohrt, PhDProfessor of Medicine

Division of Geriatric MedicineUniversity of Colorado Health Sciences Center

Denver, Colorado

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

DHEA/DHEAS

androstenedione

testosterone

dht estradiol

adrenals

gonads

95%

5%

DHEAS

DHEA androstenedione testosterone3βHSD 17βHSOR

estrone estradiol17βHSOR

aromatase aromatase

5a-androstanedione DHT17βHSOR

5α-reductase 5α-reductase

Sulfo-transferase

Sulfatase

Legrain S et al. J Clin Endocrinol Metab 85:3208-3217, 2000

DHEAS“The Mother Steroid”

DHEAS is an abundant hormone that serves as a precursor to:

� ~50% of androgens in adult men� ~75% of active estrogens in

premenopausal women� nearly 100% of active estrogens in

postmenopausal womenLabrie F et al. J Clin Endocrinol Metab 82:2396-2402, 1997

DHEA/DHEAS� Most abundant steroid in human plasma

� Concentrations in humans are much higher than in animals

� Lack of an appropriate animal model has limited the understanding of the metabolism of DHEA(S) and its biological effects in humans

� DHEA is widely distributed in the body

brain > plasma > spleen > kidneys > liver

Abundance of DHEAS

Hormone Women Men

DHEAS 8,000 nM 10,000 nM

DHEA 32 nM 20 nM

T 3 nM 30 nM

E2 0.22 nM 0.15 nM

Serum DHEAS vs Age

Age (yr)5 15 25 35 45 55 65 75 85

Seru

m D

HEA

S (µ

M)

0

2

4

6

8

10

MenWomen

Seru

m D

HEA

S, n

g/m

L

0

1

2

3

4

Seru

mC

ortis

ol,µ

g/dL

0

2

4

6

8

10

12

21-25 26-30 31-35 36-40 21-25 26-30 31-35 36-40Age (yr) Age (yr)

Serum DHEAS and Cortisol Levels in Premenopausal Women

-40%

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

Effects of DHEA Supplementation in Rodents

� Anti-obesity� prevents fat gain in obesity-prone

strains and reverses obesity

� Anti-diabetogenic� enhances insulin action

� Anti-atherogenic� diminishes atherosclerotic plaque

Mas

s, g

0

100

200

300

400

500

600

700

GD

R, m

g/kg

/min

0

5

10

15

20

25

Control DHEA

Total Mass Fat Mass Insulin Action

20 Months of DHEA Supplementation in Rats

Han DH et al. J Gerontol: Biol Sci 53A:B19-B24, 1998

Effects of a 12-wk Atherogenic Diet Plus DHEA on Aortic Plaque

Aortic Region1 2 3 4 5

Wal

l Are

a C

ompo

sed

of P

laqu

e, %

0

10

20

30

40

50

60

70Cholesterol Cholesterol+DHEA

Gordon GB et al. J Clin Invest 82:712-720, 1988

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

DHEA Reduces LDL Levels and Body Fat but does not Alter Insulin Sensitivity in Normal Men

Nestler JE et al. J Clin Endocrinol Metab 66:57-61, 1988

� 10 men, aged 22-25 yr

� placebo or DHEA, 1600 mg/d, 28 d

� body composition - hydrodensitometry

� insulin action - euglycemic, hyperinsulinemic clamp

� no side effects noted in either group

Placebo DHEABaseline ∆∆∆∆ Baseline ∆∆∆∆

DHEAS, µM 9.9 -1.2 10.9 27.9*

Total T, nM 29.0 1.4 26.6 3.3

Free T, nM 12.9 -1.3 11.0 5.9

Andro, nM 5.5 0.3 4.3 4.3*

E2, pM 117 -26 117 -14

E1, pM 193 35 194 38

SHBG, nM 17.9 2.9 17.5 -3.6

Nestler JE et al. J Clin Endocrinol Metab 66:57-61, 1988

Effect of DHEA Supplementation on Body CompositionC

hang

e in

Mas

s, k

g

-4

-2

0

2

4

6Placebo DHEA

Total Mass Fat-free Mass Fat Mass

Nestler et al. J Clin Endocrinol Metab 66:57-61, 1988

Lack of an Effect of DHEA in Obese MenUsiskin KS et al. Int J Obesity 14:457-463, 1990

� 6 men, aged 21-37 yr, BMI 28-38 kg/m2

� DHEA, 1600 mg/d, 28 d

� body composition - hydrodensitometry, BIA, anthropometry

� no side effects of DHEA

Effect of Oral DHEA on Serum Testosterone and Adaptations to Resistance Training in Young Men

Brown GA et al. J Appl Physiol 87:2274-2283, 1999

�19 men, aged 19-29 yr

�placebo or DHEA, 150 mg/d, wks 1,2,4,5,7,8

�body composition – hydrodensitometry

�strength – 1 repetition maximums

�no side effects reported

And

rost

ened

ione

(nM

)

5

10

15

20

T TO

TAL

(nM

)

15

20

25

30

Weeks0 2 4 6 8

T FR

EE (p

M)

75

85

95

105

Brown GA et al. J Appl Physiol 87:2274-2283, 1999

**

PlaceboDHEA

Estr

one

(pM

)

75

85

95

105

115

Estr

adio

l (pM

)

230

240

250

260

270

Weeks0 2 4 6 8

Estr

iol (

pM)

180

200

220

240

260

Brown GA et al. J Appl Physiol 87:2274-2283, 1999

PlaceboDHEA

Cha

nge

in M

ass

(kg)

-2

-1

0

1

2

3

4

5 Placebo DHEA

Total FatFat-free

Brown GA et al. J Appl Physiol 87:2274-2283, 1999

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

M/W Age Treat Results

Morales et al. 13/17* 40-70 3 mo ↑ IGF-1(2 W, facial hair) 50 mg ↓ HDL-C (W)

↑ well-being

Morales et al. 8/8* 50-65 6 mo ↑ IGF-1(no AE) 100 mg ↑ FFM

↓ FM (M)

Casson et al. 0/13 >50 6 mo ↑ IGF-1(no AE) 25 mg ↓ HDL-C

Villareal et al. 16/20 64-82 6 mo ↑ IGF-1(1 W, acne) 50 mg ↑ FFM, BMD

↓ FM

Baulieu et al. 140/140 60-79 12 mo ??(no AE) 50 mg

Effects of DHEA Replacement on Bone Mineral Density and Body Composition

in Elderly Women and MenVillareal DT et al. Clin Endocrinol 53:561-568, 2000

�open-label study of oral DHEA replacement, 50 mg/d

�10 women, 8 men; aged 64 to 82 yr (18 sex- and age-matched convenience controls)

�serum DHEAS <20% of mean value in young subjects

Seru

m D

HEA

S (n

mol

/L)

0

3

6

9

12

15MenWomen

YoungControls Older

Baseline 3 mo DHEA 6 mo DHEA

Villareal DT et al. Clin Endocrinol 53:561-568, 2000

Cha

nge

From

Bas

elin

e (k

g)

-3

-2

-1

0

1

2

MenWomen

BodyWeight

Trunk FatFat MassFat-freeMass

*

** **

*

Villareal DT et al. Clin Endocrinol 53:561-568, 2000

Cha

nge

From

Bas

elin

e (%

)

0

1

2

3

4

5MenWomen

Whole Body BMD Lumbar Spine BMD

* *

*

*

Villareal DT et al. Clin Endocrinol 53:561-568, 2000

Tota

l Tes

tost

eron

e, n

M

0

5

10

15

20

Men Women

E 1 + E

2, pM

0

15

30

45

60

75

Men Women

BeforeAfter

*

*

Villareal DT et al. Clin Endocrinol 53:561-568, 2000

Seru

m IG

F-1,

ng/

mL

0

20

40

60

80

100

120

140

160

1800 months 3 months 6 months

* ** *

Men Women

Villareal DT et al. Clin Endocrinol 53:561-568, 2000

Potential Beneficial Effects of DHEA in Humans

� overview of DHEA metabolism

� effects of DHEA administration

� animal models

� young men

� older women and men

� summary

Summary

� There have been few controlled trials of DHEA supplementation. Available data do not provide evidence that DHEA enhances performance.

Summary

� There are intriguing data that suggest that DHEA supplementation (replacement) can increase lean mass and decrease fat mass, but these findings are not uniform. Potential mechanisms include increases in androgens and/or growth factors in response to DHEA.

Future Research Directions

� In general, additional controlled trials are needed to better understand the sex- and age-specific responses to DHEA supplementation and the mechanisms of action.

� Preliminary studies should evaluate potential effects of DHEA supplementation in eugonadal and hypogonadal athletes.