"muscle building" nutritional supplements: is androstenedione an

"Muscle Building" Nutritional Supplements: Is Androstenedione An Anabolic Steroid?

"Muscle Building" Nutritional Supplements: Is Androstenedione An Anabolic Steroid?

Exercise Biochemistry LaboratoryDept. of Health & Human Peformance

The Iowa State University

Exercise Biochemistry LaboratoryDept. of Health & Human Peformance

The Iowa State University

Gregory A. Brown, MSGregory A. Brown, MS

Roger Maris61 Home Runs in a Season

1961

Roger Maris61 Home Runs in a Season

1961

Mark McGwire70 Home Runs in a Season

1998

Mark McGwire70 Home Runs in a Season

1998

Time After Ingestion (min)0 30 60 90

0

Serum androgen levels after intake of 100 mg Androstenedionein Two Women

(nM)

0

108642

AndrostenedioneAndrostenedione

(nM)

48

12162024

Total TestosteroneTotal Testosterone

(Mahesh & Greenblatt, 1962)(Mahesh & Greenblatt, 1962)

Androgen and Estrogen RelationsAndrogen and Estrogen Relations

A = P 450 Side Chain Cleavage B= 3 ββββ hydroxysteroid dehydrogenaseC = 17 αααα hydroxylase D = P450 17, 20 lysaseE = P450 aromatase F = 17 ββββ hydroxysteroid oxidoreductaseG = 5 αααα reductase H = ketoreductase

A = P 450 Side Chain Cleavage B= 3 ββββ hydroxysteroid dehydrogenaseC = 17 αααα hydroxylase D = P450 17, 20 lysaseE = P450 aromatase F = 17 ββββ hydroxysteroid oxidoreductaseG = 5 αααα reductase H = ketoreductase


TestosteroneTestosterone

F

DHEA-SDHEA-S DHEADHEA BAndrostenedioneAndrostenedione

DHTDHT

E

G

G

G

G

3αααα-Androstanediol

3αααα-Androstanediol

3ββββ-Androstanediol

3ββββ-Androstanediol

H

Estradiol (E2)Estradiol (E2)

Estrone (E1)Estrone (E1)

D

E

Estriol (E3) Estriol (E3)

F

Does acute androstenedione

intake alter serum hormone

concentrations in young men?

Does acute androstenedione

intake alter serum hormone

concentrations in young men?

Time After Intake (min)0 60 120 180 240 300 360

Seru

m A

ndro

sten

edio

ne (n

M)

10

15

20

25

30

35

40* vs baseline (P<0.05)

*

100

mg

And

ro.

5

0

King et al, 1999King et al, 1999

PLASD

**

*

******

*

Tota

l Tes

tost

eron

e(n

M)

020406080

100Fr

ee T

esto

ster

one

(pM

)

48

1216202428

PLASD

060 120 180 240 300 360

Time After Intake (min)

100

mg

And

ro.


Does Chronic Androstenedione

Intake Enhance The Gains In

Muscle Size and Strength

During Resistance Training?

Does Chronic Androstenedione

Intake Enhance The Gains In

Muscle Size and Strength

During Resistance Training?


• 20 untrained subjects– Male (~23 y)– No current/previous supplement or

steroid use• 8 weeks full body resistance training• 3 days/week• 80-85% 1 RM

• Random, double blind– PL (rice flour)– Androstenedione (100 mg t.i.d)

• 20 untrained subjects– Male (~23 y)– No current/previous supplement or

steroid use• 8 weeks full body resistance training• 3 days/week• 80-85% 1 RM

• Random, double blind– PL (rice flour)– Androstenedione (100 mg t.i.d)

WEEKS

2 4 6 80

Supplementation

BloodChemistry

BodyComposition

1 RMTesting

Sex Hormones


Muscle Biopsy

0

500

1000

1500

2000

2500Lo

wer

Bod

y St

reng

thK

nee

Ex +

R. L

eg F

lexi

on +

L. L

eg F

lexi

on (N

)

BeforeTraining

AfterTraining

BeforeTraining

AfterTraining

* *Placebo Androstenedione


Lean

Bod

y M

ass

(kg)

30

40

50

60

70

BeforeTraining

AfterTraining

BeforeTraining

AfterTraining

Placebo Androstenedione* *


PL ASDUN

Type

I A

rea

( µµ µµm

2 )

Type

II A

rea

( µµ µµm

2 )

0

1000

2000

3000

4000

5000

6000

7000

0

1000

2000

3000

4000

5000

6000

7000

* *

TR UN TRPL ASD

UN TR UN TR


Weeks of Supplementation2 4 6 80

And

rost

ened

ione

(nM

) * *

5

10

15

20

25

30

35

0

PlaceboAndrostenedione


Free

Test

oste

rone

(pM

)To

tal

Test

oste

rone

(nM

)


0

80100120140

604020

0

160

20242832

1612

84

36



Is Androstenedione Intake

Safe?

Is Androstenedione Intake

Safe?

(mg/

dL)

24262830323436384042444648

BeforeTraining

AfterTraining

*

BeforeTraining

AfterTraining

Placebo Androstenedione

HD

L-C

hole

ster

ol



Estr

one

(E1:

pM) * *

70

170

90110130150

Estr

adio

l (E 2

: nM

)

0.1

0.2

0.3

0.4 * *

0.0

*

Estr

iol (

E 3:n

M)

0.1

0.2

0.3

0.4

0.0



Other Notable FindingsOther Notable Findings

Control Androstenedione

%/h

our

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Pre Post

Rassmussen et al, 2000Rassmussen et al, 2000

Effect of 100 mg androstenedione/day on Muscle Protein Fractional Synthetic RateEffect of 100 mg androstenedione/day on Muscle Protein Fractional Synthetic Rate

Pre Post

1800

1600

1400

1200

1000

800

600

400

200

Test

oste

rone

(ng/

dL)

Baseline BaselinePeak Peak100 mg

Androstenedione300 mg

Androstenedione

P=0.001

Leder et al, 2000Leder et al, 2000

No Change

Effect of 100 mg androstenedione t.i.d. in different agesEffect of 100 mg androstenedione t.i.d. in different ages

406080

100120

406080

100120

Seru

m F

ree

Test

oste

rone

(pM

)

406080

100120

30 year olds

40 year olds

50 year olds

Week0 1 2 3 4

* * * *‡

Brown et al, 2000Brown et al, 2000

PL ASD

10002000300040005000

Dih

ydro

test

oste

rone

(pM

)

10002000300040005000

10002000300040005000

Week0 1 2 3 4

30 year olds

40 year olds

50 year olds

PL ASD

* * * *‡

Effect of 100 mg androstenedione t.i.d. in different agesEffect of 100 mg androstenedione t.i.d. in different ages


• Chronic androstenedione intake in doses up to 100 mg t.i.d. does not enhance

• The increase in muscle mass and strength associated with resistance training

• Serum testosterone

• Muscle protein synthesis

• Chronic androstenedione intake in doses up to 100 mg t.i.d. does not enhance

• The increase in muscle mass and strength associated with resistance training

• Serum testosterone

• Muscle protein synthesis

To SummarizeTo Summarize

• Chronic androstenedione intake in doses up to 100 mg t.i.d. does• Increase Serum Dihydrotestosterone• Increase Serum Estrogens• Decrease Serum HDL-C

• Chronic androstenedione intake in doses up to 100 mg t.i.d. does• Increase Serum Dihydrotestosterone• Increase Serum Estrogens• Decrease Serum HDL-C

To SummarizeTo Summarize

Possible Adverse Health ConsequencesPossible Adverse Health Consequences

Lowered HDL-C• Increased CV disease risk by 10-15%

Elevated Estrogens Have been linked to…• Increased CV disease risk• Pancreatic Cancer• Gynecomastia

Lowered HDL-C• Increased CV disease risk by 10-15%

Elevated Estrogens Have been linked to…• Increased CV disease risk• Pancreatic Cancer• Gynecomastia

Possible Adverse Health ConsequencesPossible Adverse Health Consequences

Elevated Androstenedione may be associated with…• Prostate Cancer• Pancreatic Cancer• Neural/Behavioral

Elevated Dihydrotestosterone has been linked to…• Benign Prostate Hypertrophy• Baldness

Elevated Androstenedione may be associated with…• Prostate Cancer• Pancreatic Cancer• Neural/Behavioral

Elevated Dihydrotestosterone has been linked to…• Benign Prostate Hypertrophy• Baldness

Compound Daily Dose Purpose

Saw Palmetto 480 mg Reduce DHT metabolism/ bindingInhibit 5 αααα reductase

Indole- 3- Carbinol 450 mg Inhibit formation of estrogens

Tribulus Terristris 1,350 mg Increase LH, FSH, Testosterone

γγγγ Linolenic Acid 1500 mg Inhibit 5 αααα reductase

Chrysin 300 mg Inhibit aromatization

Compound Daily Dose Purpose

Saw Palmetto 480 mg Reduce DHT metabolism/ bindingInhibit 5 αααα reductase

Indole- 3- Carbinol 450 mg Inhibit formation of estrogens

Tribulus Terristris 1,350 mg Increase LH, FSH, Testosterone

γγγγ Linolenic Acid 1500 mg Inhibit 5 αααα reductase

Chrysin 300 mg Inhibit aromatization

Herbal ExtractsHerbal Extracts

Brown et al, 2000 and 2001Brown et al, 2000 and 2001

• Does not prevent formation of estrogens from androstenedione, and

• Does not increase serum testosterone levels.

• Does not prevent formation of estrogens from androstenedione, and

• Does not increase serum testosterone levels.

Addition of These Herbal ExtractsAddition of These Herbal Extracts

Brown et al, 2000 and 2001Brown et al, 2000 and 2001

Future DirectionsFuture Directions

• To what extent do greater (>300 mg/d) doses of androstenedione affect serum testosterone, muscle strength and size?

• To what extent do greater (>300 mg/d) doses of androstenedione affect serum testosterone, muscle strength and size?


• What are the long term health consequences of prolonged androstenedione intake?

• Cardiovascular Risk

• Fertility

• What are the long term health consequences of prolonged androstenedione intake?

• Cardiovascular Risk

• Fertility


• What are the effects of age and gender on modifying the response to androstenedione?

• What are the effects of alternative modes of delivery?

• What are the effects of age and gender on modifying the response to androstenedione?

• What are the effects of alternative modes of delivery?


• What are the effects of other androcompounds?

• What are the effects of combining various forms of andro?

• What are the effects of other androcompounds?

• What are the effects of combining various forms of andro?

Matthew D. Vukovich, PhD

Rick L. Sharp, PhD

Marian L. Kohut, PhD

Warren D. Franke, PhD

Tracy A. Reifenrath, M.S.

Kerry A. Parsons, M.S.

David A. Jackson, M.S.

N.L. Uhl, B.S.

Emily R. Martini, B.S.

Douglas S. King, PhD

Matthew D. Vukovich, PhD

Rick L. Sharp, PhD

Marian L. Kohut, PhD

Warren D. Franke, PhD

Tracy A. Reifenrath, M.S.

Kerry A. Parsons, M.S.

David A. Jackson, M.S.

N.L. Uhl, B.S.

Emily R. Martini, B.S.

Douglas S. King, PhD

We are grateful toWe are grateful to

For their support.For their support.

• Chronic androstenedione intake in doses up to 100 mg t.i.d. does not alter serum concentrations of – Low Density Lipoprotein– Very Low Density Lipoprotein– Gamma-glutamyltransferase– Aspartate aminotransferase– Alanine aminotransferase– Globulins– Proteins– Prostate Specific Antigen

King et al, 1999 and Brown et al, 2000King et al, 1999 and Brown et al, 2000

Extra Summary of Other Clinical FindingsExtra Summary of Other Clinical Findings

• A single 100-200 mg dose of androstenedione does not increase serum serum concentrations of testosterone in young men.

• A single 300 mg dose of androstenedione may slightly increase serum concentrations of testosterone

Extra SummaryExtra Summary

• Chronic androstenedione intake in doses up to 100 mg t.i.d. does not enhance • Serum testosterone• Muscle protein synthesis• Adaptations to resistance training• lean mass• fat mass• muscle fiber size• muscle strength


Extra SummaryExtra Summary

LH (m

IU/m

l)FS

H m

IU/m

l)

123456

234567

10

0


PLASD

Extra training dataExtra training data


10

20

30

40

50

0

Seru

m H

DL

(mg/

dL)


* * *


20

40

60

80

100

120

140

0


PLASDSe

rum

LD

L (m

g/dL

)Extra training dataExtra training data

Bench Press * 647 + 68 840 + 73 851 + 95 1,047 + 119

Biceps Curl * 287 + 19 331 + 22 351 + 21 391 + 25

Knee Extension * 717 + 46 1,024 + 57 770 + 45 1,095 + 52

Lat Pulldown * 657 + 25 787 + 44 672 + 35 876 + 50

Left Leg Flexion * 277 + 17 415 + 22 307 + 11 440 + 18

Right Leg Flexion* 292 + 14 430 + 28 311 + 10 445 + 16

Shoulder Press * 420 + 28 463 + 27 494 + 51 569 + 50

Triceps Extension * 311 + 24 390 + 19 329 + 31 454 + 30

Vertical Butterfly * 774 + 107 1,081 + 94 927 + 99 1,268 + 89

* Week 8 vs week 0 (main effect; P<0.05)

Maximal Muscle Strength (N)

ASD (n=9) PL (n=10)

Wk 0 Wk 8 Wk0 Wk 8


Body Composition - * Wk 8 significantly different from Wk 0 (main effect, P<0.05)ASD (n=9) PL (n=10)

Wk 0 Wk 8 Wk0 Wk 8Height, cm 176.8 + 2.7 178.0 + 1.5Body Mass, kg * 80.6 + 4.1 81.2 + 4.2 81.1 + 5.2 83.2 + 4.9Lean Body Mass, kg * 61.2 + 2.5 64.1 + 2.4 63.1 + 2.6 66.0 + 2.5 Fat Mass, kg * 19.3 + 2.9 17.1 + 3.4 18.0 + 2.9 17.2 + 2.9 Body Fat, % * 23.5 + 2.4 20.3 + 3.0 21.3 + 1.9 19.9 + 2.1

Circumferences, cmBiceps * 31.9 + 0.8 32.4 + 0.8 32.6 + 1.4 33.4 + 1.3Shoulder * 119.3 + 1.3 121.1 + 1.4 120.3 + 3.4 120.7 + 3.3Chest * 99.6 + 2.0 99.2 + 1.9 98.0 + 3.8 100.9 + 3.4Abdomen * 89.5 + 5.2 87.7 + 5.1 87.2 + 3.8 85.9 + 3.6 Waist * 86.6 + 4.2 83.7 + 3.6 84.9 + 3.9 83.7 + 3.7Hips * 91.3 + 3.5 88.1 + 3.7 89.2 + 2.5 85.7 + 2.3Gluteal * 101.7 + 3.1 98.2 + 3.1 100.4 + 2.5 97.4 + 2.3Thigh 54.2 + 1.3 54.4 + 1.8 54.7 + 1.2 55.1 + 1.5Calf 37.8 + 0.7 37.6 + 0.8 37.4 + 1.7 38.6 + 0.9


Time After Ingestion (min)0 60 120 180 240 300 360

Seru

m D

HT

(pm

ol/L

)

1200

1600

2000

2400

2800

3200

3600

4000

* vs. 0, P<0.054400

** *

* **

PLASD

Extra Acute DataExtra Acute Data

King et al, unpublished dataKing et al, unpublished data

7

LH (m

IU/m

l)(F

SH m

IU/m

l)

234567

10

23456

10

0 60 120 180 240 300 360Time After Ingestion (min)

PLASD


-100

mg

ASD

-

Time After Ingestion (min)0 60 120 180 240 300 360

Seru

m T

otal

Tes

tost

eron

e (n

mol

/L)

0

468

1012141618202224

PL PL ASD ASD

2


Rassmussen et al, 2000Rassmussen et al, 2000

Nm

ol/L

80

70

60

50

40

30

20

10

0

0 60 120 180 240 300Minutes After Androstenedione Intake (100 mg)

Androstenedione

Testosterone

Extra Supporting Acute DataExtra Supporting Acute Data

10

2030

40Se

rum

And

rost

ened

ione

(nM

)

1020

3040

102030

40

Week0 1 2 3 4

30 year olds

40 year olds

50 year olds

* * * *‡

Extra 100 mg androstenedione t.i.d. in different agesExtra 100 mg androstenedione t.i.d. in different ages


30

0

10

20

0

10

20

30

0

10

20

30

Seru

m T

otal

Tes

tost

eron

e (n

M)

Week0 1 2 3 4

30 year olds

40 year olds

50 year olds



0.150.250.350.45

0.150.250.350.45

Week

0.150.250.350.45

0 1 2 3 4

Est

radi

ol (n

M)

PL ASD

30 year olds

40 year olds

50 year olds

* * * *



Weeks of Supplementation0 1 2 3 4

Pros

tate

Spe

cific

Ant

igen

(ng/

ml)

0

1

2

3

4

PL (n=13 44 y)ASD (n=13; 41 y)



-20

Seru

m A

ndro

sten

edio

ne (n

mol

/L)

Time (min)-20 0 30 60 90 120 150 180

* *

** *

5

10

15

20

25

30

0

SL-AndrostenediolPlacebo

Extra 20mg sublingual cyclodextrin androstenediol administration



Seru

m E

stra

diol

(nm

ol/L

)

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Time (min)-20 0 30 60 90 120 150 180

* **

**

*





* **

** *

Free

Tes

tost

eron

e (p

mol

/L)

020406080

100120140160180200

Time (min)-20 0 30 60 90 120 150 180





Michaelis Constants for Enzymes Catalyzing Conversion of Androstenedione to Other

Steroids

Michaelis Constants for Enzymes Catalyzing Conversion of Androstenedione to Other

Steroids

Estrone (E2)Estrone (E2)

AromataseAromatase

DHTDHT

5 ααααReductase5 ααααReductase

165 nM165 nM 25 nM25 nM1500 nM1500 nM

TestosteroneTestosterone

17 ββββ- Hydroxysteroid DH17 ββββ- Hydroxysteroid DH


Blomquist, 1995Blomquist, 1995

17 ß-HSD Activity(pmol/h/mg)

0

100

200

T �� A A �� T

A:T Conversions byTesticular Microsomes

↑↑↑↑ 237%??????Hacker & Mattern

↑↑↑↑ 15-20%200 mg8 men, 24 yEarnest et al, 1999

↑↑↑↑ 500%100 mg2 WomenMahesh & Greenblatt

[Testosterone ]DoseSubjectsAuthors

Evidence that Oral Androstenedione Increases Serum Testosterone

↔↔↔↔100 mg7 men, 28 yZiegenfuss et al, 1998

↓↓↓↓ 26%↔↔↔↔

1 wk: 100 mg/d 1 wk: 200 mg/d

6 menSpratt et al, 1999

↔↔↔↔100 mg6 menRassmussen et al, 1999

↔↔↔↔↔↔↔↔

100 mg300 mg/day

for 8 wk10 men, 23 yKing et al,

1999

[Testosterone ]DoseSubjectsAuthors

Evidence that Oral Androstenedione Does Not Increase Serum Testosterone

Testosterone(ng/mL)

3

4

5

6

Baseline Day 1 Day 7 Day 1 Day 7

100 mg

Effect of 100- and 200 mg Androstenedione in 6 Healthy me

Spratt et al,The Endocrine Society, 1999.

*

200 mg

AdiposeAdrenal

BreastEndometrium

LiverMuscle

MyometriumOvary

PlacentaProstate

SkinSpleenTestis

T FormationA Formation

pmol/mg protein/min0.01 0.1 1 10 100 1000

Androgenic 17 ββββ-HSD Activity In Human Tissue

"muscle building" nutritional supplements: is androstenedione an

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