1) This study investigated the effects of testosterone on plaque development in male and female rabbits. 2) It found that testosterone inhibited plaque formation in male rabbits at concentrations of 10-100 ng/ml, but increased plaque size in female rabbits at concentrations of 10-50 ng/ml. 3) The presence of androgen receptors in the arteries of both male and female rabbits suggests they are involved in the gender-specific effects of testosterone on plaque development.

1. Effect of Testosterone on neo-intimal
plaque development and arterial
androgen receptor expression in male
versus female rabbits
Hartmut Hanke, M.D., F.E.S.C.
Wolfgang Weidemann, Ph.D.*
Department of Internal Medicine and Cardiology,
University of Ulm
*Department of General Zoology and Endocrinology,
University of Ulm

2. Time course of testosterone levels in men during life
free testosterone index

3. Androgens and Atherosclerosis
• Controversial data, possible protective effects in
men are described
• Mechanism(s) of action on the level of the arterial
system not known
• Possible gender-specific links of hormonal effects
(estrogen-/androgen receptor involvement in
female/males of estrogen/testosterone) ?

4. 0
1
2
3
4
5
6
7
8
Control Estrogen Testosterone Estrogen+Testosterone
Plaquesize[mm²]
male
female
Effect of testosterone and estrogen on plaque development
in the cholesterol-fed rabbit
Bruck et al., Arterioscler Thromb Vasc Biol 1997;17:2192-2199

5. Background of the presented experimental data:
Sex steroids show complex effects on cardiovascular system.
Role of androgens in atherogenesis is discussed controversely.
Aim of the present study:
Investigation of the testosterone effect on neo-
intimal plaque development in aortic segments of male and female
rabbits.

6. For plaque development, New Zealand White rabbits were sacrificed, aortas were
ballon-denudated and cut into 5 mm segments. After culturing for 21 days, aortic ring
segments were fixed, elastica van-Gieson stained and morphometrically analyzed.
[A: Neo-intimal plaque 21 days following ballon injury; B: Control segment without
ballon denudation]
Rabbit organ culture model
A
B

7. 0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
controls 0.1 1 10 100 1000
testosterone [ng/ml]
intima/mediaratio
Effect of testosterone on neo-intimal plaque development
in male rabbits
A statistically significant inhibition was found at concentrations of
10 and 100 ng/ml testosterone

8. 0.0
0.1
0.2
0.3
0.4
0.5
0.6
controls 0.1 1 5 10 25 50 100 1000
testosterone [ng/ml]
intima/mediaratio
Effect of testosterone on neo-intimal plaque development
in female rabbits
A statistically significant increase in plaque size was found at
concentrations of 10, 25 and 50 ng/ml testosterone

9. 0
50
100
150
200
250
controls 0.1 1 5 10 25 50 100 1000
testosterone [ng/ml]
intima/media-ratio(mean)
relativevalues;controls=100%
male
female
Relative changes of neo-intimal plaque formation
in aortic segments of male and female rabbits

10. 0 0.1 1 10 100
testosterone [ng/ml]
AR
GAPDH
testosterone [ng/ml]
0
20
40
60
80
100
120
140
160
180
0 1 10 100
testosterone [ng/ml]
relativeamountsofARmRNA
nomalizedtoGAPDH
(controls=100%)
male female
0 0.1 1 10 100
Effect of testosterone on androgen receptor mRNA expression
in male and female arteries
AR mRNA amount was increased in male rabbits,
wheras in female animals no changes in AR mRNA amount
was found

11. The beneficial effect of testosterone on post-injury plaque development
in male rabbits is in sharp contrast to the atheroprogressive action of
testosterone in female rabbits.
The presence of both androgen receptor mRNA and androgen receptor
protein in aortic segments of both male and female rabbits indicates the
involvement of the androgen receptor in these processes.
Further studies are required to investigate this gender-specific testosterone
effect and its subsequent signal transduction in more detail.
Summary and conclusions
Acknowledgments
This work was supported by the DFG, SFB 451, B8.