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

Time course of testosterone levels in men during life

free testosterone index

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) ?

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Control Estrogen Testosterone Estrogen+Testosterone

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ue s

ize

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²]malefemale

Effect of testosterone and estrogen on plaque development in the cholesterol-fed rabbit

Bruck et al., Arterioscler Thromb Vasc Biol 1997;17:2192-2199

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.

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 withoutballon denudation]

Rabbit organ culture model

A B

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controls 0.1 1 10 100 1000testosterone [ng/ml]

intim

a/m

edia

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ioEffect 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

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controls 0.1 1 5 10 25 50 100 1000

testosterone [ng/ml]

intim

a/m

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ioEffect 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

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controls 0.1 1 5 10 25 50 100 1000testosterone [ng/ml]

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Relative changes of neo-intimal plaque formation in aortic segments of male and female rabbits

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testosterone [ng/ml]

AR

GAPDH

testosterone [ng/ml]

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male female

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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 amountwas found

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 receptorprotein in aortic segments of both male and female rabbits indicates theinvolvement 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

AcknowledgmentsThis work was supported by the DFG, SFB 451, B8.