Age-dependent effects of testosterone in experimental stroke.
Although male sex is a well-recognized risk factor for stroke, the role of androgens in cerebral ischemia remains unclear. Therefore, we evaluated effects of testosterone on infarct size in both young adult and middle-aged rats (Wistar, 3-month versus 14-month old) and mice (C57/BL6, 3-month versus 12-month old) subjected to middle cerebral artery occlusion. In young adult groups, castrates displayed less ischemic damage as compared with intact males and castrates with testosterone replacement (Cortex: 24% in castrates versus 42% in intact versus 40% with testosterone; Striatum: 45% versus 73% versus 70%) at 22 h reperfusion. Surprisingly, supplementing testosterone in middle-aged rats to the physiologic levels ordinarily seen in young males reduced infarction (Cortex: 2% with testosterone versus 31%; Striatum: 38% with testosterone versus 68%). Testosterone effects on infarct size were blocked by the androgen receptor (AR) antagonist flutamide and further confirmed in young versus middle-aged mice. Baseline cerebral aromatase mRNA levels and activity were not different between young and middle-aged rats. Aromatase activity increased in ischemic tissue, but only in young males. Lastly, stroke damage was not different in aging aromatase knockout mice versus wild-type controls. Our findings indicate that testosterone's effects in experimental stroke are age dependent, mediated via AR, but not cerebral aromatase.
Cheng
Jian
J
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Hu
Weidong
W
Toung
Thomas J
TJ
Zhang
Zhizheng
Z
Parker
Susan M
SM
Roselli
Charles E
CE
Hurn
Patricia D
PD
D000375:Aging / Q000378:metabolism*; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics; D002369:Castration; D005485:Flutamide / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D020521:Stroke / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology
D000726:Androgen Antagonists; D013739:Testosterone; D005485:Flutamide; D001141:Aromatase