1. ¹Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon, USA
2. ²Department of Anesthesiology and Critical Care Medicine, John Hopkins School of Medicine, Baltimore, Maryland, USA
3. ³Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA
4. ⁴Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA

Correspondence: Professor PD Hurn, Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, UHS-2, Portland, OR 97239-3098, USA. E-mail: hurnp@ohsu.edu

Received 12 August 2008; Revised 18 October 2008; Accepted 20 October 2008; Published online 12 November 2008.

Abstract

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.