Neonatal testosterone exposure protects adult male rats from stroke.
BACKGROUND
Men have a higher stroke incidence compared to women until advanced age. The contribution of hormones to these sex differences has been extensively debated. In experimental stroke, estradiol is neuroprotective, whereas androgens are detrimental. However, prior studies have only examined the effects of acute treatment paradigms; therefore, the timing and mechanism by which ischemic sexual dimorphism arises are unknown.


METHODS
The effects of exogenous neonatal androgen exposure on subsequent injury induced by middle cerebral artery occlusion in adulthood in male rats were examined. Rats were administered vehicle (oil), testosterone propionate (TP) or the non-aromatizable androgen dihydrotestosterone (DHT) for 5 days after birth. At 3 months of age, a focal stroke was induced.


RESULTS
Testosterone-treated rats (but not DHT-treated animals) had decreased infarct volumes (20 vs. 33%, p < 0.05) as well as increased estradiol levels (39.4 vs. 18.6 pg/ml, p < 0.0001) compared to oil-treated animals. TP-injected males had increased testicular aromatase (P450arom) levels (3.6 vs. 0.2 ng/ml, p < 0.0001) compared to oil-treated males. The level of X-linked inhibitor of apoptosis, the primary endogenous inhibitor of caspase-induced apoptosis, was increased in TP-treated rats compared with the oil-treated males.


CONCLUSIONS
Neonatal exposure to exogenous testosterone upregulates testicular aromatase expression in male rats and leads to adult neuroprotection secondary to changes in serum estradiol levels and cell death proteins. This study suggests that early exposure to gonadal hormones can have dramatic effects on the response to adult cerebrovascular injury.
Department of Neuroscience and Neurology, University of Connecticut Health Center, Farmington, CT 06032, USA.
Rebecca W
RW
Persky
Fudong
F
Liu
Yan
Y
Xu
Gillian
G
Weston
Stephanie
S
Levy
Charles E
CE
Roselli
Louise D
LD
McCullough
D000818:Animals; D000831:Animals, Newborn; D001141:Aromatase / Q000378:metabolism; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051381:Rats; D020521:Stroke / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D013737:Testis / Q000378:metabolism; D043343:Testosterone Propionate / Q000008:administration & dosage / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D051636:X-Linked Inhibitor of Apoptosis Protein; D013196:Dihydrotestosterone; D004958:Estradiol; D001141:Aromatase; D043343:Testosterone Propionate