Long‐term hypogonadism diminishes the neuroprotective effects of dietary genistein in young adult ovariectomized rats after transient focal ischemia

Increasing age disproportionately increases the risk of stroke among women compared to men of similar age, especially after menopause. One of the reasons for this observation is a sharp drop in circulating estrogens. However, the timing of initiation of estrogen replacement after menopause is associated with mixed beneficial and detrimental effects, hence contributing to widespread mistrust of estrogen use. Agents including soy isoflavones are being assessed as viable alternatives to estrogen therapy. In this study, we hypothesized that the neuroprotective effects of genistein, a soy isoflavone are less sensitive to the length of hypogonadism in young adult ovariectomized rats following cerebral ischemia. We expected that long‐term hypogonadism will worsen motor and cognitive function, increase post‐stroke inflammation with no effect on the neuroprotection of genistein. We compared the effect of treatment with dietary genistein (GEN) on short‐term (2 weeks) and long‐term hypogonadism (12 weeks) in young adult ovariectomized Sprague–Dawley rats on sensorimotor function, cognition and inflammation after focal ischemia. Dorsal Silastic implant of 17β‐estradiol (E2) was used as a control for hormone therapy. Long‐term hypogonadism stroked rats performed worse than the short‐term hypogonadism stroked rats on the motor and cognitive function tests. GEN did not improve neurological assessment and motor learning after either short‐term or long‐term hypogonadism. GEN improved cognitive flexibility after short‐term hypogonadism but not after the long‐term. Both GEN and E2 reduced tissue loss after short‐term hypogonadism and reduced GFAP expression at the contralateral side of ischemia after long‐term hypogonadism. The length of hypogonadism may differentially influence the neuroprotective effects of both GEN and E2 on the motor and cognitive functions in young adult rats. After short‐term, but not after long‐term hypogonadism, estrogen and genistein reduced strike‐induced infarct in ovariectomize female rats. Estrogen improved neurological function after long‐term hypogonadism. Genistein improved aspects of cognition independent of length of hypogonadism. These data support differential benefits of estrogen and genistein after loss of endogenous steroids.