Timing of Cyclic Estradiol Treatment Differentially Affects Cognition in Aged Female Rhesus Monkeys

Some evidence suggests that there may be a limited window of opportunity for beneficial effects of hormone therapy after menopause in women. We tested whether the timing of cyclic estradiol (E2) treatment impacted its effect on cognitive function in aged, surgically menopausal (ovariectomized) rhesus monkeys. Monkeys were assigned to one of four treatment conditions after ovariectomy: either vehicle or E2 treatment for the duration of the protocol, vehicle for the first 2 years of the protocol followed by E2 for the remainder (delayed treatment), or E2 for the first 11 months of the protocol followed by vehicle for the remainder (withdrawn treatment). Delayed treatment addressed the hypothesis that E2 treatment initiated more than 2 years postovariectomy would have a reduced effect on cognitive function. Withdrawn treatment mirrored current clinical advice to women to use hormone therapy in the initial postmenopausal period then discontinue it. Two periods of cognitive testing assessed treatment effects on cognition over time. E2 treatment predominantly affected a prefrontal cortex-dependent test of spatiotemporal working memory (delayed response). Monkeys with delayed E2 treatment modestly improved in delayed response performance over time, whereas vehicle-treated monkeys declined. Monkeys with withdrawn E2 treatment maintained their performance across assessments, as did monkeys treated with E2 across the entire protocol. These findings suggest that a window of opportunity for hormone treatment after cessation of ovarian function, if present in nonhuman primates, lasts longer than 2 years. They also support the notion that beneficial effects of hormone therapy may persist after discontinuation of treatment.