Oral administration of ethinyl estradiol and the brain-selective estrogen prodrug DHED in a female common marmoset model of menopause: Effects on cognition, thermoregulation, and sleep.

Abstract

Menopausal symptoms of sleep disturbances, cognitive deficits, and hot flashes are understudied, in part due to the lack of animal models in which they co-occur. Common marmosets (Callithrix jacchus) are valuable nonhuman primates for studying these symptoms, and we examined changes in cognition (reversal learning), sleep (48 h/wk of sleep recorded by telemetry), and thermoregulation (nose temperature in response to mild external warming) in middle-aged, surgically-induced menopausal marmosets studied at baseline, during 3-week phases of ethinyl estradiol (EE₂, 4 μg/kg/day, p.o.) treatment and after EE₂ withdrawal. We also assessed a brain-selective hormonal therapy devoid of estrogenic effects in peripheral tissues on the same measures (cognition, sleep, thermoregulation) after treatment with the estrogen prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, 100 μg/kg/day, p.o) and DHED withdrawal. Reversal learning performance was improved with EE₂ or DHED treatment relative to phases without hormone administration, as indicated by a faster reversal of the stimulus/reward contingencies. Both EE₂ and DHED increased non-REM sleep and reduced nighttime awakenings relative to baseline, but to the detriment of REM sleep which was highest at baseline. Nasal temperature in response to mild external warming was highest, and overnight core body temperature lowest, in the DHED treatment phase compared to both the EE₂ and baseline phases. These results suggest that low dose estradiol, delivered either peripherally or centrally via DHED, benefits selective aspects of cognition and sleep in a marmoset menopause model. DHED appears a promising therapeutic candidate for alleviating the cognitive and sleep disruptions associated with estrogen deficiency in primates.