Estradiol treatment improves biological rhythms in a preclinical rat model of menopause

Abstract

The perimenopausal transition at middle age is often associated with hot flashes and sleep disruptions, metabolic changes, and other symptoms. Whereas the mechanisms for these processes are incompletely understood, both aging (AG) and a loss of ovarian estrogens play contributing roles. Furthermore, the timing of when estradiol (E) treatment should commence and for how long are key clinical questions in the management of symptoms. Using a rat model of surgical menopause, we determined the effects of regimens of E treatment with differing time at onset and duration of treatment on diurnal rhythms of activity and core temperature and on food intake and body weight. Reproductively mature (MAT, ∼4 months) or AG (∼11 months) female rats were ovariectomized, implanted intraperitoneally with a telemetry device, and given either a vehicle (V) or E subcutaneous capsule implantation. Rats were remotely recorded for 10 days per month for 3 (MAT) or 6 (AG) months. To ascertain whether delayed onset of treatment affected rhythms, a subset of AG-V rats had their capsules switched to E at the end of 3 months. Another set of AG-E rats had their capsules removed at 3 months to determine whether beneficial effects of E would persist. Overall, activity and temperature mesor, robustness, and amplitude declined with AG. Compared to V treatment, E-treated rats showed (1) better maintenance of body weight and food intake; (2) higher, more consolidated activity and temperature rhythms; and (3) higher activity and temperature robustness and amplitude. In the AG arm of the study, switching treatment from V to E or E to V quickly reversed these patterns. Thus, the presence of E was the dominant factor in determining stability and amplitude of locomotor activity and temperature rhythms. As a whole, the results show benefits of E treatment, even with a delay, on biological rhythms and physiological functions.