Effect of estradiol replacement on hippocampal concentrations of estrogens in aged rhesus macaques maintained on an obesogenic diet

Replacement involving estrogens has proven efficacy at treating a wide range of disorders that develop with menopause or after surgical removal of the ovaries. Here, we tested whether an estradiol (E2) replacement paradigm that recapitulates physiological E2 levels in the circulation also recapitulates physiological E2 levels within the hippocampus. E2 was delivered continuously to old ovariectomized (OVX) rhesus macaques, maintained on a high-fat, high-sugar Western-style diet (WSD) for ∼30 months, via subcutaneous implants; this resulted in physiological concentrations of both estrone (E1) and E2 in the circulation (determined by LC-MS/MS). Surprisingly, however, hippocampal concentrations of E2 were markedly (P < 0.01) higher than in ovary-intact animals maintained on a regular chow diet. The data suggest that E2 replacement paradigms that appear to recapitulate physiological E2 concentrations in the circulation may produce hyper-physiological E2 levels within some brain areas, especially when individuals are maintained on a WSD.