Hippocampal responsiveness to 17β-estradiol and equol after long-term ovariectomy: Implication for a therapeutic window of opportunity

A ‘critical window of opportunity’ has been proposed for the efficacy of ovarian hormone intervention in peri- and post-menopausal women. We sought to address this hypothesis using a long-term ovariectomized non-human primate (NHP) model, the cynomolgus macaque (Macaca fascicularis). In these studies, we assessed the ability of 17β-estradiol and equol to regulate markers of hippocampal bioenergetic capacity. Results indicated that 17β-estradiol treatment significantly increased expression of mitochondrial respiratory chain proteins complex-I and -III in the hippocampus when compared to non-hormone-treated animals. Expression of the TCA cycle protein succinate dehydrogenase α was decreased in animals treated with equol compared to those treated with 17β-estradiol. There were no significant effects of either 17β-estradiol or equol treatment on glycolytic protein expression in the hippocampus, nor were there significant effects of treatment on expression levels of antioxidant enzymes. Similarly, 17β-estradiol and equol treatment had no effect on mitochondrial fission and fusion protein expression. In summary, findings indicate that while 17β-estradiol induced a significant increase in several proteins, the overall profile of bioenergetic system proteins was neutral to slightly positively responsive. The profile of responses with the ERβ-preferring molecule equol was consistent with overall nonresponsiveness. Collectively, the data indicate that long-term ovariectomy is associated with a decline in response to estrogens and estrogen-like compounds. By extension, the data are consistent with a primary tenet of the critical window hypothesis, i.e., that the brains of post-menopausal women ultimately lose their ability to respond positively to estrogenic stimulation.

Research Highlights
► E2 induces moderate mitochondrial bioenergetic response after extended ovariectomy.
► Equol induces no mitochondrial bioenergetic response after extended ovariectomy.
► These results may affect hormone therapy timing in post-menopausal women.