Neuroestrogens are important modulators of hippocampal function and memory.

Ovarian estrogens are hypothesized to regulate levels of hippocampal neuroestrogens.

Hippocampal neuroestrogen levels decline after long-term loss of ovarian function.

Short-term midlife estradiol treatment promotes lasting synthesis of neuroestrogens.

Maintenance of hippocampal neuroestrogen synthesis enhances cognitive aging.

Research conducted over the last several decades implicates ovarian estrogens as important modulators of hippocampal function. More recently however, the importance of estrogens synthesized in the brain de novo for hippocampal function has been recognized. These brain-derived neuroestrogens act in the hippocampus to regulate dendritic spine dynamics and synaptic plasticity as well as hippocampus-dependent memory. The current report provides an overview of research conducted in model systems elucidating the actions of neuroestrogens in the hippocampus and the subsequent consequences for cognition. We highlight the relationship between ovarian estrogens and brain-derived estrogens and discuss implications for female cognitive aging of the putative decline in hippocampal levels of neuroestrogens following loss of ovarian function. Finally, we propose a model of menopause in which a short-term period of midlife estradiol treatment changes the trajectory of hippocampal neuroestrogen production long-term, resulting in sustained interactions of neuroestrogens, insulin-like growth factor-1, and estrogen receptor signaling in the hippocampus, interactions that support successful brain and cognitive aging.

Estrogen

Estradiol

Neuroestrogens

Hippocampus

Menopause

Cognition

Memory

Aging

Estrogen receptor

IGF-1

© 2025 The Authors. Published by Elsevier Inc.