Estrogens and Memory Basic Research and Clinical Implications

“A book about the influence of estrogens on memory would have been unthinkable as recently as 30 years ago. Although a few small studies in the late 1970’s reported a beneficial effect of estrogens on memory in human women (Hackman and Galbraith, 1976; Fedor-Freybergh, 1977), examination of the role of estrogens in memory did not truly capture more widespread attention until the pioneering work of Barbara Sherwin and colleagues in 1988 and beyond. In her initial paper, Sherwin showed that bilateral removal of the ovaries (aka surgical menopause) led to impaired short-term and long-term memory, whereas treatment of surgically menopausal women with estradiol alone, testosterone alone, or estradiol plus testosterone prevented this decline (Sherwin, 1988). As a search for the terms “estrogen” and “memory” in PubMed illustrates, well over 2000 papers have been published on the subject of estrogens and memory in the ensuing decades. The vast majority of these studies have focused on the hippocampus, a bilateral medial temporal lobe structure essential for the formation of episodic memories, particularly those with spatial, contextual, relational, temporal, and recognition components (Olton et al., 1979; Morris et al., 1982; Kim and Fanselow, 1992; Squire, 1992; Cohen and Stackman, 2015; Tonegawa et al., 2015; Eichenbaum, 2017). Although various forms of learning and memory are mediated by numerous brain regions, including the prefrontal cortex, medial temporal lobe cortices, amygdala, striatum, and cerebellum, the hippocampus has received the lion’s share of attention due to its central importance for episodic memory formation. Hippocampal damage produces profound retrograde amnesia for facts and events, as well as anterograde amnesia for new information and impairments in spatial navigation (Winocur, 1990; Anagnostaras et al., 2001; Clark et al., 2002; Gilboa et al., 2006). Hippocampal dysfunction in middle-aged and aged subjects is a primary contributor to age-related memory decline (Golumb et al., 1996; Grady et al., 2003; Apostolova et al., 2010; Burke and Barnes, 2010; Small et al., 2011; Yassa et al., 2011), and has also been implicated in the cognitive impairments observed in diseases such as schizophrenia and depression (Small et al., 2011; Nakahara et al., 2018; Santos et al., 2018; Ott et al., 2019). Moreover, the hippocampi of patients with Alzheimer’s disease are substantially atrophied and burdened with copious amounts of amyloid plaques and neurofibrillary tangles, the hallmark pathologies of this insidious disease (Hyman et al., 1984; Walsh and Selkoe, 2004; Selkoe and Hardy, 2016). As such, understanding how estrogens influence hippocampal functioning may provide important insights not only about the fundamental neurobiology of memory processes, but also into the etiology of neuropsychiatric and neurodegenerative diseases”–