Estrogen Receptors May Hold the Key to Anesthesia’s Hidden Effects on the Brain

Every year, hundreds of millions of people undergo surgery under general anesthesia, and while most wake up and recover without incident, a troubling question has lingered for decades: why do some patients—particularly the very young and the very old—experience lasting cognitive problems after going under? A new review published in the journal Biology of Sex Differences offers one of the most comprehensive explanations yet, pointing to an unexpected player in the story: estrogen receptors, the molecular switches traditionally associated with reproductive biology, but which turn out to be deeply involved in how the developing and aging brain copes with anesthetic drugs.

The review, led by Nuo Yang and colleagues at Tianjin Medical University General Hospital together with Feixiang Li of Beijing Chao-Yang Hospital at Capital Medical University, synthesizes evidence on how three estrogen receptor subtypes—estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and the G protein-coupled estrogen receptor 1 (GPER1)—are expressed across the lifespan in the brain regions most critical for cognition, including the hippocampus and the prefrontal cortex. The central argument is striking: these receptors do not simply sit still. Their expression shifts dramatically across developmental stages, and those shifts create windows of vulnerability during which anesthetic exposure can derail the delicate hormonal signaling that neurons depend on to grow, connect, and communicate.

To understand why this matters, it helps to appreciate what estrogen receptors actually do in the brain. Far from being limited to reproductive functions, they act as master regulators of neurogenesis, synaptic plasticity, and cell survival. The classical nuclear receptors, ERα and ERβ, function as ligand-activated transcription factors: when bound by estrogen, they migrate to the genome and attach to specific DNA sequences called estrogen response elements, dialing up or down the expression of genes involved in neuronal growth and maintenance. They can also act through other transcription factors such as AP-1 and SP-1, giving them flexible control over gene programs. ERα and ERβ differ in their activation domains—the AF-1 and AF-2 regions—and this structural divergence means they often regulate different gene sets, sometimes in opposing directions. Meanwhile, GPER1 operates at the cell membrane, triggering rapid signaling cascades through G proteins, including the stimulatory Gαs, inhibitory Gαi, and the Gβγ subunits, which in turn activate pathways such as PI3K/Akt, MAPK/ERK, and other kinase networks within minutes rather than hours.

The review emphasizes that the balance among these receptor subtypes changes with age in a region-specific manner. During the perinatal period, when the brain is laying down its foundational circuits, estrogen signaling helps orchestrate the birth of new neurons and the formation of synapses. Markers of neurogenesis, such as doublecortin (DCX), and structural components of synapses, such as postsynaptic density protein 95 (PSD-95) and synaptophysin (SYP), are all influenced by estrogen receptor activity. In the hippocampus—a seahorse-shaped structure essential for forming new memories—and in the prefrontal cortex, which governs executive function and working memory, the relative abundance of ERα, ERβ, and GPER1 shifts as the brain matures, remodels during adolescence, and eventually declines in old age. This dynamic ebb and flow forms what the authors describe as a molecular basis for the regulation of cognitive function across the entire lifespan.

Against this backdrop, the review examines how general anesthetics can interfere with endogenous estrogen signaling. Many commonly used anesthetic agents act on gamma-aminobutyric acid type A receptors (GABAAR) and NMDA receptors, producing the sedation and immobility that surgery requires. But accumulating evidence indicates that anesthetic exposure can also disrupt estrogen receptor pathways in the brain, and this disruption appears to converge on several damaging mechanisms. The review identifies four key processes: synaptic injury, neuroinflammation, mitochondrial stress, and Tau pathology. Each of these can be modulated by estrogen receptor signaling, which means that the state of a patient’s estrogen system at the time of anesthesia may shape how much harm the drugs do.

Of the three receptor subtypes, ERα-mediated pathways emerge as the most established mechanistic targets in anesthetic neurotoxicity. Studies summarized in the review suggest that when anesthetics perturb ERα signaling, the downstream consequences ripple through the PI3K/Akt pathway, which normally promotes cell survival, and through CREB-dependent gene expression, which supports long-term potentiation (LTP)—the cellular substrate of learning and memory. Disruption of these pathways can weaken synapses in the CA1 region of the hippocampus and impair memory consolidation. ERα also interacts with neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which neurons rely on to maintain their connections. When this support system falters, synaptic proteins like PSD-95 and synaptophysin decline, and the structural integrity of neural circuits erodes.

The other two subtypes present a more complicated picture. ERβ has often been described as neuroprotective, and evidence suggests it can counteract inflammation by modulating nuclear factor kappa B (NF-κB) signaling, a central hub of the inflammatory response. It may also influence the clearance of amyloid beta (Aβ), the peptide that accumulates in Alzheimer’s disease, partly through enzymes such as neprilysin (NEP). GPER1, the newest and least well-characterized member of the family, activates fast signaling through EGFR transactivation and other membrane-proximal mechanisms, but the review is candid that its role in anesthetic-induced cognitive dysfunction remains under-validated. The authors note that while ERα pathways are the best supported, ERβ and GPER1 require further investigation before they can be considered reliable therapeutic targets.

One of the review’s most consequential themes is the role of sex and age in determining vulnerability. Perioperative neurocognitive disorders (PNDs)—an umbrella term covering the delirium and longer-lasting cognitive decline that can follow surgery—do not strike uniformly. The developing brain, with its immature and still-shifting estrogen receptor landscape, appears especially susceptible, as does the aging brain, where estrogen signaling homeostasis is already fragile. Sex differences add another layer of complexity: ovarian estrogen production, and its loss after menopause or ovariectomy, changes the hormonal milieu in ways that alter how the brain responds to anesthetic challenge. Clinical studies, including trials such as the General Anesthesia compared with Spinal anesthesia (GAS) study, have attempted to untangle the real-world consequences of early anesthetic exposure, though the review suggests that laboratory findings on receptor mechanisms have not yet been fully translated into clinical prevention strategies.

The mechanistic detail extends to pathology usually associated with neurodegenerative disease. The review describes how anesthetic exposure can promote Tau pathology, the tangle-forming protein hallmark of Alzheimer’s disease, potentially through kinases such as Tau tubulin kinase 1 (TTBK1), and how mitochondrial stress and calcium dysregulation feed into a self-reinforcing cycle of damage. Inflammatory signaling molecules, including high mobility group box 1 (HMGB1), link the synaptic and immune dimensions of anesthetic neurotoxicity. Estrogen receptors sit at the crossroads of all these processes: when their signaling is intact, they buffer the brain against stress; when anesthetics disrupt them, the buffers fail.

Looking forward, the authors argue that the field needs to move beyond broad correlations and toward precision. They propose integrating cell-specific gene editing—using tools delivered by adeno-associated viruses (AAV)—with brain organoids, the lab-grown miniature brain models that can recapitulate human developmental processes, and with clinical cohort investigations that track real patients over time. Such approaches could finally resolve which receptor subtype matters most at which age, in which sex, and in which brain region, paving the way for targeted interventions that protect the estrogen signaling system during surgery. For now, the review’s message is a sobering but hopeful one: the hormones that build the brain may also be the key to defending it from one of modern medicine’s most routine interventions.

Subject of Research: The role of dynamic estrogen receptor subtype expression in brain development and anesthetic-induced cognitive dysfunction

Article Title: Dynamic expression of estrogen receptor subtypes during brain development and their mechanistic roles in anesthetic-induced cognitive dysfunction: a review

Article References: Yang, N., Li, F., Liu, Y., Yang, Y., & Yu, Y. (2026). Dynamic expression of estrogen receptor subtypes during brain development and their mechanistic roles in anesthetic-induced cognitive dysfunction: a review. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00994-7

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00994-7

Keywords: estrogen receptor, anesthetic neurotoxicity, perioperative neurocognitive disorders, hippocampus, prefrontal cortex, synaptic plasticity, neuroinflammation, ER alpha, ER beta, GPER1, brain development, sex differences