Hormonal basis of sex differences in anesthetic sensitivity

Andrzej Z. Wasilczuk, Cole Rinehart, Adeeti Aggarwal, Martha E. Stone, George A. Mashour, Michael S. Avidan, Max B. Kelz, Alex Proekt

Research output: Contribution to journalArticlepeer-review


General anesthesia-a pharmacologically induced reversible state of unconsciousness- enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

Original languageEnglish
Article numbere2312913120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - 2024


  • behavior
  • EEG
  • hormones
  • sex differences
  • whole brain c-Fos imaging


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