The study investigates the hormonal basis of sex differences in anesthetic sensitivity. Using behavioral measures, the researchers found that female mice are more resistant to volatile anesthetics than males at identical brain anesthetic concentrations. Anesthetic sensitivity is modulated by testosterone, with castration increasing resistance and testosterone administration increasing sensitivity. The conversion of testosterone to estradiol by aromatase is partially responsible for this effect. Oophorectomy had no effect. Whole-brain c-Fos activity mapping revealed fewer active neurons in the ventral hypothalamic sleep-promoting regions in females compared to males. In humans, females also regained consciousness and recovered cognition faster after identical anesthetic exposures. Despite behavioral differences, EEG recordings did not show sex differences in anesthetic sensitivity. These findings suggest that sex differences in anesthetic sensitivity are evolutionarily conserved and may explain the higher incidence of unintended awareness under general anesthesia in females.The study investigates the hormonal basis of sex differences in anesthetic sensitivity. Using behavioral measures, the researchers found that female mice are more resistant to volatile anesthetics than males at identical brain anesthetic concentrations. Anesthetic sensitivity is modulated by testosterone, with castration increasing resistance and testosterone administration increasing sensitivity. The conversion of testosterone to estradiol by aromatase is partially responsible for this effect. Oophorectomy had no effect. Whole-brain c-Fos activity mapping revealed fewer active neurons in the ventral hypothalamic sleep-promoting regions in females compared to males. In humans, females also regained consciousness and recovered cognition faster after identical anesthetic exposures. Despite behavioral differences, EEG recordings did not show sex differences in anesthetic sensitivity. These findings suggest that sex differences in anesthetic sensitivity are evolutionarily conserved and may explain the higher incidence of unintended awareness under general anesthesia in females.