Sex Differences in Response to Anesthesia
When anesthesia providers administer anesthesia to relieve pain, relax and sedate patients, prevent movement during surgery, ensure that patients have no awareness or memory of procedures, or achieve a combination of those goals, anesthesia must be adjusted to the individual patient’s responses. Many factors affect how anesthesia affects different people, including differences associated with sex.
Sex, referring to the set of frequently consistent biological variables resulting from one’s chromosomal composition,1 will be represented in dichotomy (i.e., “woman” or “man”) in this article. It is important to note that (1) at times, chromosomal composition and the resultant phenotype do not always match in a way consistent with typical patterns, (2) sexual chromosomal compositions are not limited to XX or XY, (3) sex and gender are separate concepts, the latter of which will not be addressed in this article, and (4) many prior scientific articles have conflated sex and gender; thus, this article will use only sex-based terms, though the data from which it is produced may have proxied gender for sex or vice versa.
Sexual dimorphism among humans extends to physiological differences that can affect the metabolism of volatile and intravenous anesthetics.2 Some of these differences for women often include a smaller cardiac mass—estimated to be on average 15–30% smaller in women compared to men—lower lung volumes, a greater stress glucocorticoid response, and a greater sensitivity to baroreflex stimulation.2
Women on average have a greater volume of distribution for and clearance of the highly-lipophilic anesthetizing agent, propofol; therefore, greater doses are likely to be required for women when compared to men.3 Specifically, a 2003 study suggested that men might require a 30–40% reduction in the dose of propofol when compared to women.3
Additionally, for those who experience menstruation, progesterone, the predominant hormone during the luteal phase, can accentuate the effects of propofol through increases in cortical agonism of the gamma-aminobutyric acid type A (i.e., GABA-A) receptor functioning.4,5 As such, one study demonstrated that propofol requirements for loss of eyelash reflex—an estimate of loss of consciousness—and time for bispectral index—a proprietary tool used for measuring the degree of consciousness—to reach 50 were found to be statistically significantly the least and shortest, respectively, for participants currently in the luteal phase. In other words, study participants in the luteal phase were more sensitive to propofol than participants in other menstrual phases.
Similar non-human animal studies have supported the existence of sex-mediated physiological differences in the metabolism of and response to volatile anesthesia. In a 2024 study using mice, researchers demonstrated that female mice regained consciousness and sentience more quickly following anesthetic exposure, demonstrated through observation of neuronal activity within sleep-promoting regions of the ventral hypothalamus. Thus, it was discovered that female mice regain consciousness at a faster rate than their counterparts.6 This sexual dimorphism is hypothesized to be mediated by differential concentrations of testosterone, which produces increased sensitivity to anesthesia.6 The role of testosterone in increasing sensitivity to volatile anesthetics was further supported when the administration of letrozole, an aromatase inhibitor which prevents the conversion of testosterone to estrogens, diminished anesthetic sensitivity.6
Data suggest that physiological sex differences in humans extend to differing responses to volatile and intravenous anesthesia. On average, women tend to be more resistant to the sedating effects of anesthetics, largely mediated by a larger volume of distribution for lipophilic anesthetics, as well as by the estrogenic protective effects on the regions of the hypothalamus responsible for consciousness and awakening.
References
1. Johnson JL, Repta R. Sex and Gender: Beyond the Binaries. In: Designing and Conducting Gender, Sex, & Health Research. SAGE Publications, Inc.; 2012:17-38. doi:10.4135/9781452230610.n2
2. Filipescu D, Ştefan M. Sex and gender differences in anesthesia: Relevant also for perioperative safety? Best Pract Res Clin Anaesthesiol. 2021;35(1):141-153. doi:10.1016/j.bpa.2020.12.006
3. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand. 2003;47(3):241-259. doi:10.1034/j.1399-6576.2003.00036.x
4. Bitran D, Purdy RH, Kellog CK. Anxiolytic effect of progesterone is associated with increases in cortical alloprenanolone and GABAA receptor function. Pharmacol Biochem Behav. 1993;45(2):423-428. doi:10.1016/0091-3057(93)90260-Z
5. Liu YW, Zuo W, Ye JH. Propofol stimulates noradrenalin-inhibited neurons in the ventrolateral preoptic nucleus by reducing GABAergic inhibition. Anesth Analg. 2013;117(2):358-363. doi:10.1213/ANE.0b013e318297366e
6. Wasilczuk AZ, Rinehart C, Aggarwal A, et al. Hormonal basis of sex differences in anesthetic sensitivity. Proc Natl Acad Sci. 2024;121(3):e2312913120. doi:10.1073/pnas.2312913120