In the nearly 25 years since scientists first discovered differences in the sensitivity of men and women to anesthetics, new research suggests that sex hormones make men more responsive to this unconscious state, while women are much less responsive.
Early research shows that women take longer to "go into anesthesia" than men, emerge from anesthesia more quickly than men, and are more likely to develop rare disorders of consciousness on the operating table. But why this happens, people are still mostly in the theoretical stage, and the research is not in-depth enough. This is not surprising, because gender bias is prevalent in the medical field.
Now, Penn researchers have shown in mouse and human models that hormones play a key role in drug metabolism and their sleep effects, and that women are more resistant to the hypnotic effects of general anesthesia.
"Anesthetic-induced coma is partly due to effects on hypothalamic sexually dimorphic and hormone-sensitive circuits that regulate sleep and wakefulness. Therefore, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones," the authors noted in the study report.
In a mouse study, the team found that female mice were more resistant than male mice to the same anesthetic concentration. However, when the experiment was replicated in castrated mice, their resistance increased, consistent with female mice. Therefore, this appears to confirm a role for testosterone in drug sensitivity.
They added: "Anesthetic sensitivity is bidirectionally regulated by testosterone. Castration increases anesthetic resistance. Conversely, administration of testosterone acutely increases anesthetic sensitivity. The conversion of testosterone to estradiol by aromatase is partly responsible for this effect."
There were no discernible differences between women and men, or between the 30 human participants in the trial, who read brain signals via electroencephalography (EEGs are used in clinical settings to help medical staff monitor the 'depth' of anesthesia). But when the mice's entire brain activity was mapped, the area of the hypothalamus that promotes natural sleep was found to be significantly more stimulated in males.
Researchers believe this may be why more women experience unconsciousness or some kind of awakening during surgery.
"Sex differences in anesthesia sensitivity are primarily driven by testosterone," the authors added.
This study opens the door to further research into sex differences across life stages and also calls for a re-evaluation of how anesthetic doses are calculated. Currently, anesthetic doses are calculated based on body weight, which does not take into account other physiological factors, such as fat (which can alter the effectiveness of hypnotics), and hormones, which this study highlights. On average, men are larger than women, so although men are more sensitive to the effects of the drug, they usually receive more of the drug.
"In clinical settings, anesthetic use is often guided by data on male excess. As we show, this approach may significantly underestimate the anesthesia needs of female patients," the researchers said.
The research was published in the Proceedings of the National Academy of Sciences (PNAS).