In 1846 William G. Morton, a young Boston-based dentist, showed that inhaling ether in a proper dose can make a person insensible to pain without affecting their vital physiologic functions. This first successful public demonstration of modern anesthesia revolutionized the field of medicine.
Thank you for reading this post, don't forget to subscribe!Today general anesthetic drugs enable doctors to perform more than 300 million surgeries each year. Increasing evidence has shown that these drugs induce loss of consciousness in part by acting on the hypothalamus, the part of the brain that controls the body’s sleep-wake cycle. Yet the exact mechanism by which these drugs work in the brain remains poorly understood.
Highlighting these fundamental gaps in knowledge, a group of researchers recently discovered why male and female mice respond differently to general anesthesia. The study, published in Proceedings of the National Academy of Sciences USA, shows that testosterone modulates susceptibility to volatile general anesthetics that are administered through inhalation, rendering males more sensitive to the effect of general anesthesia than females. This finding adds to the growing body of literature backing the need to include both sexes in biological research.
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Finding sex differences in the response to anesthetics was “an accident,” says study author Alex Proekt, an associate professor of anesthesiology and critical care at the University of Pennsylvania. The researchers were studying fluctuations in the brain activity of mice under a constant anesthetic dose when they observed that female mice took longer to become anesthetized and regained consciousness faster than male mice.
To understand the basis of these differences, the researchers treated mice with a range of so-called volatile anesthetics: isoflurane, sevoflurane, halothane and desflurane. They compared the concentration of the anesthetics in the brains of males and females and found similar amounts. This suggested that the differences did not arise from different drug distributions in male and female mice.
So they turned to the next somewhat obvious prospect that might account for this difference in males and females: sex hormones. They repeated their experiments with castrated male mice and found increased resistance to anesthesia. Injecting testosterone into the castrated male mice increased their sensitivity to anesthesia, and the animals showed similar responses as uncastrated males. They went under anesthesia faster and emerged from the state more slowly than female mice, confirming that testosterone modulated the effect of anesthetics.
Testosterone increased anesthetic sensitivity within an hour of injection, which the researchers realized was too rapid for a response altered by the switching on of genes. So the researchers probed whether the other way by which testosterone acts on the brain—its conversion to estradiol by the enzyme aromatase—could be responsible for this response. Inhibiting aromatase in male mice reduced anesthetic sensitivity, while injecting estradiol increased it. This indicated that testosterone mediates sensitivity to anesthesia through its conversion to estradiol by the aromatase enzyme in the brains of male mice.
These results were a “genuine surprise,” Proekt says. They also challenge an inherent bias that hormonal cycles in female animals contribute to sex differences, he adds, which often drives researchers to exclusively experiment on males.
To peek inside the brains of anesthetized animals to find out what was going on, the researchers measured cortical activity using electroencephalograms (EEGs), which are used to monitor the depth of anesthesia in clinical settings. This probe did not reveal any differences between the sexes in the cerebral cortex, suggesting that any disparities may lie elsewhere. Using whole-brain mapping to visualize active neurons on anesthetized animals, they found that sleep-promoting neurons in the hypothalamuses of females were less active than those of males.
Digging into clinical literature to see whether female humans are more resistant to anesthesia than male ones, Proekt’s team found widely contradictory results. While early work indicated no sex differences, newer studies suggest that women are more likely to retain awareness of their surroundings under anesthesia and emerge from an unconscious state faster than men. Some colleagues who studied awareness under anesthesia shared their observations of a greater degree of awareness in female patients during surgery, prompting the team to explore further.
Proekt’s team reanalyzed data from an old clinical trial in which researchers had assessed the behavior and brain activity of 30 people exposed to isoflurane. The reanalysis showed similar findings in people as in mice: women took longer to become anesthetized and emerged from that state faster than men. Consistent with results in mice, the EEGs of men and women did not show any significant differences between the sexes in the neuronal activity in the cerebral cortex under anesthesia, suggesting that any disparities may lie elsewhere.
The authors note that these insights highlight the importance of collecting more data about women’s dosing requirements when using anesthetics. The unexplored sex differences could contribute to women waking up sooner after surgery, Proekt says. “Whether it’s because of the same reasons [as those in mice] is hard to say,” he adds.
Sex hormones are important in determining sensitivity to anesthesia, agrees Nisha Gowani, an anesthesiologist at Ruby Hall Clinic in India, who was not associated with the study. But there are other factors, she adds. “You would need to compare body mass index, age, and consumption of alcohol and drugs,” Gowani says. She further notes that we need more studies in humans with larger sample sizes than 30 because not all studies from mice can be extrapolated to humans.
Alyssa Burgart, an anesthesiologist and bioethicist at Stanford University, who wasn’t associated with the study, says that this research highlights the need to consider sex variables seriously. “Many assumptions are made about women based solely on studies of men,” she says. Burgart adds that several factors can cause some people to have an increased risk of awareness under anesthesia.
While Burgart has not observed any significant sex differences in her patients, Gowani has observed that women usually go under anesthesia faster than men. Both of them emphasize that this highlights that sex hormones are just one of the factors controlling anesthetic response.
Proekt concurs and cautions doctors against increasing the anesthetic dosage for their female patients based on this basic biology study.
His team’s next focus is to answer bigger questions about consciousness and the brain. Anesthetics and the unique states of consciousness they induce are key tools in this search. “The most interesting thing about the brain is that it makes us human,” he says. “And I think anesthetics are a great tool to study this.”
