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Testosterone alters isoflurane sensitivity

Mouse research suggests a mechanism for controversial sex difference in response to anesthesia

by Laurel Oldach
January 18, 2024

Structure of the volatile anesthetic molecule isoflurane.
Even with identical isoflurane concentrations in their brains, male and female mice behave differently under anesthesia.

Not many drugs are as widely used yet poorly understood as anesthetics. “We’ve used them for over a century, but nobody understands how they work,” says Alex Proekt, an anesthesiologist and neuroscientist at the University of Pennsylvania. Researchers in Proekt’s lab recently published work on another wrinkle besides mechanism of action: that sex hormone differences in the brain may drive differences in sensitivity to anesthesia (Proc. Natl. Acad. Sci. U.S.A. 2024, DOI: 10.1073/pnas.2312913120) .

Researchers have sometimes reported sex differences in how people recover from anesthesia—specifically, that men regain consciousness more slowly than women. But the phenomenon is not always observed, making it controversial. In addition, clinical studies of anesthesia are challenging, and have historically focused on men.

While studying how consciousness comes back online as an anesthetic drug called isoflurane wears off, Penn postdoctoral researcher Andrzej Wasilczuk observed that anesthetized female mice are more likely to retain certain reflexes, go under more slowly, and wake up more quickly than male mice. By testing castrated male mice and female mice with ovaries removed, Wasilczuk and colleagues determined that testosterone drove the observed reawakening differences. Castrated male mice, like female mice, were more likely to right themselves from a vulnerable belly-up position while anesthetized. Treatment with testosterone or a downstream metabolite, estradiol, made the castrated mice more sensitive to the effects of isoflurane. Conversely, blocking the enzyme that converts testosterone to estradiol made uncastrated male mice less sensitive.

Using a whole-brain activity imaging technique, the researchers found sex differences in activity in part of the hypothalamus, a brain region with roles in both sleep and the endocrine system.

The scientists revisited human data from a study of reacquiring consciousness after isoflurane treatment and found that men were less likely than women in that trial to respond to stimuli, like an instruction to squeeze a hand. The difference is undetectable using electroencephalography (EEG), a noninvasive measure of brain activity, which anesthetists use to monitor unconsciousness. Proekt says this lack of detection is because the hypothalamus is deep in the brain—too deep to detect using the external electrodes that EEG relies on. That may be part of why any sex difference has been so hard to identify for certain in people.

According to Margaret Sedensky, a University of Washington anesthesiologist who studies anesthetic mechanisms, the work is interesting, but the mechanistic relationships will need to be examined further. Although the mouse studies used a drug concentration the researchers confirmed was the same in males and females, it’s possible that in humans, attributes correlated with sex could cause different amounts of drug to reach the brain or affect the rate of drug metabolism, she says in an email. In addition, the study focused on a single inhaled anesthetic, whereas human patients anesthetized for surgery usually receive a mixture of painkillers and multiple anesthetics.

Fortunately, becoming aware during anesthesia is quite rare. But the research suggests it might happen more often in people with lower testosterone, such as cisgender women.


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