The hormone estrogen regulates excessive alcohol consumption in women, causing them to consume large amounts of alcohol within the first 30 minutes after being offered it, according to a preclinical study led by scientists at Weill Cornell Medicine. The study establishes, for what is believed to be the first time, that circulating estrogen increases excessive alcohol consumption in women and contributes to known sex differences in this behavior.
The findings, published December 30 in the journal Nature Communicationscould lead to novel approaches to treating alcohol use disorder.
“We know much less about what drives drinking behavior in women because most studies on alcohol use have been done in men,” said senior author Dr. Kristen Pleil, associate professor of pharmacology. . However, women also overindulge and are more susceptible than men to the negative health effects of alcohol.
Recent studies indicate that, during the pandemic confinement, women increased their excessive alcohol consumption more than men. Such behavior has important consequences for women’s health, Dr. Pleil said, “because many studies show that this pattern of drinking increases the harmful effects of alcohol.” In fact, women had many more hospital visits and alcohol-related complications than men during and since the pandemic.
Peak estrogen levels associated with increased alcohol consumption
In a 2021 study, Dr. Pleil and her team showed that a specific subpopulation of neurons in a brain region called the bed nucleus of the stria terminalis (BNST) was more excitable in female mice than in males. This improved activity was correlated with their heavy drinking behavior.
But what makes this neural circuit more excitable in women? “Estrogen has very powerful effects on many behaviors, particularly in women,” Dr. Pleil said. “So it makes sense that it would also modulate alcohol consumption.”
To evaluate the possible involvement of estrogen, the researchers, including first author Dr. Lia Zallar, who was a graduate student in Pleil’s lab at the time of the research, began by monitoring hormone levels throughout the estrous cycle of female mice. Then, they served the alcohol. They found that when a woman has a high level of circulating estrogen, she drinks much more than on days when her estrogen level is low.
That improved binge eating behavior was reflected in increased activity in those same neurons in the BNST. “When a woman takes her first sip from a bottle containing alcohol, those neurons go crazy,” Dr. Pleil said. “And if she’s in a high estrogen state, they go even crazier.” That extra boost of neural activity means the mice hit the bottle even harder, particularly within the first 30 minutes after the alcohol became available, a behavior Dr. Pleil refers to as “front-loading.”
Surprising discovery: Cell surface receptors allow estrogen to act quickly
Although the researchers suspected that estrogen would have an effect on alcohol consumption, they were surprised by its mechanism of action. This steroid hormone normally regulates behaviors by binding to receptors that then travel to the nucleus, where they alter the activity of specific genes, a process that could take hours. However, Dr. Pleil and her team realized something else must be going on when estrogen infused directly into the BNST excited the neurons and caused binge drinking within minutes.
So the researchers tested estrogen that had been manipulated so that it couldn’t enter cells and bind to nuclear receptors, a feat of chemical engineering performed by Dr. Jacob Geri, assistant professor of pharmacology at Weill Cornell Medicine. They determined that when estrogen promotes binge eating, the hormone binds to receptors on the surface of neurons, where it directly modulates communication between cells.
“We believe this is the first time that anyone has shown that during a normal estrous cycle, endogenous estrogen produced by the ovaries can use such a rapid mechanism to control behavior,” Dr. Pleil said. That rapid action drives the initial dose of alcohol when estrogen is high.
The team identified the estrogen receptor that mediates this effect and determined that it is expressed in excited BNST neurons and in neurons in other brain regions that excite them. The researchers are now investigating the signaling mechanisms of this effect and will also examine whether the same system regulates alcohol consumption in men.
“The whole infrastructure is also present in men: the estrogen receptors and the basic circuit organization,” Dr. Pleil said. The only difference will be the source of the estrogen, which in men without an ovarian source depends on the local conversion of testosterone to estrogen in the brain.
Inhibiting the enzyme that synthesizes estrogen could offer a novel treatment to selectively reduce alcohol consumption when hormone levels increase. An FDA-approved version of this inhibitor is currently used to treat women with estrogen-sensitive cancers.
“Combining this drug with compounds that modulate the downstream effects of chemicals produced by BNST neurons could provide a new, targeted approach to treating alcohol use disorder,” Dr. Pleil said.