The hormone estrogen influences binge drinking among females, prompting them to drink excessively, especially in the initial 30 minutes after alcohol is available, according to a groundbreaking preclinical study by researchers at Weill Cornell Medicine. This research importantly reveals for the first time that the presence of circulating estrogen boosts binge drinking behaviors in females and highlights established gender differences regarding this issue.
The hormone estrogen influences binge drinking among females by causing them to “pregame”—ingesting considerable amounts of alcohol shortly after it’s offered, as revealed in a pioneering study conducted by scientists at Weill Cornell Medicine. This study, which is believed to be the first of its kind, shows that circulating estrogen heightens binge drinking in females while contributing to recognized gender disparities in this behavior.
The results, released on December 30 in the journal Nature Communications, may pave the way for new treatment methods for alcohol use disorder.
“We still have limited understanding of what motivates alcohol consumption in females since most research has focused on males,” noted senior author Dr. Kristen Pleil, a pharmacology associate professor. Nonetheless, females also engage in heavy drinking and are more vulnerable to the health risks associated with alcohol compared to males.
Recent findings show that during the pandemic lockdown, women increased their heavy drinking more than men did. This trend has significant implications for women’s health, Dr. Pleil explained, saying, “Numerous studies indicate that this drinking pattern exacerbates the detrimental effects of alcohol.” In fact, women experienced more alcohol-related emergency room visits and complications than men both during and after the pandemic.
Estrogen Peaks Linked to Higher Alcohol Intake
In a study conducted in 2021, Dr. Pleil and her research group demonstrated that a certain group of neurons in the bed nucleus of the stria terminalis (BNST), a brain region, exhibited greater activity in female mice than in male mice. This heightened activity was associated with their binge drinking habits.
But what’s responsible for making this neural circuit more active in females? “Estrogen significantly influences various behaviors, especially in females,” Dr. Pleil explained. “Thus, it’s logical that it would also impact drinking.”
To explore estrogen’s potential role further, the team, including first author Dr. Lia Zallar, who was then a graduate student in Dr. Pleil’s lab, monitored hormone levels throughout the estrous cycle of female mice before introducing alcohol. Their experiments revealed that during periods of high circulating estrogen, female mice consumed significantly more alcohol compared to days with low estrogen levels.
This increase in binge drinking corresponded with amplified neuron activity in the BNST. “As soon as a female takes her first sip of alcohol, those neurons become highly active,” Dr. Pleil stated. “And during a high-estrogen phase, their activity spikes even more.” This additional neural excitement leads to a more intense drinking behavior, especially in the first 30 minutes after alcohol intake, a phenomenon Dr. Pleil describes as “front-loading.”
Unexpected Finding: Rapid Action Mechanism of Estrogen
While the researchers anticipated estrogen would influence drinking, they were taken aback by the speed of its action. Typically, this steroid hormone alters behaviors by attaching to receptors which then travel to the nucleus to modify gene activity— a process that can take hours. However, the team’s observations, where direct infusion of estrogen into the BNST excited neurons and sparked binge drinking almost instantly, indicated that a different mechanism was at play.
To investigate this, the team used a modified form of estrogen that couldn’t penetrate cells or engage nuclear receptors, thanks to the chemical engineering skills of Dr. Jacob Geri, a pharmacology assistant professor at Weill Cornell Medicine. They found that when estrogen prompts binge drinking, it binds to receptors located on the neuron’s surface, directly influencing cell-to-cell communication.
“We believe this is the first time it’s been shown that during a regular estrous cycle, the endogenous estrogen produced by the ovaries can operate through such a quick mechanism to regulate behavior,” Dr. Pleil remarked. This prompt action encourages increased alcohol consumption during periods of high estrogen.
The researchers identified the specific estrogen receptor responsible for this rapid effect and confirmed it was present in the activated BNST neurons, as well as in neurons from other brain regions that stimulate them. They are currently delving into the signaling mechanisms behind this phenomenon and will examine whether a similar process governs drinking in males.
“The necessary structures exist in males as well: the estrogen receptors and the fundamental circuit organization,” Dr. Pleil explained. The primary distinction would be the estrogen’s origin, which, in males, typically results from the local conversion of testosterone to estrogen in the brain since they do not produce ovarian estrogen.
Blocking the enzyme responsible for synthesizing estrogens could lead to innovative treatments aimed at selectively diminishing alcohol consumption during hormone level spikes. An FDA-approved version of such an enzyme inhibitor is currently in use for treating women with estrogen-sensitive cancers.
“Combining this medication with agents that modulate the downstream impacts of the chemicals produced by BNST neurons could create a new, targeted strategy for addressing alcohol use disorder,” Dr. Pleil noted.
