New findings indicate that estrogen induces specific proteins, influencing nicotine addiction and suggesting a gender-specific pathway to dependency.

A newly discovered feedback loop involving estrogen may explain why women might become dependent on nicotine more quickly and with less nicotine exposure than men.

The researchers found that the sex hormone estrogen induces the expression of olfactomedins, proteins that are suppressed by nicotine in key areas of the brain involved in reward and addiction. The findings suggest that estrogen–nicotine–olfactomedin interactions could be targeted with therapies to help control nicotine consumption.

“Studies show that women have a higher propensity to develop addiction to nicotine than men and are less successful at quitting,” says Sally Pauss, a doctoral student at the University of Kentucky College of Medicine who led the project, in a release. “Our work aims to understand what makes women more susceptible to nicotine use disorder to reduce the gender disparity in treating nicotine addiction.”

Pauss will present the research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, which will be held March 23–26 in San Antonio.

“Our research has the potential to better the lives and health of women struggling with substance use,” she says in a release. “If we can confirm that estrogen drives nicotine seeking and consumption through olfactomedins, we can design drugs that might block that effect by targeting the altered pathways. These drugs would hopefully make it easier for women to quit nicotine.”

For the new study, the researchers used large sequencing datasets of estrogen-induced genes to identify genes that are expressed in the brain and exhibit a hormone function. They found just one class of genes that met these criteria: those coding for olfactomedins. They then performed a series of studies with human uterine cells and rats to better understand the interactions between olfactomedins, estrogen, and nicotine. 

The results suggested that estrogen activation of olfactomedins—which is suppressed when nicotine is present—might serve as a feedback loop for driving nicotine addiction processes by activating areas of the brain’s reward circuitry such as the nucleus accumbens.

The researchers are now working to replicate their findings and definitively determine the role of estrogen. This knowledge could be useful for those taking estrogen in the form of oral contraceptives or hormone replacement therapy, which might increase the risk of developing a nicotine use disorder.

The investigators also want to determine the exact olfactomedin-regulated signaling pathways that drive nicotine consumption and plan to conduct behavioral animal studies to determine how manipulating the feedback loop affects nicotine consumption.

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