High levels of estrogen seem to make the brain more vulnerable to stress, says new research from Yale University.

That finding may explain why stress-related disorders such as depression occur twice as often in women as in men, the study authors suggest.

The area of the brain called the prefrontal cortex is sensitive to stress. Studies have found cognitive functioning of that part of the brain becomes impaired under uncontrollable stress. What researchers don't know is what role estrogen might play in impairing prefrontal cortex function.

"We need to figure out the mechanisms by which estrogen is having this effect," says Rebecca Shansky, lead author of the study, which will appear in the March issue of Molecular Psychiatry.

One in five women can expect to develop depression in their lifetime, regardless of age, race or income, according to the National Mental Health Association. Why women are more vulnerable to stress is not known, although research suggests biological differences, such as hormonal changes and genetics, may contribute to depression.

"I think what this study does is add a new avenue to explaining the discrepancy between the rates of depression in men and women," says Kathy Hogan Bruen, senior director of prevention at the National Mental Health Association.

The Yale team used rats to examine sex differences in how the brain responds to stress. Male and female rats were exposed to different levels of stress and then tested on a short-term memory task.

Exposing female rats to moderate levels of stress impaired their performance. Males, by contrast, performed the same under moderate stress as they did with no stress at all.

What's more, the study found mild levels of stress, which had no effect on male rats, only affected female rats when their estrogen levels were high.

"Basically, it tells us that estrogen can influence the way the brain responds to stress, especially with this area of the brain that's so important for stress-related disorders," explains Shansky, a graduate student in neurobiology at Yale School of Medicine.

While there are probably many factors contributing to depression in women, its higher prevalence in women suggests that biology -- and estrogen in particular -- play a role, the authors conclude.

A better understanding of sex-related responses to stress might lead to better treatments, perhaps even medicines that are gender-specific, Shansky adds.

"If there is a drug that can help alleviate someone's symptoms of depression, that's fantastic," Hogan Bruen says.

But she also sees a potential downside if more people go for the quick pharmacologic fix and skip needed therapy sessions to deal with the consequences of depression, such as lack of motivation, failed relationships and inability to hold a job.

"If people feel that it's just a medical illness, something that they just need a drug to address, that leaves a hole in terms of the psychosocial issues that potentially are not being addressed," Hogan Bruen says.

More information

You can learn more about women and depression at the American Psychological Association or the National Institute of Mental Health.

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