The ancients blamed women’s susceptibility to mental illness on low body temperature, which made them prone to “cold” diseases caused by black bile. More recent theories blamed the pressures of balancing a career and family life. A new study suggests that the vulnerability may hinge on hormones.

High levels of estrogen amplify the effects of stress on the prefrontal cortex, an area of the brain associated with mental disorders such as depression and post-traumatic stress disorder, the Yale study found. This could explain why such illnesses occur twice as often in women as in men and why the discrepancy is most marked between puberty and menopause.

For a study published in the May issue of Molecular Psychiatry, neurobiology graduate student Becca Shansky and associate professor of neurobiology Amy Arnsten, Ph.D., exposed rats to different levels of stress and then tested them on a working memory task that depends on the prefrontal cortex. Female rats were more sensitive than males to moderate levels of stress, but only when the females were in the high-estrogen phase of their estrus cycle. The same sensitivity was seen in females that had their ovaries removed and were then implanted with time-release estrogen capsules. It was not observed in females that received a placebo instead of estrogen.

Now Shansky is trying to sort out the mechanism underlying the effect. Previous research in Arnsten’s lab offers a few hints. Stress releases excess dopamine and norepinephrine in the prefrontal cortex, which activate receptors that cause stress-related impairment, says Shansky. “It’s also known that estrogen regulates the expression of these receptors. Now we’re trying to see which one or ones are involved in mediating this activity.”

Research by another group at the University of Pittsburgh Medical Center has added to the picture. Genetic studies of people with depression turned up an alteration in CREB1, a gene that encodes the regulatory protein CREB.

“We really perked up when we heard that, because the very intracellular pathways that impair the prefrontal cortex turn on this gene product,” Arnsten said, adding that in young women with circulating estrogen, “the activity of the intracellular pathway might be sufficient to cause significant prefrontal cortical dysfunction, leading to depression.” Shansky has experiments under way to determine whether female rats with high estrogen are more vulnerable to activation of CREB1 than those with low estrogen.

“It’s very important that our results are not interpreted as saying that women shouldn’t take stressful jobs or expose themselves to stress,” says Shansky. “It’s more a matter of looking at the mechanisms involved to see if we can find new ways of treating depression.” It’s also important to note that these brain changes occur with uncontrollable stress, Arnsten adds. A long history of animal and human research has shown that a sense of control over the stressor protects cognitive and physiological responses.

Though the Yale experiments involve lab animals, they may apply to people, says Arnsten. The genetic studies show changes in the same molecular pathway that we are studying in rats. It is very encouraging.”