Estrogen Source of Stress

Last Editorial Review: 1/28/2004

Background: Stress-related disorders such as depression occur twice as often in women than in men. The question is what accounts for this big difference between men and women?

Study: Male and female rats were exposed to different levels of stress. Their estrogen levels were also determined. Since depression is difficult to determine in rats, their ability to function was determined with a short-term memory task. It turned out that even mild levels of stress (which had no effect on male rats) affected female rats when their estrogen levels were elevated. This goes along with a previous study (reported by the same researchers last fall) in which females rats with their ovaries removed showed increased stress sensitivity only after they were given estrogen replacement.

Comments: Can these observations in rats be extrapolated to women dealing with stress and depression? Are these findings relevant to women who have been or who are taking hormone therapy?

Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.
Medical Editors,

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Estrogen Makes the Brain More Vulnerable to Stress

New Haven, Conn. -- High levels of estrogen may enhance the brain's response to stress, making women more vulnerable to mental illnesses such as depression and post-traumatic stress disorder (PTSD), according to a Yale study.

This finding may explain why stress-related mental illnesses occur at least twice as often in women as in men. It also may explain why the discrepancy in prevalence begins in women at puberty, continues through the childbearing years, and then declines in postmenopausal years, said Becca Shansky, a graduate student in neurobiology at Yale School of Medicine and lead author of the study to be published in the March issue of Molecular Psychiatry.

The researchers exposed male and female rats to different levels of stress and then tested them on a short-term memory task. The authors found that without stress, males and females performed at the same level. After exposure to high levels of stress, both genders made significant memory errors. However, after exposure to a moderate level of stress, the female rats were impaired, but the males were not, suggesting that females were more sensitive to the effects of stress. Male rats performed the same with moderate stress as they did without any stress.

The authors also found that the female rats showed this sensitivity only when they were in a high-estrogen phase. To investigate how estrogen was involved the researchers removed the ovaries of a new group of female rats to eliminate any circulating estrogen. They then implanted a time-release capsule containing either estrogen or placebo and repeated the experiment. Animals with estrogen capsules displayed the same sensitivity to stress that females in a high-estrogen phase did, while animals with placebo capsules were unimpaired.

It is known that estrogen can interact with molecular processes involved in the stress response and that certain genetic variations have been demonstrated in clinically depressed women. "How these factors combine to produce the disparity in the prevalence of this disorder is unknown," Shansky said. "Such knowledge will hopefully lead to the development of new, more effective treatments for depression."

The senior author was Amy Arnsten, M.D., associate professor of neurobiology; Courtney Glavis-Bloom, David Lerman, Paulette McRae, Christopher Benson, Katherine Miller, Louise Cosand and Tamas Horvath, all of Yale.

Source: Yale News Release, January 21, 2004


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