At Molecular Level, Stress May Show a Gender Bias

by Elizabeth Norton Lasley

October 19, 2010

Some stress-related disorders, such as depression and post-traumatic stress disorder, are twice as common in women as in men. A new study suggests that the difference may not be merely a matter of personality.

In certain cells in the female brain, the receptors for a key stress hormone, corticotropin releasing factor (CRF), respond differently to increases in the hormone’s levels--making this part of the brain more sensitive to stress and less able to adapt. The finding provides a biochemical basis for the prevalence of stress-related illness in women.

Rita Valentino, Debra Bangasser, and colleagues at The Children’s Hospital of Philadelphia, knew from previous research in female rats that neurons in a region called the locus ceruleus respond to lower levels of CRF than are needed for activation in male brains. The locus ceruleus is a storehouse of norepinephrine, one of the chief chemical messengers in the fight-or-flight response.

Their study, published online June 15 in Molecular Psychiatry, offers a twofold explanation for the observed sex difference.   

In rats not subjected to stress, CRF receptors in female brains bind more tightly with the protein linking the receptor to the hormone, allowing the neurons to respond to lower levels of CRF. But this distinction disappears after a test in which male and female rats had to swim for brief periods in an acrylic tank from which they couldn’t climb out on their own. After this stressor, CRF receptors bind as tightly to the hormone in males as in females.

But after several stressful episodes, another difference emerges. In male rats, CRF receptors appear to cope with chronic stress by moving from their usual station on the cell membrane—withdrawing into the cell’s interior, thus closing down the contact points through which CRF can activate the neuron. In females, in contrast, the CRF receptors stay perched on the cell membrane, and the neurons keep responding to CRF—producing more norepinephrine and continuing to activate stress pathways in the brain.

“Our study provides a molecular mechanism that could explain why women are more sensitive to acute stress and less able to adapt to chronic stress,” says Valentino.

Yvette Tache of the University of California, Los Angeles, is impressed by the study’s thoroughness. “The researchers compared male rats to both normal females and those whose ovaries had been removed,” she says. “This means the sex-based differences are not related to cycling sex hormones, but may be a built-in feature.” Tache adds that the locus ceruleus is distinctive in females from birth; the area is larger and the neurons more plentiful than in males, in rodents, at least.

The fact that differences in the CRF receptors are innate, not related to the estrus cycle, may halp explain why stress-related disorders in women don’t go away after menopause, suggests Tache. Her own area of specialization, irritable bowel syndrome, which is regulated by CRF, often occurs together with stress and anxiety, and is also more prevalent in women.

Sex differences on a molecular level have profound implications for drug development, says Bangasser. “Many drugs in the pipeline target CRF receptors,” she says. “But currently they are tested exclusively on male rats. If the receptor works differently in female brains, that has to be taken into account.”

Valentino adds that the study has significance for drug development in general. “There may be many more sex-based differences in receptors and neurotransmitter signaling that we don’t know about,” she says. Valentino, Bangasser, and their colleagues are now trying to find out what makes the CRF receptor behave differently in females.

The researchers also wonder why females would have a molecular interaction that leaves them vulnerable to stress-related disorders. “Logically, the increased sensitivity to CRF might provide a heightened state of alertness. This could be an evolutionary advantage for the female as she guards the nest,” says Valentino—adding that this speculation refers to rats only.