"Our study of female monkeys indicates that stress affects estrogen levels and can lead to the development of heart disease - even before menopause," said Kaplan, professor of comparative medicine. This is the first publication of Kaplan's results, which were reported at a national conference in 2001. An accompanying editorial by Sarah Berga, M.D., from the University of Pittsburgh, emphasizes that stress-induced hormonal changes in pre-menopausal women is an under-appreciated clinical problem requiring intervention.
"This study adds to the growing body of evidence that cardiovascular health after menopause is influenced by hormone levels many years earlier," said Kaplan. "The message for women is that anything that reduces estrogen levels in young adulthood - whether it be stress or exercise and diet habits - may put women on a high-risk course for heart disease."
Women have traditionally been considered immune from heart disease until after menopause, when their estrogen levels dramatically drop. Kaplan's study showed that in monkeys, stress can actually reduce estrogen levels much earlier in life and cause the buildup of fatty deposits in the arteries (atherosclerosis) that can lead to heart attacks and strokes.
"This research demonstrates that a deficiency of estrogen before menopause places these females on a high-risk trajectory, even if they got estrogen treatment after menopause," said Kaplan.
In the study, female monkeys were placed in groups so they would naturally establish a pecking order from dominant to subordinate. Monkeys that are socially stressed - because they are subordinate in their group - produce reduced amounts of the hormone estrogen. Kaplan and his colleagues reasoned that the stressed, estrogen-deficient animals would have an acceleration of their heart disease that would persist after menopause.
To test this idea, all animals were first studied for two years before menopause and for three years after their ovaries were removed to induce menopause. One group of animals was given estrogen before menopause, and another group was treated with estrogen after menopause.
Kaplan's study showed that, at the end of this "lifetime" study, the monkeys that were estrogen-deficient pre-menopausally had two times more atherosclerosis in their heart vessels than dominant monkeys that produced normal levels of estrogen. When the subordinate, or "stressed," monkeys received estrogen treatments before menopause, their rates of atherosclerosis were cut in half and they became equivalent to dominants. Kaplan said this outcome emphasizes the importance of pre-menopausal behavioral and hormonal conditions for post-menopausal health.
An ongoing study of human autopsy results supports Kaplan's findings. Results showed that by age 35, one-third of women have substantial atherosclerosis in the vessels leading to their hearts. In women, stress, anorexia nervosa and hormone imbalances can all reduce estrogen levels to the point that menstrual periods stop. But Kaplan and colleagues theorize that more moderate drops in estrogen - that don't produce symptoms - can also affect health.
"We know from monkey studies that stress can lower estrogen levels to the point that health is affected, even though the animals still have menstrual periods," he said.
In a study of 66 women having normal-length menstrual periods, estrogen levels were low enough in half of the participants to cause the bone loss that can lead to osteoporosis. Kaplan theorizes that if reduced estrogen levels can cause bone loss in women, they can also cause atherosclerosis.
The research was funded by the National Heart, Lung and Blood Institute.