Estrogen May Lower Women's Risk of Heart Disease by Working as Damper on Inflammation, UB Study Shows

SAN FRANCISCO -- Estrogen's ability to reduce a woman's risk of heart disease during her reproductive years may be based on a previously unexamined mechanism of the hormone: its anti-inflammatory effects.

In the first demonstration in humans of this capacity of estrogen, endocrine researchers at the University at Buffalo have shown that estrogen may suppress production of several pro-inflammatory components at the cellular, molecular and plasma levels.

Results of this preliminary study were presented here today (June 20, 2002) at the annual meeting of the Endocrine Society.

"If estrogen has a prominent anti-inflammatory effect, this action may help to explain why women have a much lower risk of atherosclerosis (which begins as an inflammation of the blood vessel walls) than men until menopause," said Paresh Dandona, M.D., UB professor of medicine and head of the Division of Endocrinology in the UB School of Medicine and Biomedical Sciences, who is senior author on the study. "Once women hit menopause, their heart-disease risk rises to that of men.

"This is the first demonstration in vivo of estrogen's precise molecule anti-inflammatory behavior," he said.

In this preliminary study, Dandona and colleagues from the Diabetes-Endocrinology Center of Western New York, located in Kaleida Health's Millard Fillmore Hospital, used men as subjects to avoid the estrogen fluctuations that take place during a woman's menstrual cycle, which would interfere with results.

Nine healthy men of normal weight with a mean age of 32 provided blood samples before receiving a 5 mg. injection of estrogen in the form of Premarin, the most commonly prescribed drug for estrogen-replacement therapy. Dandona chose this amount of estrogen for a "single slug," which is about four times the upper limit contained in daily doses of hormone-replacement therapy, to determine if an anti-inflammatory effect would occur over the short-term. Additional blood samples were drawn at two, four, six and 24 hours after the injection.

Researchers measured the generation of reactive oxygen species, or oxygen free radicals -- components known to damage cells in blood-vessel walls and induce inflammation -- in specific cells (mononuclear cells), molecules (polymorphonuclear leukocytes) and in plasma. They also assessed concentrations of three factors known to be markers of the inflammatory process: intranuclear nuclear factor-(B (NF-(B), C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1).

Results showed that estrogen significantly inhibited the generation of free radicals by mononuclear cells and leukocytes, with peak inhibition -- 39.9 percent and 47.3 percent respectively -- reached at four hours after estrogen infusion.

NF-(B activity fell to a low of 24 percent at six hours after infusion, and C-reactive protein concentration dropped a maximum of 19.5 percent at four hours, results showed. In addition, plasminogen activator inhibitor-1 fell nearly 50 percent at six hours.

'These early results allow us to understand the mechanism and to say that estrogen works in this fashion," said Dandona, who plans to conduct a similar study in postmenopausal women.

"It should be possible to separate estrogen's feminizing effects from its anti-inflammatory effects," he said. "In the long run, estrogen may prove helpful as an addition to current therapy in the treatment and prevention of heart disease."

Additional researchers on the study, all from the UB Department of Medicine, were Priya Mohanty, M.D.; Hasam Ghanim; Ahmad Aljada, Ph.D.; Deborah Hofmeyer, and Arindam Bandyopadhyay, M.D.