By William J. Cromie

Gazette Staff

The female hormone progesterone gives women a significant advantage over men when it come to heart disease. Harvard scientists have discovered how this happens.

A woman in her reproductive years enjoys a much lower risk of heart attack and stroke than a male of the same age, thanks to her natural levels of progesterone and estrogen. Once past menopause, a female who takes estrogen decreases her risk of getting heart disease by 40 percent. If she adds progesterone to the estrogen, the chances of suffering a heart attack drop 60 percent compared to women who take no hormone-replacement drugs.

"The reason, we have found, is that progesterone prevents the multiplication and migration of smooth muscle cells, which are involved in forming plaques that block arteries in the heart and brain," says Edgar Haber, Elkan R. Blount professor of biological sciences at the School of Public Health (SPH).

Haber and his colleagues made the discovery in test-tube experiments, not by working with patients. Therefore, he says, "there are no immediate applications for people at risk of heart disease. However, it raises the possibility of using some derivative of progesterone to arrest or prevent atherosclerosis in males."

Estrogen can't be given to men because of unwanted side-effects, such as enlarged breasts. Haber's research shows that progesterone inhibits heart disease in a different way from estrogen, and so opens the way to giving men the same protection as women.

However, Haber cautions, "we're in the earliest stages of our research, so, for now, this is just a speculation."

Muscle-Cell Buildup

Last year, researchers at the Medical School and Brigham and Women's Hospital concluded from a study of more than 120,000 nurses that postmenopausal women who take progesterone plus estrogen have a significantly lower risk of heart disease than those who take estrogen alone.

"When I saw that result, I wondered what accounts for it," recalls Haber, who is also director of the Center for Prevention of Cardiovascular Disease at SPH. "I decided to explore the effect of progesterone on the smooth muscle cells that surround blood vessels and regulate how they expand and contract."

Normally these muscle cells don't multiply much, but in atherosclerosis they increase in number and migrate to the inside of arteries. Once there, they can join white cells containing fatty cholesterol to build plaque deposits. Eventually, such obstructions block vessels that supply blood to the heart or brain, causing heart or brain attacks (strokes).

Haber and his team examined these smooth muscle cells carefully. Inside them, they found molecules that readily receive molecules of progesterone. When they combined the hormone and muscle cells, growth of the cells was inhibited.

To be sure, they added the abortion drug RU 486 to the mixture. During the menstrual cycle, progesterone causes the lining of the uterus to thicken in preparation for implantation of a fertilized egg. RU 486 blocks this activity. In Haber's experiments, it blocked progesterone receptors in the smooth muscle cells, and the latter did not show the stunted multiplication induced by the hormone.

Looking even closer, the researchers found out how the hormone stops abnormal proliferation of smooth muscle cells. To reproduce themselves, the cells copy their genes, or DNA, making twice the normal amount. They then divide, with half the DNA going to each daughter cell. Certain proteins, or enzymes, make this basic process of life possible. Progesterone interferes with the activity of two of these enzymes, freezing the cycle before smooth muscle cells replicate themselves.

It is not known in such detail how estrogen provides protection against heart disease. That protection apparently involves two mechanisms. One, estrogen dilates arteries and veins so more blood flows through them. Two, estrogen increases the healthful cholesterol (high-density lipoprotein) while decreasing the harmful variety (low-density lipoprotein). Which process dominates remains a mystery. On the downside, estrogen raises the risk of uterine cancer; progesterone is added to hormone-replacement therapy to neutralize that risk.