JoAnn Manson: "Designer estrogens are doing more things women want them to do."

Evidence is growing that new designer drugs now being tested on women will protect them against heart disease and weakened bones in their postmenstrual years without raising their risk of breast and uterine cancer. In fact, some of these synthetic estrogens may even provide protection against invasive breast cancer.

"Designer estrogens are very promising and the field is undergoing rapid change," says JoAnn Manson, associate professor of medicine at the Harvard Medical School. "Several drugs already in the pipeline are doing more of the things women want them to do without serious risks and side effects."

Of course, any drug that protects the hearts of women is a good bet to do the same for men, who have higher rates of heart disease. Estrogen drugs now available cause side effects like breast enlargement, but designer estrogens don’t appear to have such problems. Manson calls this "a wide open field that needs to be explored."

Women’s bodies are peppered with estrogen receptors that eagerly take up these hormones. Receptors exist not only in the breast, but in the uterus, bones, liver, heart, blood vessels, and brain. Natural estrogens stimulate these tissues more or less uniformly. This activity decreases cholesterol production in the liver, protecting the heart, and it increases the density of bones, making them stronger. But at the same time, stimulation of breast and uterine tissues increases likelihood of breast and uterine cancer.

Designer estrogens are custom-tailored to fit snugly into receptors, where they are wanted, but not into pockets and seams, where they cause problems. Their tailored structure creates an awkward fit that blocks natural estrogens from receptors where they are not wanted. That action gives them their name: selective estrogen receptor modulators, or SERMs.

All SERMs boast similar structures. By snipping a chemical component here and adding one there, they can be customized to do what physicians want done. "There are vast opportunities for different designs," comments Manson, who is also co-director of women’s health at Brigham and Women’s Hospital in Boston.

In 1997, the U.S. Food and Drug Administration approved a SERM called raloxifene for treatment of osteoporosis, a thinning of bones with age. Postmenopausal women are especially vulnerable because their ovaries no longer produce estrogen, a major factor in maintaining strong bones.

When researchers gave raloxifene to postmenopausal women with osteoporosis over a period of three years, they found that it decreased the risk of breast cancer by 76 percent. Thus, raloxifene, sold commercially as Evista, stimulates bones but not breasts, where extra estrogen raises the risk of cancer. It also does not increase a woman’s chances of getting uterine cancer, a problem side effect of untailored estrogens.

"Raloxifene is promising and exciting," admits Manson, but it’s not perfectly tailored for all women. Unlike conventional estrogen, it does not increase the amount of "good," or heart-helping cholesterol, and it’s not been tested enough to see if it provides protection against heart disease. It also increases the risk for clots in deep leg veins, just as estrogen does. Finally, it does not relieve hot flashes and may even worsen them.

Another SERM, known as tamoxifen, also reduces the chances of breast cancer in women with a high risk for the disease, which includes all females older than 60. In one test, women who took the drug enjoyed a 49 percent reduction in breast cancer compared with a matched sample of women who took a placebo. The result so impressed researchers that they stopped the trial and told women taking the placebo that they could take the active drug.

Tamoxifen also preserves bones and may protect the heart by raising good cholesterol and lowering the bad variety that leads to clogged arteries. As exciting as that sounds, the drug is not yet ready for general use because it raises the danger of uterine cancer and blood clots in the legs.

"The number of breast cancer cases prevented with tamoxifen is almost offset by excess cases of uterine cancer and blood clots," Manson points out.

Also, tamoxifen doesn’t relieve hot flashes and night sweats, one of the prime reasons postmenopausal women take estrogen supplements. In fact, this SERM, like raloxifene, may even increase these debilitating symptoms.

To determine whether raloxifene or tamoxifen is better for lowering the risk of breast cancer while still protecting the heart and bones, researchers will test the two drugs on 22,000 women. Called STAR (Study of Tamoxifen And Raloxifene), the trial, which has just started, could run for 5 to 10 years.

At the laboratory level, researchers heatedly work on other SERMs with names like droloxifene, idoxifene, and toremifene. The hope is that these custom-tailored compounds will provide even more protection with fewer side effects than tamoxifen and raloxifene.

In the meantime, a nationwide study, begun in 1993, continues to probe the pros and cons of using conventional estrogen combined with progesterone to reduce the risk of uterine cancer. This treatment is available to all women in at least a dozen commercial variations, but without conclusive information about how much benefit a woman gets and how much risk she must take to get it.

Called the Women’s Health Initiative, this study involves more than 164,000 subjects and seeks answers to a number of questions about diet and calcium-vitamin D supplements in addition to hormone replacement therapy. "This landmark study is slated to end in 2005," notes Manson, who serves as one of its principal investigators. "At that time, we should have conclusive answers about the balance of benefits and risks of conventional estrogens."

One of the most intriguing questions is whether estrogen use improves memory and thinking, perhaps even slowing the onset and progression of Alzheimer’s Disease. The Women’s Health Initiative is the largest study to address this question.

The brain has newly found estrogen receptors in areas associated with learning and memory, and one small study actually showed that estrogen activates these regions when women undergo tests of thought, perception, and memory. If further tests reveal that estrogens can boost cerebral activity, similar drugs may work for men.

All this lies in the future, however. What’s a woman to do now to obtain the best protection for the least risk?

One strategy involves taking hormones for two to three years at the time of menopause to relieve hot flashes, night sweats, and other unpleasant symptoms. "Hot flashes can interfere with sleep and adversely affect mood and concentration," Manson says. "Many women with these symptoms want the relief estrogen can provide."

Afterward, Manson advises a strategy of giving up the hormones until age 65 or later, when risks of heart disease and osteoporosis increase significantly. Research to date indicates that estrogens can reduce the risk of heart disease by 44 percent. After five or more years of use, however, the risk of breast cancer starts to offset this advantage.

"From what we know now, it’s better to limit the total duration of estrogen use, rather than to take it continuously after about age 51, the average age of menopause," Manson concludes.

SERMs could offer another option. Women can take estrogens to ward off hot flashes and other symptoms, then switch to SERMs, which may offer protection against breast cancer while still reducing the risk of heart disease and osteoporosis.

Complicating the choices even more: the evidence that hormone replacement prevents heart attacks is not yet conclusive. That’s one of the answers the Women’s Health Initiative should provide in another five years; namely, how much protection does a woman really get, and is that protection offset by the risk of breast cancer?

Manson offers yet another solution. Take hormones to relieve hot flashes, then rely on lifestyle changes, together with drugs, to lower cholesterol and risk of osteoporosis. So-called "statin" drugs, like lovastatin and pravastatin, have proved effective at lowering cholesterol and preventing heart disease. Drugs such as Fosamax strengthen bones, as does physical exercise and extra calcium and vitamin D.

"With a healthy lifestyle and use of non-estrogenic drugs, it’s possible to significantly reduce the risk of heart disease, breast and uterine cancer, and osteoporosis," Manson maintains. "With the jury still out on hormone replacement, this offers a reasonable option."

When seeing patients who are trying to make this decision, Manson gives heavy weight to individual preferences. "Some women feel strongly about treating hot flashes, others don’t have a problem with them," she says. "Some women think estrogen helps them look or feel younger. If a patient has a mother or sister with breast cancer, I try to discourage her from using hormone therapy because of the increased risk."

Someday, women may have access to SERMs that offer protection with small or no risk. Until then, it’s every woman’s personal decision and one of the most complex, if not frustrating, choices she faces in her lifetime.