For more than 50 years now, there has been only one drug around to combat the immediate and longer-term effects of menopause: estrogen.
The plusses of estrogen are extraordinary — reduced hot flashes, less vaginal dryness, lower levels of “bad” and higher levels of “good” cholsterol, reduced risk of osteoporosis, cardiovascular disease and maybe even Alzheimer’s. Not to mention better mood and intellectual function, at least for some women.
But the minus is a frightening one: a possible 30 to 40 percent increase in the risk of breast cancer. That’s not huge if you’re at normal risk to start with, but it’s big enough that many women say “No, thanks,” even though the lifetime risk of dying of cardiovascular disease is six times higher than the risk of dying of breast cancer.
At long last, there may soon be an option for women trying to juggle the risks and benefits of estrogen therapy. It’s called raloxifene, the first of the “designer estrogens” that manufacturers are racing to bring to market.
On Thursday, an advisory panel of the US Food and Drug Administration will consider whether to recommend approval of raloxifene as a way to prevent one post-menopausal problem, osteoporosis. If it passes that hurdle, the FDA will probably approve it for marketing soon.
But like Premarin — the 40-cents a day pill used by most American women who take estrogen supplements — raloxifene, whose price has not yet been set, falls well short of the ideal.
The big advantage, researchers say, is that it seems not to stimulate breast tissue, as estrogen does. In fact, if early studies are correct, raloxifene may actually lower the risk of breast cancer.
That’s probably because, like its chemical cousin tamoxifen, which is already being marketed to treat breast cancer and is being studied as a way to prevent it in high risk women, raloxifene acts like estrogen in some tissues, but in others like an estrogen blocker. Estrogen is known to promote some breast tumors.
Moreover, unlike both estrogen and tamoxifen, raloxifene does not seem to stimulate uterine tissue, which means it does not cause bleeding and may not raise the risk of uterine cancer. (To offset the increased risk among women taking estrogen, doctors often prescribe another hormone, progesterone.)
Like estrogen, raloxifene also prevents bone loss, though not as powerfully. In studies of 12,000 women in 25 countries, raloxifene increased bone mineral density by 2 to 3 percent, according to Eli Lilly, the manufacturer, though it’s too soon to tell whether this translates into fewer broken bones.
The big drawback to raloxifene is that it does nothing for hot flashes, the main reason many women start taking estrogen around age 50. In some women, raloxifene actually triggers them. It also does nothing to combat vaginal dryness and doesn’t boost good cholesterol as much as estrogen. Perhaps most important, raloxifene has only been studied for three years, versus decades for Premarin, which is made by Wyeth-Ayerst.
“Many view this as a wonder drug,” says Dr. Nananda Col, an internist at New England Medical Center who has analyzed the risks and benefits of estrogen. “But I am very cautious.”
Raloxifene “has a lot of promise, but we don’t have concrete information on long-term risks and benefits,” she says, adding that some drugs initially thought to be safe, like the fen-phen diet pills, later turn out not to be.
On the other hand, it’s progress “just to have any alternative to estrogen,” says Dr. Bruce Kessel, a reproductive endocrinologist at Beth Israel Deaconess Medical Center who also advocates diet and exercise to keep the heart and bones healthy.
Dr. Isaac Schiff, chief of obstetrics and gynecology at Massachusetts General Hospital, agrees. “I believe this is a big step forward, but it’s not necessarily going to be the last agent we come to,” he says.
Currently, Pfizer Inc. is working on one new drug called droxolifene, Wyeth-Ayerst on something they call TSE-424, and SmithKline Beecham on idoxifene.
As with all designer estrogens — or SERMS, selective estrogen receptor modulators — the goal is to concoct a drug that prevents hot flashes, vaginal dryness, osteoporosis, heart disease, and possibly Alzheimer’s, but does not raise breast cancer risk. Unfortunately, nothing in the pipeline so far can do all this.
And because raloxifene, to be marketed under the name EVISTA, does not reduce hot flashes, estrogen will likely remain the drug of choice for women in the immediate throes of menopause.
“Raloxifene isn’t a substitute for estrogen for menopausal symptoms. That’s not what this is all about,” says V. Craig Jordan, director of breast cancer research programs at the Robert H. Lurie Cancer Center at Northwestern University Medical School in Chicago and a consultant to Eli Lilly.
But after a few months or years on estrogen, when hot flashes naturally abate and the reason for taking estrogen becomes prevention of heart disease and osteoporosis, it might make sense to switch to raloxifene, says Kessel, who is about to start a study on the new drug.
“If you’re taking estrogen for osteoporosis and you’re concerned about breast cancer, I would make the switch,” adds Schiff in Boston, though he notes that women should always taper off estrogen slowly and under a doctor’s supervision.
And raloxifene “would be a good initial choice for a woman who has no hot flashes and is concerned about osteoporosis,” says Dr. Ethel Siris, a raloxifene investigator for Eli Lilly and director of the osteoporosis program at Columbia Presbyterian Medical Center in New York.
Another option for such women, she and others note, is Fosamax, an already approved drug that prevents osteoporosis but has none of the other risks or benefits of estrogen.
What has people most excited about raloxifene is its apparent lack of effect on breast tissue.
“It is clear that you don’t stimulate breast cell growth with raloxifene,” Siris says, adding that preliminary data suggest there may even be “a decreased risk of breast cancer, but we don’t want to overly excite people.”
In fact, when Jordan, the Chicago researcher, studied the mammograms of thousands of women taking raloxifene or a placebo in research studies, he found “about half as many women develop breast cancer on raloxifene as on placebo over a two-year period.”
Jordan and other researchers caution that longer studies are needed. With estrogen, for instance, the increased risk of breast cancer shows up only after five or more years of use.
Another unanswered question is what effect raloxifene and its chemical cousins may have on the brain. Some scientists hypothesize that estrogen has a positive effect, which might be why women on estrogen may be less susceptible to Alzheimer’s disease. If raloxifene acts as an anti-estrogen (or estrogen blocker) in the brain as it does in the breast, it would theoretically have no such protective effect.
Figuring out precisely why the same drug boosts estrogen in some tissues yet blocks it in others is big puzzle itself, especially now that scientists know there are at least two distinct types of estrogen receptors, molecules in cells with which estrogen and estrogen-like drugs interact.
But many researchers believe that even before all these answers are in, many women may turn to raloxifen if it gets FDA approval.
That would be good news for women. And there might even be a silver lining for Wyeth-Ayerst, which makes more than $1 billion a year worldwide selling Premarin, until now without competition.
“Raloxifene will have a niche,” according to the company’s party line, “but it will not replace Premarin. It will broaden the market.”