Menopause Hormone Therapy: 'Safe' Time?

New Studies Probe Timing of Hormone Replacement Therapy and Breast Cancer Risk

Medically Reviewed by Louise Chang, MD on February 04, 2009
From the WebMD Archives

Feb. 4, 2009 -- New research confirms that taking estrogen plus progestin as hormone replacement therapy for menopausal symptoms raises breast cancer risk, but that risk fades within about two years after quitting hormone therapy.

The findings come from two new studies, one published in The New England Journal of Medicine and the other in Cancer.

Here's what the researchers want women to take away from the findings:

  • It's still advisable to have hormone therapy only if needed and at the lowest dose for the shortest time to be effective. And women should weigh the pros and cons of hormone therapy in consultation with their doctors.
  • The longest "shortest time" might be as brief as two years, which some of the researchers say may be a "safe" period, though that's not certain.
  • Working with their doctors, women may want to take a break from hormone replacement therapy after three to five years to see if they still need it.
  • The increased risk of breast cancer is mostly about taking estrogen plus progestin, not estrogen alone. But about two years after quitting hormone therapy, that risk may be gone.


Hormone Replacement Therapy and Breast Cancer Risk

Hormone replacement therapy is approved to treat hot flashes and vaginal dryness related to menopause.

The Women's Health Initiative (WHI), a national women's health study, showed that long-term use (at least five years) of hormone replacement therapy combining two hormones -- estrogen plus progestin -- raised women's risk of heart disease, stroke, blood clots, and breast cancer (and lowered the risk of colorectal cancer and bone fractures) compared to women taking a placebo.

In the wake of those findings, the FDA recommended that menopausal hormone therapy using estrogens and progestins should be used at the lowest doses for the shortest duration to reach treatment goals.

But how short is the "shortest duration"? And what about hormone therapy that only includes estrogen without progestin, a treatment plan typically limited to women who've had their uterus surgically removed (a hysterectomy)? And is the breast cancer risk linked to hormone therapy reversible? Those are some of the questions tackled by the two new studies.

New Findings on Hormone Replacement Therapy

The two new studies agree on four things:

1. The long-term breast cancer risk from estrogen-plus-progestin therapy is real. Rowan Chlebowski, MD, PhD, who worked on The New England Journal of Medicine study, says that risk has been characterized as being "small," but at least 20,000 cases of breast cancer per year in the U.S. may be due to hormone therapy. "It's not a hypothetical number, something that never happens," Chlebowski tells WebMD.

2. Quitting hormone therapy cuts breast cancer risk. The increased breast cancer risk from hormone replacement therapy appears to end about two years after quitting hormone therapy. That's "good news," Chlebowski tells WebMD. In the WHI data, "it looked like the risk starts to go down right away. And after between one and two years, it looks like pretty much like that risk is gone," says Chlebowski, who works at the Los Angeles Biomedical Research Institute at the Harbor-UCL Medical Center.

Eugenia Calle, PhD, who worked on the study published in Cancer, agrees. "For women who've stopped using estrogen plus progestin, our data suggest that their risk for breast cancer will go back down in a fairly short period of time," says Calle, who recently retired as the American Cancer Society's vice president of epidemiology.

3. Mammography rates don't explain the drop in breast cancer after quitting hormone replacement therapy. Using WHI data, Chlebowski's team confirmed that breast cancer rates really did drop after women quit hormone replacement therapy; it wasn't because of a change in mammography use.

4. Breast cancer risk is greater with estrogen-plus-progestin than estrogen alone. "We do not have evidence from the WHI clinical trial that estrogen increases breast cancer. It's the combination of estrogen and progestin" that's the issue, Marcia Stefanick, PhD, tells WebMD. Stefanick works at the Stanford Prevention Research Center and was one of Chlebowski's colleagues in reviewing the WHI data.

Calle puts it this way: "Estrogen plus progestin is considerably worse in terms of breast cancer risk than estrogen alone, and we've known that for some time."

Just taking estrogen probably isn't a solution for women who still have their uterus, because doing so would raise their risk of uterine and endometrial cancer. Women who've had a hysterectomy don't have to worry about that.

"We had a huge increase in endometrial cancer back in the '70s that was reported when women were taking just estrogen if they had a uterus. So I don't think very many people would want to go back to unopposed estrogen [estrogen without progestin] as the approach," says Stefanick.

But the studies have their differences, too.

First Two Years: 'Safe' or Not?

Calle's team looked at breast cancer risk in more than 67,000 postmenopausal women, including those taking estrogen only or estrogen-plus-progestin for at least a year or not taking any hormone therapy. The data came from an observational study; the women weren't assigned to any particular treatment plan.

The researchers identified a possible window of two to three years in which there was no sign of increased breast cancer risk in women taking estrogen plus progestin.

"In terms of our data, it looks pretty safe; there is absolutely no increased risk," Calle tells WebMD. But she cautions that that finding of a possible "safe" period "needs to be replicated in other studies ... the numbers are small in our study."

Stefanick and Chlebowski point out that taking hormone therapy can increase breast density, making it harder to spot breast cancers. "Do we have evidence that there really are fewer cancers or are we seeing that it's harder to detect them?" Stefanick asks. "If you have something that interferes with diagnosis, you're going to have a really hard conceptual time defining a completely safe interval," says Chlebowski.

Asked about that, Calle says that "theoretically, it could be that screening is not as effective in picking up these tumors" because of increased breast density while women are taking hormones. "We can't directly study that," says Calle, explaining that her team didn't have the women's mammograms to review. Calle says that Stefanick and Chlebowski's hypothesis is "not unreasonable," but that "there's not really a way to test it or to refute it" with the data she used.

The breast density issue "is something they could look at in a future study," says breast cancer specialist Jennifer Litton, MD, an assistant professor of medicine at the University of Texas M.D. Anderson Cancer Center. Litton wasn't involved in either study.

Bigger Risk for Leaner Women?

Calle and colleagues noticed that in their study data, there was a small but significantly increased risk of breast cancer among lean women taking estrogen only.

"This is not something that's a surprise," says Calle.

Women with higher body mass index (BMI) tend to have higher estrogen levels because their fat cells make estrogen, so taking estrogen may make a bigger difference to thin women's risk, explains Litton, who says she found the BMI results to be "really interesting."

BMI wasn't a factor in the WHI study, Chlebowski notes. That may be because the women in the WHI study were "heavy," says Calle.

Weighing the Risks and Benefits

"Every woman is different," says Calle. "Some women don't really need [hormone replacement therapy] at all. Some women suffer greatly, and it may be that it would be more difficult for them to use it for a short period of time, but women are very different in this regard."

Chlebowski agrees and says that the breast cancer risk from hormone therapy is "almost certainly going to be small for short-term use, and many, many women probably need to take something" to cope with menopausal symptoms.

Chlebowski points out that continuing hormone therapy for five years roughly doubles breast cancer risk. So he suggests that after three to five years on hormone therapy, women and their doctors consider stopping hormone therapy to see if it's still needed. That time frame isn't set in stone; Calle's paper suggests that the time frame might be more like two to three years.

Litton doesn't rule out hormone therapy for women with severe symptoms who haven't had breast cancer, but she says she wouldn’t feel comfortable not trying to ease women off hormone therapy "as soon as possible and certainly in two years."

Litton points out that there are ways to treat hot flashes and vaginal dryness without hormones. For instance, some doctors use antidepressants to treat menopausal symptoms. "I think we need to look more into ... non-hormone ways to manage these pretty significant side effects" of menopause, says Litton.

WebMD Health News



Chlebowski, R. The New England Journal of Medicine, Feb. 5, 2009; vol 360: pp 573-587.

Calle, E. Cancer, March 1, 2009, (print edition) and Jan. 20, 2009, advance online edition.

Rowan Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif.

Marcia Steanick, PhD, Stanford Prevention Research Center, Stanford, Calif.

Eugenia Calle, PhD, vice president of epidemiology (retired), American Cancer Center.

Jennifer Litton, MD, assistant professor of medicine, department of breast medical oncology, University of Texas M.D. Anderson Cancer Center.

FDA Fact Sheet.

National Heart, Lung, and Blood Institute: "Women's Health Initiative."

WebMD Medical Reference: "Hormone Replacement Therapy Q&A."

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