Estrogen? Antidepressants? Black cohosh?

Fred Hutch researchers offer guidance to women facing the menopause muddle
Image: Women facing menopause
Science Photo Library via AP

Menopause and the treatment of its symptoms are in the news again with the publication of new guidelines from the American College of Obstetricians and Gynecologists. And sadly, women seem just as confused as ever about how they should handle symptoms like hot flashes without risking their health.

“I feel so baffled by the choices out there,” wrote one reader in the comments section of a New York Times story that examined the guidelines, published in the January 2014 issue of the journal Obstetrics & Gynecology. “I would like to take charge of my health, but all the information seems so contradictory.”

That confusion is understandable, said Dr. Katherine A. Guthrie, a statistician and menopause researcher in Fred Hutchinson Cancer Research Center’s Public Health Sciences Division.

“It’s a complex issue and it’s important to consider where you are as an individual,” she said.

“Everyone and their brother seem to have a recommendation for women about what they should do about this,” Guthrie said. “Women are suffering, their quality of life is suffering and they’re being told to waste their time and money on solutions that we have good evidence don’t work.”

Hormone replacement therapy does work but it’s problematic because of its well-documented health risks.

Twelve years ago, the Women’s Health Initiative, based at Fred Hutch, halted a long-term clinical trial examining the health benefits of HRT due to these risks. A landmark study, published in 2002, determined that the most popular treatment for menopause symptoms – a pill combining estrogen and a synthetic progesterone known as progestin – increases the risk of breast cancer, heart disease, stroke, blood clots, dementia and other health problems. That same study also found estrogen alone was associated with an increased risk of stroke.

Complicating matters further is the uterus.

“If a woman has already had a hysterectomy, we can consider estrogen alone,” said Dr. Garnet Anderson, director of Fred Hutch’s Public Health Sciences Division and principal investigator of the WHI Clinical Coordinating Center. “But we have to consider women with an intact uterus differently. Estrogen increases the risk of endometrial cancer fivefold.”

Anderson said low-dose estrogen alone may be a reasonable treatment for women who’ve had a hysterectomy. However, these women may want to weigh the risk of stroke against the severity of their menopause symptoms.

“A woman having a few moderate hot flashes may not want to take the risk of a stroke to relieve those,” she said. “But for a woman waking up nightly from hot flashes or night sweats, for a woman going for days without any quality sleep, that trade-off may seem much more reasonable.”

Anderson said women who go this route will want to re-evaluate over time, though.

“A woman might be on [estrogen] for a year or two and then see if she still needs it,” she said. “Don’t stay on it by default because your risk of stroke goes up with age. An increased risk over time may start to be more important than hot flashes, which typically diminish with time.”

As for women considering combined HRT – estrogen plus progestin – that’s much riskier.

“Estrogen plus progestin has all of these adverse effects – breast cancer, heart disease, stroke, blood clots, dementia,” she said. “It’s much more risky and the adverse effects were the same in younger women in their 50s as in women in their 60s and 70s. And breast cancer in some ways is the bigger concern.”

Indeed, a 2008 follow-up study conducted by Fred Hutch’s Dr. Christopher Li found that postmenopausal women who took combined estrogen-progestin HRT for just three years faced a fourfold risk of developing lobular breast cancer.

Anderson admitted that the WHI findings have received a lot of push back over the years, both from menopausal women and members of the medical community, but said the data are sound and strong.

They’re also lifesaving. Researchers estimate that due to the decrease in HRT following the WHI findings, there have been 15,000 to 20,000 fewer breast cancer cases in the U.S.

“No one at WHI is going to contradict the efficacy of HRT for menopausal symptoms,” Anderson said. “The question is, is it good for women in the long term – for their heart, their bones, their risk of cancer? These issues are still being assessed in the research world. Mostly, we’re trying to figure out if we can do something for menopausal women that doesn’t invoke even that little risk of stroke.”

To that end, Anderson, Guthrie, and colleagues are looking for other options for menopausal women via a series of National Institutes of Health-funded studies known collectively as MsFLASH, or Menopause Strategies: Finding Lasting Answers for Symptoms and Health. These studies, conducted at Fred Hutch and five other clinical research centers across the U.S., examine non-hormonal and hormonal treatments for menopausal symptoms.

Although none of MsFLASH’s work was cited in the report issued by the American College of Obstetricians and Gynecologists, the group has made some promising discoveries, Guthrie said.

“What MsFLASH has found success with is antidepressants,” she said, pointing to a new study presented at the North American Menopause Society’s annual meeting last October that compared both low-dose estrogen and Effexor XR (venlafaxine), a serotonin-norepinephrine reuptake inhibitor, with placebo for the relief of hot flashes. The study was the first of its kind to pit estrogen head-to-head with an SNRI.

“We had one group of women take a low-dose oral estrogen and another group take Effexor XR, and we found very similar benefits in those two medications,” Guthrie said.

According to the data, low-dose estrogen reduced hot flashes by 53 percent while Effexor XR reduced them by 48 percent. The placebo reduced hot flashes by 29 percent. The findings build on an earlier MsFLASH study that found a “modest but meaningful” improvement in hot flashes after the use of the serotonin-reuptake inhibitor Lexapro (escitalopram).

“Antidepressants are a very viable option and there are many things to promote them,” Guthrie said. “The two medications we’ve studied are in generic form so they’re not expensive. And these kinds of medications have been prescribed for a long time. Doctors are comfortable using them, even though they’re not FDA approved for this application. And they also have minimal side effects and are not known to have any long-term risks like breast cancer.”

MsFLASH has also looked into behavioral therapies for menopause, including the use of omega-3 fatty acid supplements (fish oil), aerobic exercise and yoga.

“We found no evidence to show these interventions were effective in reducing hot flashes,” she said.

As for natural remedies, another Fred Hutch study done in collaboration with Group Health determined that black cohosh and other popular natural remedies do not reduce the frequency or severity of hot flashes.

Guthrie said the next area of focus for MsFLASH is a clinical trial aimed at treating the vaginal symptoms women experience during menopause. Anderson said there is also a need for follow-up studies on how to treat menopausal symptoms in breast cancer survivors.

All in all, though, she stressed the importance of women making the right choices based on their own individual status.

“Menopause is not a disease, it’s a stage of life,” she said. “We don’t want to over-medicalize it, but we do want to help women through it, especially those who really need it. They should have choices, and we want them to be well-documented choices. That’s where WHI comes in. We’ve provided the best data available for the chronic disease side of hormone therapy. That’s part of the picture that’s important for women to know as they make individual decisions about their menopausal symptoms.”

Contact writer Diane Mapes at

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