The eyes of the hormone storm

Vexed by a riddle wrapped in a mystery inside an enigma deviled by hot flashes


It’s easy to criticize people who don’t do what’s good for them, whether it be giving up cigarettes, getting more exercise or eating healthy. But what happens when medical experts disagree about the right course of action? Perhaps nothing illustrates this dilemma as vividly as menopausal hormone therapy. Studies published during the past decade have illuminated hormone therapy’s dangers, causing prescriptions to plummet. Yet some physicians and scientists remain adamant in the belief hormone therapy helps women. So, what’s a woman to do?


Sympathy is a word that seems wholly inadequate to describe what Marcia Stefanick feels for the millions of women who have gone through menopause in the last five years.  These women plagued with hot flashes, sleep difficulties, depression and the other surprises that come as they approach menopause discovered that the treatment of choice — hormone therapy — might cause more harm than good.

Paul Blow

In 2002, the Women’s Health Initiative, the largest-ever study to examine the health of postmenopausal women, reported that the most commonly prescribed type of hormone therapy, a combination of estrogen and progestin, increased the risk of heart attacks, stroke, breast cancer and blood clots. Hundreds of thousands of women tossed out their prescriptions for hormone therapy, and those battling hot flashes wrestled with a dilemma: Do I take pills that will make me feel better right now, even though they might raise my risk for breast cancer or a stroke?

“Any woman who has gone through menopause in the last five years has been a wreck when it comes to, ‘Are hormones good or are they bad?’” says Stefanick, PhD, professor of medicine at the Stanford Prevention Research Center and chair of the WHI steering committee. “I’m totally sympathetic. I’ve been there.”

As fate would have it, Stefanick, now 55, faced the same difficult decisions about hormone therapy in the past few years. And she remains frustrated that, despite the gains in understanding women’s health and hormone therapy since the mid-1990s, there are many questions that remain unanswered — and might not be definitively answered for years to come.

“With hormones, you had a huge body of literature from both the scientific and medical communities pretty much agreeing that hormones were good for women, and then along comes not just one study but a whole set of studies showing the opposite,” Stefanick says. “I just can’t understand why we haven’t studied this normal physiological process better.”

Current guidelines from the U.S. Food and Drug Administration counsel women to take the lowest dose of hormone therapy for the shortest amount of time necessary to treat moderate to severe menopausal symptoms. Even the safety of low dosages of estrogen hasn’t been put to the test in randomized clinical trials, Stefanick notes, but it’s the best that science has to offer for now.

And that uncertainty is a huge disservice to women who need medical guidance during one of the most vulnerable stages of their lives. “Besides being uncomfortable for most women, and downright debilitating for some, menopause is emotionally charged because it carries the whole issue of, ‘Face it kid, you’re getting old,’” Stefanick says. “It means that your ovaries are done and that a whole part of you is no longer the same. If that’s not enough, now you have to wonder if you should take a drug that may give you immediate relief but causes later problems.” One of those problems is the difficulty of withdrawing from the drug; many women end up with a new bout of menopausal symptoms, even in their 60s and 70s, when they try to come off of hormones.

Part of the ongoing debate about hormone therapy stems from the fact that, scientifically speaking, menopause is poorly understood and hasn’t been well-studied — primarily because of the physiologic instability of women undergoing menopause. Menopause is the time in a women’s life when her ovaries stop producing “female” hormones, or estrogen, and she no longer has a period. However, the onset of menopause varies widely (the average age is 51 but ages ranging from 40 to 60 are not uncommon), and the hormonal changes leading up to it can cause symptoms for years before and after. In addition to hot flashes, which are uncomfortable surges of a fever-like body heat, women can experience sleep difficulties, mood swings, changes in their sex drive, vaginal dryness and itchiness, and difficulty concentrating.

The unpredictable fluctuations of natural hormones in a woman’s body years before the onset of menopause make it challenging to tease out the effects of medical therapies and lifestyle changes initiated during this time of transition, so researchers generally exclude these women from participating in clinical trials. Women must generally be either premenopausal, meaning that they are having regular menstrual periods, or postmenopausal, meaning that they have gone at least 12 months without a menstrual period. In fact, these criteria generally apply even to studies of menopausal therapies.

“What we have is a huge chunk of a woman’s life missing from all the data sets, and that is the four to five years of transition — the perimenopausal woman who is no longer having regular menstrual cycles but has not yet gone 12 months without a menstrual period,” Stefanick says. “And that is the woman who’s experiencing the most suffering.”

Even those interested in studying perimenopausal women face a challenge because there is no set age at which menopause occurs. A researcher would need to recruit huge numbers of premenopausal women and track them for 10 years or more, and hope that enough of the women experienced menopause during the study to give the findings statistical power. That’s just not easy to do, Stefanick notes.

But it’s not impossible, she adds, and she is not the only scientist to wonder whether sex discrimination is a factor in menopause research. “I can’t help but feel that if this affected middle-aged men, money would have gone into studying it,” Stefanick says.

Also, although menopause causes some degrees of discomfort to most women, it’s relatively short-lived, it’s not a disease and it isn’t life-threatening. When deciding how to allocate research funding, those facts have kept menopause low on the priority list.

But Stefanick and other experts note that while menopause isn’t fatal, it can play havoc with a woman’s quality of life for two or three years, and sometimes much longer. For example, vaginal dryness can hurt her sex life — and her partner’s. “It’s frustrating that menopause has been written off as not really a serious medical problem,” she says. “It’s still important to find a solution.”

Trials and tribulations

Milestones in hormone therapy research

1890s   Ovarin, derived from cow ovaries, used for treating menopause

1928    Estrogen patch for menopausal symptoms introduced by Searle

1930s   Oral products derived from pregnant women’s urine used for menopausal symptoms

1930s   Oral products derived from pregnant horse urine used for menopausal symptoms

1941    FDA approves marketing of Diethylstilbestrol (a synthetic estrogen) for treating menopausal symptoms

1942    FDA approves Premarin for treating menopause

1975    Increased endometrial cancer risk reported in estrogen users; FDA orders labeling changes to reflect the risk

1978    FDA mandates that all estrogen products contain warnings that estrogen has proved effective only for hot flashes and vaginal dryness, and carries risks of cancer and blood clots

1985    Conflicting studies regarding cardiovascular risk in estrogen users: Framingham Heart Study reports increased risk, while the Nurses’ Health Study reports reduced risk

1990    FDA declines a request to approve estrogen as a treatment to prevent heart disease

1995    PEPI trial suggests reduced heart disease risk associated with estrogen use. First combination estrogen-progestin pill, Prempro, is introduced

1998    HERS trial of women with coronary heart disease (with intact uterus) reports that estrogen-progestin therapy provides no heart disease benefits over 4.1 years, and increases heart disease risk in the first year

2002    WHI estrogen-progestin trial (for women with intact uterus) reports that the risks of the therapy outweigh the benefits over 5.2 years

2003    FDA orders “black-box” warnings that estrogen and progestin products should not be used to prevent heart disease; recommends limiting hormone use

2004    WHI estrogen-alone trial (for women without a uterus) reports no overall benefit over 6.8 years

Source: Stefanick, M.L., “Estrogens and Progestins, ” The American Journal of Medicine, Dec. 19, 2005.

Stefanick is veteran of hormone therapy research, with WHI being the third large, multicenter trial that she’s been involved in. The first, in the 1990s, already had her thinking that hormone therapy was not the benign panacea that others claimed. In that study, the Postmenopausal Estrogen/Progestin Interventions trial, researchers examined how both estrogen and estrogen-progestin therapy affected heart disease risks in postmenopausal women. Though it was already known that women who took estrogen alone had a higher risk of uterine cancer, researchers were surprised by the high proportion of these women who developed pre-cancerous uterine problems within just three years of taking the medication.

Stefanick, who was already in the middle of the second large hormone therapy study and was beginning to recruit patients for the WHI study, gathered the participants in Stanford’s portion of the PEPI trial in 1995 to brief them on the outcomes. During her presentation, she mentioned the upcoming WHI study, which, at that time, was to include an estrogen-alone arm for women who had not had a hysterectomy.

“There were eight women in the Stanford part of the PEPI trial who had intact uteruses and who had really adverse reactions to estrogen alone, and one of them was in the audience that night,” she recalls. “She got up and said, ‘How could you ever ask another woman to go on estrogen after what’s happened to me?’ It just shakes you up.”

Stefanick couldn’t get the woman’s comments out of her mind, and later made a call to Jacques Roussow, MD, director of the WHI trial at the National Institutes of Health. “I told him, ‘We have to change the design of the study. We can’t have an estrogen-alone arm for women with a uterus. We can’t do it,’” she recalls. By that time, Roussow and others had begun reviewing the PEPI data and arrived at a similar conclusion, so they scrapped the estrogen-alone arm for women with a uterus.

“That was the first time that I felt like this is not a wonder drug. This could be a really horrible experience for someone,” Stefanick says. “We’re dealing with a drug that will take away the misery of menopause, but it’s not without real risk.”

The second hormone therapy study, the Heart and Estrogen/Progestin Replacement Study, involved women who had already been diagnosed with heart problems. The HERS findings published in 1998 showed that hormone therapy made no difference in the rates of heart disease or heart attack over four years, even though the women’s cholesterol levels improved significantly on the hormones. In fact, in the first year of medication, hormone therapy increased the women’s risk for heart disease. “From that point on, I just felt like we couldn’t assume that WHI would come out positively regarding the use of hormone therapy for primary prevention of heart disease,” Stefanick says.

Nevertheless, she was puzzled when she got a call in 2000 from Claude Lenfant, MD, then-director of the NIH’s National Heart, Lung, and Blood Institute, asking her to come to Washington, D.C., for a meeting about an unspecified problem with the WHI trial. Stefanick had been elected by the 39 other WHI investigators as chair of the steering committee — in fact, she was the only person to hold the post throughout the duration of the study — and served as a liaison between the investigators and the NIH.

At the meeting, Lenfant told her that the trial’s data and safety monitoring board had uncovered some disturbing trends after most of the women had completed roughly two years on the medication. The women taking estrogen-progestin were experiencing more heart attacks, blood clots and strokes than those taking a placebo.

The question was what to do: Stop the trial, or let it continue. “We had the HERS story spinning around in our minds — early harm, with a hypothesis of a later benefit — and so we thought that almost all of the women were past the point where the early harm would happen, so we informed the women of the unexpected findings but encouraged them to continue in the trial to see if there was a later benefit,” Stefanick says. A year later, the monitoring board reported that there was still no evidence of a benefit. By 2002, when the data showed significantly increased health risks (heart attacks, strokes and breast cancer) overshadowing the benefits (fewer hip fractures), the NIH decided to halt the estrogen-progestin portion of the trial.

Once the decision was made, Stefanick’s life became a frenzy of activity. She needed to brief all of the WHI investigators about the decision and oversee the preparation of the study findings for publication as well as the creation of written materials explaining the stunning news to study participants, physicians and the public. That’s when irony struck. In the days before briefing the other WHI researchers, Stefanick, who had turned 50 earlier in 2002, experienced her first hot flash. “I didn’t know what it was because I had never had one before,” she remembers. Over the next several months, her symptoms intensified and she had to decide whether to take hormone therapy.

“I’ll tell you, there were plenty of times when I felt, ‘Shoot, I wish we didn’t have this result because this is miserable,’” Stefanick says with a laugh, before turning serious again. “I understand the misery of hot flashes and night sweats and not being able to sleep. But I asked myself every single time I went through it: Is preventing this phenomenon right now worth even a small risk of later harm? And for me, there was never a point when it was worth it.”

She made lifestyle modifications to lessen the severity of the hot flashes and other symptoms. She cut back her coffee consumption, and eliminated two favorite food items: hot-and-sour soup and single-malt Scotch. “At first you think, I have to give up some of these pleasures, but the reality is that they weren’t really pleasurable because they precipitated these physical events. I mean, who wants a hot flash?” Stefanick says.

She packed away her turtlenecks and sweaters and began practicing deep-breathing exercises. “Because I’m a physiologist, I got really interested in studying myself and trying to figure out what I was going through,” she says. “I can honestly say now that I’ve lived all of my lectures that I give to women about menopause.”

In 2004, the NIH halted the estrogen-alone arm of the WHI trial, reporting that the women taking estrogen experienced a slight increase in the risk of stroke without showing any benefit in terms of heart disease prevention after an average of 6.8 years on estrogen.

In the years since the 2002 estrogen-progestin results were announced, a small but vocal group of critics have faulted the WHI study and urged women not to be scared of using hormone therapy. Follow-up studies published in recent months by the WHI investigators, who have continued to tease out the data from both arms of the trial, have heightened the debate.

To help determine whether the women who were in their 50s during the WHI trial received some heart-protective benefits from estrogen therapy, the researchers studied the calcified plaque levels in a subset of the participants from the estrogen-alone arm. They found that this younger group of women who had taken estrogen had much lower levels of calcified plaque in their arteries than did those who were assigned to a placebo. Because calcified plaque is a risk factor for heart disease, the lower levels prompted some WHI critics to charge that the 2002 announcement about the risks of estrogen-progestin therapy was too dire and that women shouldn’t be concerned about taking hormones during menopause.

But Stefanick, who was the senior author of the follow-up study, says hormone therapy advocates are overstating the actual findings. First, she points out, the follow-up study dealt only with women who originally participated in the estrogen-only part of the trial. Second, calcified plaque is just one indicator of heart-disease risk, and women still need to consider the other health risks — such as stroke and blood clots — before deciding whether to take hormones. However, she adds that the follow-up study “offers some reassurance that it’s reasonably safe, in terms of the risk of heart attack, for younger women to take estrogen for a few years,” because the risk of heart attack is low for most women of menopausal age.

Other hormone therapy proponents argue that the latest findings support the “timing hypothesis,” meaning that estrogen use might have beneficial effects on heart health if initiated close to or during menopause. The same hypothesis holds that if the therapy is initiated several years after menopause, it might be harmful.

However, Stefanick says that these claims are based on animal studies and lab experiments, and have yet to been proven in clinical trials. “If you haven’t proven that it works in a person, all you have is a very interesting basic science outcome and you don’t know if it’s good or bad,” she says.

And she is concerned that all of the talk about a window of opportunity when hormone use would be beneficial is making an already-confusing situation even worse. “How is a woman supposed to know where she is on the ‘risk’ spectrum since the onset of menopause varies so much?” Stefanick asks. “I think it’s more frustrating for menopausal women now than it was three years ago.”

Recently she gave a talk to a gathering of gynecologists about the hormone therapy debate that the organizers titled “Now That the Dust Has Settled.” And, in a pattern that has played out repeatedly over the past five years, Stefanick drew heated comments from doctors who disagreed with the WHI findings and supported broader use of hormone therapy.

“After I got blasted again, I thought that my next talk should be titled, ‘Will the Dust Ever Settle?’” Stefanick says. “I don’t think it ever will.”


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