After the HRT Ache: Managing Menopausal Symptoms in a New Era

Wulf H. Utian, M.D., Ph.D., is the Arthur H. Bill professor emeritus of reproductive biology and obstetrics and gynecology at Case Western Reserve University. He also is a consultant in women's health to the Cleveland Clinic and the executive director and honorary founding president of the North American Menopause Society. A pioneer in menopause research, he founded the world's first menopause clinic in Cape Town, South Africa, in 1966.

Q. When data on the risks of extended use of combination hormone replacement therapy from the Women's Health Initiative were released July 9, 2002, you called the news a "bombshell." Why?

A. Actually, I called the way the news was presented a bombshell. The news was not at all unexpected; the study outcomes came remarkably close to predictions. But the way the data were presented, women weren't able to understand what the numbers meant and became frightened about their personal risks from HRT use.

Q. Even when only used to control menopausal symptoms?

A. Yes, and I think this is where people are getting most confused.

The WHI is looking at the prevention of health problems, primarily cardiovascular disease, in women after menopause. The participants who received combination HRT were 50 to 79 years old at the start of the study and took the HRT for at least 5.2 years.

But when we're talking about managing menopausal symptoms, we're generally dealing with women between the ages of 45 and 55, even younger if the menopause is surgically induced. Cardiovascular risk is extremely low in women of this age. Plus, we're talking short-term use; the extra risk with regard to breast cancer is almost nonexistent.

So the risk-benefit equation for the use of hormones to treat menopausal symptoms is very different from what has been the recent focus of discussion, the risk-benefit equation for prevention.

Q. Do any of the WHI findings to date cast new doubts on using HRT strictly short-term for relief of menopausal symptoms?

A. Just the opposite. The new data on combination HRT are actually very reassuring for short-term use. Women who were new to hormones at the time that they entered the WHI showed no statistical increase in breast cancer from combination estrogen-progestin therapy used after natural menopause, even five years out. The women with the increased risk were those who had been using hormones prior to coming into the study.

Moreover, no increased risk of breast cancer has been seen in the group receiving estrogen only.

Q. What are the main symptoms for which women seek relief around the time of menopause?

A. There are very few specific symptoms related to the change in ovarian function around the time of menopause. These are vasomotor symptoms - hot flashes and night sweats - disrupted sleep, vaginal thinning (atrophy) and possibly dry eye. A secondary, snowball set of symptoms follow - for example, irritability in women who are aroused multiple times during the night and lose their REM sleep.

Q. Which symptoms are most likely to prompt a woman to seek relief?

A.Those which, in her personal experience, are severe and have a negative impact.

We've seen that, worldwide, women can get hot flashes that, objectively, rate the same - let's say, 8 on a scale of 1 to 10. But one woman's perception of their severity and her response can be very different from another's.

Something I've found in South Africa and that has been reported in other parts of the world is that in societies that essentially punish people for getting older, a hot flash is a negative reminder of getting older, a nuisance. But in a society that rewards a woman for getting older, a hot flash is a positive experience.

Q. Several speakers at a recent NIH conference noted that women need more support than ever to make informed decisions at menopause. How can that be accomplished?

A. Medicine has been so restructured in this country in the last decade and so many OB/GYNs have been driven out of private practice by the cost of malpractice insurance that there's almost always a timekeeper at the door. So more than ever, women and doctors need to rely on aids that help them make the most of their time together.

I think that practice offices should distribute an educational summary, reliable information that a woman can read prior to her appointment.

There has been a huge increase in the materials developed by expert panels for the North American Menopause Society, available at www.menopause. org. We have a program called "First to Know," intended to keep women and physicians informed about the options at menopause and beyond.

We're also developing a menopause questionnaire for the woman to complete before her visit, so she can go in armed with more information about herself and her health-related issues - for example, how afraid she is of cancer, her values and how various options and risk factors relate to her. A well-directed questionnaire such as this will also help the physician pick up the key issues for discussion, such as the woman's subjective experience of her symptoms; what she's taking, including dietary supplements; her feelings about certain medications; her health concerns and so on.

Interestingly, NAMS has a long list of physicians who have said that menopausal health is an area in which they have a specific interest. I think that what's going to happen more and more is that women will be going to menopause specialists.

Q.Do behavioral approaches, such as exercise and healthier eating, offer symptomatic relief?

A. There's lots of narrative to indicate this but nothing good in the way of published evidence. The assumption is that someone who has a healthy diet, doesn't smoke, uses alcohol in moderation, exercises and so on, is fitter and has a greater sense of well being. That makes her more adapted to coping with any problem, including menopausal symptoms.

Q. So if nothing else, they may reduce her perception of symptom severity?

A. Correct. And these are changes a woman should consider in midlife in order to reduce her risk of osteoporosis, heart disease and other problems to which she becomes more vulnerable after menopause.

Q. How effective are antidepressants?

A. If estrogens are about 90 percent effective in reducing hot flashes, antidepressants called SSRIs, or selective seratonin reuptake inhibitors, are about 60 percent effective and placebos are about 40 percent effective. So they do offer lasting relief, but you have to deal with other effects, such as potential loss of libido.

I also wonder about possible long-term effects on the brain that we don't yet know about when these are given to women who aren't depressed. When one of my patients uses an SSRI for hot flashes, I prefer to use it for six months if that's all that's needed, one year maximum.

Q. Is there strong evidence to show that dietary supplements reduce hot flashes?

A. No. One of the interesting things in studies of hot flash remedies is that there's always a substantial placebo effect, at least for a while. Studies have shown that most of the common supplements - including soy isoflavones, black cohosh and vitex (chaste tree berry) - have effects that are either no better, or barely better, than those of placebos.

Q. What general advice do you have for a woman considering supplements?

A. She's free to try them but I cannot guarantee their safety or efficacy. Or if they work, how long the relief will last. Partly, that's because most of the studies on these products have serious limitations: very short term, not placebo controlled, not blinded and so on.

Also, these products are not regulated in the same fashion as drugs and so their composition cannot be guaranteed. We've seen several instances where dietary supplements have been tested and don't contain what's on the label, or don't contain the amount listed on the label, or contain ingredients they aren't supposed to.

Q. Given that the pharmaceutical industry cannot patent plants or plant derivatives and have no real impetus to conduct rigorous studies of their use in menopause, are publicly funded institutions getting more involved?

A. Yes. The National Center for Complementary and Alternative Medicine is studying black cohosh and hot flashes. There's also quite a lot of study on phytoestrogens, estrogen-like substances from plants, especially those extracted from soy.

Q. All things considered, how would you rank HRT as an option for managing menopausal symptoms?

A. Based on the evidence we have, I think the best bet for the woman who is having hot flashes, night sweats, vaginal drying and sleep disruption and is seeking relief is some form of hormones - unless, of course, her personal or family history indicates otherwise.

For the woman who has undergone a hysterectomy, that would be estrogen only. For the woman with an intact uterus, that would be estrogen with as minimal progesterone as possible to keep the uterus healthy.

Q. By "minimal progesterone," do you mean a different regimen from the most commonly prescribed one used in the WHI?

A. Absolutely, one where progestin is given in spurts instead of continuously. Based on what we know, it's entirely possible that the negative effects on cardiovascular health and breast cancer seen in the WHI and other studies are largely the result of continuous progestin administration.

I would also tend to prescribe a much lower dose overall. We're learning that you can get virtually the same levels of symptomatic relief with lower doses and maybe reduce the side effects. [11,12]

Q. How long would the hormones be needed?

A. Prior to the WHI, national data showed that 75 percent of women prescribed estrogen and progestin had stopped taking the hormones within 24 months. The majority either felt they didn't need the hormones anymore or didn't like the side effects. I try tapering the hormones off at the end of two years, to see how the woman reacts.

Q. Are there any special considerations when a woman experiences menopause at a young age?

A/ When a woman goes through early menopause, surgically or otherwise, I think she is in a different risk category from a woman going through menopause at the expected age. Her body is being deprived of estrogen at a time when it would normally be exerting a protective effect.

Women who go through premature menopause or premature ovarian removal have a higher risk of heart attacks, have earlier heart attacks and get early osteoporotic fractures. I believe she should consider taking the estrogen not just long enough to relieve her menopausal symptoms, but instead until at least the expected time of menopause.

Checking Out the Alternatives

A woman's alternatives for managing menopausal symptoms lie across a broad spectrum, including behavioral changes, alternative healing modalities, dietary supplements, prescription medications typically used for other purposes, mind-body techniques, hormone therapy and simply letting the symptoms run their course.

How good or bad are the alternatives to hormones? According to Lorraine A. Fitzpatrick, M.D., from the Mayo Clinic, the studies supporting their use can be described by a movie title: "The Good, the Bad and the Ugly." Fitzpatrick's discussion of hot flash remedies at a recent conference included the following points:

• There is little evidence, and the evidence that exists is of poor quality, that many popular dietary supplements are more effective than placebos.

• SSRIs look good in clinical trials, which may actually underestimate their efficacy in menopausal women because most trial participants had breast cancer and many were taking selective estrogen receptor modulator, or SERMs.
• Black cohosh and Vitex (chastetree berry) show promise but need more study.
• Magnets are even less effective than placebos (which, in hot flash studies, are typically 30 percent to 40 percent effective). [15]

Interview:

Depression: More Than a Mood Swing

Diana L. Dell, M.D., is assistant professor in the Department of Psychiatry and Behavioral Sciences as well as the Department of Obstetrics and Gynecology at Duke University Medical Center and is board-certified in both specialties. A fellow of the American College of Obstetricians and Gynecologists, Dr. Dell is a member of ACOG's Primary Care Committee and serves on the editorial advisory board of its publication Managing Menopause Magazine.

Q. How common is menopausal depression?

A. Before talking about "menopausal depression," I'd like to clarify that that we are actually talking about depression during the perimenopause. Perimenopause is that transitional period, typically four to five years long, between the end of a woman's normal reproductive years and the point where she has not had menstrual bleeding for one year.

The literature about menopause and risk of depression is inconsistent. Most of it indicates that this is not a likely time for a first occurrence of major depression. For example, Nancy Avis, who examined data gathered on 2,565 women in the Massachusetts Women's Health Study, found no increase in risk of major depression during natural menopause - that is, menopause not induced by surgery, chemotherapy or other means. [13]

Q. Are some women more likely than others to become depressed?

A. During natural menopause, Avis and others have seen that women with a prior history of depression are the ones most likely to experience major depression.

More severe menopausal symptoms also carry a higher risk. Avis noted that a long perimenopause - in this case, irregular bleeding lasting 27 months or more - tended to precipitate transient depression. More recently, Joffe reported that hot flashes and night sweats produced a greater than fourfold increase in the incidence of depression, regardless of prior history of depression. [14]

We also know that menopause brought on by the surgical removal of both ovaries is more likely than natural menopause to precipitate severe depressive symptoms.

Q. But for most women in natural menopause, depression isn't likely?

A. That's correct. Most women actually do fine with respect to mood.

Q. Are all menopausal mood problems due to depression?

A. Night sweats and hot flashes tend to disrupt REM sleep and can produce daytime fatigue, poor concentration and depressed mood that can be hard to distinguish from symptoms of depression. [2]

Q. How can you tell if depression is the problem?

A. I check for other signs that I would associate with depression and a history of depression. If I see evidence of moderate to severe depression, I try an antidepressant; if that improves her mood, we're looking at depression. But if it seems that her issue might be strictly menopausal, I try hormones to restore normal sleep and see if that works. Sometimes the only way to tell is to try one treatment and then the other and see what restores her mood.

Q. What causes this depression?

A. We've seen that changes in estrogen and other reproductive hormones during perimenopause have direct effects on brain chemistry and function, including neurotransmitter activity, that affect mood. Severe physical symptoms exert an influence too.

Psychosocial circumstances and culture also factor in. You can't generalize about these; you have to look at each woman individually.

If a woman's children are grown and leaving home, she might find her role change distressing; but if she has been faced with raising small children most of her adult life, she might be elated to be relieved of that burden. In a youth-adoring culture such as ours, it's common for an older woman to feel ostracized, although many women like the invisibility that goes with being past their reproductive years. Some women treasure every wrinkle and gray hair because they've earned them, while others deplore them.

Q. If a woman with menopausal depression came to your office, what would you typically recommend?

A. I would first try a more modern antidepressant, a selective serotonin reuptake inhibitor (SSRI) or a serotonin/ norepinephrine re-uptake inhibitor (SNRI), because women respond best to these. If she didn't respond to the first, I would try another.

Then, if her response to anti-depressant treatment was suboptimal, I would add hormones. If she had undergone a hysterectomy, that would be just estrogen. Otherwise, that would be estrogen and, if she could tolerate it, progesterone; estrogen alone increases the risk of uterine cancer. After that, it would be a question of adjusting the hormone dosage to obtain the desired result.

Q. By estrogen and progesterone, do you mean the type of combination HRT used in the WHI trial?

A. Yes. The recently released WHI data and the discontinuation of that arm of the trial don't affect my basic thinking, because the circumstances are very different. The WHI is looking for the protective cardiovascular effects secondary to long-term postmenopausal HRT use. Here we are talking about what may only be short-term use as treatment for a menopausal symptom.

Q. What would you tell a woman who is reluctant to take an SSRI because it may decrease libido, and she's already feeling less sexy than usual?

A. That yes, SSRIs can have that effect on libido - but it's not as bad as the effect untreated depression has.

Q/ Is psychotherapy a viable alternative to antidepressants?

A/ Mild to moderate menopausal depression is equally well treated by psychotherapy and by medication. However, once a woman has severe depression, she needs treatment with an antidepressant.

Q/ What about behavior change, such as exercise?

A/ Exercise, relaxation techniques and stress reduction can promote a sense of well being and enhance mood. But my clinical experience is that more severely depressed women often have difficulty getting motivated to do these things. Once they start responding to another form of treatment, then I find they're more likely to act on my recommendations to try these activities.

Q/ Is there any scientific evidence that dietary supplements are useful?

A/ There is little or no research showing that dietary supplements - including soy isoflavones, black cohosh, chaste tree berry (vitex), ginseng, dong quai and valerian - are effective in treating major menopausal depression, despite the fact that many have components with estrogen-like actions. For example, soy products can help with hot flashes but don't produce the global increase in a person's sense of well being that goes with improved mood.

Because studies have focused on major depression, we really don't know much about how helpful these products might be in cases where small relief of not very severe symptoms would be enough to make a difference in mood.

Q/ How would you advise a woman who wants to try one of these supplements before an antidepressant?

A/ If, after discussion of her options, she wants to try a supplement, I say, "Try it for four to six weeks. If you don't see significant improvement, we need to talk about other options." Q/ How long does treatment last?

A/ For the antidepressant, we may be talking weeks. For a woman with a history of depression, length of antidepressant use is based on the number of prior episodes. With one prior episode, we keep her on the antidepressant for about six months from the time she begins to feel well; with two prior episodes, it's a year; with three prior episodes, we recommend lifelong treatment.

If a woman needs hormones to keep her mood intact, I would want to use it them as long as required, checking in at intervals. That could be only a year or two, but sometimes it's longer, possibly indefinitely.

In some cases, it's possible to switch from estrogen to a type of drug called a selective estrogen receptor modulator. But if the woman gets too many hot flashes, or her mood doesn't remain intact, I put her back on estrogen.

Q/ Might continued hormone use be appropriate even for a woman with an intact uterus, despite the known risks?

A/ Absolutely, if that's what it takes to control her depression. It's important to remember that each woman needs to compare the very personal risks and benefits of her treatment options. The increased risk of certain problems from extended use of hormones and need for greater vigilance may be acceptable to a woman when weighed against the risks associated with failure to treat her depression.

Q/ What are some of the risks of untreated menopausal depression?

A/ In the short term, the woman may be risking her life if she is suicidal, or jeopardizing her health if she cannot take adequate care of herself.

In the long term, the brain of a person with untreated depression learns to be depressed. The longer a woman's depression goes untreated, the more treatment-resistant it becomes. Moreover, every time she gets depressed, she increases her chances of having another, and more severe episode.

Q/ So untreated depression doesn't always end after menopause?

A/ Correct. All the more reason why women who might be experiencing menopausal depression should seek proper diagnosis and treatment, instead of trying to "live with it until it's over."

Checking Out the Alternatives

A woman's alternatives for managing menopausal symptoms lie across a broad spectrum, including behavioral changes, alternative healing modalities, dietary supplements, prescription medications typically used for other purposes, mind-body techniques, hormone therapy and simply letting the symptoms run their course.

How good or bad are the alternatives to hormones? According to Lorraine A. Fitzpatrick, M.D., from the Mayo Clinic, the studies supporting their use can be described by a movie title: "The Good, the Bad and the Ugly." Fitzpatrick's discussion of hot flash remedies at a recent conference included the following points:

* There is little evidence, and the evidence that exists is of poor quality, that many popular dietary supplements are more effective than placebos.

* SSRIs look good in clinical trials, which may actually underestimate their efficacy in menopausal women because most trial participants had breast cancer and many were taking selective estrogen receptor modulator, or SERMs.

* Black cohosh and Vitex (chastetree berry) show promise but need more study.

* Magnets are even less effective than placebos (which, in hot flash studies, are typically 30 percent to 40 percent effective). [15]

Risks of Short-Term Combination HRT: A Closer Look at the WHI Results

At a recent National Institutes of Health conference [15] to facilitate informed decision making on the part of women and their care providers, speakers continually emphasized that the process should be tailored to the individual woman and her circumstances.

Data presented by the principal investigators from the Women's Health Initiative showed that risks for specific problems were quite different for various study subpopulations. For example, data presented by Rowan T. Chlebowski, M.D., Ph.D., revealed that risk of invasive breast cancer among women taking the combination HRT varied with age and history of HRT use prior to the study.

Speaker Deborah Grady, M.D., Ph.D., demonstrated how age-specific WHI risk factors - not the summary risk factors for the entire study population that are most commonly cited - could be coupled with data from other sources to estimate risks faced by a woman of menopausal age, in good health, who is contemplating one or two years of combination HRT to manage her menopausal symptoms.

Based on the results, Grady concluded that the risk appears to be low in the average healthy woman. But because there is some risk, she advises that combination HRT "isn't appropriate for a woman if her symptoms are tolerable - which is something only the woman herself can judge." She also advises a conservative decision if the woman's personal or family history indicates already-elevated risk. When a woman does opt for combination HRT, Grady recommends taking the hormones only long enough to make the symptoms tolerable.

Chlebowski and other WHI principal investigators concurred with Grady that the early WHI findings by no means rule out short-term use of combination HRT for symptomatic relief. And, like Grady, they advised taking severity into account. Marian C. Limacher, M.D., went a step farther, suggesting that the woman needs to ask, "How severe are the symptoms that can only be treated with hormones?"

WHI principal investigator Susan L. Hendrix, D.O., tied the concepts together. If women get a clear message regarding their risk from their practitioners, she said, "they'll be able to determine whether their symptoms are severe enough that they want to take that individual risk."

More detailed risk data from the combination HRT study are being calculated and should be published within a year. In general, these will be more specific with respect to such factors as age and minority status. Current analyses of the breast cancer data, Chlebowski noted, are using the "extensive risk information" collected on all participants, including family history, type of prior hormone exposure (including oral contraceptives), body mass index and tumor characteristics.

WHI principal investigator Marcia Stefanick, Ph.D., and colleagues said they will continue to monitor women from the combination HRT study. Among other things, the results should indicate whether, and how much, the risks and benefits of combination HRT fade after use stops.

Online Resources

For more information on menopausal symptom management and research updates, try:

The North American Menopause Society

The American College of Obstetricians and Gynecologists

The Office of Research on Women's Health

The National Heart, Lung and Blood Institute's portal to extensive information about postmenopausal hormones, alternative treatments and the WHI findings in lay language

The National Institute of Aging's booklet on menopause

A listing of current NIH-funded clinical trials, including those in the recruiting stage

The Center for the Advancement of Health is an independent nonprofit organization that promotes greater recognition of how psychological, social, behavioral, economic and environmental factors influence health and illness. The Center advocates the highest quality research and communicates it to the medical community and the public. The fundamental aim of the Center is to translate into policy and practice the growing body of evidence that can lead to the improvement and maintenance of the health of individuals and the public. The Center was founded by the John D. and Catherine T. MacArthur Foundation and the Nathan Cummings Foundation, which continue to provide core funding. Funding for this series was provided by the Robert Wood Johnson Foundation.

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