Confusion Lingers Over Hormone Therapy Use
By Sherry Marts, PhD
Today’s Dietitian
Vol. 8 No. 10 P. 38

The results of studies conducted by the Women’s Health Initiative hope to provide a clearer vision of how to treat menopause.

Hormone therapy is often prescribed for women going through menopause for its benefits in relieving the uncomfortable symptoms of hot flashes and night sweats, as well as preventing osteoporosis.

Until recently, observational studies comparing women who used hormone therapy to women who did not indicated that the therapy could lower the incidence of cardiovascular disease in women who are postmenopausal. In search of better answers to this and related questions, the National Institutes of Health launched the Women’s Health Initiative (WHI) in 1991. The ambitious 15-year research program included a set of clinical trials to test the effects of postmenopausal hormone therapy on heart disease, fractures, and breast and colorectal cancers.

The WHI included two studies of hormone therapy, both of which were large, randomized, placebo-controlled clinical trials. One trial examined a combination pill containing estrogen and progestin, a synthetic form of the hormone progesterone. The second trial included women who previously had a hysterectomy and compared the same estrogen preparation without progesterone vs. placebo.

At the start of the estrogen-plus-progestin trial, concerns were raised that the women given the inactive placebo would be at a much higher risk for developing cardiovascular disease than the women given active hormones or that women taking hormones would be at higher risk for developing breast cancer than those taking placebo. As a result, the researchers agreed to stop the study if differences between the treatment and control groups reached a predetermined threshold on these or other serious health conditions.

In 2002, three years before the study was complete, the threshold for increased incidence of breast cancer in the treatment group compared with the control group was reached. Investigators stopped the study because they found that “overall health risks of coronary heart disease events, strokes, and breast cancer exceed the benefits of the treatment, which include lower rates of fractures and reduced risk of colon cancer.”

In 2004, the estrogen-only study was stopped when researchers found that the increased risk of stroke and blood clots exceeded the benefits of treatment.

The decision to stop the estrogen-plus-progestin study received a great deal of attention from the news media, women, and healthcare providers. Media coverage offered messages that ranged from the “hormone isn’t as helpful as we thought” to “hormone therapy is dangerous for women.”

Women taking hormone therapy feared for their health and overwhelmed their healthcare providers with calls, e-mails, and office visits. Healthcare providers were often as confused as their patients.

In response to the results of this and other hormone therapy trials, the FDA added a warning on the label of all hormone therapy products stating that hormone therapy should be taken at the lowest effective dose for the shortest time and only for relief of menopausal symptoms and bone loss prevention.

Gradually, the attention given to the initial announcement died down. Researchers, healthcare providers, and women’s health advocates continued analyzing the results, which has led to more complete and rational conclusions about hormone therapy’s risks and benefits.

Among the issues raised in subsequent discussion of the WHI results were the following:

• A woman’s risk for developing heart disease or breast cancer was very low.

• All the women in the study were past menopause. Only one third of the women in the study were between the ages of 50 and 59. Most women who use hormone therapy are under the age of 60, and most start hormones early in the menopausal transition.

• The estrogen-plus-progestin trial was stopped because of an apparent increased risk of breast cancer in women taking hormones, but the estrogen-only study did not show an increased risk of breast cancer in women taking estrogen.

• The average age of the WHI participants was 63 and many of them had at least one other factor for cardiovascular disease, so it is likely that many participants had already developed some vascular damage before taking hormones. Therefore, the WHI study did not answer the question of whether taking hormones before vascular disease develops can prevent it from developing.

• An increased risk of blood clots and stroke in response to estrogen has been recognized and was part of the information provided to prescribers well before the WHI studies began.

• The studies looked at only one type of estrogen and one progesterone drug—both high-dose regimens delivered via a pill. Since then, the FDA has approved many forms of estrogen and natural and synthetic progesterone. The choice of products allows women and their healthcare providers to carefully tailor the treatment to the individual woman.

Unfortunately, the WHI did not provide the most complete answers to questions about hormone therapy because of how the study was designed and the health of the study’s participants.

“One could argue that the study population, described by the WHI as ‘generally healthy postmenopausal women,’ was in fact anything but,” says Wulf H. Utian, MD, PhD, executive director and honorary founding president of The North American Menopause Society. Utian points out that 40% of the study’s participants had high blood pressure, more than 7% had diabetes, 15% had high cholesterol, and more than 3% had previously suffered a heart attack. These preexisting conditions could have had an impact on the study’s results.

Other research on hormone therapy is continuing in new clinical trials comparing low doses of hormones and various delivery systems (pills, creams, patches) with placebo. More studies of hormone therapy are planned or ongoing, and the results should further clarify the appropriate role of hormone therapy in symptom relief and disease prevention.

A WHI report published in the February 14 issue of the Archives of Internal Medicine suggests that taking estrogen alone does not increase the risk of heart disease in women who have had a hysterectomy. In women aged 50 to 59, when the investigators compared the total occurrence of heart attack, bypass surgery, angioplasty, and treatment for angina, the women receiving estrogen were less likely to need treatment than those receiving a placebo.

These results only apply to women who have had hysterectomies, which is important to note because women who have had a hysterectomy receive estrogen without progesterone. Further research is needed to better understand the risks and benefits of beginning hormone treatment early in menopause.

So how should women view the evidence collected on hormone therapy? The results so far indicate that hormone therapy should not be prescribed for the single and specific purpose of protecting against heart disease. Some observers believe that emerging, further analysis of the WHI indicates that the overall risks do not outweigh the benefits for all women.

“In my own opinion,” Utian says, “these results should be extraordinarily reassuring for average-aged symptomatic women considering” starting hormone therapy before the age of 60.

The choice to use hormone therapy should not be made without careful consideration. Women who experience menopausal symptoms such as hot flashes, night sweats, or vaginal dryness, or who are at risk for osteoporosis, should consult their healthcare providers, weigh the evidence, evaluate the advantages and disadvantages, and make informed decisions.

— Sherry Marts, PhD, is a member of the Society for Women’s Health Research.

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Depression: More Than a Mood Swing
In an interview with the Center for the Advancement of Health, Diana L. Dell, MD, an assistant professor in the department of psychiatry and behavioral sciences, as well as the department of obstetrics and gynecology at Duke University Medical Center, discusses managing menopause.

Q. How common is menopausal depression?

A. Before talking about “menopausal depression,” I’d like to clarify that we are actually talking about depression during perimenopause. Perimenopause is that transitional period ... 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 E. Avis, PhD,] 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.

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, [Hadine Joffe, MD, principal investigator at Massachusetts General Hospital,] reported that hot flashes and night sweats produced a greater than fourfold increase in the incidence of depression, regardless of prior history of depression.

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.

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 reuptake inhibitor because women respond best to these. If she didn’t respond to the first, I would try another.

Then, if her response to antidepressant 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 hormone replacement therapy (HRT) used in the Women’s Health Initiative (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.

— Source: Center for Advancement of Health; Facts of Life, Vol. 8, No. 1