Menopause

• Depression at perimenopause: More than just hormones
• Nighttime awakenings in menopause may be caused by
  sleep disorders, not hot flashes
• Revisiting hormone therapy's risks and benefits
• Breast pain: Not just a premenopausal complaint
• What to do about gallstones
• Hormone therapy’s unanswered questions
• Hormone therapy revisited: What about quality of life?
• Alternative therapies for hot flashes
• Medications for postmenopausal osteoporosis prevention
• Chemotherapy not needed for all breast cancers
• ERT and the Risk of Ovarian Cancer
• New Developments in Hormone Replacement Therapy
• Menopause Home Test Kit
• Inhalers Lead to Hip Bone Loss
• Ipriflavone Not Effective for Osteoporosis
• FDA Approves Weekly Dose of Fosamax (alendronate) for Osteoporosis Treatment and Prevention
• High-Fiber Diet Doesn't Lower Colon Cancer Risk
• Alendronate versus Calcitonin for Osteoporosis
• Estrogen and Alendronate for Osteoporosis May Be Better Than Either Treatment Alone
• Statins Better Than Estrogen to Reduce a Woman’s Chances of Second Heart Attack?
• More News and Less Clarity on Hormone-Replacement Therapy and Breast Cancer
• Osteoporosis Drug May Offer Protection Against Breast Cancer
• New Information on Hormone Replacement Therapy and Breast Cancers
• Clonidine for Tamoxifen-Induced Hot Flashes
• Hormone-Replacement Therapy and the Risk of Blood Clotting
• Calcium Carbonate's Effect on the Absorption of Levothyroxine

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Medications for postmenopausal osteoporosis prevention

Risk of osteoporosis increases after menopause, when levels of estrogen — which helps preserve bone density — drop. Until recently, most doctors recommended long-term hormone replacement therapy (HRT) to treat postmenopausal women who need medication to prevent bone loss. But things changed after results from a large trial on a common HRT drug showed that estrogen plus progestin (as the medication Prempro) did more harm than good. An increased risk for breast cancer and cardiovascular events outweighed the benefits of less colorectal cancer and fewer fractures. (See the Update from July 2002 for more information on the trial.)

Health experts now encourage most women who have been taking long-term HRT for osteoporosis prevention to consider an alternative. Fortunately there are several options. Each of the FDA-approved treatments (see chart) has potential benefits and risks that women and their doctors should weigh before making a decision. Even with HRT’s proven risks, it may still be a good choice for certain women — especially in lower doses, which recent data have shown to have bone benefits comparable to higher, standard doses.

December 2002 Update

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Chemotherapy not needed for all breast cancers

Chemotherapy may not be necessary for all breast cancer patients. A study published in the July 17, 2002, issue of the Journal of the National Cancer Institute indicated that postmenopausal women whose breast cancer is sensitive to estrogen may not benefit from adding chemotherapy to the estrogen-blocking drug tamoxifen.

The International Breast Cancer Study Group’s Trial IX looked at 1,669 women whose breast cancer had not spread to their lymph nodes. After being grouped according to their cancer’s estrogen sensitivity — estrogen receptor-positive or -negative — half of the women received chemotherapy followed by five years of tamoxifen, while the other half received only tamoxifen.

Those with ER-negative breast cancer enjoyed a statistically significant benefit in terms of disease-free survival (time before relapse; appearance of another cancer; or death) and overall survival when treated with chemotherapy followed by tamoxifen. But for those in the ER-positive group there was no difference in disease-free survival or overall survival when treated with the combined therapy.

Chemotherapy, in addition to tamoxifen, is regularly prescribed for the majority of postmenopausal patients with lymph-node negative, ER-positive breast cancer. The researchers hope that results from this and similar studies will encourage clinicians to treat postmenopausal women with a more individualized program, one that takes the estrogen sensitivity of their cancers into account.

September 2002 Update

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ERT and the Risk of Ovarian Cancer

Another strike against hormone replacement therapy has emerged. The results of a study published in the July 17, 2002, issue of the Journal of the American Medical Association show women who take estrogen replacement therapy, particularly for an extended period, have an increased risk for ovarian cancer.

The study involved over 44,000 women enrolled in a nationwide breast cancer-screening program between 1979 and 1998. Follow-up interviews and questionnaires revealed 329 women in the study developed ovarian cancer over the 20-year period. Use of estrogen-only replacement therapy for any length of time was associated with an increased risk of ovarian cancer. The researchers found the results were consistent regardless of other risk factors for ovarian cancer, such as age, type of menopause (surgical or natural), and use of oral contraceptives. The risk of cancer also appeared to increase with the length of estrogen use; women who took estrogen for over 20 years had 3 times the risk of developing ovarian cancer. The results were similar in women who had a hysterectomy; such women are more likely to take estrogen for prolonged periods of time.

Women who have not had a hysterectomy are usually prescribed an estrogen-progestin combination to protect against endometrial cancer. Results of the study showed women taking short-term combined hormone therapy did not have an increased risk for ovarian cancer. However, women who took combined therapy after having taken estrogen-only therapy were still at an increased risk. The practice of taking combined hormone therapy is relatively recent; therefore, further time and study may be needed to accurately evaluate the risk of ovarian cancer associated with its use.

Combination therapy was the subject of controversy surrounding the Women’s Health Initiative, which found that such therapy increased risk for breast cancer, blood clots, and stroke. However, the estrogen-only arm of the study is still ongoing, having found no significant adverse effects.

The risk of ovarian cancer should not be considered lightly — this form of cancer causes more deaths than any other genital cancer. Ovarian cancer is also notoriously difficult to diagnose at an early stage. These factors, combined with the results of the study, add one more issue for women to consider when deciding whether to take or continue estrogen replacement therapy.

September 2002 Update

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New Developments in Hormone Replacement Therapy

In July 2002, the government halted a major study of hormone therapy three years early because of a slight but significant increase in the risk of invasive breast cancer. Researchers concluded that the long-term risks of taking hormones outweigh the benefits for a woman who still has her uterus.

More than 16,000 women took part in the study, known as the Women's Health Initiative, the largest to compare postmenopausal hormones with a placebo. The therapy was a combination of estrogen and progestin (Prempro), a treatment used by an estimated six million women to replace the declining levels of hormones at menopause.

The study sought to determine whether this combination hormone therapy could prevent such ailments as osteoporosis and heart disease. But while there were small decreases in hip fractures and colorectal cancer, the increases in breast cancer, heart attacks, strokes, and blood clots were too unsettling.

The data suggested that for every 10,000 women on the estrogen-progestin combination, an additional 8 will develop invasive breast cancer, when compared with women not taking the therapy. An additional 7 will have cardiovascular disease, 8 will have a stroke, and 8 will have blood clots in the lungs (pulmonary embolism).

In the aftermath of the trial, it seems that many doctors will be reconsidering prescribing estrogen and progestin. Some women may want to lower their doses or limit the duration of the use of these combinations, while others will elect to try other treatments to combat their hot flashes, vaginal dryness, and other menopausal symptoms.

However, it is important for women already on hormone replacement therapy (HRT) to know that there is no urgency to stop, and waiting until an annual exam to discuss it with a doctor is fine. There is also no harm in stopping immediately, if a woman is more comfortable doing so.

It's important to remember that only combination therapy appears to have these effects. Estrogen alone taken by women who have had a hysterectomy has not displayed such risks. A separate trial, with 10,000 women who have had a hysterectomy randomly assigned to either estrogen or a placebo, has not indicated an increased breast cancer risk. The trial is scheduled to go until 2005.

The full report on the Women's Health Initiative appeared in the Journal of the American Medical Association on July 17, 2002.

July 2002 Update

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Menopause Home Test Kit

For years women have been taking pregnancy tests in the privacy of their own bathrooms. Now they can also administer their own tests to see if they are transitioning out of their childbearing years. The makers of Revival Soy recently began selling the Revival Menopause Home Test, the first such test approved by the FDA, on their Web site (www.menopausehometest.com).

The kit works by measuring the amount of follicle-stimulating hormone (FSH) in a woman's urine. When a woman enters menopause, the pituitary gland releases more FSH into the blood in an attempt to stimulate the ovaries to produce more estrogen. Most experts say that a woman has entered menopause when her FSH remains at 30–40 mIU/mL or higher. Birth control pills also affect FSH levels, and therefore invalidate results of tests based on this hormone.

In order to get FDA approval, the accuracy of the home test must be close to that of blood tests administered by doctors. Still, many doctors believe that a woman's symptoms are a much better indicator of the "change of life" than any test. "A woman only does the test at one point in time. Menopausal women's FSH levels go up and down for a while before they go and stay up," says Dr. Anthony Komaroff, a professor at Harvard Medical School and a senior physician at Brigham and Women's Hospital in Boston. "Periods of fluctuation last for a year, year and a half. If FSH temporarily fluctuates back down to perimenopausal levels, and a woman happens to test her urine at that moment, the test will give a falsely negative result."

Dr. Komaroff also notes that because women hear so much about menopause from their mothers and friends, they don't usually need a test — be it a blood test administered at their doctor's office or a urine test taken in their bathrooms — to tell them they're entering menopause. A home test may actually do some harm if a woman with menopausal symptoms delays seeking treatment because of a falsely negative result on a test. On the flip side, if a woman gets a falsely positive response and stops using birth control, she may be faced with an unexpected pregnancy.
March 2002 Update

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Inhalers Lead to Hip Bone Loss

Medications commonly used for the long-term treatment of asthma may lead to hipbone loss in premenopausal women.

Researchers at Brigham and Women's Hospital in Boston found bone mass in the hip and trochanter decreased in women taking inhaled glucocorticoids, a type of steroid used for treating asthma. The rate of bone loss also increased with the rate of dosage. The three-year prospective study involved 109 women aged 18 to 45. Bone density was measured at the beginning of the study, after six months of treatment and at one, two, and three years.

Bone density was found to decline 0.00044 grams per square centimeter per puff of medicine per year of treatment. Although that's a small amount, it can be significant in the long run. If a woman with asthma is treated with six puffs of triamcinolone acetonide (the glucocorticoid studied) twice a day for 20 years, she could expect to have 0.106 grams per square centimeter less bone in her hip than she would have had without the treatment, according to this study. That degree of bone loss has been associated with a risk of hip fractures more than double that of normal women 65 and older.

Besides the hip, measurements were also taken at the spine and femoral neck, but no changes were found there. The rate of decline also varied between patients in the same dosage group and no reason for that could be found.

Though osteoporosis is a major health problem for women, the study's authors admit that inhaled glucocorticoids are among the most effective and safest medicines for asthma. They suggest doctors prescribe the lowest effective dose and patients using high doses should ask their doctors to periodically assess their bone density.
The results of previous, less extensive studies on inhaled steroids and bone density have been mixed.
October 2001 Update

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Ipriflavone Not Effective for Osteoporosis

For years, estrogen replacement therapy was the drug of choice for treatment of osteoporosis in postmenopausal women. But the potential risks of HRT sent women searching for alternatives. One option was phytoestrogens — plant-based compounds that bind to estrogen receptors in the body, presumably mimicking the beneficial effects of estrogen without its potential risks. Of the phytoestrogens, the most promising was ipriflavone, a synthetic version of a naturally occurring isoflavone, a type of phytoestrogen.

But a well-designed study published in the March 21, 2001, Journal of the American Medical Association refutes the positive results of previous studies, demonstrating that ipriflavone does not prevent bone loss or reduce the risk of fracture in postmenopausal women. It also cautions that ipriflavone lowers levels of lymphocytes, an effect that could make women more vulnerable to infection.

In the JAMA study, members of the Ipriflavone Multicenter European Fracture Study Group assigned 474 postmenopausal white women with low bone mass aged 45 to 75 to either 200 mg of ipriflavone taken three times per day or a placebo for the three-year duration of the trial.

At the end of the trial, the researchers found no significant difference between the treatment groups in regard to bone mineral density measured at the lumbar spine, total hip, and distal radius; in biochemical markers of bone formation or bone resorption; or in the number of vertebral fractures suffered by the women.

The major difference was that women treated with ipriflavone experienced significant drops in their lymphocyte concentration. 13.2% of the ipriflavone-treated women developed lymphocytopenia, a condition defined as a total lymphocyte concentration below 500/µL. Of these women, 52% returned to normal lymphocyte values within one year of discontinuation of the drug; 81% returned to normal within two years.

In reviewing their findings, the researchers cautioned against the use of ipriflavone to treat osteoporosis.

Women throughout much of the world have used ipriflavone since 1969 to treat osteoporosis. More recently it has been sold over-the-counter in the United States as Ostovone.
April 2001 Update

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FDA Approves Weekly Dose of Fosamax (alendronate) for Osteoporosis Treatment and Prevention

FDA recently approved once-a-week doses of Fosamax (alendronate) for the prevention and treatment of osteoporosis. The weekly dose for prevention is 35 mg while the weekly dose for treatment is 70 mg. Fosamax, which was already approved for once-a-day use, works by slowing bone loss.

The main advantage of the once-a-week version is convenience. Doctors recommend that Fosamax be taken first thing in the morning, on an empty stomach, approximately 30 minutes before breakfast, and that patients not lie down for at least 30 minutes after taking the medication. Patients may find that they prefer to adhere to this routine only once a week, rather than every day.

FDA approval was based largely on a two-year clinical trial that showed that for postmenopausal women, a weekly 70 mg dose of alendronate was just as effective at increasing bone mineral density as a 10 mg daily dose. The study included 1,258 postmenopausal women with a mean age of 67. The once-weekly alendronate dose was effective regardless of the women’s underlying condition, age, bone mineral density (BMD), or pre-existing fractures.

Compared with the daily dose, 70 mg of alendronate once a week was better tolerated and produced fewer serious upper gastrointestinal and esophageal problems. The weekly dose also produced similar gains in bone mineral density at the lumbar spine, total hip, femoral neck, hip, and total body sites.
February 2001 Update

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High-Fiber Diet Doesn't Lower Colon Cancer Risk

Observational studies have suggested a link between diet and the risk of developing colon cancer. Consuming lots of red meat and fatty foods has been associated with a higher risk of this disease, while a diet high in fiber and fruits and vegetables seemed to lower that risk. Two recent studies in the New England Journal of Medicine suggest otherwise. In these clinical trials, researchers examined the role diet might play in the development of adenomatous polyps in the colon. (These growths are the precursors of most colon cancers.)

The first study followed 2,079 men and women who had had such polyps removed within the previous six months. These volunteers were assigned to one of two groups. The first group ate a diet that was low in fat (20% of total calories), high in fiber (18 grams of fiber per 1,000 calories of food consumed), and included 3.5 servings of fruits and vegetables per 1,000 calories of food eaten. Researchers provided the second group with a pamphlet on healthy eating and told these patients to follow their normal diets. Both groups were followed for roughly four years and had a colonoscopy (examination of the colon) once a year during this period. Surprisingly, the rate of recurrence of large polyps did not differ significantly between the two groups, leading study investigators to conclude that a low-fat, high-fiber diet rich in fruits and vegetables did not help prevent recurrence of these precancerous polyps.

The second study focused on cereal fiber, specifically wheat bran. Again, study participants included only patients who had had adenomatous polyps removed within three months of the trial's start. Of the 1,303 people who completed the study, investigators assigned 719 to a high-fiber diet (13.5 grams per day) and 584 to a low-fiber diet (2 grams per day). At the end of three years, the polyp recurrence rate was 47% in the high-fiber group and 51.2% in the low-fiber group. Again, not a significant difference.

Does this discouraging news about fiber mean people should abandon whole grains and fruits and vegetables? No. First, it is important to remember that these studies looked at whether or not the polyps returned within four years, but couldn't really assess whether diet may or may not play a role in preventing those polyps from turning into cancer. Observational studies do show that people who eat diets higher in fiber and fruits and vegetables have a lower risk of colon cancer and that when their diets change, so does their level of risk. But researchers are not yet sure why. Second, these dietary elements are important for general health and have been shown to reduce the risk of heart disease and diabetes. So make sure you eat enough fruits and vegetables and whole grains.

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Alendronate versus Calcitonin for Osteoporosis in Postmenopausal Women

Postmenopausal women who are unwilling to take estrogen for the treatment of osteoporosis commonly take nasal calcitonin or oral alendronate. Until now there has never been a direct comparison of the positive effects of these two drugs at their treatment doses.

In a randomized trial, researchers compared the two drugs against one another and against a placebo on 299 postmenopausal women over a period of 12 months. The researchers measured the bone mineral density of the hip, spine, and femur on each woman before starting treatment and after six and 12 months. Results showed that alendronate produced greater increases in bone mineral density at all three sites when compared to both calcitonin and the placebo. Calcitonin outperformed the placebo only in the femur. In both the spine and hip, calcitonin produced changes similar to the changes produced by the placebo. The researchers also measured markers of bone loss in serum and urine samples before and after treatment. Alendronate produced a greater decrease in these markers than calcitonin and the placebo did. The researchers could not measure the effect of the drugs on fracture risk because the study was small and over a short period.

The results of this study suggest that alendronate is more effective than calcitonin at treating osteoporosis in postmenopausal women over a period of 12 months.

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Estrogen and Alendronate for Osteoporosis May Be Better Than Either Treatment Alone

Osteoporosis is a bone-thinning disease that puts many postmenopausal women at increased risk for fractures. The characteristic loss of bone density and mineral content occurs when new bone is not created as quickly as old bone is broken down. Treatment for osteoporosis often involves hormone replacement therapy (HRT) or alendronate (Fosamax). Both treatments have been shown in previous studies to effectively treat osteoporosis. Women who take HRT for five years have a 50%-80% decrease in vertebral fractures and a 25% decrease in other fractures compared to those who don't take hormones. And alendronate reduces fractures of the spine, hip, and wrist by 50% in people with osteoporosis.

In a study published in the February 2000 issue of The Journal of Clinical Endocrinology & Metabolism, researchers sought to determine whether treatment with a combination of HRT and alendronate leads to a greater increase in bone mass than either treatment alone. They reasoned that this might be the case because HRT and alendronate have different mechanisms of action.

The study participants consisted of 425 postmenopausal women with low bone mass who had undergone hysterectomies and were not taking HRT prior to the start of the study. They were assigned a daily dose of either 10 mg of alendronate, 0.625 mg of conjugated equine estrogen (a type of HRT), a combination of 10 mg of alendronate plus 0.625 mg estrogen, or a placebo. The treatment lasted two years during which all the women also took a daily 500 mg supplement of calcium.

At the end of the two-year period, researchers found that combination therapy was significantly more effective at increasing bone mineral density at the spine and thigh bone than the placebo, alendronate alone, or estrogen alone. However, there were no significant differences between the combination therapy or alendronate or estrogen alone for increasing total-body bone mineral density, although all three of these treatments were significantly more effective than the placebo. The study participants did not experience significant side effects from any of the therapies.

In light of these results, combination therapy may be appropriate for women with very low bone density, for whom even an incrementally greater increase in bone mineral density and bone strength could be important. Combined therapy may also be useful for women who lose bone mass despite taking estrogen therapy, but who want to continue taking HRT for other reasons such as relief from menopausal symptoms such as hot flashes.

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Statins Better Than Estrogen to Reduce a Woman’s Chances of Second Heart Attack?

Results from the Heart and Estrogen/progestin Replacement Study (HERS) turned on its ear the conventional wisdom that estrogen-replacement therapy helps prevent coronary heart disease in postmenopausal women. The HERS data showed that women who had been given estrogen plus progestin-replacement therapy after their first heart attack were just as likely to have a second heart attack as those women who were given a placebo after their first heart attack.

The findings are especially puzzling because over the course of the study (roughly four years), the women who took the hormone-replacement therapy experienced an 11% drop in LDL ("bad") cholesterol and a 10% gain in HDL ("good") cholesterol, compared to the women on a placebo. Because beneficial effects on cholesterol levels were believed to be partly responsible for the protective effects of hormone-replacement therapy, the HERS study casts doubt on whether it should be used to prevent heart attack in postmenopausal women with risk factors for CHD.

At the same time, series of research trials over the past few years have indicated that statins significantly reduce the chances of a second heart attack in women with average cholesterol levels. Results from the Cholesterol and Recurrent Events (CARE) trial found that women with a mean total cholesterol of 209 mg/dL and a mean LDL cholesterol of 139 mg/dL, who were given 40 mg of pravastatin per day, were 46% less likely to have a second major heart attack than patients given a placebo.

Based on this data, other statin study data, and results of the HERS trial, a 1999 consensus panel statement by the American Heart Association (AHA) and the American College of Cardiology (ACC) recommended that women with heart disease use statins, rather than estrogen-replacement therapy, as a first-line lipid-lowering treatment.

Because the participants in the HERS trial were women who had already had heart attacks, it is difficult to draw a definitive conclusion about potential benefits of hormone-replacement therapy in reducing the risk of heart disease in healthy women. Every woman should talk with her doctor about her particular risk factors for heart disease, the potential risks and benefits of both hormone-replacement therapy and statins, and her personal preferences in choosing an approach.

Journal of the American Medical Association, Vol. 280, No. 7, pp. 605–13.
New England Journal of Medicine, Vol. 335, No. 14, pp. 1001–9.

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More News and Less Clarity on Hormone-Replacement Therapy and Breast Cancer

Menopausal and postmenopausal women might choose to take hormone (estrogen) replacement-therapy for a number of reasons. Short-term HRT can help relieve discomforts associated with menopause, for example, hot flashes. Longer-term HRT may help ward off osteoporosis and also has been associated with a lower risk of heart disease. Estrogen taken alone greatly increases the risk of developing cancer of the uterine lining (endometrial cancer). If a woman has not had her uterus removed, typically progesterone is also taken as part of the hormone-replacement therapy and brings the risk of endometrial cancer back to baseline. Another potential downside of HRT is the possible increase in breast cancer risk associated with this therapy, which scientists believe may be related to estrogen's effect on breast tissue. Recent analysis of a large body of epidemiological data suggests that having used HRT recently and for a longer time increased breast cancer risk, particularly among leaner women. Having taken HRT in the past did not seem to influence this risk.

A recent study conducted at the National Cancer Institute (NCI) set out to examine whether combined therapy (estrogen and progesterone) affected breast cancer risk beyond what one might expect from estrogen alone. Study investigators followed 46,355 postmenopausal women for an average of 10 years. The study volunteers' average age was 58 years old at the start of the study. Based upon the number of breast cancer cases during follow-up, researchers calculated that taking estrogen alone increased breast cancer risk by 1% per year for each year a woman takes HRT. Taking combined estrogen and progesterone raised that risk considerably to 8% per year. Calculated out over several years, that prospect can be terrifying for many women. This conclusion does not come totally out of the blue for researchers. For example, the Harvard Nurses' Health Study data also have shown an association between combined therapy and increased breast cancer risk when compared with estrogen taken alone.

However, as with all clinical studies, there are factors in the NCI study that make it hard to tease out firm conclusions from this research. First, there are several ways to take combined therapy. A woman might take estrogen every day and progesterone only some days of the month, mimicking the menstrual cycle and producing a "period" each month. In fact, most of the women in this study followed this regimen. However, women can also choose to take both hormones every day to avoid monthly bleeding. It is hard to say if the results of this study apply equally to this method of combination HRT. Another interesting aspect of this research was that investigators sorted results by the women's body mass index (BMI) (a woman was considered overweight if her BMI was above 24.4). This threw another wrench into the conventional wisdom. Being overweight is generally associated with a higher breast cancer risk. The theory is that fat tissue produces a weak form of estrogen that may affect breast tissue. However, data from this study suggested that for the women who were overweight, HRT of any type did not increase breast cancer risk: and even more strangely, that estrogen taken alone reduces that risk in overweight women. It is difficult to say whether this is due to biology or simply because their risk was higher to begin with. Similarly, the increased breast cancer risk found for thinner women could be due to some biological aspect of body weight, or perhaps because slim women often have smaller breasts and it may be easier to catch breast cancer when breast tissue is less dense.

Rather than offer enlightenment to women facing the HRT decision, this research has muddied the waters further. An editorial written by Harvard Medical School doctors that accompanied the publication of this study makes the following suggestions. Given what we know now, short-term HRT (two to three years) taken to alleviate menopausal symptoms is very unlikely to alter breast cancer risk. Women thinking of HRT for this purpose should not be discouraged by this new study. Women who do not have a uterus do not need progesterone along with estrogen and should not take combination therapy. Women who do have a uterus and are thinking about long-term HRT to reduce the risk of osteoporosis or heart disease should carefully weigh the potential risks and benefits of HRT for this purpose. There are new drugs available to treat and help prevent osteoporosis, and recent data on hormone replacement and heart disease suggest that cholesterol-lowering drugs (statins) can do as good a job as HRT without many of the risks. And no matter what a woman decides about HRT, there is no substitute for careful attention to a healthy diet, adequate exercise, and following her doctor's recommendations for screening tests and physical exams.

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Osteoporosis Drug May Offer Protection Against Breast Cancer

A drug designed to combat osteoporosis greatly reduced the risk of some forms of breast cancer in a study of postmenopausal women. Researchers from the University of California at San Francisco were originally testing Raloxifene's ability to reduce bone fractures in postmenopausal women with osteoporosis. Women with osteoporosis are particularly vulnerable to bone fractures because estrogen production drops sharply after menopause. The 7,705 participants were also monitored for breast cancer, and it was this secondary purpose that revealed the drug's effects on breast cancer risk.

Raloxifene reduced the overall risk of breast cancer by 76%, and estrogen receptor-positive breast cancer by 90% in the three-year study. Estrogen receptor-positive is the most common form of breast cancer in older women. However, Raloxifene did increase the chance of venous thromboembolic disease, a rare disorder that causes blood clots in the veins, but it did not increase the risk of endometrial cancer, which is cancer of the uterine lining.

Raloxifene's side effects included hot flashes, leg cramps, and sinusitis, but fewer than 1% of the subjects dropped out because of them. Researchers caution against euphoria. The original intent of the study was Raloxifene's effect on osteoporosis, not breast cancer and neither the long-term benefits, nor the long-term risks of the drug are known. However, Raloxifene offers hope for a way to reduce the risk of breast cancer.

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New Information on Hormone-Replacement Therapy and Breast Cancers

Menopausal women deciding about whether to start hormone-replacement therapy (HRT) must weigh the potential benefits, which include a reduced risk for heart disease and osteoporosis, against the potential risks — the most serious being an increased risk of breast cancer. A 1995 analysis of 51 combined studies did show an increase in breast cancer risk for women taking HRT for five or more years when compared to women who had never taken HRT. The researchers who performed this analysis, however, also proposed that HRT exposure promotes the growth of less aggressive, slower-growing forms of breast cancer.

A recent report from the Iowa Women's Health Study appears to support this hypothesis. For the purposes of this report, study investigators followed the health of 37,105 women who were 55 to 69 years old in 1986 for 11 years. Over this period, 1,520 of the women developed breast cancer. Researchers found that while postmenopausal use of hormone-replacement therapy may increase the risk of breast cancer by 15%-30%, HRT use was most strongly associated with breast cancers with a favorable prognosis.

This information may help women better weigh their health concerns and personal preferences when deciding whether or not postmenopausal hormone-replacement therapy is right for them. For more information on postmenopausal hormone-replacement therapy, see page 1049 in the Family Health Guide.

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Clonidine for Tamoxifen-Induced Hot Flashes

Hot flashes are a common side effect in postmenopausal women taking tamoxifen for breast cancer. While many of these women are able to keep their hot flashes from interfering with their daily activities, others are not. Even though low doses of megestrol, and other progestational agents, have been found to control hot flashes, doctors are reluctant to prescribe them for women taking tamoxifen because both progestational agents and tamoxifen can cause side effects, including blood clots.

A recent report suggests that clonidine, a nonhormonal drug, appears to be effective in reducing the frequency of hot flashes in this group of women. During this study, participants who took 0.1 mg of clonidine at bedtime for eight weeks reported a significant reduction in the number of hot flashes they experienced and a small beneficial effect on the severity and duration of these episodes. Women in the group taking clonidine had been experiencing an average of eight hot flashes a day at the start of the research. After eight weeks of taking clonidine daily, these women experienced an average of 2.2 fewer hot flashes per day.

While clonidine showed significant benefit for most of the women taking it in the study, it should be noted that some women experienced no benefit. Only one major side effect, difficulty sleeping, was reported by 41% of the women taking clonidine. Though the study did not evaluate clonidine’s long-term benefits, the researchers involved believe that its continued use would prove valuable.

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Hormone-Replacement Therapy and the Risk of Blood Clotting

Researchers have found yet another factor for women to consider when deciding whether or not to take hormone-replacement therapy. A recent study shows that taking estrogen and progestin after menopause increases the risk of venous thromboembolisms. (A venous thromboembolism occurs when blood clots formed in the deep veins become dislodged.) The clots travel through the blood stream and can become lodged in smaller vessels where they block blood flow.

In the Heart and Estrogen/progestin Replacement Study (HERS), researchers evaluated the effect of postmenopausal hormone therapy on the rate of coronary events in women with heart disease. According to the results, women receiving the hormone therapy had a threefold risk of thromboembolic events compared to women receiving a placebo. Since both estrogen and progestin were part of the hormone therapy, researchers were unable to detect which substance was responsible for the increased risk. However, estrogen seems the most likely culprit because similar results appeared in studies involving oral contraceptives and estrogen-like drugs such as tamoxifen. Researchers do not know precisely how estrogen increases the risk of venous thromboembolism, but some believe that estrogen may affect the liver’s ability to produce or breakdown substances that prevent clotting.

The study also found that fractures to the lower limbs, cancer, heart attacks, surgery, and hospitalization increased the risk of blood clots. These findings suggest that women with these risk factors should try to stay active and may need drugs to reduce clotting. In addition, the results showed that women who take aspirin or lipid-lowering drugs called statins have a 50% lower risk of clotting.

Women who are considering taking hormone-replacement therapy should discuss the risk of blood clots with their doctors. The benefits of therapy may outweigh the risks in some cases. However, women who have cancer, a lower limb fracture, or a history of blood clots should avoid hormone therapy.

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Calcium Carbonate's Effect on the Absorption of Levothyroxine

A recent study has revealed that calcium carbonate may reduce the body's ability to absorb the thyroid medication levothyroxine. The people who are probably most affected by this discovery are postmenopausal women, since they often end up taking both levothyroxine and calcium carbonate. However, anyone taking levothyroxine and calcium carbonate concurrently can experience the same effect.

Patients participating in the study ranged in age from 27 to 78 years old and were almost evenly divided between men and women. They all had hypothyroidism (low thyroid function) and were taking levothyroxine. During the study, they were asked to take 1,200 mg of calcium carbonate daily over a three-month period. The majority of patients had significantly lower levels of thyroxine by the end of this period. They were then asked to discontinue taking the calcium carbonate, and their thyroxine levels were measured again after two months. At the end of the two-month period, their thyroxine levels were found to have returned to normal range.

In light of the fact that patients participating in the study were instructed to take the calcium carbonate daily with the levothyroxine on an empty stomach, researchers believe that the acidity level in the stomach may be a factor in how much levothyroxine is absorbed by the body. Researchers have suggested that one way to curb calcium carbonate's effect on levothyroxine is to take the calcium carbonate after a meal in order to optimize the body’s absorption of levothyroxine. They add that if while taking calcium carbonate and levothyroxine concurrently, a patient's thyrotropin level rises, it would be advisable to separate the times at which he or she takes calcium carbonate and levothyroxine on a given day. In some cases, physicians might want to increase the dosage of levothyroxine, to compensate for the effects of calcium carbonate.
October 2000 Update

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