Researchers Stop HRT Study Due to Breast Cancer Risk July 10 , 2002

After closely following the women taking estrogen and progestin in the Women's Health Initiative (WHI) clinical trial, researchers announced on July 9 that the trial has found that the risks of HRT outweigh its benefits and that they are calling a halt to the study. The study results, which will appear in the July 17, 2002 issue of the Journal of the American Medical Association, were released early because of the importance of the researchers' findings

While much of the media coverage has expressed physicians' amazement at the study's results, it was no surprise to Dr. Susan Love, who predicted these findings in Dr. Susan Love's Hormone Book and has advocated that women only stay on HRT for as short a time as necessary to relieve menopausal symptoms.

Background

Estrogen was approved by the FDA to treat menopausal symptoms in 1942, and in 1965 pharmaceutical companies began actively marketing estrogen as a way for women to keep themselves healthy and "feminine." Progestin was added to estrogen in the mid-1970s after studies found that giving women estrogen alone increased the risk of uterine cancer. Since then, the HRT combination of estrogen and progestin has become the second most frequently prescribed medication in the US.

Until recently, the only data supporting HRT's use came from observational studies - studies that compared women who chose to take HRT with women who chose not to. These studies found that the women who took HRT had fewer heart attacks and strokes and were less likely to develop osteoporosis. But because these studies were observational in nature they couldn't answer the question of whether HRT made women healthy or healthy women took HRT.

To determine whether HRT was effective, in 1993 the National Institutes of Health began the WHI, the first long-term randomized placebo-controlled study designed to measure the benefits and risks of HRT use. Randomized placebo-controlled trials are the gold standard of medical research because, unlike observational studies, they can prove cause and effect. More than16, 000 women between the ages of 50-79 were enrolled between 1993 and 1998 in the WHI trial. Half of the women were given HRT; the other half was given a placebo.

The WHI trial began around the same time that Wyeth, the drug company that makes the leading HRT drug Prempro, began a randomized, controlled trial called the Heart and Estrogen/progestin Replacement Study (HERS). This trial included about 2700 women; half were given Prempro while the other half received a placebo. The most recent results from HERS, published on July 3, 2002 in the Journal of the American Medical Association, indicated that HRT did not prevent heart attacks in older women with heart disease and that it increased blood clots and gallbladder disease. This confirmed previous results from the HERS trial that had been published in 1998

The Trial's Findings

The researchers expected to stop the trial in 2005. But to ensure women's safety during the trial they established an independent data and safety monitoring board (DSMB) to review interim results semi-annually. During the tenth analysis, on May 31, 2002, the DSMB found an increased risk for breast cancer, coronary heart disease, stroke, and blood clots that outweighed the benefit of reduced fractures or colon cancer risk. This finding led the DSMB to recommend that the trial be stopped.

This is the first randomized trial to confirm that HRT increases the risk of invasive breast cancer. The study could not determine if HRT increases a woman's likelihood of dying of breast cancer because of the short follow-up time. In looking at heart disease, the study confirms the findings of the Heart and Estrogen/progestin Replacement Study (HERS), which found that HRT increased the risk of stroke and did not decrease risk of heart disease.

Although the new data from the WHI trial does provide the first definitive evidence that HRT can prevent fractures at the hip, vertebrae, and other sites in postmenopausal women, other options are available - like Raloxifene

- that, unlike HRT, decrease the risk of osteoporosis without increasing the risk of breast cancer and cardiovascular disease.

How big of a risk did the study find? If 10,000 women were taking HRT for a year and 10,000 women were not taking HRT, in the HRT group 8 more women would develop invasive breast cancer, 7 more would develop heart disease, 8 more would have a stroke, and 8 more would develop blood clots. There would also be 6 fewer colorectal cancers and 5 fewer hip fractures.

The trial was stopped at a point when all of the women had been enrolled for at least 3.5 years, with an average follow-up of 5.2 years. The longest any woman had been enrolled in the trial was 8.5 years. During the trial, 42% of the women in the HRT group and 38% of the women in the placebo group stopped taking their drugs. While this number is high for a study, it reflects the number of women who are prescribed HRT and then choose to go off treatment in less than five years.

What Should Women Currently on HRT Do?

Women who were enrolled in the estrogen and progestin arm of the trial will be receiving letters from the researchers telling them to discontinue their HRT use.

A separate trial enrolled women who had had a hysterectomy and could take estrogen alone. This trial is still continuing. But if the results from this trial are consistent with previous data it will show that estrogen alone increases breast cancer risk by 1% per year and increases heart disease as much as the estrogen and progestin combination.

Although the North American Menopause Society is emphasizing that this study only applies to Prempro, there is no reason to believe that it would not be applicable to other types of HRT.

With the results of this trial, the evidence is stronger than it has ever been that HRT is not the woman's wonder drug that it was expected to be and that it should not be considered a treatment that improves postmenopausal women's long-term overall health. The bottom-line: Short-term use of HRT for symptom relief is okay, but then women should taper off or get down to as low a dose as possible.

HRT: When, Why, and How to Go Off July 10 , 2002

"HRT will be good for your heart and good for your bones and is something you can be on for the rest of your life." Those are the words many women heard when they were first prescribed Hormone Replacement Therapy (HRT) for their menopausal symptoms.

It sounded too good to be true - and it is.

As knowledge of HRT has advanced, it has become increasingly clear that HRT isn't the women's wonder drug that many thought it would be. We now know that HRT:
* If used for more than five years, increases the risk for invasive breast cancer.

* Increases the risk for heart attacks, strokes, and blood clots.

* Increases the rate of incontinence and uterine prolapse.

* Doesn't appear to prevent heart disease.

* Has not been proven to prevent Alzheimer's disease.

* Does not improve quality of life in women who do not have menopausal symptoms.

Why to Taper Off

One of the myths about HRT is that all women decide to take hormones when they reach menopause. Actually less than half of all women go on HRT, and only 20% of these women continue to take hormones for more than a few years. This means learning how to stop HRT is just as important as deciding when and how long to take hormones.

It is now recommended that women stay on hormones for as short a time as is possible - at most three to five years - to help with menopausal symptoms, like severe hot flashes, night sweats, or vaginal dryness, and then begin tapering off. Women who begin taking hormones in their thirties and forties following an oophorectomy should begin tapering off in their early fifties.

Women who choose to stay on HRT should take low-dose HRT. Several studies have shown that low dose HRT (.3 mg or .18 mg of Premarin, Menest, Esratab, Ogen, Ortho-Est or Cenestin) combined with a daily supplement of 1000mg of calcium maintains bone density as well as high dose HRT.

How to Taper Off

As women who have been diagnosed with breast cancer know firsthand, it is possible - and from a medical perspective perfectly okay - to stop hormones cold turkey. In fact, about half of all women who stop taking hormones cold turkey will do just fine. The other half, though, will find that the menopausal symptoms that led them to take hormones in the first place come back with a vengeance. This is because stopping hormones turns on the menopausal switch, and that is likely to result in the side effects that women typically go on HRT to avoid - hot flashes, vaginal dryness, and sleep problems.

Since there is no way to predict which women will experience symptoms and which women won't when they go off HRT, every woman must determine which method of going off HRT is right for her. One option is to taper off HRT gradually, which allows the body adjust to decreasing doses of hormones and helps to reduce side effects. The second option is to quit cold turkey and then see if you are one of the lucky one who doesn't have symptoms. If you are in the lucky 50%, you can throw your HRT away. If you're not, you can go back on and then begin tapering off gradually.

If you take combination HRT, which has estrogen and progesterone in the same pill, to begin tapering off you should ask your doctor for two separate prescriptions. This will allow you to better control the dose of each aspect of your HRT as you taper off. As you taper off you should also begin taking a daily supplement of 1000 mg of calcium. One you have tapered off completely, you should take a daily supplement of 1200mg of calcium along with 400-800 IU of vitamin D.

The standard HRT regimen is 0.625 mg if you are taking Premarin, Menest, Esratab, Ogen, Ortho-Est or Cenestin, and 1 mg if you are taking Estrace. Women who have a uterus also take a progesterone to keep the uterine lining from building up, which reduces the risk for endometrial cancer. Women take this pill daily or at a higher dose for 12 days per month.

If you are taking standard HRT the best way to begin tapering off is to start taking low dose HRT - 0.3mg (.5mg of Estrace). At this level you may also be able to stop taking your progesterone, as low dose HRT does not appear to affect the uterus. (This is something you can decide in consultation with your clinician.) If you have symptoms on the lower dose, you will need to raise your dose and decrease more gradually. You can do this by alternating low and high dose pills (Monday=high dose, Tuesday=low dose, Wednesday=high dose, Thursday=low dose, etc) for three to six months before trying to take only the lose dose pills.

A second option is to take the high dose pills Monday through Friday and not take any pills on the weekends. After you have done this for three to six months, you can then try the low dose pills again. The only way to know when you can fully drop down to the low dose is by trying it and then seeing if symptoms develop. If they do, and are unbearable, you will need to go back to the routine you were on and taper more gradually. If you are alternating a high dose pill with a low dose pill you can do this by replacing one of the days you are taking a high dose pill with a low dose pill. (Monday=high dose, Tuesday=low dose, Wednesday=low dose, instead of high dose, Thursday=low dose, etc). Once you have done this for a few months, then try adding in another low dose day.

If you are taking HRT Monday through Friday and skipping weekends, try skipping another day, like Wednesday. Then, after a few months, you can try skipping another day. In general, the rule to follow is to go as slowly as you need to and to not go to the next reduction until symptoms that may have developed are easy to handle.

After a few months on the lower dose, you have two options: you can discontinue estrogen all together or you can continue to take a smaller amount by cutting your pills first in half, and taking a half dosage for a few weeks, and then cutting the pills in quarters and taking a quarter dose for a few weeks. Another option is to take a low dose pill every other day.

If you are currently taking a higher dose of HRT - 1.25mg (2mg Estrace), you should begin tapering by dropping down to the standard dose - .635 mg (1mg Estrace). You should continue to talk the progesterone until you taper down to the low-dose level - 0.3mg (.5mg of Estrace). Once you are at the lower dose, you can discuss with your clinician whether to remain on the progesterone while you finish tapering off.

Money tip: HRT costs the same regardless of the dosage you are prescribed. To help reduce your costs you may want to keep your prescription dosage the same, but cut your pills in half.

Handling Side Effects

Tapering off hormones should help to reduce hot flashes, but you may still have them. To learn about some of the recommendations for relieving hot flashes, read our Update on Hot Flashes, which discusses treatments like soy, vitamin E, and anti-depressants.[link here]

As you taper off hormones you may also find that you experience vaginal dryness. There are a number of ways to address this problem.

* Sexual exercise - either masturbating or with a partner - will increase your natural lubrication.

* Drink lots of water. Eight 8--ounce glasses a day can help your whole body, including your vagina, stay hydrated.

* Try water-based lubricants, like Astroglide, or vaginal moisturizers, like Replens.

* Talk to your clinician about a prescription for an estrogen vaginal cream, like Premarin or Estrace, or vaginal inserts like the Estrogen ring and Estratab.

Osteoporosis Concerns

One of women's biggest fears is that if they go off of HRT they will immediately begin to develop bone problems due to osteoporosis. You won't crumble or shrink as you taper your dose. But you should still be concerned about osteoporosis - and you should use that concern to begin taking steps now to keep your bones healthy as you age.

The best means of warding off osteoporosis is eating a diet that is rich in calcium, taking calcium and vitamin D supplements, and starting an exercise program that includes weight-bearing exercises like walking and weight-lifting.

It is now recommended that women have their first bone density test at age

This test can help determine if you are at risk for osteoporosis. If you have osteoporosis, your clinician can prescribe a bisphosphonate, a drug that helps to reduce bone loss and prevent hip and other fractures. These drugs have been proven more effective than estrogen in reducing fracture risk, have fewer side effects than HRT does, and do not increase breast cancer risk.

For more information on all aspects of hormone replacement therapy, look to Dr. Susan Love's Hormone Book, soon to be out in its second edition.

Preventive Medicine, Properly Practiced July 16 , 2002

By SUSAN M. LOVE re-printed The New York Times July 16, 2002

LOS ANGELES - There are at least 6 million women in this country who are asking themselves, "What happened?" Over the last several years they have read books and magazine articles, listened to TV pundits and talked to doctors and friends - all of whom assured them that taking hormone replacement therapy for the rest of their lives would keep them healthy.

Then one bright summer day, their world shifted. Their little daily pill carried not the promise of health but the risk of disease. How could this be?

What happened is that medical practice, as it so often does, got ahead of medical science. We made observations and developed hypotheses - and then forgot to prove them.

We start with observational studies, in which researchers look at groups of people to see if we can find any clues about disease. But all this observation can do is find associations: it can't prove cause and effect.

With hormone replacement therapy, we did many observational studies. We found that women who were on hormone therapy had a lower incidence of heart disease, stroke, colon cancer and bone fracture. And we accepted these findings before we did the definitive research, overlooking the fact that these women were also more likely to see a doctor (which is how they were put on hormone therapy in the first place), and probably more likely to exercise and to eat a healthful diet, than women who were not taking the drug. It wasn't clear whether hormones made women healthy or whether healthy women took hormones. To answer this question we needed randomized, controlled research.

The latest study, sponsored by the National Institutes of Health, enrolled

16, 608 healthy women from ages 50 to 79 and randomly assigned them to take hormone replacement therapy or a placebo. Much to everyone's surprise, after

2 years the study showed that the risks of hormone treatment outweighed the benefits in preventing disease.

Many are already arguing that the study was poorly designed or that its results are limited to one type of hormone therapy, or even that "bioidentical" hormones will be safe. In fact what the study really questions is the idea that we need to replace hormones in post-menopausal women for the long term. Menopause is normal. We need high levels of hormones to reproduce, but we shift down to a lower level for the second half of life. The symptoms of menopause are really not the symptoms of low estrogen but the symptoms of hormonal change - puberty in reverse.

And, as with puberty, the symptoms are transient, usually lasting between three and four years. In one study following women through menopause, 50 percent of the participants complained about hot flashes but only 16 percent felt they were really bothersome. For these women, it is perfectly reasonable to take hormone therapy for up to four years. At that point, a woman can either stop cold turkey (50 percent of women will do fine with this approach) or taper off over several months.

There is a bigger issue than simply hormone therapy, however. There is a tendency, driven by wishful thinking combined with good marketing and media hype, to jump ahead of the medical evidence. In the 1950's, it was DES, a drug given to pregnant women to prevent miscarriages. It was many years later that a randomized, controlled study showed that it had no effect in preventing miscarriages. Finally, in 1971 it was learned that daughters of women who took DES were at increased risk of developing vaginal cancer.

In the 1990's, the bone marrow transplant - high-dose chemotherapy with stem-cell rescue - was proposed to treat aggressive breast cancers. It was widely used until four randomized, controlled studies showed it was no better than standard therapy, and had far more side effects. Arthroscopic surgery for osteoarthritis was commonly performed but just last week a controlled study showed it had no objective benefit. Hormone replacement therapy is just one more example of this phenomenon.

These examples show the importance of taking the time to determine the safety and efficacy of a particular therapy before we embrace it. This is particularly true in preventive medicine, since such therapy can create one disease in trying to prevent another that might not occur at all.

The foundation of prevention still should be lifestyle changes: quitting smoking, eating a healthy diet and exercising regularly. Drugs, whether to prevent heart disease, bone fractures or breast cancer, should be secondary. This is not necessarily an easy lesson, but we need to demand medicine based on solid evidence, not hunches or wishful thinking.

Susan M. Love is author of "Dr. Susan Love's Hormone Book'' and an adjunct professor of surgery at U.C.L.A. Medical School.