MENOPAUSE: Hormone Replacement Therapy

W hether or not to undergo hormone replacement therapy (HRT) may be one of the most difficult decisions facing a woman at mid-life. The medical community itself is divided on the issue. Some experts recommend hormone treatments for all menopausal women who have no outright reason to avoid it; others are opposed to the treatment for most women. Many doctors cautiously recommended hormone therapy for some, but not all, women.

The question of whether hormone therapy is right for you cannot be answered with a simple yes or no. The decision should be influenced by a number of factors, including:

• The severity of the immediate physical symptoms caused by declining hormonal levels.
• Your individual risk for osteoporosis and heart disease.
• Your individual risk for cancers of the breast and reproductive system.

The attempt to balance short- and long-term health concerns against HRT's potential risks has been a source of great uncertainty for many women. In fact, one survey found that one-third of the women who are given prescriptions for hormones don't bother to fill them. Rather than avoiding the issue, or staying in the dark about hormone replacement therapy, each woman needs to know the full range of both the benefits and risks. The goal of this chapter is to help you make an informed decision based on your individual needs.

The Controversy

In the 1950s and 1960s, doctors enthusiastically prescribed estrogen to relieve menopausal symptoms. The drug was promoted by many doctors and the popular media as a "fountain of youth" that would slow the aging process and make women feel more attractive. By 1975, estrogen was one of the top five prescription drugs in the United States.

Then, in the mid-seventies, the darker side of estrogen replacement therapy came to view. Estrogen use was linked to a four- to ten-fold increase in the risk of endometrial cancer (cancer of the uterine lining). A panic spread among many users, and after 1976 the use of estrogen declined. In response, doctors cut the standard dose of estrogen in half. Soon they learned that the risk of uterine cancer could be dramatically cut or even eliminated by combining estrogen with progestin, a synthetic form of the female hormone progesterone.

Today, lower dosages and combination therapy have become the norm, and new forms of estrogen and estrogen alternatives are now in circulation. However, despite these modifications, HRT remains controversial, with opposing views on menopause fueling the dispute. Some scientists view the changes that occur in a woman's body in midlife as the onset of a "hormone deficiency disease." Noting the many ways that a lack of estrogen has a negative, aging effect on the body, they encourage women to replenish their body's supply of reproductive hormones for the rest of their lives, if possible. Thus, hormone therapy is urged not only as treatment for symptoms in the short-term, such as hot flashes or vaginal dryness, but recommended as a long-term preventive measure against heart disease and osteoporosis.

And, indeed, the evidence is piling up that, for a significant percentage of women, the hormonal changes brought by menopause do contribute to chronic disease and early death. In 1991, a Food and Drug Administration committee recommended that hormone therapy be made available to "virtually all" postmenopausal women, except those for whom it is clearly a danger.

Those who oppose hormone replacement therapy criticize the "medicalization" of menopause -- that is, the tendency to view the changes at mid-life as a disease that automatically requires medication, rather than a natural life process. They question whether hormone therapy -- especially the use of progestin in combination with estrogen -- should be prescribed as a long-term preventive measure before there are enough long-term clinical trials to fully guarantee its safety and effectiveness. In addition, some object to the routine prescribing of hormones for healthy women because of the known risks associated with the treatment.

Women's health groups also fear that the marketing of long-term hormone therapy to doctors by pharmaceutical companies, combined with these companies' financial domination of hormone research, has restricted the scope of public discussion. Still, currently ongoing studies, discussed later in this chapter, should yield definitive findings on the benefits and risks of hormone therapy. Some women have also accused the male medical establishment of promoting the use of hormones to keep women "younger." However, HRT advocates aren't necessarily men. One 1989 study from Massachusetts General Hospital in Boston found that female doctors are 19 times more likely than their male counterparts to prescribe HRT (though the ratio dropped to 50/50 among male and female gynecologists.)

Although HRT usage is on the increase, the majority of postmenopausal women still do not take hormones. Hormonal changes are a normal part of mid-life, and many women experience menopause with few discomforts. For those who do experience intense, unpleasant symptoms during menopause, however, hormone replacement therapy can bring effective relief.

The Basics

The main role of estrogen is to control the functioning of the reproductive organs, though researchers have found estrogen receptors -- which are taken as evidence of estrogen sensitivity -- in the brain, liver, skin, bone, fat, muscle, and blood vessels. At menopause, a woman's estrogen levels decline dramatically.

Estrogen replacement therapy (ERT) is a medical treatment in which a woman's estrogen level is artificially increased, restoring premenopausal levels on a short- or long-term basis. HRT refers to a treatment that combines both estrogen and a progestin, a form of the hormone progesterone. Developed to sever the link between ERT and endometrial cancer, HRT is not needed if you have had your uterus removed by a hysterectomy.

No one form of estrogen or progestin is better than another in terms of benefits, though women who experience side effects with one form may get better results if they switch to another. The most common prescription has been for conjugated equine (horse) estrogen. Several newer forms of estrogen derived from plant sources, as well as synthetic and naturally-occurring progestins, are now available.

A new class of drugs, known as selective estrogen receptor modulators (SERMs), offer yet another choice for postmenopausal women. Tamoxifen (Nolvadex), the first SERM to be approved, has relatively limited applications. It is used to treat breast cancer (and to prevent it in very high risk women).

The newer SERM, raloxifene (Evista) has much broader benefits. Approved for the prevention of osteoporosis in postmenopausal women, it offers positive estrogen-like effects on bone density and cholesterol levels without negative cancer-promoting effects on the uterus and breasts. In a three-year trial in over 7,700 postmenopausal women, Evista reduced the number of vertebral fractures by 47 percent in women who had suffered a fracture earlier, and by 40 percent in those without a prior history of fractures. In addition, it was responsible for a 76 percent decline in the number of new breast cancer cases during the period of the study.

On the negative side, Evista triples the risk of clots in the circulatory system (thromboembolisms) and is therefore not recommended for women who've ever had such a problem. And, unlike HRT, it provides no relief from hot flashes.

Available Methods

Hormone Pills are the most often prescribed and easiest way of taking HRT. The benefit of this method is that when estrogen in pill form is processed by the liver (where cholesterol is produced), it more readily increases the level of high-density lipoproteins (HDL), the "good" cholesterol, than do some other methods. However, the hormone can be changed when processed in the liver, resulting in unwanted side effects if the dose proves too high.

Injections are one way of bypassing the liver. With this method, you receive hormone shots directly into the muscle. The drawback is that injections fail to maintain steady blood levels of the hormone; initially high levels decrease over time. Because shots can be spaced no more than a month apart, this method imposes the cost and inconvenience of frequent visits to the doctor, plus the need for regular monitoring of hormone levels in the blood.

An estrogen-filled patch , usually placed on the buttocks or upper arm, feeds hormones directly into the bloodstream, again bypassing the liver. Each patch lasts several days. Unfortunately, this method does not seem to have the same beneficial effects on HDL levels as estrogen taken orally.

Implants -- pellets surgically placed under the skin twice a year -- were popular in the 1960s and 1970s. But because of a cumulative effect, after several years, estrogen levels in the blood were shown to rise as much as 2 to 3 times higher than those obtained from the standard oral dose. Because hormone levels delivered by implants cannot be easily adjusted, most doctors now view them as outdated. In addition, insertion can be uncomfortable and result in infection. If you do choose implants, your estrogen blood levels should be monitored regularly.

Creams containing estrogen and progestin can be applied directly to the skin -- usually over the abdomen, arms or thighs. This method also bypasses the liver, eliminating the possibility of high-dose side effects generated by liver metabolism. Creams allow for balanced treatment because a specific dose is administered daily; but applications can be messy, and you can inadvertently apply an improper amount. Like implants, creams can produce higher blood levels of estrogen than standard oral regimens so your blood estrogen levels should be monitored if you opt for this method.

Vaginal creams containing estrogen can be helpful for women who have only vaginal menopausal symptoms, such as dryness, itching, or painful intercourse. Contrary to common belief, estrogen does enter the bloodstream when applied vaginally, so the same risks and benefits apply to this method as for other forms of estrogen.

Dosage

The most common prescription for menopause is an oral dose of 0.625 milligram of conjugated estrogens -- a combination of naturally occurring estrogens -- taken with 5 milligrams of the progestin medroxyprogesterone acetate. This usual prescription contains about one-sixth the amount of estrogen and progestin found in birth control pills.

Discuss with your physician whether lower or higher doses of hormones may be right for you. Some women use low dose HRT, such as 0.3 milligram of estrogen rather than the standard 0.625, and 2.5 milligrams of progestin instead of 5 milligrams. Doses as low as 0.3 milligram of estrogen may relieve symptoms, but may also offer little or no protection against osteoporosis or heart disease. Thus, lower doses may be appropriate for a woman who is not at high risk for heart disease or osteoporosis, but who does suffer from menopausal symptoms such as hot flashes.

Regimen

Combined therapy. A common sequential regimen for oral administration is a daily dose of estrogen with a daily dose of progestin added for the first 14 days of the month. Another sequential regimen is a dose of estrogen for the first 25 days of each month with progestin taken during days 15 to 25. (This regimen is losing favor, however, because it's difficult to keep track of the doses.)

These regimens can result in side effects such as breast tenderness, bloating, fluid retention, and depression. In addition, menstrual bleeding occurs in 80 to 90 percent of women on a sequential regimen when the progestin is withdrawn. Lowering the dose of progestin usually remedies these symptoms, but the lowest effective progestin dose required to offset the risk of uterine cancer in sequential regimens has not been established.

A continuous, daily regimen, as opposed to traditional sequential treatment, allows the use of lower doses of progestin. Thus, progestin-induced side effects, such as bleeding, tend to improve with continuous therapy. However, even in a continuous regimen, 40 to 60 percent of patients still experience some bleeding during the first six months of treatment. Since no method of drug alteration has been found to prevent this bleeding, the only approach is to wait it out. Though the bleeding will usually cease over time, some women find its irregularity difficult to manage. Some opt to return to a sequential program, where withdrawal bleeding occurs predictably each month.

Estrogen-only treatment. A woman can safely take estrogen "unopposed," that is, without the addition of progestin, if she has had her uterus removed. However, many women who cannot tolerate treatment with progestin because of adverse side effects such as menstrual-like bleeding, mood swings, and bloating also opt for unopposed estrogen. When there is no progestin to offset the uterine cancer risk of estrogen alone, doctors recommend an annual endometrial biopsy.

The Benefits of HRT

Despite the ongoing controversy, HRT is still widely prescribed because there do appear to be clinically proven benefits: protection against osteoporosis and heart disease, and relief of menopausal symptoms.

Preventing Osteoporosis

Bone loss, which begins naturally around age 35, accelerates dramatically at menopause. The prevention of osteoporosis, the progressive thinning of bone, is one major reason why women are advised to take long-term hormone or estrogen therapy (see the preceding chapter). Hormone therapy's effectiveness in preventing bone loss is firmly established. In numerous studies, postmenopausal women who have undergone some form of hormone therapy -- either estrogen alone or estrogen with progestin -- for at least a decade, show significantly less bone loss than women who have not. For women with a high risk of osteoporosis, hormone replacement therapy provides a clear benefit and could be lifesaving.

Contrary to popular belief, hormone or estrogen therapy is not useless if you have already developed osteoporosis. Although calcium supplements, proper nutrition, and exercise can help preserve bone mass, estrogen can effectively halt and even reverse the degenerative process of osteoporosis. The treatment can be started at almost any point after menopause. Continued hormone treatment is needed in order to sustain its preventive effects against bone deterioration. Once the therapy is stopped, postmenopausal bone loss resumes. Since osteoporosis-induced fractures are most likely in women aged 75 to 80, this can translate into decades of preventative hormone therapy.

Preventing Heart Disease

The mechanisms by which estrogen protects the heart are not fully understood, but one significant contribution is its capacity for improving a woman's metabolism of fats and cholesterol. Estrogen's protective effect comes from its ability to raise the "good" high- density (HDL) cholesterol associated with a reduced risk of heart disease, while also decreasing low-density (LDL) cholesterol or "bad" cholesterol. For this reason, a woman's risk of heart disease is lower than that of men the same age until shortly after she passes menopause. Eventually risk levels even out, but nonetheless, 40 percent of a woman's greater life expectancy can be attributed to early protection from heart disease.

With the declining estrogen levels that accompany menopause, the risk of heart disease doubles for women as HDL cholesterol declines and LDL cholesterol increases. While very few premenopausal women are affected by cardiovascular disease, it has now become the number-one killer of women over the age of 50 in the United States. (See chapter 12, "Heart Disease: The Greatest Threat of All.")

Within the last few years, doctors have begun advising long-term hormone replacement therapy as a heart disease preventive, especially for those women at high risk of the disease. The ongoing Nurses' Health Study, coordinated by Harvard University, has followed 48,470 postmenopausal women with no previous heart disease and found that those who take estrogen have 50 percent fewer heart attacks than those who do not, and the death rate from cardiovascular disease is about 50 percent less. Although these results are impressive, other variables may be involved. Women who take estrogen therapy tend to be healthier, and therefore at a lower risk of heart disease, anyway. Better diet and health care among women on hormone replacement therapy also may contribute, to some extent, to the lower death rate.

Though an overwhelming majority of studies have now shown that estrogen therapy significantly reduces a postmenopausal woman's risk of heart disease, it's still not clear how heart disease risk is affected when a woman takes progestin as part of her treatment. Short-term studies indicate that by increasing the levels of the "bad" LDL cholesterol, the progestins blunt -- but do not negate -- estrogen's beneficial effect on the heart. But because the impact of progestin is influenced by dose and duration of the hormonal therapy, long-term studies are needed.

As a preventative measure, long-term hormone therapy has proven its value against heart disease and osteoporosis. However it's misleading to suggest that taking HRT works as a quick fix for such voluntary risk-taking as cigarette smoking, heavy drinking, poor diet, or lack of exercise, all of which contribute to both heart disease and osteoporosis. In fact, 60 to 70 percent of the decrease in mortality from heart disease that has occurred over the last three decades in the United States can be directly attributed to preventative health strategies, such as giving up smoking, reducing blood pressure, and lowering cholesterol.

Relief of Menopausal Symptoms

Temporary hormone replacement therapy can reduce or eliminate many of the uncomfortable symptoms of menopause. Some women find relief by taking HRT for a year or two, and have no menopausal symptoms when the hormones are stopped. If your symptoms do recur, as they do for some women, your doctor may then recommend long-term treatment.

Hot flashes. About 75 percent of women entering menopause experience hot flashes -- a sudden reddening of the skin on the upper body and face accompanied by a feeling of intense heat and often by profuse perspiration. These frequent and unpredictable episodes may awaken you at night, causing sleep deprivation. In most women, hot flashes occur for a year or two after the onset of menopause; but in 25 to 50 percent of women, they continue for more than 5 years. Although the physiology of the hot flash is still not understood, its correlation with lower levels of estrogen following menopause has been clearly established. Most women find relief from hot flashes with hormone therapy.

Alternative treatments, such as drug therapy with the clonidine patch (Catapres-TTS), are designed to target hot flashes specifically, though they offer less effective relief than hormone therapy. Their advantage is that, unlike hormone therapy, they do not affect your entire body chemistry. If controlling hot flashes is your main concern, discuss treatment options with your physician.

Vaginal atrophy. Because low estrogen production brings a loss of elasticity in the skin, many postmenopausal women experience atrophic changes of the vagina -- a loss of muscle tone and strength in the vaginal wall. Vaginal dryness, which can result in burning, itching, and painful intercourse, can be remedied with postmenopausal hormone therapy. Recurrent urinary tract infections that result from abrasions due to vaginal dryness are also effectively prevented with hormone treatment.

Some women get significant relief in a month, but therapy can take 6 to 12 months, so don't be discouraged if you do not see immediate results. To maintain relief, you will most likely have to continue taking estrogen. Stopping treatment usually brings a recurrence of the problem.

Nonhormonal, water-soluble, over-the-counter lubricants (such as Replens or Astroglide) can be an effective alternative to hormonal treatment.

Urinary incontinence. The postmenopausal loss of pelvic tone that causes urinary stress incontinence in some women can be improved with hormone therapy. However, the Kegel exercises described in Chapter 29 are a more effective way of restoring muscle tone, and you don't need a prescription. Most doctors recommend diligently performing these exercises rather than using HRT solely to cure incontinence.

Emotional distress. Women do not experience a greater rate of mental illness with the onset of menopause. However, if you are plagued by debilitating menopausal symptoms such as hot flashes, you may succumb to other problems such as fatigue, nervousness, irritability, and depression. Hormonal therapy can restore your sense of well-being by alleviating such symptoms. However, emotional distress that goes beyond the normal sadness that accompanies serious life events, such as the death of a loved one, is probably better treated by a psychiatrist or psychologist than by hormonal treatment.

Other symptoms. Hormone therapy may improve short-term memory and slow overall body deterioration. It also improves skin collagen, bringing smoother and thicker skin, firmer breasts, and improved muscle tone.

The Major Risks of HRT

As most women who are familiar with HRT know, the major drawback of hormone replacement therapy is an increased risk of certain types of cancer. For many women, cancer strikes greater fear than do uncomfortable menopausal symptoms, osteoporosis, or even heart disease, despite the fact that heart disease is a far greater killer. The best way to make a decision on HRT is to learn as much as you can, consider your own health, and discuss your situation with your doctor.

Uterine Cancer

Estrogen therapy, unopposed by progestin, increases a postmenopausal woman's chances of developing uterine cancer from an average of 1 in 1,000 to as much as 1 in 100. The risk increases with the duration of exposure and the dose of estrogen. For example, women taking estrogen for 8 years show an eight-fold increase in the rate of uterine cancer at 8 years, a ten-fold increase at 10 years, and so forth.

Estrogen's ability to cause cell growth, indispensable when it thickens the uterine lining during your monthly cycle, helps explain its notorious connection to uterine cancer. It has been suggested that the more cells made in a particular organ, the greater the likelihood that a few of those new cells will be abnormal and turn cancerous.

Uterine cancer is the most serious risk of estrogen therapy. However, adding progestin, which inhibits the growth of the uterine lining, to the hormonal regimen dramatically reduces that risk. The appropriate dose of progestin continues to be an important issue, because of its tendency to undermine estrogen's cardiovascular benefits. In addition, progestin-induced side effects cause problems for many women, forcing them to opt for estrogen-only treatment or to abandon hormone therapy altogether. Only women who have had their uterus removed may safely take estrogen alone. If you do take estrogen alone and you have not had a hysterectomy, yearly examination of the uterine lining is crucial. Even if you are on combination therapy, monitoring for uterine cancer is advisable if you experience any abnormal bleeding.

Breast Cancer

Sufficient evidence exists to indicate the possibility of a slightly increased risk of developing breast cancer with prolonged postmenopausal estrogen use. Most studies show that the increase in the incidence of breast cancer occurs after 10 to 15 years of estrogen use. Aside from duration, it's thought that high doses may be at fault. The type of estrogen may also affect your level of risk. Interestingly, several studies found that breast cancers in women who take hormones tend to be more localized -- and therefore, more curable -- than those in women who don't. The bottom line: Women who take hormones get breast cancer slightly more often but die of it less often.

Because of estrogen's possible link with breast cancer, many doctors advise women to take the therapy for 5 years or less following menopause. Though this strategy can remedy the short-term symptoms of menopause, discontinuation of the therapy allows bone loss to resume at its postmenopausal, pre-HRT rate. If you are at greater risk of developing osteoporosis than breast cancer, you may want to consider continued hormone treatment.

The evidence on the impact of combined estrogen-progestin treatment on a woman's risk of breast cancer is still limited. Future studies, along with more experience should provide better answers to the outstanding questions about using both estrogen and progestin.

Though the possibility of a link between hormone replacement therapy and breast cancer is controversial, you should keep it in mind as a part of making an informed decision. As a preventive measure, you should be checked thoroughly for any tumors with a careful physical examination and a mammogram before you start hormone or estrogen therapy. Once you are on hormone therapy, you should examine your own breasts monthly and have yearly mammograms and physical exams. (See chapter 37, "Your Best Insurance Against Breast Cancer.")

Because there is evidence that breast cancer is a hormone responsive tumor, hormone therapy is not recommended for women who have had breast cancer. The interplay between a family history of breast cancer and HRT is less certain, but still something to take into account. So, if you are suffering from severe hot flashes, vaginal dryness, or other menopausal symptoms, and you have a family history of breast cancer, you need to weigh the risks and benefits with your doctor.

Gallbladder Disease

As with oral contraception, taking hormone or estrogen therapy can double your risk of developing gallstones. For women at high risk of gallstone attacks, oral hormone therapy should be avoided because it contributes to the formation of cholesterol crystals in the bile duct, which in turn supports the growth of gallstones. If you do decide to take hormone therapy, consider taking it via patch or vaginal cream.

Side-Effects of HRT

Although most women respond well to hormone replacement therapy, you may notice one or more of the following side effects.

Vaginal Bleeding

Uterine bleeding is the most common reason for stopping hormone therapy. This menstrual-like bleeding is called withdrawal bleeding, because it occurs when progestin is withdrawn from the treatment. While bleeding diminishes and ceases within a year for about two-thirds of women on progestin, some women will continue to bleed periodically as long as they take the therapy. Breakthrough bleeding, which is spotting at other than the expected time, may also occur. Whether you are troubled with bleeding depends on the dose, regimen, hormone chosen and your individual response.

One way to reduce or eliminate this side effect is to alter the way progestin is given. Research is currently underway for new ways to take the hormone that will eliminate bleeding. If this side effect is unmanageable for you, discuss treatment alternatives with your doctor.

Breast Pain

Hormone therapy may cause swollen or tender breasts, especially if progestin is added to your treatment. It's unpleasant, but rarely is the pain so severe that the medication needs to be changed or stopped. If you do experience severe ongoing pain, hormone therapy may have to be discontinued and started at a lower dose.

Other Side Effects

A 2- to 3-month adjustment period is often necessary for women beginning hormone replacement therapy. Other reported side effects include: nausea, cramping, headaches, fluid retention, vaginal discharge, depression, irritability, weight gain, and bloating.

Estrogen may also have adverse effects on some patients with seizure disorders and migraine headaches. In rare cases, it can also interfere with liver function, raise blood pressure, or promote the growth of benign uterine fibroids. The amount of hormone that can cause side effects, as well as the amount needed to remedy menopausal symptoms, varies from woman to woman, so tell your physician about any problems you may have. Changes can be made in the method, dosage, or schedule of your treatment.

Making the Decision

The decision to use or not to use HRT ultimately belongs to you. It can be a tough decision informed by competing influences.

Trying to decide whether to take medication now to prevent disease that may occur in 20 years is a daunting prospect. Most women base their decision on matters much closer to home. For example, a woman with a family history of breast cancer may resist taking hormones until she can no longer tolerate her severe menopausal symptoms. But after being on estrogen and progestin, she may become reconciled to the therapy as it eliminates her hot flashes, restoring her normal sleep patterns and improving her mood. She worries about cancer, but believes with her doctor that she can monitor her situation through monthly self-exams, an annual checkup and an annual mammogram. Given the uncertainty of the statistics on heart disease and cancer, another woman may choose to avoid hormone therapy altogether. Though the risk of heart disease is greater than that of breast cancer, many women tend to be more worried about breast cancer because of the disease's physical and emotional toll. A woman may reason that there are other ways to prevent heart disease but no known ways to prevent breast cancer, and so resolve to eat a low-fat diet and exercise regularly instead of taking hormones.

Every woman entering menopause should have a physical examination and then talk with her doctor about her overall health, her family history and her physical and psychological concerns. Working with your doctor to assess your risk factors accurately should help you determine whether the benefits of hormone replacement therapy outweigh the risks for you personally. If you are concerned about HRT, consider other effective nonmedical therapies for addressing your needs, and seek a second opinion before initiating a course of treatment.