Hormone Replacement Therapy

Hormone replacement therapy (HRT) is the use of synthetic or natural female hormones to make up for the decline or lack of natural hormones produced in a woman's body. HRT is sometimes referred to as estrogen replacement therapy (ERT), because the first medications that were used in the 1960s for female hormone replacement were estrogen compounds.

Estrogens

In order to understand how HRT works and the controversies surrounding it, women should know that there are different types of estrogen medications commonly prescribed in the United States and Europe. These drugs are given in a variety of prescription strengths and methods of administration. There are at present three estrogen compounds used in Western countries. Only the first two are readily available in the United States.

• Estrone. Estrone is the form of estrogen present in women after menopause. It is available as tablets under the brand name Ogen. The most commonly prescribed estrogen in the United States, Premarin, is a so-called conjugated estrogen that is a mixture of estrone and other estrogens.
• Estradiol. This is the form of estrogen naturally present in premenopausal women. It is available as tablets (Estrace), skin patches (Estraderm), or vaginal creams (Estrace).
• Estriol. Estriol is a weaker form of estrogen produced by the breakdown of other forms of estrogen in the body. This is the form of estrogen most commonly given in Europe, under the brand name Estriol. It is the only form that is thought not to cause cancer.

In addition to pills taken by mouth, skin patches, and vaginal creams, estrogen preparations can be given by injection or by pellets implanted under the skin. Estrogen implants, however, are used less and less frequently.

Progestins

Most HRT programs include progestin treatment with estrogen compounds. Progestins—sometimes called progestogens—are synthetic forms of progesterone that are given to reduce the possibility that estrogen by itself will cause cancer of the uterus. Progestins are commonly prescribed under the brand names Provera and Depo-Provera. Other common brand names are Norlutate, Norlutin, and Aygestin.

Estrogen/testosterone combinations

Women's ovaries secrete small amounts of a male sex hormone (testosterone) throughout their lives. Women who have had both ovaries removed by surgery are sometimes given testosterone along with estrogen as part of HRT. Combinations of these hormones are available as tablets under the brand name Estratest or as vaginal creams. Women who cannot take estrogens can use 1% testosterone cream by itself for problems with vaginal soreness.

Estrogen/tranquilizer combinations

There are several medications that combine estrogen with a tranquilizer like chlordiazepoxide (sold under the trade name Menrium) or meprobamate (sold under the trade name PMB). Many doctors warn against these combination drugs because the tranquilizers can be habit-forming.

Purpose

HRT has two primary purposes: preventive treatment against osteoporosis and heart disease; and relief of physical symptoms associated with menopause.

Menopausal symptoms

Women in midlife enter a stage of development called menopause, when their menstrual periods become irregular and finally stop. The early phase of this transition is called the perimenopause. In the United States, the average age at menopause is presently 50 or 51, but some women begin menopause as early as 40 and others as late as 55. It can take as long as 10 years for a woman to complete the process. Women who have had their ovaries removed surgically are said to have undergone surgical menopause.

Doctors have not always agreed on definitions of the menopause. Some use age as the baseline. Others define menopause as the point when a woman has had no menstrual periods for a full calendar year. Still others define menopause as the end of ovulation. It is not always clear, however, when a woman has had her last period or when she has stopped ovulating. In addition, women who take oral contraceptives can have breakthrough bleeding long after they have stopped ovulating. As a result, some doctors now measure the level of follicle-stimulating hormone (FSH) in a woman's blood to estimate whether the woman has entered menopause. During perimenopause, the FSH levels in a woman's blood rise as her body attempts to stimulate the release of ripe ova. An FSH level over 40 is considered an indicator of menopause.

During the menopausal transition, the levels of estrogen in the woman's body drop. The lowered estrogen level is responsible for a group of symptoms that include hot flashes (or flushes), weight gain, changes in skin texture, mood swings, heart palpitations, sleep disturbances, a need to urinate more frequently, and loss of sexual desire. The estrogen that is given in HRT can eliminate hot flashes, night sweats, lack of vaginal lubrication, and urinary tract problems. HRT will not prevent weight gain or wrinkles. It also does not cure depression in most women.

Preventive care

HRT is recommended by many doctors on the grounds that estrogen replacement helps to protect women against two serious midlife health problems.

OSTEOPOROSIS. Osteoporosis is a disorder in which the bones become more brittle and more easily fractured. It is a particular problem for postmenopausal women because the lower levels of estrogen in the blood lead to weakening of the bone. About 25% of Caucasian women will develop severe osteoporosis; Asian women have a slightly lower risk level; Latino and African American women are least at risk.

In addition to race, there are other factors that put some women at higher risk of developing osteoporosis. Women in any of the following groups should take bone loss into account when considering HRT:

• family history of osteoporosis
• menopause before age 40
• kidney disease and dialysis
• thin body build or being underweight
• history of colitis, Crohn's disease, or chronic diarrhea
• thyroid medications
• childlessness
• chronic use of antacids
• lack of exercise
• poor food choices, including high salt intake, lack of vitamin D, high caffeine consumption, and low calcium intake
• smoking and alcohol abuse
• cortisone therapy

HEART DISEASE. Heart disease is a major health concern of women in midlife. It is the leading cause of death in women over 60. The primary disorders of the circulatory system in postmenopausal women are stroke, hypertension, and coronary artery disease. Current studies of women on HRT do not yield a completely clear picture. In particular, although estrogen given without progestins has been shown to offer some protection against heart disease, the effect of progestins in offsetting the benefits of estrogen complicates the research findings. It seems likely that estrogen levels are only part of the picture in evaluating a woman's risk of heart disease.

The major factors that are known to increase the risk of heart disease include:

• history of smoking
• being overweight
• high-fat diets
• alcohol abuse
• family history of heart disease
• high blood pressure
• high blood cholesterol levels
• diabetes.

Less important risk factors include being African American, having a sedentary lifestyle, undergoing menopause before age 45, and having high levels of family- or job-related stress.

Precautions

Medical conditions

Certain groups of women should not use HRT. They include women with:

• breast cancer
• cancer of the uterus
• abnormal vaginal bleeding that has not been diagnosed
• high blood pressure that rises when HRT is used
• liver disease
• gallstones or diseases of the gallbladder

Drug interactions

HRT can interact with other prescription medications that a woman may be taking. Women who are taking corticosteroids, drugs to slow the clotting of blood (anticoagulants), and rifampin should ask their doctor about possible interactions.

Combining estrogens with certain other medicines can cause liver damage. Among the drugs that may cause liver damage when taken with estrogens are:

• acetaminophen (Tylenol), when used in high doses over long periods
• anabolic steroids such as nandrolone (Anabolin) or oxymetholone (Anadrol)
• medicine for infections
• antiseizure medicines such as divalproex (Depakote), valproic acid (Depakene), or phenytoin (Dilantin)
• antianxiety drugs, including chlorpromazine (Thorazine), prochlorperazine (Compazine), and thioridazine (Mellaril).

In addition, estrogens may interfere with the effects of bromocriptine (Parlodel), used to treat Parkinson's

Estrogen replacement patches adhere to a patient's skin and slowly administer estrogen to the body. (Illustration by Argosy Inc.)

disease and other conditions; they may also increase the chance of toxic side effects when taken with cyclosporine (Sandimmune), a drug that helps prevent organ transplant rejection.

Description

HRT medications come in several different forms, including tablets, stick-on patches, injections, and creams that are worn inside the vagina. The form prescribed depends on the purpose of the hormone replacement therapy. Women who want relief from vaginal dryness, for example, would be given a cream or vaginal ring. Women using HRT to relieve hot flashes or to prevent osteoporosis and heart disease often prefer oral medications or patches. All HRT medications used in the United States are available only with a doctor's prescription.

HRT treatment regimens

One of the complications of HRT is the number of treatment options, including combinations of types of estrogen; dosage levels; forms of administration; and whether or not progestins are used with the estrogen to offset the risk of uterine cancer. This variety, however, means that a woman who wants to use HRT while minimizing side effects can try different forms of medication or dosage schedules when she consults her doctor. It is vital, however, for women to follow their doctor's directions exactly and not change dosages themselves.

At present, women who are taking a combination of estrogens and progestins are placed on one of three dosage schedules:

• Estrogen pills taken daily from the first through the 25th day of each month, with a progestin pill taken daily during the last 10–14 days of the cycle. Both drugs are then stopped for the next five to six days to allow the uterus to shed its lining.
• Estrogen pills taken on a daily basis with low-dose progestin pills, also on a daily basis. Both medications are taken continuously with no days off.
• Estrogen pills and low-dose progestins taken on a daily basis for five days each week, with both medications stopped on the last two days of each week.

Controversies over HRT

It is important to know that there is still considerable disagreement over the advantages and disadvantages of HRT. Further research is ongoing and intensive concerning the benefits and/or risks.

INCREASED RISK OF BREAST CANCER. The most important controversy over HRT is whether it increases a woman's risk of developing breast cancer. Some studies not only indicate a connection, but suggest that the risk of breast cancer rises with the length of time that a woman has been taking HRT. According to an American study published in June 1998, the risk of breast cancer increases by 2.3% for each year that a woman takes HRT. A Swedish study found that the risk of breast cancer doubled after six years of HRT, which agrees with American findings that risk is connected to length of treatment.

TIMING AND LENGTH OF TREATMENT. One of the disagreements about HRT concerns the best time to begin using it. Some doctors think that women should begin using HRT while they are still in perimenopause. Others think that there is no harm in a woman's waiting to decide. Either way, the question of timing means that a woman should keep track of changes in her periods and other signs of perimenopause so that her doctor can evaluate her readiness for HRT.

The other question of timing concerns length of treatment. Some women use HRT only as long as they need it to relieve the symptoms of menopause. Others regard it as a lifetime commitment because of concerns about osteoporosis. One study found that the average length of time that women stay on HRT is 23 months.

UNWANTED SIDE EFFECTS. Much of the disagreement about unwanted side effects from HRT concerns the role of progestins in the estrogen/progestin combinations that are commonly prescribed. Many women who find that estrogen relieves hot flashes and other symptoms of menopause have the opposite experience with progestin. Progestin frequently causes moodiness, depression, sore breasts, weight gain, and severe headaches.

Other treatment approaches

Women who are uncertain about HRT, or who should not take estrogens, should know about other treatment options, such as natural progesterone. Progestins, which are synthetic hormones, were developed because natural progesterone cannot be absorbed in the body when taken in pill form. A new technique called micronization has made it possible for women to take natural progesterone by mouth. Many women prefer this form of hormone because it lacks the side effects of the synthetic progestins even though it is somewhat more expensive. The most common form of natural progesterone is called Prometrium and it is available by prescription only. Another form of natural progesterone consists of the hormone suspended in vitamin E oil. It is absorbed through the skin and is available without a prescription.

Alternative therapies are also available. Many mainstream as well as alternative practitioners recommend changes in diet and nutrition as helpful during menopause. Women who limit their intake of fats and salts, increase their use of fresh fruits and vegetables, cut out smoking, and drink only in moderation often find that these dietary changes help them feel better. Naturopaths typically recommend vitamin and mineral supplements for general well-being as well as for relief from hot flashes and leg cramps. In addition, herbal teas and tonics are helpful to some women in treating water retention, insomnia, constipation, or moodiness.

Women who find menopause emotionally stressful because of negative social attitudes toward older women are often helped by meditation, biofeedback, therapeutic massage, and other relaxation techniques. Yoga and tai chi provide physical exercise as well as stress reduction. Exercise is an important safeguard against osteoporosis.

Preparation

Women who are considering HRT should visit their doctor for a series of tests to make sure that they do not have any serious health disorders. They should have a Pap smear and breast examination to rule out cancer. They should also have a urinalysis,a bone density test, and blood tests to measure their red blood cell level, blood sugar level, cholesterol level, and liver and thyroid function.

In addition to these tests, most doctors will also give a progesterone challenge test. It consists of doses of progesterone given over a 10-day period to see if the woman is still producing her own estrogen. If she bleeds at the end of the test, she is still producing estrogen.

Aftercare

Aftercare is a very important part of HRT. Women who are taking HRT will need to see their doctor more frequently. At a minimum, they should be checked twice a year with a blood pressure test and breast examination. They should have a complete physical on a yearly basis. Any abnormal bleeding must be reported to the doctor as soon as it occurs. The doctor will need to order a tissue biopsy or dilation and curettage (D & C) in order to rule out cancer of the uterus.

Women who are taking HRT and decide to stop should taper their dosage over a period of several months rather than discontinuing abruptly. A gradual reduction minimizes the possibility of hot flashes and other side effects.

Risks

The short-term risks associated with HRT include a range of physical side effects. Common side effects include fluid retention, bloating, weight gain, sore breasts, leg cramps, vaginal discharges, migraine headaches, hair loss, nausea and vomiting, acne, depression, shortness of breath, and dizziness. Potentially serious side effects include tissue growths in the uterus (fibroids), gallstones, thrombophlebitis, hypoglycemia, abnormal growth (hyperplasia) of uterine tissue, thyroid disorders, high blood pressure, and cancer.

Normal results

Normal results of HRT include relief of hot flashes, night sweats, vaginal dryness, and urinary symptoms associated with menopause.