hormone replacement therapy

More about Hormone Replacement Therapy: Purpose Precautions Preparation Aftercare Risks Normal results Resources

Definition

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.

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.

— Laith Farid Gulli, M.D.

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n. (Abbr. HRT)
The administration of estrogen and progestin to women to relieve the symptoms of menopause, prevent osteoporosis, and reduce the risk of heart disease.

Ovarian function starts to decline from as early as the twentieth week of embryological life, with oestrogen production falling to a critical level during a period known as the ‘climateric’.

De Gardanne (1816) coined the term ‘La Menespausie’ from the Greek men (month) and pausis (cessation). The menopause is normally diagnosed when a woman has not had a period for 12 months. Aristotle (384-22 bc) recognized that menstruation normally stopped around the age of 40 years but that some women could continue with their periods until their fiftieth year. In the seventeenth century less than a third of women lived to experience the menopause. However, the increase in life expectancy in the twentieth century has meant that most women will spend a third of their adult lives in the postmenopausal years.

The menopause, now occurring on average at 51 years in developed countries, is associated not only with a cessation of menstrual periods but also a wide range of symptomatic and physiological effects. These include hot flushes, night sweats, loss of energy, urogenital atrophy, osteoporosis, and ischaemic heart disease. A number of non-hormonal remedies have been used to treat menopausal problems, with varying degrees of success. Galen (ad 129-216) advised phlebotomy so that any ‘retained poisons’ could be released; the use of purgatives and the application of leeches was popular in the sixteenth century. In 1777 John Leake recommended

‘where the patient is delicate and subject to female weakness, night sweats or an habitual purging, with flushing in the face and a hectic fever: for such; ass's milk, jellies and raw eggs, with cooling fruits. At meals she may be indulged with half a pint of old, clear London porter, or a glass of Rhenish wine.’

Brown-Sequard (1889) is credited with pioneering the concept of hormone replacement therapy (HRT). He reported the rejuvenating effects of injections of testicular extracts, and postulated that ovarian extract would have the same effect. Two years later Murray developed the first effective form of HRT when he administered oral thyroid gland to treat myxoedema. The first three clinical trials of dried or fresh ovarian tissue to treat climateric symptoms were published in 1896, and in 1912 Adler produced the changes of oestrus by injecting watery extracts of ovary into virgin animals. However, it was not until 1923 that Allen and Doisy isolated the ovarian hormone oestrogen. The first commercial preparations of HRT were based on the work of Zondek and Laquer and became available in 1926. Premarin, derived from pregnant mares' urine, was introduced in 1943 and is probably still the most widely used preparation. The publication of Feminine Forever in 1966 brought HRT to the attention of the public, with many demanding that it should be a NHS benefit. General practitioners were initially divided, with some prescribing it enthusiastically and others being completely dismissive.

The three natural oestrogens in women are oestrone (E1), 17-beta-oestradiol (E2), and estriol (E3). Free oestrogens are lipophilic and freely transverse cell membranes, exerting their metabolic effect by binding to nuclear receptors. This stimulates the production of mRNA and hence protein production. E2, the most active oestrogen, because it binds to the receptor complex for the longest time, is found mainly before the menopause, as its serum concentration falls when ovarian follicular development ceases. E1 is the main postmenopausal oestrogen and is produced by conversion of adrenal androgens in peripheral fat. Oestrogens are conjugated in the liver and excreted in the urine or bile.

HRT can be administered orally, transvaginally, as an implant, or through the skin as a percutaneous cream, gel, or patch. There is clear evidence that it is effective in reducing the vasomotor symptoms of the menopause and enhances the quality of life. Skin, hair, and mood are also improved. Atrophy of the lower urogenital tract can be treated effectively with HRT, with many women finding a vaginal cream or oestrogen-releasing ring helpful. HRT is used for prophylaxis against a number of conditions as well as for treatment. The years immediately following the menopause are associated with an increase in bone loss, and by the age of 70 a woman may have lost 10-30% of her bone mass. HRT delays this period of accelerated loss: five years of treatment can halve the risk of osteoporotic fractures. This may be particularly important in thin women who smoke, take little exercise, and have a family history of osteoporosis, as they are particularly at risk of this problem. The increased risk of cardiovascular disease after the menopause is also reduced, presumably because of the favourable effect of oestrogens on lipids and blood flow in the coronary arteries.

The main side-effect of HRT is vaginal bleeding in those women who still have a uterus. Unopposed oestrogen therapy leads to an increased risk of endometrial carcinoma (cancer of the lining of the uterus), so progestogen therapy needs to be given for at least 12 days each month, inducing a regular withdrawal bleed. However, recently the use of Tibolone, a synthetic compound which combines oestrogenic and progestogenic activity with weak androgenic properties, and other continuous preparations have helped to overcome this problem. There is also a slightly increased incidence of breast carcinoma for those women who take HRT for more than 10 years, but the beneficial effects in terms of a reduction in deaths from osteoporotic fractures and heart disease far outweigh the potential risks. HRT can therefore be given indefinitely.

— Linda Cardozo

Bibliography

• Wilson R. A. (1966). Feminine forever. Mayflower-Dell, London

See also bone; menopause; osteoporosis; sex hormones.

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