Hormone Replacement Therapy
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.
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 perimenopausal 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.
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.
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 alone for problems with vaginal soreness.
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.
Hormone replacement therapy has been prescribed for two primary purposes: preventive treatment against osteoporosis and heart disease; and relief of physical symptoms associated with menopause.
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 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 has been shown to 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.
HRT has been recommended by some doctors to protect women against two serious midlife health problems, including osteoporosis and heart disease. While clinical trials have continued to demonstrate HRT's effectiveness in preventing osteoporosis, women must weigh the risk of the therapy with the benefits. The trials also showed that HRT actually increased rather than decreased risk of heart disease.
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
- 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. While doctors once believed that HRT helped decrease heart disease and stroke among postmenopausal women, a major clinical trial discovered the opposite to be true. In 2002, the Women's Health Initiative (WHI) stopped giving HRT to the women enrolled in the study because of adverse effects. Among these effects was a 29% increase in coronary heart disease and 41% increase in stroke in postmenopausal women taking HRT.
Other 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
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.
The findings of the WHI presented new problems for the women relying on hormones to ease their transition to menopause and postmenopausal years and for doctors prescribing HRT. The combination of estrogen and progesterone also was found to increase risk of invasive breast cancer by 26%, which was the reason researchers halted the study. In addition, while some clinicians have thought that HRT helped delay dementia (a disorder of the mind that affects memory and perception), the WHI also found that combined estrogen/progesterone increased the risk of probable dementia in women age 65 and older. Physicians and women were advised not to panic about HRT, however. Short-term use of the therapy may not produce these risks. Women have been advised to meet with their physicians and weigh the benefits against the risks on an individual basis.
Certain groups of women should not use HRT. They include women with:
- breast cancer
- cancer of the uterus
- heart disease
- 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
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 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.
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.
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. Information from the WHI released in 2002 and 2003 would indicate that long-term HRT use produced too many risks for the expected benefits.
UNWANTED SIDE EFFECTS. In addition to the identified health risks mentioned above, 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. which 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 also are 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, quit 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.
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 also should 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 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.
Dilation and curettage (D & C)— A surgical procedure in which the patient's cervix is widened (dilated) and the endometrium is scraped with a scoop-shaped instrument (curette).
Estrogen— The primary sex hormone that controls normal sexual development in females. During the menstrual cycle, estrogen helps prepare the body for possible pregnancy.
Follicle-stimulating hormone (FSH)— A hormone produced by the pituitary gland that stimulates the follicles in the ovaries to swell and release ripe ova. Doctors sometimes use its levels in a woman's blood to evaluate whether she is in menopause.
Hormone— A substance secreted by an endocrine gland that is carried by blood or other body fluids to its target tissues or organs.
Hot flash— A warm or hot sensation on the face, neck and upper body, sometimes accompanied by flushing and sweating. Some women refer to hot flashes as hot flushes.
Osteoporosis— A bone disorder in which the bones become brittle, porous, and easily broken. It is a major health concern for postmenopausal women.
Ovary— The female sex gland that produces eggs and female reproductive hormones.
Ovulation— The cyclical process of egg maturation and release from the ovary.
Progesterone— A female hormone produced by the ovary. It functions to prepare the lining of the uterus to receive a fertilized ovum.
Progesterone challenge test— A test that is given to see if a woman is still secreting estrogen. It consists of doses of progesterone given over a 10-day period.
Progestin— Synthetic progesterone available as an oral medication.
Testosterone— A male sex hormone that is sometimes given as part of HRT to women whose ovaries have been removed. Testosterone helps with problems of sexual desire.
Uterus— The hollow organ in women in which fertilized eggs develop during pregnancy. The uterus is sometimes called the womb.
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.
Long-term risks should be discussed with a woman's physicians before considering hormone replacement therapy. Identified risks for combined (estrogen plus progestin) HRT use include increased incidence of invasive breast cancer, stroke, heart disease, and pulmonary embolism.
Normal results of HRT include relief of hot flashes, night sweats, vaginal dryness, and urinary symptoms associated with menopause.
Goldman, Lee, et al, editors. Cecil Textbook of Medicine. 21st ed. W. B. Saunders, 2000.
Goroll, Alan H. Primary Care Medicine. 4th ed. Lippincott Williams & Wilkins, 2000.
Doering, Paul L. "Treatment of Menopause Post-WHI: What Now?" Drug Topics April 21, 2003: 85.
Elliott, William T. "HRT, Estrogen, and Postmenopausal Women: Year-old WHI Study Continues to Raise Questions." Critical Care Alert July 2003: 1.
Menopausal Hormone Replacement Therapy. Fact sheet. National Cancer Institute. 〈http://rex.nci.nih.gov〉.
"Hormone Replacement Therapy." Gale Encyclopedia of Medicine, 3rd ed.. . Encyclopedia.com. (June 25, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/hormone-replacement-therapy-0
"Hormone Replacement Therapy." Gale Encyclopedia of Medicine, 3rd ed.. . Retrieved June 25, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/hormone-replacement-therapy-0
hormone replacement therapy
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.
Wilson R. A. (1966). Feminine forever. Mayflower-Dell, London.
See also bone; menopause; osteoporosis; sex hormones.
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