Hormone replacement therapy - Continuing Education - Chain Pharmacy supplement

The use of hormone replacement following menopause is one of the most controversial topics in women's health today. The issues include determining which women should take replacement, deciding when therapy should be initiated and how long it should be continued, evaluating which products are best and what the possible risks of use might be.

Estrogen replacement therapy is known to be beneficial for reducing symptoms of estrogen deficiency, such as hot flushes and urogenital atrophy, and also for preventing osteoporosis and cardiovascular disease. Unopposed estrogen use, however, greatly increases the risk of endometrial hyperplasia, a precursor to malignancy. There is also some evidence that breast cancer may be increased in women who take estrogen replacement for many years.

Menopause may be strictly defined as permanent cessation of menstruation due to loss of ovarian function; thus, it is the last menstrual period. The climacteric is the transition period from reproductive capability to a woman's post-menopausal years. During the climacteric, ovarian function is declining and most women report erratic menstrual periods. In some women, loss of ovarian function is manifested by periods that gradually decrease in frequency and length and eventually disappear; in other women, periods become closer together, longer and heavier.

Perimenopause is the time (i.e., the few months to years) before menopause. The average age of women in the United States for the beginning of the perimenopausal stage is 47.5. The average age of menopause in the same population is about 51 years; therefore, the climacteric lasts about four years. About 95 percent of American women will have reached menopause by age 55. A woman is considered to be post-menopausal after six to 12 months of amenorrhea (lack of menstrual bleeding due to natural menopause) or has her ovaries removed (surgical menopause).

Although the age at menarche (first menstrual period) has decreased in the past century, the average age at menopause has remained constant. In 1900, the average life expectancy for a woman was 48; therefore, women did not Eve to experience menopause and the problems resulting from estrogen deficiency. Hormonal replacement is a relatively recent concern because most women alive today can expect to live to about age 80. Thus, if menopause occurs at age 51, a third of a woman's life will be post-menopausal.

Many psychological and behavioral changes and alterations observed in middle-age women are attributed to menopause. Most of these changes are negative, and more likely result from lifestyle and social changes rather than from hormonal decline. Events that often occur at middle-age, the time of the climacteric, include personal retirement or that of a spouse, death of a spouse or friends, onset of illness, care of aging parents and freedom from dependent children. Hormonal changes may also impact a woman's life; however, they are more likely to be a compounding factor rather than a sole cause of negative behavior, attitude or feelings. Women who remain happy and healthy through the climacteric are less likely to consult a healthcare professional, and this fact may erroneously skew the perception that all women have a difficult time during this transition.

Pathophysiology and clinical manifestations of estrogen deficiency

Physically, declining estrogen levels can be detrimental to the aging woman. The four most significant physical problems resulting from estrogen deprivation are genitourinary atrophy, vasomotor instability, osteoporosis and cardiovascular disease. Some women are fortunate and do not experience any of the physical symptoms of estrogen deficiency, such as hot flushes or vaginal dryness, or have very mild symptoms. However, long-term problems associated with estrogen deficiency, such as osteoporosis and cardiovascular disease, may not produce symptoms until the disease is well established.

Genitourinary atrophy occurs with the decline of circulating estrogens. All mucosal surfaces in the reproductive and urinary system may develop atrophy due to a lack of estrogen support. Genitourinary atrophy may lead to vaginal problems including vaginitis, pruritus and vaginal dryness, contributing to painful or difficult intercourse.

In the urinary tract, estrogen deficiency may cause stenosis and urethritis producing such symptoms as dysuria, frequency and urge incontinence. The most common type of incontinence in post-menopausal women is stress incontinence, and it is not usually improved by estrogen replacement.

Vasomotor instability is most commonly manifested as the hot flush. While the hot flush, or hot flash as it is referred to by many women, is truly uncomfortable, embarrassing and capable of altering the quality of a woman's life, it is not harmful to her health. Physiologically, hot flushes have been associated with luteinizing hormone surges which are common during the transition to menopause.

The hot flush often begins with an aura, followed by reddening of the skin of the head and neck. To an observer, the coloration seems to creep up from the shoulders to the neck and face. The woman may have a feeling of intense heat, and serial recordings indicate an increase of core temperature during hot flushes. Profuse perspiration may conclude the attack.

About 85 percent of women will have hot flushes at some time during the phase of climacteric. The flushes vary in frequency from a rare event to occurring every 10 minutes; in some women they last a few seconds, in others several minutes to several hours.

Hot flushes may continue for two to five years. Some women notice that the hot flushes are more severe and occur more frequently at night. The fatigue reported by some women may be traced to the nocturnal hot flushes that are interrupting sleep. Some women perspire so heavily during nighttime hot flushes that they must change bed sheets and their nightclothes.

For couples sharing a bed, this may also contribute to fatigue and irritability of both partners. For other women, hot flushes are a minor inconvenience and do not interfere with normal activities. These women typically do not seek medical care, and may not appreciate the necessity of estrogen replacement therapy for prevention of cardiovascular disease or osteoporosis.

A decline in estrogen levels causes an alteration in bone structure, which in turn causes bone fragility, resulting in osteoporosis. Women who do not receive hormone replacement following menopause will usually lose 1 percent to 2 percent of their bone mass annually. About 50 percent of this bone loss occurs during the first five to seven years after menopause. Seventy-five percent of the bone loss in the first 20 years after menopause is therefore attributable to estrogen deficiency, rather than aging. Risk factors for osteoporosis other than estrogen deficiency include Caucasian or Oriental race, thin or petite body habitus, positive family history, alcohol abuse, tobacco use, sedentary lifestyle and low dietary calcium intake.

Osteoporosis is a major health concern in the United States, especially because of the large number of women who will develop the disease and the tremendous cost associated with treating fractures resulting from the disease. About 250,000 women sustain hip fractures each year in this country; one-sixth of these women will die from complications of the surgery within three months. Fifty percent of those who return home will require assistance with daily activities. Osteoporosis and its complications can be very costly in terms of finances and quality of life.

Men may also develop osteoporosis, however it usually occurs later in life, and due to their shorter life expectancy the condition does not pose a health problem of the same magnitude as in women.

Studies show that 30 minutes of weight-bearing exercise at least three times a week is helpful in minimizing the development of osteoporosis. Also helpful is an intake of 1500mg of elemental calcium a day. Most women probably get about 500mg of calcium in their diet; therefore, they would need only 1000mg of supplemental calcium each day.

The addition of vitamin D is probably not necessary for most women. Active women, particularly those who live in geographic areas where there is sunlight all year, get enough exposure to sunlight to maintain vitamin D at an acceptable level. Women who are homebound, institutionalized or live in areas where it stays cloudy during the winter months, may need 400-800 IU of supplemental vitamin D daily.

All women, including those women who cannot take estrogen or those who choose not to do so, as well as women taking estrogen, should get adequate calcium intake. However, only by taking estrogen are post-menopausal women adequately protected from osteoporosis. For the greatest effect in minimizing fractures, a combination of hormone replacement, supplemental calcium and regular exercise is necessary.

The beneficial effect of estrogen on bone metabolism is only evident while the patient is maintained on the medication and perhaps for a few years following discontinuation. A common suggestion from physicians is to tell women that they should take replacement until age 80, then they will re-assess whether it should be continued. Women who are at high risk for developing osteoporosis should probably be continued on replacement indefinitely, unless they are also at high risk of developing breast cancer. For a woman at high risk for breast cancer, osteoporosis and/or cardiovascular disease the risks and benefits of estrogen should be carefully weighed by both physician and patient.

The cardiovascular effects of estrogen deprivation can be easily appreciated when we look at the numbers of cardiac deaths in men and women.

Prior to menopause, women are much less likely than men to develop coronary heart disease, but following menopause, women quickly close the gap. The No. I cause of death in older women in the United States is heart disease.

About 30 percent of menopausal women not taking estrogen replacement die from heart disease, 3 percent from breast cancer, 3 percent from complications of hip fracture and less than 1 percent from endometrial cancer.

Estrogen protects women of reproductive age against coronary heart disease. Estrogens increase HDL, the good cholesterol, but decrease LDL, the bad cholesterol, and total cholesterol. Following menopause, levels of total cholesterol and LDL rise, while HDL decreases. The pharmacological effect of estrogen on lipids is responsible for a dramatic effect on the development cardiovascular disease. There is now some evidence that estrogen may also have a direct effect on arterial vessels.

Most of the decrease in cardiovascular disease may be explained by the positive influence of estrogen on lipids. However, there is also evidence that estrogen decreases development of atherosclerosis by an action independent of decreasing circulating lipids. The mechanism for this direct effect on arterial walls is unknown, but it may be due to vasodilation or decreased platelet aggregation or a combination of these actions.

The use of estrogen after menopause decreases the risk of death from cardiovascular disease by 50 percent in current users. This beneficial effect seems to continue for up to 10 years after estrogen is discontinued.

Other symptoms of the menopausal or perimenopausal patient include skin changes, emotional instability and a general decrease in the quality of life. Although evidence that estrogen replacement is beneficial in alleviating these complaints is lacking, women who take estrogen seem to feel better, look better and have a more positive outlook.

Patient evaluation

Patients should be evaluated carefully before beginning hormone replacement therapy to rule out any possible contraindications. This evaluation should include a detailed history, basic physical examination (including weight and blood pressure), pelvic examination with PAP smear, and a breast examination that includes mammography.

Many physicians also require that an endometrial biopsy be obtained from women with an intact uterus to verify that the patient does not have endometrial hyperplasia or other abnormalities before beginning HRT.

A mammogram is necessary to ensure that the patient does not have undiagnosed breast cancer which could be worsened by estrogen. Annual mammograms are recommended for all women over age 50 by both the American College of Obstetricians and Gynecologists and the American Cancer Society. This recommendation is made regardless of whether or not the patient is taking HRT.

The history should begin with the date of the last menstrual period or surgical menopause. (Remember, the term hysterectomy only denotes removal of the uterus; surgical menopause occurs only with removal of the ovaries which produce estrogen.)

Patients with a personal or family history of breast cancer should carefully evaluate the risks and benefits of estrogen replacement. Cardiovascular history is also very important; particularly in view of new data suggesting the breast cancer risk may be greater than previously believed. A patient with a great risk of cardiovascular disease or who already has cardiac problems may decide that the benefit of estrogen replacement on decreasing heart disease outweighs the possible increased risk of breast cancer.

Pregnancy must also be ruled out before initiating therapy, due to teratogenic potential of these medications. This is probably a consideration only in younger women experiencing premature menopause.

Undiagnosed vaginal bleeding is also a contraindication to the use of hormone replacement because, particularly in older women, this may be a sign of cancer.

A past history of thromboembolic disorders is not necessarily a contraindication to the use of estrogens for replacement because the dose of estrogen used is much less than that found in oral contraceptives. Women who have active thromboembolic disease or a history of thromboembolism associated with estrogen (either oral contraceptives or pregnancy) should not take estrogen. Patients with controlled hypertension may receive estrogen and it may, in fact, aid in the control of their blood pressure.

Gallbladder disease is increased with the use of estrogen and patients with this disorder may experience an exacerbation of symptoms. Because gallbladder disease is easily treated, especially now that most cholecystectomies are done with laparoscopy and lasers, and is rarely life-threatening, this is not usually a contraindication.

Hormone replacement

The benefits of estrogen replacement include prevention and reversal of atrophic changes in the genitourinary tract, alleviation of vasomotor symptoms (hot flashes), prevention of cardiovascular disease, and prevention of osteoporosis. The risks of estrogen replacement include an increase in the incidence of endometrial hyperplasia and perhaps an increase in the risk of breast cancer in some women.

There are several forms of estrogen available in the United States. None of the estrogens currently has FDA-approved indication for the prevention of cardiovascular disease but several, including oral conjugated estrogens and transdermal estradiol, have FDA indications for prevention of osteoporosis. Conjugated estrogens are perhaps the most commonly used; however, esterified estrogens, micronized estradiol and estropipate are also used for estrogen replacement.

No evidence is available that one particular form of estrogen is any better than another for replacement. The vast majority of clinical trials indicating that estrogen replacement prevents osteoporosis and cardiovascular disease have used conjugated estrogens, and this has made them the standard.

The minimum dose of conjugated estrogens necessary to prevent osteoporosis is 0.625mg. Any oral or transdermal estrogen may be used as long as it is equivalent to 0.625mg of conjugated estrogens. A larger dose may be used to alleviate symptoms if necessary, but the dose should be decreased back to 0.625mg for long-term maintenance. A lower dose may be given to women who cannot tolerate 0.625mg, but less protective benefits may be expected.

Women who lose ovarian function at younger ages through oophorectomy or premature menopause often require larger doses of replacement hormone to control symptoms. At the expected age of menopause, the dose should be decreased to usual replacement doses.

Some women experience greater improvement of symptoms with different forms of estrogen. If the patient is not satisfied with the effect of the first product prescribed, a different form may be tried in an equivalent dose. The specific product is not as important as the fact that the patient receives and continues replacement with estrogen.

For the prevention of cardiovascular disease, there is some difference of opinion as to whether transdermal estrogen is as beneficial as the oral dosage forms. This controversy arises from the fact that transdermal estrogen avoids the first-pass through the liver. It is believed that the reason that estrogen decreases cardiovascular disease results from its effect on lipids which occurs in the liver. New evidence does not support this theory.

Estrogens are well absorbed from the vagina, but do not achieve serum levels high enough to maintain protection from osteoporosis or cardiovascular disease or to alleviate hot flushes in most women. The most appropriate use of vaginal estrogen products is to treat atrophic symptoms. Twice-weekly administration of vaginal estrogen will usually alleviate symptoms such as vaginal dryness, dyspareunia and pruritus in women who have contraindications to a regular regimen of oral estrogen. Vaginal estrogen may also be useful in patients who have severe vaginal symptoms until oral estrogens re-estrogenize the vaginal tissues and reverse the atrophy.

Women usually see improvement in vasomotor symptoms after a few days of oral therapy but reversal of atrophic changes in the genitourinary tract usually takes two to three weeks after oral replacement is initiated.

The addition of a progestogen to estrogen replacement therapy in women with an intact uterus is essential to prevent the development of endometrial hyperplasia which is a precursor to malignancy. Also, because the risk of endometrial cancer increases six-fold with unopposed estrogen, progestogens must be given to all women with an intact uterus. There is no data available to suggest that a progestogen should be given to patients who have undergone a hysterectomy. It is also important to note that women who have an intact uterus and are receiving estrogen by any route of administration must take oral progestogens. This is often overlooked in women using the transdermal estrogen product.

There are two disadvantages to the addition of a progestogen to estrogen replacement; neither of which is a valid reason for omitting it.

The first is that progestogens may decrease the positive cardiovascular benefit derived from estrogen therapy. Progestogens have a negative effect on lipids and this may negate some of the cardioprotective effect This effect is probably small in comparison to the benefit of estrogens.

The second disadvantage has an impact on compliance rather than a direct decrease in the benefit of the estrogen. However, if women do not take the hormones, there is no benefit. The addition of progestogen to estrogen replacement causes withdrawal bleeding in many women. This bleeding is unacceptable to many patients although it is usually just inconvenient and rarely associated with PMS or dysmenorrhea. Such bleeding is more likely in women who have recently become menopausal and in those who take progestogens cyclically rather than continuously.

Progestogens, norgestrel, norethindrone acetate and medroxyprogesterone acetate have all been used to oppose estrogen during replacement therapy. MPA is preferred because it is a more pure progestogen; norgestrel and norethindrone are 19-nortestosterone derivatives and are more androgenic. The more androgenic compounds usually have a greater negative effect on lipids and, therefore, are used less often. In the United States., the dosages of norgestrel and norethindrone are only available as the progestin-only oral contraceptives; however, these compounds have been used in Europe and are effective for preventing endometrial hyperplasia. It has been suggested that the negative progestogenic effect on lipids may be time-related, and may lessen after months or years of use.

MPA must be given in doses of 10mg daily for at least 10 days per cycle to prevent endometrial hyperplasia. Keeping the dose below 130mg per month minimizes the negative effect on lipids. The most recent recommendation is to give 2.5mg daily continuously primarily to minimize bleeding and increase compliance. Studies document that this regimen also prevents endometrial hyperplasia.

Perimenopausal women who have begun to experience symptoms, and have erratic periods, may be prescribed low-dose combination oral contraceptives. This practice has several benefits. It will alleviate the symptoms and regulate bleeding patterns in most women. Also, although fertility decreases greatly as menopause approaches, pregnancy is still a possibility with irregular ovulation, and these products provide contraception. Once the patient reaches her early 50s, she should be changed to the usual replacement regimen because the doses are much smaller than those found in oral contraceptives.

There are several regimens that are used by physicians when prescribing hormone replacement. Of course, women without a uterus may be given only daily, oral unopposed estrogen or twice weekly transdermal estrogen.

All oral regimens include the same dose of estrogen: 0.625mg conjugated estrogens or its equivalent. There are two common variations of the cyclic regimen. In the first, estrogen is given on calendar days 1-25 of each month and 10mg of MPA on calendar days 16-25. A slight variation of this regimen is estrogen daily and MPA 10mg, 10 to 14 days per month, usually on calendar days 1-10 for ease of recall. This method was initiated because there is no physiologic reason to discontinue the estrogen for a week and many patients experienced symptoms during the last week of the month. The most recent method is the continuous regimen. In this case, estrogen is taken daily with 2.5mg of MPA.

Two new products, Prempro(R) and Premphase(R), have simplified these regimens. Prempro(R) contains 0.625mg of conjugated estrogens and 2.5mg of medroxyprogesterone acetate in each tablet and is supplied on cards labeled with days 1-28. Premphase(R) contains two cards of 14 tablets each. The first 14 tablets contain only 0.625mg of conjugated estrogens and the tablets for days 15-28 contain 0.625mg conjugated estrogens and 2.5mg of medroxyprogesterone acetate.

Women taking unopposed estrogen rarely report significant side effects. The addition of a progestogen may produce breast tenderness, bloating, fluid retention and depression. These side effects, combined with withdrawal or breakthrough bleeding, may greatly reduce patient compliance.

Women who take either cyclic regimen should expect withdrawal bleeding two to three days following the last MPA tablet (just as with oral contraceptives). This bleeding should occur on the same days each month, and the patient should report any bleeding at any other time during the month to her physician. Bleeding not associated with withdrawal from the progestogen may be suggestive of a malignancy, and should be evaluated.

Withdrawal bleeding tends to decrease with an increase in years since menopause. Most women usually achieve amenorrhea after some years of use. The advantage to the continuous regimen is an eventual cessation of bleeding. Fortunately, 80 percent of women who continue this regimen for one year will achieve amenorrhea. The disadvantage is unpredictable breakthrough bleeding in 50 percent of patients during the first six months of use.

A patient with a history of severe dysmenorrhea may experience some menstrual cramps with the vaginal bleeding, but it is rarely as severe as during menstruation. Unless contraindicated, these women usually respond satisfactorily to over-the-counter non-steroidal anti-inflammatory medications. Premenstrual syndrome is not likely to be a problem with estrogen and progestogen replacement therapy.

The duration of therapy is another consideration. Until the recent information that may indicate an increase in the risk of breast cancer after many years of estrogen replacement, it was recommended that women continue estrogen replacement for the rest of their lives. This may or may not continue to be recommended. The duration of therapy would also depend on other factors such as the patient's risk of cardiovascular disease, osteoporosis and breast cancer.

Another common question concerns the initiation of estrogen replacement in women who are many years past menopause. There is no doubt that the greatest impact, particularly on the prevention of osteoporosis, is in the early post-menopausal patient. However, benefits, such as the prevention of any further decrease in bone loss or cardiovascular disease, are also seen in elderly women. It has been speculated that estrogen replacement is not continued in older women who are primarily cared for by internal medicine or family practice physicians because these practitioners prefer not to monitor estrogen therapy with pelvic exams (which can be difficult to perform in elderly women), breast exams and mammograms.

Pharmacists also have a responsibility to monitor patient therapy by inquiring about side effects and concerns, as well as by verifying physician monitoring by requiring that the patient get a new prescription at least annually. With an increase in medical liability, the latter suggestion is strongly recommended, if it is not required by state law. Pharmacists should also remember that patient package inserts are required to be dispensed with all estrogen and progestogen products, and this includes those used for hormone replacement therapy.

Summary

It has been estimated that less than 20 percent of post-menopausal American women take estrogen replacement. Of those women who refuse treatment or discontinue treatment, fear of cancer and the inconvenience of vaginal bleeding are the reasons given most often. Pharmacists can make an important contribution to women's health and indirectly, public health, by helping to educate women about the benefits of hormone replacement and the minimal risk of endometrial hyperplasia when progestogen is taken with the estrogen.

Women also need to be aware that estrogen replacement is available and that the transition to the post-menopausal years and later life can be a pleasant time. They should also realize that the use of estrogen can help to prevent more serious health problems in later life. Pharmacists should recognize that women may not understand the potential risks and benefits of these medications and should take the time to discuss these concerns with their patients.

Table I
Relative estrogenic doses

Conjugated estrogens    0.625mg-1.25mg
Micronized estradiol                 1mg
Estradiol transdermal     0.05mg-0.1mg
Estropipate                       0.75mg
Esterified estrogen              0.625mg

Table II
Relative progestogenic doses

Medroxyprogesterone
  acetate             10mg 10-14 days a month
                               or 2.5mg daily
Norethindrone                     .35mg daily
Norgestrel                       .075mg daily

Table III
Calcium supplements

Elemental calcium
Calcium gluconate (9% calcium) 1g tablet    90mg calcium
Calcium citrate (21% calcium)               0.05mg-0.1mg
Citracel 950mg tablet                      200mg calcium
Calcium carbonate                            40% calcium
Os Cal 500 1.25g tablet                    500mg calcium
Caltrate 600 1.5g tablet                   600mg calcium
Tums 500mg tablet                          200mg calcium
Tums EX 750mg tablet                       300mg calcium

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