M ore than 40 million American women are postmenopausal, and an additional 30 million are expected to reach menopause during the next decade. l It has been estimated that 1 of 4 women in the United States who reaches menopause does so as a result of surgical removal of the ovaries.2 Menopause, defined as the permanent cessation of menstruation resulting from loss of cyclic ovarian function, occurs spontaneously at a mean age of about 5 1 ?4 Because current life expectancy exceeds 80 years, American women at age 50 can expect to live - and must prepare for - another 30 years after menopause.1,5
As ovarian function wanes, total daily estrogen production falls gradually to a small fraction of premenopausal levels.1 Following surgical removal of the ovaries, however, a premenopausal woman may be plunged into an abrupt and severe menopause as estrogen drops to 60% of the presurgical level within 3 hours.6 This depletion of naturally occurring hormones and the issue of hormone replacement therapy have become fundamental concerns in women's health care today.7 Given the growing number of women and the fact that they will be spending at least one third of their lives after menopause, it has become increasingly important for nurses to be knowledgeable regarding current perspectives in estrogen replacement therapy (ERT). Such knowledge is essential if we are to be effective in helping the women who look to us for information, support, and assistance in making informed decisions regarding this matter.
This article describes current perspectives in estrogen replacement therapy in light of recent research findings. TTie goal is to provide guidelines for nurses to use in educating and counseling women about ERT. These guidelines are for the present, however, since changes will certainly occur in the future.
INDICATIONS FOR ERT
Treating Symptoms of Estrogen Deficiency
The most widely known reason for prescribing ERT is to treat the constellation of vasomotor, somatic, and psychological symptoms of estrogen defi ciency sometimes referred to as tht menopausal syndrome . " 8 Vasomo tor flushes or hot flashes are the mos common symptom.9 As menstrual peri1 ods cease, about 75% of women begin to experience these feelings of extreme heat that come on unexpectedly anc last anywhere from 30 seconds tc about 5 minutes.4,10 They are öfter accompanied by other vasomotor symptoms, including nausea, dizziness, headaches, palpitations, diaphoresis, and night sweats. Eighty-five percent of women with these symptoms experience them for more than % year, whereas 25% to 50% continue to be troubled by them for more than 5 years.9 Vasomotor flushes are usually mild and infrequent, but about 12% are so extreme that they result in severe insomnia or nervousness and interfere with a woman's ability to function socially or professionally.11
Although the exact cause of vasomotor flushes is not completely understood, the current concept is that they are triggered by a mechanism in the hypothalamus that is involved with catecholamine metabolism.9,12,13 With the decline of ovarian function, catecholamine levels are elevated due to the absence of negative feedback from estrogen. Loss of this negative feedback results in higher levels of norepinephrine, which spills into the thermoregulatory center of the hypothalamus and triggers hot flashes. ERT is Effective in relieving vasomotor symptoms because it restores negative feedback.12
Behavioral symptoms such as fatigue, insomnia, inability to concentrate, lack of satisfaction with personal performance, irritability, and depression can also be troublesome for some menopausal women.10 In a prospective study of women with severe hot flashes Campbell and Whitehead found that ERT was associated with improved memory and marked reduction in insomnia, anxiety, and irritability, compared with a placebo.14 The authors suggest that these improvements may have been due to the alleviation of hot flashes during sleep, which secondarily improved mood by promoting sounder sleep and preventing the adverse effects of chronic sleep disturbance.
When relief of vasomotor symptoms is the only indication for ERT, most practitioners follow the Rxxí and Drug Administration's recommendation and use the smallest dose for the shortest time (perhaps 6 months to 2 or 3 years).13,15 Cessation of estrogen therapy often results in the recurrence of symptoms, but these are usually milder and of shorter duration, especially if there is a gradual weaning process.15,16 In the absence of hot flashes, ERT is much less effective in alleviating behavioral symptoms and is not recommended in these cases.10,17
Hot flashes may occur immediately following removal of the ovaries in a premenopausal woman unless estrogen replacement is started promptly. In addition, her genitourinary tract may become atrophic in the absence of estrogen, and she will also become a prime candidate for osteoporosis. Bilateral oophorectomy in postmenopausal women is less dramatic in its effect, but it still alters a woman's body chemistry. Normally, a menopausal woman's ovaries continue to produce important amounts of androgens, which are converted to estrogen elsewhere in the body and provide some natural hormonal support. 18
In addition to treating symptoms of estrogen deficiency, it has become increasingly evident that an important long-term goal of ERT is to prevent disease. Urogenital atrophy, osteoporosis, and atherosclerotic cardiovascular disease are of particular concern in postmenopausal women. According to many authorities, it is the preventive aspect of estrogen therapy that should prompt serious consideration of ERT for all women at the time of spontaneous or surgical menopause. 8
A variety of genitourinary disorders occur as a result of decreased estrogen production. The vulva may be affected by atrophic, dystrophic, and pruritic changes, whereas vaginal atrophy may lead to dyspareunia and vaginitis. 12 Deterioration of sexual function may accompany these changes.8 Cystourethritis, frequency or urgency, and stress incontinence may also occur as estrogen levels fall. When estrogen is replaced, vaginal dryness usually disappears completely and other genitourinary symptoms improve markedly.1
Because estrogen plays a major role in maintaining skeletal integrity, bone loss occurs whenever estrogen levels fall. Initially, estrogen-dependent bone loss is quite rapid; in the 5 or 6 years after menopause, women lose bone twice as quickly as men of comparable age.15 After 10 to 15 years of estrogen deficiency, the annual rate of bone loss decreases. By that time, however, a woman has lost one third to one half of her youthful bone mass. I9
This bone erosion leaves a significant number of women at high risk for fractures. One of every 4 women has at least one vertebral fracture by the age of 60; by the age of 75, that number jumps to 1 of 2. The incidence of hip fracture doubles every 5 years after age 60. 20 This means that the average woman has a 15% probability of fracturing a hip during her lifetime.19
Estrogen retards postmenopausal (Type 1 ) bone loss and reduces the risk of fracture. At a recent National Institute of Health consensus conference on osteoporosis, participants concluded that ERT should be started as soon after the onset of menopause as possible, before accelerated bone loss robs a woman of significant skeletal mass.21,22 Because of its side effects, however, estrogen should only be given to women who are at high risk for osteoporosis (Figure 1), who have no contraindications to its use (Figure 2), and who will comply with a careful follow-up program.
RISK FACTORS FOR OSTEOPOROSIS
Although significant osteoporosis risk reduction has been demonstrated in women who used estrogen for as little as 5 to 10 years, stopping therapy after this relatively short period allows resumption of bone loss and some increase in fracture risk.23,24 Therefore, most experts currently recommend continuing estrogen therapy for as long as it is acceptable and beneficial for the individual, which may mean lifelong therapy for some women. 19 In a recent consensus report, physicians at the Mayo Clinic indicated that estrogen therapy until age 75 has been safe in their practice16; however, they do not prescribe ERT for women over age 75. Longterm therapy can decrease the incidence of vertebral fracture by approximately 90% and hip fracture by 50%."
Coronary artery disease is the leading cause of death in older women.26 Tbe relationship between cardiovascular disease and ERT remains controversial, even though this topic has received wide attention in the medical literature in recent years.1,12 Estrogen seems to provide some protection against cardiovascular disease in postmenopausal women.27 Studies have shown that women with premature surgical menopause have a 2.2-fold increase in their relative risk of developing coronary artery disease. This increased risk may be reduced to normal by ERT.28 One mechanism that has been proposed to influence this effect is estrogen's ability to decrease serum low-density lipoprotein (LDL) and increase high-density lipoprotein (HDL) cholesterol levels.1,12,16
The epidemiological data relating to this issue are confusing, however. In a prospective study of postmenopausal estrogen therapy and coronary artery disease, Stampfer and colleagues concluded that the use of conjugated estrogens without progestin substantially protects women against nonfatal myocardial infarction and fatal coronary artery disease.29 In contrast, Wilson et al found that the use of similar hormones significantly increases the risk of death from cardiovascular disease, including myocardial infarction and stroke.30 In an attempt to clarify these important issues, studies are currently underway at the National Heart, Lung, and Blood Institute, the National Institute on Aging, and other institutes within the National Institutes of Health.
A number of epidemiologic studies have shown an increased risk of endometrial cancer in postmenopausal women who received ERT. This augmented risk appears to be related toboth dose and duration of therapy. In most studies, the risk of uterine caner was approximately four to eight time, greater than that of the normal popular tion (100 cases per 100,000). 16 A major precursor to cancer of the uterus is endometrial hyperplasia. This occurs as a result of unopposed estrogen therapy (that is, estrogen without concurrent use of a progestin). Endometrial hyperplasia is considered a poten tially premalignant condition because 1.57% to 25% of cases may progress to adenocarcinoma.4
Addition of a progestin causes endometrial regression and shedding and a return of menses-like bleeding In 95% of women, the endometrium is restored to normal, which virtuality eliminates the risk of endometrial cancer. In fact, the incidence of endometrial cancer may even be lower than that seen in women who receive no hormonal therapy.31 Because of this major benefit, it is now standard practice to add a progestin whenever long-term estrogen therapy is given to a woman with an intact uterus. ,2'16,31
We do not know if ERT increases the risk of breast cancer because many of the relevant studies have methodological deficiencies and inconsistencies.16 Some studies have shown a slight but statistically insignificant increase in the risk of breast cancer assodated with oral estrogen use. Others have concluded that there is no increased risk and that estrogens may actually improve the prognosis in women who develop breast cancer during estrogen therapy.4 In any case, the risk appears to be minimal and has no been found consistently, even in recent case-control studies.16
Until this question is answered, caution is advised. Women should undergo mammography prior to starting ERT to detect occult cancer. In addition, they should perform monthly breast self-examinations and have mammography repeated at the intervals recommended by the Americaii Cancer Society. 16 Estrogen is contraindicated in women with a history ol breast cancer.
Although the synthetic estrogens used in oral contraceptives may induce hypertension in susceptible individuals, any association between natural estrogens (those used in ERT) and hypertension is less clear.4 Some practitioners believe that ERT may cause or exacerbate hypertension, but most evidence shows no such causal relationship.32 At present, it appears that lowdose estrogen therapy is unlikely to cause significant hypertension in most postmenopausal women. Because there are occasional reports of marked, idiosyncratic hypertension ascribed to ERT, blood pressure measurements should be taken shortly after the initiation of ERT and at regular intervals thereafter.4 Pre-existing hypertension is a relative contraindication for ERT.
Although thromboembolic disease has been associated with oral contraceptive use, clinical studies currently show no increased risk of thromboemholism in postmenopausal women during orally administered ERT.2? The natural estrogens used in replacement therapy do not appear to be thrombogenic per se, but they may predispose to a hypercoagulable state.4 Therefore, pending Jarge, prospective studies, it would be prudent for women with major risk factors for thrombosis to avoid any use of estrogens.33 These risk factors include immobilization, sepsis, trauma, surgery, acute myocardial infarction, stroke, congestive heart failure, and estrogen-dependent tumor.
The Boston Collaborative Drug Surveillance Program showed a slight (2.5-fold) increase in the relative risk of cholelithiasis in postmenopausal women taking estrogen.4 The mechanism for this apparent increase is as yet unexplained. Because gallbladder disease has been associated with changes in HDL cholesterol, it is likely that estrogen induces an alteration in lipid balance or bile salt content in the gallbladder.4
Although there are conflicting data, it appears that estrogens create a mild glucose intolerance, but that they are unlikely to precipitate frank diabetes.4 For this reason, estrogen therapy is not absolutely contraindicated in diabetic women. However, their glucose levels should be monitored on a regular basis.
CONTRAINDICATIONS FOR ESTROGEN USE
There are a variety of treatment regimens and estrogen-progestogen combinations used to provide hormone replacement therapy. The cyclic regimen most frequently administered in the United States includes conjugated equine estrogen, 0.625 mg orally on days 1 through 25, with 10 mg of medroxyprogesterone added the last 10 to 12 days of the cycle; no hormones are taken for the remainder of the month.12,34 Opponents claim that this regimen is difficult for women to remember and that symptoms may return during the drug-free period.31
A regimen that is widely used in Europe and is gaining popularity in the US calls for continuous daily administration of estrogen with progestogen added for 12 to 14 days at the beginning of each month. Proponents say that in addition to its simplicity, this schedule produces a predictable withdrawal bleeding pattern; bleeding before the 10th day of the month indicates the need for a higher dose of progestogen to cause adequate secretory transformation of the endometrium.31
When cyclic progestins are combined with estrogen, 97% of women with an intact uterus experience withdrawal bleeding until age 60; this gradually declines from ages 60 to 65, when 60% of women continue to have withdrawal bleeding as long as they continue hormone replacement therapy.35 To prevent this monthly bleeding, some practitioners have begun to prescribe continuous daily estrogen plus low-dose, continuous progesterone. Many women on this regimen have no withdrawal bleeding. Unfortunately, those who do so have irregular bleeding and sometimes it is quite heavy.31
Weight gain, nausea, breast tenderness, increased cervical mucous secretion, and breakthrough bleeding are among the reported side effects of estrogen.15,17 These may be alleviated by reducing the dosage. Side effects of progestins include bloating, acne, breast tenderness, headache, changes in libido, insomnia, loss of scalp hair, itching, rashes, growth of excess hair, depression, and premenstrual tension. 18,17 Adjusting the treatment regimen may minimize these effects.12 The current trend is to give a lower dose of medroxyprogesterone (5 mg), but for a longer time (12 to 14 days).16 Larger doses of progestins may reverse the favorable HDL-LDL balance that estrogen therapy alone can bring. Because progestins may have this undesirable effect, unopposed estrogen therapy is recommended for women who have had their uterus surgically removed. 12
The newest method of administering estrogen is the transdermal patch (Estraderm), which is available in three doses: 0.025 mg, 0.05 mg; and 0. 1 mg. 17 The 0.05 mg dose is equivalent to 0.625 mg of orally administered conjugated estrogen. Patches are worn on the abdomen or other part of the trunk and are change twice weekly on a (25-day per month) cyclic or continuous basis. Progestin is added as in the oral estrogen regimens.
Transdermal administration offers several advantages over oral ERT.17 Because none of the drug is lost in the digestive tract, the beneficial effects are achieved with a lower dosage and with fewer systemic side effects. Transdermal patches also offer the advantage of closely mimicking natural ovarian function. The active drug is estradiol- 17ß, the predominant estrogen during the reproductive years; a relatively constant level of the drug is maintained, in contrast to the daily fluctuations with oral therapy. Because a bolus dose to the liver is eliminated, there is no apparent change in clotting factors or other liver proteins (such as renin substrate).17 Its cost is a disadvantage, however, since transdermal estrogen is almost twice as expensive as an equivalent oral dose. In clinical trials, the most commonly reported adverse reaction to Estraderm was redness and irritation at the application site (seen in 17% of treated women). Although transdermal estradiol has FDA approval for treatment of menopausal symptoms, it has not been determined that the currently recommended doses are appropriate for the treatment or prevention of osteoporosis. 17
Women on estrogen therapy should understand the importance of regular, ongoing care.15,34 Their general health must be continuously monitored and the dosage of hormones adjusted as necessary. They should be taught to report any unusual discomfort, pain, or other symptoms to the care provider at once. Possible danger signs include abnormal vaginal bleeding; pain in the calves or chest; sudden shortness of breath; severe headaches; unusual lumps or swelling; jaundice; vision changes; and dizziness.17 After initiation of therapy, women should be reevaluated at 3 and 6 months, unless problems occur in the interim.34 Subsequently, they should be seen every 6 months, or at least yearly. An annual endometrial biopsy is usually performed on women taking estrogenonly therapy. Breast and pelvic examinations and blood pressure measurement should be done at each visit; Pap smears should be done annually.4,16 Monitoring total cholesterol levels is also reasonable and inexpensive, and provides useful information regarding the effects of therapy.31
An ever-expanding number of women will be spending a greater proportion of their lives after menopause. The cessation of ovarian secretion of estrogen at the time of menopause results in a number of changes in target tissues, some of which cause unpleasant or disabling symptoms. Many experts now advise estrogen-progestin replacement therapy to prevent osteoporosis in all women at high risk for this disorder, and for vasomotor flushes, genitourinary symptoms, and changes in mood in women who have no contraindications to this therapy. Although the benefits of hormone replacement therapy appear to exceed the risks, the latter must remain a prime concern Through careful candidate selection education, examination, treatment and follow-up, these hazards can minimized . Hormone replacement ther apy has a pivotal role to play in pre serving good health and vitality, but should be presented within the context of other health-promoting measures to be adopted by menopausal and post menopausal women.
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