Hormone replacement therapy

Hormone replacement therapy

Int J Gynecol Obstet, 1993, 41: 194-202 International Federation of Gynecology and Obstetrics 194 Hormone replacement therapy ACOG Technical Bulle...

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Int J Gynecol Obstet, 1993, 41: 194-202 International Federation of Gynecology and Obstetrics


Hormone replacement


ACOG Technical Bulletin Number 166 - April 1992 (Replaces No. 93, June 1986) In 1989, it was estimated that in 1990 there would be approximately 250 million people in the United States, including 36 million women who were 50 years of age or older (1). Since the average age of menopause is 52 years and the average life expectancy of women in North America is 76 years, it can be estimated that women now live approximately one third of their lives in the postmenopausal period. After menopause, estrogen production decreases substantially, leading to the occurrence of symptoms and enhancement of specific risk factors. Estrogen replacement can relieve these symptoms and reduce these risks, but its use may be associated with several patentially harmful side effects. This Technical Bulletin discusses the indications, contraindications, and side effects of ovarian hormone replacement. It reviews specific strategies to maintain the benefits of this therapy while reducing and, in some cases, eliminating its risks.

Indications Vasomotor

Vasomotor symptoms (hot flushes or flashes) are the most common complaint of patients during the climacteric period. Of those women having flushes, 80% complain of them for more than 1 year and 25-50% for more than 5 years. Hot flushes result from a disruption of the function of thermoregulatory centers within the hypothalamus. This disruption is a consequence of enhanced hypothalamic activity secondary to loss of ovarian hormonal feedback (2). Changes in skin temperature and resistance, core temperature, and pulse rate have been documented at the time of subjective symptoms. When flushes are experienced at night, they can disrupt sleep patterns. Estrogen therapy effectively decreases the frequency and severity of subjective symptoms as well as Int J Gynecol



the objective signs of menopausal flushes (3). With discontinuation of therapy, symptoms may recur; gradually reducing the dose of estrogen in this situation, however, frequently minimizes the problem. Progestins such as medroxyprogesterone acetate and megestrol acetate also reduce the symptoms. Nonsteroidal medications such as clonidine, alpha-methyldopa, and veralipride have also been shown to decrease objectively measured hot flushes. Osteoporosis

Osteoporosis is one of the most important health hazards associated with menopause. It has been reported that 1.2 million new fractures due to osteoporosis occur annually in the United States, About two thirds of these fractures occur in women. These fractures cost more than $7 billion in health care dollars annually for acute and long-term care (4). Age-related bone loss is greater in women than in men. This loss is accentuated by the cessation of ovarian function, which is a particular problem in women who have undergone oophorectomy at an early age or have gonadal dysgenesis. The mechanisms responsible for bone loss with menopause have not been completely defined. Reduction of ovarian estrogen production appears to play a key role, as evidenced by the measurement of increased bone loss with discontinuation of ovarian function and the reduction in parameters of bone resorption with estrogen replacement. Several studies indicate that estrogen therapy can arrest bone loss and reduce the incidence of fractures, even if treatment is begun in later life (ie, after age 65) or after an interruption of treatment. To establish minimal effective doses, investigators have conducted drug trials and made bone density measurements before and after l-2 years of estrogen therapy. Early studies used measurements of the metacarpals or radius. Based on these studies, the lowest effective dose of conjugated estrogens was 0.625 mg (5), while micronized estradiol

ACOG Technical Bulletin

(1 mg) was shown to retard bone loss of the radius in a nonrandomized study (6). Recent investigations have shown that data based on bones of the upper extremities may not reflect findings in the spine or hip. Randomized trials have shown that 0.625 mg of conjugated estrogens and 0.05 mg of estradiol administered by transdermal skin patch prevent bone loss in both the spine and hips (7), while the minimal effective doses of estrone sulfate that prevent loss of bone in the spine and hip are 0.625 mg and 1.25 mg, respectively (8). Currently, estrogen is the only medication approved for the prevention of osteoporosis. Recently, the diphosphonate etidronate has been reported to prevent bone loss and fractures (9). Unfortunately, long-term data have been less encouraging. A variety of other therapeutic modalities have been recommended, including weight-bearing exercise, vitamin D, norethindrone, and calcium. The effectiveness of these altematives against bone loss, however, is unclear. A generally accepted approach for the prevention of osteoporosis is a program of hormone replacement therapy, calcium supplementation, and exercise. Treatment of established osteoporosis is more problematic. Salmon calcitonin is approved for this indication. Sodium fluoride has been used for more than 30 years. It increases cancellous bone mass as much as twofold. However, only a few rigorous studies have been performed to test its efficacy. One trial showed a significant decrease in new vertebral fractures in women during a 24-month study (10). Another double-blind trial of 75 mg of sodium fluoride per day showed a very significant increase of bone density of spinal bone mass, but no reduction in vertebral fractures. Of concern was the observation that peripheral fractures were increased in the women taking the medication (11). At present, it must be stated that sodium fluoride remains an experimental therapy. More work is needed to define its role in the treatment of established osteoporosis.

Cardiovascular Cardiovascular disease is the leading cause of death in women in the United States. Coronary heart disease is much less prevalent in women than in men before the age of 55, but this difference decreases after this age, and the ratio reaches unity by the ninth decade of life. The presence of ovarian activity in younger women has been postulated as providing a protective effect, and the loss of this function at menopause may be partly respon-


sible for the increased rate of death from myocardial infarction in older women. Many cohort and case-control studies have examined the connection between loss of ovarian function and heart disease, with most reporting an association (12). The preponderance of evidence supports the hypothesis that loss of ovarian function increases the risk of coronary heart disease. There is also controversy regarding the role of hormone replacement in the prevention of heart disease. To date, no large, randomized drug trial has been performed to answer this question. Such a study is urgently needed. Support for this benefit comes mainly from epidemiologic studies. These studies. however, strongly suggest that hormone replacement therapy decreases the risk of cardiovascular disease (13, 14). There are several possible mechanisms by which estrogens could have a favorable impact on heart disease. Estrogens increase levels of high-density lipoprotein and decrease levels of low-density lipoprotein cholesterol (12, 13). In animals, estrogens have been shown to retard atherogenesis, decrease cholesterol deposition in vascular walls, and increase coronary blood flow and synthesis of vascular wall cyclooxygenase. Each of these could potentially explain the probable beneficial effect of estrogen on heart disease. Although the preponderance of data suggests that estrogen use may prevent heart disease, the U.S. Food and Drug Administration has not approved the prevention of heart disease as an indication for any estrogen preparation. If this association is established, it will become the primary factor in balancing the risks and benefits of estrogen replacement. Concern has been raised regarding whether progestins administered with replacement estrogens may offset the apparent cardioprotective effect of estrogens administered alone. This concern is largely based on progestin-induced changes in lipoprotein metabolism (increase in low-density lipoprotein cholesterol). Although these changes could theoretically increase the risk of atherosclerosis, their clinical effects remain unclear.

Genitourinary Symptoms Following menopause, atrophic changes of the vagina occur and are accompanied by vaginal dryness, buming, itching, dyspareunia, discharge, and, occasionally, bleeding. Patients may also experience dysuria and Inr J Gynecol Ohstet 41


ACOG Technical Bulletin

urinary frequency, even when urine cultures are negative for infection. It is well recognized that estrogens are effective in ameliorating atrophy of the vaginal epithelium and associated symptoms. Clinical experience indicates that estrogens are also effective in relieving some urinary tract symptoms, although only one randomized trial has documented this finding (15). Estrogen receptors have been identified in the urethra, and an increase in the number of superficial cells of the urethral epithelium has been reported with estrogen administration. It is therefore likely that properly designed studies will confirm a beneficial reduction in the symptoms of urgency, nocturia, and frequency in some postmenopausal women with estrogen replacement. Hypogonadism Hormone replacement therapy is indicated for sexually immature, adolescent girls with hypogonadism to help them achieve full sexual maturation, maintain good health, and assist in closure of the epiphyseal lines. Hormone replacement therapy is also indicated for adult women who develop premature ovarian failure or hypogonadism due to hypothalamic-pituitary suppression, such as that occurring with exercise-induced amenorrhea and anorexia nervosa. Other Considerations Psychologic Indications

Large population-based studies now indicate that midlife (after 45 years of age) is associated with a sharp decrease in the prevalence of psychiatric disorders in men and women (16). However, the data on minor psychologic and somatic complaints are inconsistent, with some reporting an increase (17) and others finding no change (18) in these problems with the occurrence of the menopause. This is not surprising in light of methodologic difficulties such as the use of nonstandardized questionnaires, the study of clinic populations, reliance on cross-sectional study designs, and measurement of subjective end points. It is clear, however, that menopause is not associated with an increase in severe psychiatric illness. More consistent results have been observed with drug trials of hormone replacement therapy. Several randomized, double-blind, crossover, placebo-controlled drug trials have shown improvement in both cognitive and affective end points with estrogen use in areas Int J Gynecol Obstet 41

including memory, insomnia, anxiety, and irritability (19,20). These data clearly support a role of estrogen in relieving some mild psychologic complaints at the time of the climacteric. It is well recognized that vaginal atrophy leads to dyspareuniaand problems with sexual function. Whether the loss of ovarian function has an impact on other aspects of sexuality in women remains controversial (18, 21). The role of hormone replacement on sexual function is clearer. Several well-designed,double-blind, crossover studies indicate that estrogens improve sexual symptoms (19,22). It has been suggested that testosterone also may have an impact on sexual function, but these data are mixed, with one double-blind study showing no benefit of androgen over estrogen (23) and another showing an increase in sexual desire and arousal but not coital frequency (24). Clearly, more studies are needed in this area. Dermatologic Effects

With aging, noticeable changes in the skin occur. A generalized thinning is accompanied by a loss of elasticity, which results in wrinkling. Decreases in skin thickness and collagen content have been identified in the skin of the thighs and forearms of women after menopause (25). Estrogen replacement has been shown to increase both the thickness and the collagen content of the skin, with the greatest effects seen in women with low values before therapy (26). These observations have been interpreted to indicate that in women with reduced skin thickness and collagen content, estrogen therapy may be therapeutic as well as prophylactic, while in women with high values just after menopause, it can only prevent loss. Although these studies are of great interest, they are flawed by the lack of a placebo-controlled, randomized design.

Complications Hyperplasia and Endometrial Cancer Studies suggest an association between the prolonged use of unopposed estrogens by postmenopausal women and an increased risk of endometrial hyperplasia and cancer (27). This risk has been correlated with the dose and duration of treatment, and administration of estrogen in a cyclic fashion provides little or no protection.


Protection can be achieved by continuous or periodic administration of a progestin, but the minimum number of days of progestin use that is required to reduce the risk of endometrial cancer is not known. Some studies suggest that longer intervals of exposure to a progestin increase its effectiveness and that most patients will be protected by a regimen of 12 days of progestin administration each month (19). Dosage also plays a role: most patients are protected with a cyclic dose of 10 mg of medroxyprogesterone acetate; continuous doses as low as 2.5 mg also afford endometrial protection while minimizing adverse impact on lipoproteins. Patients receiving combined hormone therapy including a progestin have a decreased incidence of endometrial hyperplasia or carcinoma compared with untreated patients (28).

Breast Cancer The much higher rate of breast cancer in women than in men, coupled with extensive data from animal studies in which estrogens have been associated with the development of breast tumors, has resulted in heightened awareness of the possible role of exogenous estrogen therapy in the development of breast cancer in older women. Factors that increase the relative risk of breast cancer, including low parity, first childbirth after age 30, obesity, anovulatory infertility, early menarche, and late menopause, have also suggested that prolonged exposure, particularly to unopposed estrogens, may enhance the risk of cancer. It has been difficult to substantiate an association between estrogen replacement therapy and an increased risk of breast cancer (29). Numerous well-designed cohort and case-control studies published in the 1980s examined this issue. Most have reported no increase in the overall risk of breast cancer with estrogen replacement. However, none of these studies is sufficiently large to fully evaluate whether subgroups of patients using estrogen replacement therapy are at risk. Several studies have reported increases in risk with prolonged use, but the increased risk identified has been twofold or less and has frequently not been statistically significant. Further complicating this issue is that some studies have shown no increased risk with long-term use (30). Two basic interpretations of these data now exist. The first is that the relative risk increases from l/10 in the general population to 1S/10 in patients who have used estrogen replacement therapy for 15 years or longer (3 1). The

Terhnicul Bulletin


second is that any increase in risk with long-term use is not established due to the small increases in risk ratios observed and the heterogeneity of findings among studies (32). Overall, however, most evidence suggests that estrogen replacement therapy does not increase the risk of breast cancer. Whether the increased risk with longterm use that is observed in some studies is real must await clarification by future research. The addition of a progestin to estrogen therapy has also been examined for risks, but many fewer studies of this issue have been published (29,33). The results have been inconsistent, with those of various investigators reporting increased risk, no effect, or even protection. Therefore, it cannot be stated with certainty whether the administration of a progestin to a woman without a uterus has any effect on her risk of breast cancer. Until the role of progestins is more clearly defined, most experts have not recommended their use in women without a uterus. Theoretically, the addition of testosterone to estrogen treatment should have a beneficial effect on the risk of breast cancer. However, the full effects of such therapy are not well defined and await further study. Physicians who prescribe hormone replacement should be diligent in assessing the possibility of breast disease and should perform regular examinations and mammograms as recommended for all women by the American College of Obstetricians and Gynecologists and other organizations, such as the American Cancer Society. Physicians also need to be alert to any new findings regarding this issue but can be reassured that, to date, estrogen replacement for less than 15 years’ duration appears to have little. if any, effect on the risk of breast cancer.

Hypertension Several attempts have been made to link hormone replacement with hypertension. At least seven casecontrol studies were published between 1976 and 1988. with five showing no association ( 13. 34). In the two studies that found an increase in blood pressure, either the temporal relationship between hormone use and hypertension was not determined, or. when it was assessed, it was discovered that most of the hypertensive women had elevated blood pressure before therapy commenced. At least five prospective drug trials also have been conducted, three of which were randomized (13, 34). In none of these studies was a significant Ini J Gvnrcol Ohsrrt 41


ACOG Technical Bulletin

increase of blood pressure found, while in several a tendency for a decrease in blood pressure was mentioned. Thus, it appears that the increase in blood pressure that occurs with oral contraceptive use has not been found to occur with hormone replacement therapy. Thromboembolic Disease Estrogens exert several effects on the blood clotting mechanism. These effects include increased vascular endothelial proliferation, decreased venous blood flow, and increased coagulability of blood due to changes in the platelet, coagulation, and fibrinolytic systems. Although thrombophlebitis has been reported with hormone replacement therapy in noncontrolled studies, this association has not been observed in controlled clinical trials (35). Caution should be exercised, however, in administering hormone replacement therapy to women who are at risk for vascular thrombosis or embolism. In the presence of thrombosis or embolism, therapy should be discontinued. Transdermal estrogen administration is associated with less hepatic production of clotting factors, thus theoretically posing less risk of thromboembolic disease. Hepatic Effects Estrogens have an impact on both protein and lipid metabolism by hepatocytes. These effects are more pronounced when the medication is given by mouth, is absorbed by the gastrointestinal organs, is delivered directly to the liver through the portal circulation, and acts on the hepatocytes before being partially metabolized to less active compounds. Estrogen stimulates the hepatic synthesis of angiotensinogen, the renin substrate, and certain clotting factors, while suppressing the synthesis of some anticlotting factors (36). At doses recommended for replacement therapy, these effects seem to elicit few, if any, problems (36). Whether this confers long-range benefits to women has yet to be established. Orally administered estrogens also alter hepatic lipid metabolism. The metabolism of low-density lipoprotein cholesterol is enhanced, leading to a decrease in its circulating level but an increase in the entry of cholesterol into bile (37). This, possibly coupled with mild alterations of bile acids, leads to supersaturation of cholesterol in bile and to stone formation. The latter problem appears to be a consequence of both oral contraceptives and replacement therapies (35). The Int J Gynecol Obsret 41

administration of estradiol by nonoral routes reduces the hepatic actions of the hormone by bypassing the socalled “first pass” effect (36).

Contraindications to estrogen replacement therapy include: ?? Unexplained vaginal bleeding ?? Active liver disease ?? Chronic impaired liver function ?? Recent vascular thrombosis (with or without emboli) ?? Carcinoma of the breast ?? Endometrial carcinoma, except in certain circumstances (38) Conditions that may constitute relative contraindications include: ?? Seizure disorders ?? Hypertension W Uterine leiomyomas i Familial hyperlipidemia ?? Migraine headaches ?? Thrombophlebitis ?? Endometriosis ?? Gallbladder disease Although estrogen use is not associated with an increased risk of thrombosis, the risk posed by estrogen use in a patient with a past episode of thrombosis is unknown. The risk of recurrence of breast cancer following estrogen therapy is also unknown. There is no increased risk of recurrence of carcinoma of the cervix or ovary with hormone replacement therapy. For all patients, the severity of menopausal symptoms must be considered in light of the known risks and potential benefits of therapy.

Initial hormone replacement therapy is directed toward the relief of hot flushes, atrophic vaginitis, and some psychiatric complaints. Caution should be exercised with the last indication, since most psychiatric symp-

ACOG Technical Bulletin

toms have other causes. Prevention of osteoporosis and a decrease in the risk of heart disease are the goals of long-term therapy. Before hormone replacement therapy is begun, the patient’s physical condition should be assessed. This evaluation should include obtaining a medical history, with specific reference to contraindications and precautions; a physical examination, including measurement of blood pressure and cholesterol levels; breast and pelvic examinations; and cervical smears. Because of the controversy relating to the effect of hormone replacement therapy on breast cancer, it is also important that the patient have a screening mammogram in accordance with published guidelines (39). Hormone therapy is often given according to a cyclic schedule, but continuous administration is becoming increasingly common. Continuous administration is less confusing to the patient and avoids the return of symptoms during the medication-free interval. Another principle of therapy is to use the lowest dosage compatible with effective treatment of symptoms and prevention or arrest of osteoporosis. Severe hot flushes may require higher doses, but these should be limited to a finite period of time, followed by a gradual reduction to the standard dose. For the prevention of osteoporosis, the use of 0.625 mg of conjugated estrogens or 0.05 mg of transdermal estradiol has been shown to prevent bone loss in the spine and hip. One milligram of micronized estradiol has been shown to prevent bone loss in the radius, while 1.25 mg of estrone sulfate has been reported to prevent bone loss in the spine and hip. The addition of calcium alone appears to provide little or no additional protection (40). A lower dose of estrogen (0.3 mg of conjugated estrogens) combined with greater calcium intake (total of 1,500 mg daily) has been shown to be effective in preventing bone loss in one study (41). In women who have not had a hysterectomy, sequential addition of a progestin, such as medroxyprogesterone acetate (10 mg), during the last 12 days of estrogen administration is recommended to lower the incidence of hyperplasia and endometrial cancer (42. 43). Lower doses (5.0 and 2.5 mg) also provide protection when given continuously, but less completely than the IO-mg dose when given in a cyclic fashion. C-21 progestins, such as medroxyprogesterone acetate, have been preferred over 19-norprogestins, such as norethindrone, because the latter may possibly alter the


beneficial rise in high-density lipoprotein and fall in low-density lipoprotein induced by estrogens. Longterm dose-response studies of the various progestins are not yet available to settle this important issue. In women who do not have a uterus, it is not known whether administration of a progestin has any effect on the risk of breast cancer. Therefore, until the role of progestins is more clearly defined, most experts do not recommend their use in women without a uterus. Recently, there has been a great deal of interest in the daily administration of estrogen in combination with a progestin, at a lower dosage of the latter (2.5 mg of medroxyprogesterone acetate) (44). Preliminary results indicate that this regimen promotes endometrial atrophy and frequently eliminates vaginal bleeding. When bleeding does occur, it occurs at unpredictable intervals and is therefore a drawback of this form of therapy. If treatment with sequential estrogen-progestin therapy is instituted, endometrial biopsy is not required before treatment is begun. The patient should be alerted to the probability of some monthly withdrawal vaginal bleeding after cessation of progestin therapy and counseled concerning the benign nature of this event. If breakthrough bleeding occurs at an unscheduled time (before day 6 of progestin therapy), an endometrial biopsy should be performed to rule out the development of abnormal endometrial histology. Endometrial biopsy by aspiration curettage performed in the office is diagnostically reliable and cost effective and usually is preferred to dilation and curettage. Under some circumstances, dilation and curettage under general anesthesia may be necessary. The timing of further biopsies, should any be needed, is a clinical decision that must be based on previous histologic results and the patient’s bleeding history. Some patients may object to withdrawal bleeding and refuse to accept the addition of a progestin to their estrogen replacement regimen. Others may experience adverse reactions to the progestin component (such as breast tenderness, fluid retention, weight gain, dysmenorrhea, and depression). Without progestin, however, long-term estrogen replacement therapy carries an increased risk of endometrial hyperplasia and, eventually, endometrial carcinoma. With this in mind, the physician should be aware of the following guidelines:

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ACOG Technical Bulletin

?? It is a clinical impression that symptoms associated with the progestin component may resolve when the daily dose of medroxyprogesterone acetate is reduced from 10 mg to 5 mg. It appears that the lower cyclic dose does not offer quite as much protection as the higher one. ?? Withdrawal bleeding often can be eliminated by reducing the conjugated estrogen dose from 0.625 mg to 0.3 mg (41) or by adding 2.5 mg of medroxyprogesterone daily. To prevent osteoporosis, daily calcium intake should be increased to 1,500 mg. The long-term effectiveness of this lower dose of estrogen in providing protection against osteoporosis is unknown, and it may be ineffective in providing relief of climacteric symptoms. ?? Estrogen-only therapy can be given, but endometrial biopsy should be performed prior to the initiation of therapy and annually thereafter. The presence of endometrial hyperplasia requires either discontinuation of estrogen therapy or addition of a progestational agent. In either case, a repeat endometrial biopsy is essential to ensure clearing of the hyperplasia. Transvaginal ultrasound endometrial measurements are useful in detecting the possibility of excessive endometrial proliferation (>6 mm).

Regardless of the route of administration, patients should be counseled about the need for protection against endometrial hyperplasia. The dosage equivalence and biologic effectiveness of these alternative methods of administration are less well characterized. If estrogen is given parenterally, progestin in similar doses and duration as previously mentioned should be administered. If estrogen is given vaginally, the use of progestin challenge as a bioassay of the endometrial proliferation has been advocated. If administration of progestin as a challenge does not result in vaginal bleeding, then the patient is at low risk and the challenge may be repeated at periodic intervals. If bleeding occurs in response to the progestin challenge, then the estrogen administration should be combined with a continuous or periodic progestin as described previously. If estrogen replacement therapy is contraindicated, other medications can be used and are helpful for a woman who has vasomotor symptoms. Medroxyprogesterone acetate (1wO mg daily), megestrol acetate (20-80 mg daily), and clonidine (0.24.4 mg daily) reduce the occurrence of hot flushes.

Oral administration of cyclic estrogen-progestin therapy has been the preferred method of therapy in the United States. Administration by injection has not been recommended by most experts because of cost, uncertainty regarding dose effectiveness, and the hazards of prolonged action. Transdermal administration may be preferred by some patients, since this method may reduce gastrointestinal side effects such as nausea. Vaginal cream is effective for relieving the symptoms of vaginal atrophy, and at high doses (24 g of conjugated estrogen cream daily), some of the medication that is absorbed can have systemic actions. At low doses (1 mg daily or less frequently), the cream can convert the vaginal smear to a pattern similar to that found in premenopausal women, but will have little systemic actions (45). Micronized estradiol tablets, if placed in

All patients receiving hormone replacement therapy should be evaluated annually. During these evaluations, breast and pelvic examinations should be performed and a Pap smear taken, and attention should be directed to cholesterol, blood pressure, and the effectiveness of treatment. In women given adequate progestins (medroxyprogesterone acetate, 10 mg each day for 12 days a month), endomehial biopsy should be reserved for women with clinical problems such as excessive or prolonged bleeding. In women taking no progestins, pretreatment and yearly biopsies are required. In addition, annual mammograms should be obtained on women over the age of 50. Hormone replacement therapy, although not suited to all patients, can confer health benefits, enhance quality of life, and prolong life expectancy (46).

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of osteoporosis: treatment of Obstet Gynecol 1988;72(5