CHAPTER 49—HORMONE REPLACEMENT THERAPY
TREATMENT OF MENOPAUSAL SYMPTOMS
TREATMENT OF UROGENITAL SYMPTOMS
PREVENTION AND TREATMENT OF OSTEOPOROSIS
PREVENTION OF CARDIOVASCULAR DISEASE
TREATMENT AND PREVENTION OF COGNITIVE DISORDERS
BREAST CANCER AND ESTROGEN REPLACEMENT THERAPY
ENDOMETRIAL CANCER AND ESTROGEN REPLACEMENT THERAPY
Many of the symptoms and signs of hormone deficiency mimic those classically associated with aging. The fact that many hormones also decline with aging has led to an enthusiasm for attempting to reverse unwanted changes associated with aging by the use of hormonal replacement. The evidence for this approach is limited, with the exception of that for estrogen replacement in women and, to a lesser extent, testosterone replacement in men.
Estrogen replacement therapy (ERT) is approved by the Food and Drug Administration for the treatment of menopausal symptoms and urogenital dryness and for the prevention and treatment of osteoporosis, but it is used by clinicians for other reasons as well, in both women and men. The common short- and long-term uses, common prescribing practices, and risks of ERT are reviewed herein.
Menopause on average occurs at age 51 in the United States; with a life expectancy of 78 years, the average woman is postmenopausal one third of her life. Despite some controversy about the need for ERT, many women and their physicians choose to treat or prevent the sequelae of estrogen deficiency in menopause.
Vasomotor symptoms or hot flushes are the most common symptom of the climacteric, occurring in 40% to 60% of perimenopausal women. Symptoms persist beyond 5 years in 25% of women and are lifelong in a small minority. Although the cause of the vasomotor response remains unknown, vasomotor symptoms are usually relieved within the first cycle of estrogen treatment. Low-dose therapy can be initiated and estrogen doses titrated until symptoms improve. When estrogen is contraindicated or not acceptable, progestins are considered the second most effective therapy; clonidine, methyldopa, or sustained-release tablets of belladonna alkaloids, phenobarbital, and ergotamine tartrate may relieve some symptoms.
Estrogen deficiency causes atrophy of both the vagina and urethra. (See Gynecologic Diseases and Disorders, and Disorders of Sexual Function.) Both have a high density of estrogen receptors. Although randomized trials are lacking, clinical experience with oral and vaginal estrogen indicates that they may relieve dysuria, incontinence, and urethral pressure in some cases.
Estrogen therapy is approved by the Food and Drug Administration for the prevention and treatment of osteoporosis. Estrogen prevents bone loss and hip and spine fractures in early postmenopausal women, and studies suggest that it likely benefits older postmenopausal women. Estrogen decreases markers of bone turnover in both early and later postmenopausal women. A few studies also demonstrate increased distal radius and spinal bone mineral density. Moreover, withdrawal of estrogen after age 65 produces a decline in bone density resembling the loss at menopause. The Framingham Study showed that women taking estrogen for more than 7 years had greater bone density than did women not on estrogen.
For women with osteoporotic fractures, estrogen should be considered among the treatments available for osteoporosis. Women with osteopenia or osteoporosis who have not sustained a fracture should be considered for preventive treatment. (See Osteoporosis and Osteomalacia.)
Estrogen therapy is effective in maintaining bone density in postmenopausal women; the addition of progestogens does not reduce the efficacy. The oral, transdermal, and implant routes are all effective. Available preparations and dosages are given in Table 49.1. Dosages of 0.3 to 0.625 mg per day of conjugated equine estrogen, 0.5 mg per day of micronized estrogen, or 2 mg per day of estradiol valerate are adequate to maintain bone. Hormone replacement therapy can be delivered in a continuous or cyclic fashion. Estrogen and progesterone are taken daily for the entire month for continuous dosing, and estrogen is taken for days 1 to 25 and progesterone for days 1 to 10 or 14 for cyclic dosing. Preliminary studies suggest that calcium and estrogen may work synergistically, allowing lower doses of estrogen to be used. Bone mineral density should be followed during ERT since 15% of women continue to lose bone and may require a higher dose of estrogen, or a bisphosphonate or calcitonin. (See Osteoporosis and Osteomalacia.)
Although cardiovascular death rates increase exponentially with age, the rate of increase begins in women aged 65 to 74 years rather than at menopause. Age at menopause is inversely correlated with risk of cardiovascular disease.
Three meta-analyses of observational studies have demonstrated an association of ERT use in women with a reduction in heart disease by half. Current use of estrogen is the factor most strongly associated with reducing risk, and prolonged use is the second most important factor. The association occurs whether or not cardiovascular disease risk factors are present. Preliminary studies suggest that the effects are similar when progesterone is added.
However, long-term prospective studies are needed to decide if the cardiovascular benefit of ERT is as great as that suggested by epidemiologic studies. Estrogen users are healthier, more health conscious, and seek more medical care than women not on estrogen, factors that confound interpretation of these results. The benefit of ERT on overall mortality comes from cardiovascular health, and that benefit needs to be more clearly defined. Of particular concern, a randomized, controlled trial of estrogen with progesterone replacement in women with established coronary disease did not find that estrogen improved cardiac outcome. The estrogen treatment group demonstrated increased mortality in the first year on therapy but improved outcomes in years 2 through 5, leading to no net benefit. Another evaluation of approximately 300 women with coronary artery disease found no benefit from estrogen for angiographic changes of atherosclerosis. These two studies suggest that estrogen is not beneficial for secondary prevention of cardiovascular disease; the results of a primary prevention trial are expected to be completed in the next 3 years.
Observational studies have suggested that estrogen may be neuroprotective. Proposed mechanisms include increased synthesis of neurotransmitters, suppression of apolipoprotein E, and increased cerebral blood flow. Case-control studies of women with and without dementia and epidemiologic studies have demonstrated mixed results. Studies of estrogen in women with mild dementia demonstrate improved memory, orientation, and calculation skills, but these studies are small and limited by selection bias. A placebo-controlled trial of estrogen replacement given to 120 women with early to moderate Alzheimer’s dementia for 1 year found no improvement in affective or cognitive outcomes. A primary prevention trial is ongoing. (See Dementia.)
Evidence that estrogen causes or promotes breast cancer is strong. Breast cancer is associated with nulliparity, early menarche, and late menopause. Early oophorectomy protects against breast cancer. Whether ERT causes breast cancer is less clear. Two of the four meta-analyses found no increased risk of breast cancer with ERT; the remaining two found a relative risk of 1.3 and 1.06. These meta-analyses found that women using estrogen for 5 years or less had no increased risk of breast cancer but that treatment for 15 years or more was associated with a 30% increased risk.
Meta-analyses may underestimate the actual risk of breast cancer since women on estrogen are more likely to have had oophorectomy, more physician visits, and more preventive care and screening for breast cancer prior to estrogen use. The largest study evaluating estrogen use by postmenopausal women, the Nurses Health Survey, found that women currently using estrogen had an increased risk of breast cancer but that past users did not. The few studies that have evaluated the estrogen-progesterone combination show inconsistent results, with a suggestion of an increased risk, specifically in two of the larger cohort analyses by a collaborative group at the National Cancer Institute and the Nurses Health Study. There is some suggestion that cyclic therapy may worsen the risk, but there is insufficient information on the use of continuous progesterone to compare. Similarly, there is not adequate information to discriminate the effects of micronized and synthetic progesterones. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found increased breast density with medroxyprogesterone or micronized progesterone, cyclically or continuously.
Hormone therapy in women with a history of breast cancer is controversial and under study. Opponents believe that it will activate micrometastasis; proponents believe that the presumed cardiovascular benefits and improved bone mineral density outweigh the risk in women successfully treated for breast cancer.
Unopposed estrogen (either endogenous or exogenous) increases the risk for endometrial cancer by 2% to 8%. Progesterone was not usually used with estrogen until discovery of this association. The risk of endometrial cancer increases with increasing duration of use in the usually prescribed dosages; risk is also probably increased with lower dosages. Any mode of administration that results in significant systemic levels of estrogen has similar effects on the endometrium. Most cancers caused by exogenous estrogen use are detected as early, low-grade lesions in the course of investigation of bleeding. (See the section on postmenopausal bleeding in Gynecologic Diseases and Disorders.) Aggressive, anaplastic endometrial cancers also can arise during estrogen therapy.
Progesterone reduces or negates the risk of endometrial cancer associated with estrogen. Endometrial hyperplasias without atypia usually can be treated with progestins. Those with atypia are treated surgically. The best proven therapy to prevent hyperplasia is to use a progestin at least 10 to 12 days per month. Daily low-dose combination therapy is also effective.
There is no evidence that estrogen increases the risk of ovarian cancer and little information on the effects of estrogen on vulvar or cervical cancer.
The potential benefits of estrogen are such that therapy should be discussed with all postmenopausal women with life expectancy sufficient to realize a benefit. Women at high risk for osteoporosis or with established osteoporosis should be considered for long-term therapy, since estrogen is most clearly beneficial for osteoporosis. The answer is less clear for cardiovascular and cognitive benefits.
Women with breast or endometrial cancer should not be given ERT. Undiagnosed vaginal bleeding or active thromboembolic disease are also contraindications. Whether to treat those with a history of breast or endometrial cancer is being studied. Other conditions, including a history of gallbladder disease and menstrual migraine headaches, are considered relative contraindications to ERT. Continuous estrogen dosing may prevent such headaches.
Estrogen is delivered orally, topically to vaginal mucosa, or by the transdermal route (see Table 49.1). Intramuscular estrogen is not recommended. Nonvaginal preparations that ensure systemic treatment are preferred if systemic effects are desired. Estrogen may be given daily or cyclically, since efficacy does not differ. However, each regimen has characteristics that may affect adherence. The addition of medications mid-month or the resumption of withdrawal bleeding may dissuade some from using cyclic therapy; the uncertainty of vaginal bleeding may dissuade others from continuous therapy. The optimal dosage is also not clearly defined. It is prudent to use the lowest effective dose of estrogen to minimize side effects and ensure symptom relief or disease prevention. Conjugated equine estrogen 0.625 mg and 50 μg of 17β-estradiol stabilize bone, and both are associated with improved cardiovascular health, but little information is available on lower doses of estrogen.
With an intact uterus, progestins—most commonly medroxyprogesterone acetate—must be given to avoid the increased risk of endometrial cancer. Progestins may be given cyclically (10 to 14 days per month) or continuously. With cyclic therapy, 80% of women experience withdrawal bleeding. Endometrial biopsies reveal hyperplasia rates to be ≤ 1%. Continuous therapy diminishes bleeding and protects against endometrial hyperplasia; amenorrhea is achieved in 50% to 90% of women at 12 months of therapy, and endometrial biopsies are atrophic or hypotrophic in 50% to 75%. (See Gynecologic Diseases and Disorders.)
The most common adverse effect of estrogen is breast tenderness, which usually subsides after 2 to 3 months. If tenderness is troublesome for more than 4 months, the dose can be reduced but with less clear benefit. Headaches and rarely idiosyncratic elevation in blood pressure have been described. The adverse effects of progesterone include fluid retention, depression, and irritability. Estrogen therapy has consistently been found to increase the risk of venous thromboembolism two- to fourfold. One study found risk factors to be lower-extremity fracture, cancer, the first 90 days following inpatient surgery or nonsurgical hospitalization, and a history of myocardial infarction. Women using aspirin or statins were found to be at lower risk.
Only about 10% of American postmenopausal women receive ERT. Reasons women report for having started ERT are that it was recommended by a physician, they needed symptom relief, and they received reassurance that the cancer risk is low. Women most likely to begin ERT have higher socioeconomic status, lower body weight, and an active life style. Studies show that 20% to 30% of women never fill the prescription for ERT, 10% use it sporadically, and 20% stop treatment within 9 months. The reasons women give for stopping treatment include these: that the symptoms abated, the symptoms were not adequately alleviated, the regimen was too complex, and the adverse effects were unacceptable.
Testosterone levels decrease by 28% at menopause because of a decrease in adrenal androstenedione. Testosterone increases libido in women whose baseline testosterone levels are low. Low testosterone levels are correlated with higher fracture risk in women. There have been no studies of testosterone alone in women with osteoporosis, but in studies comparing estrogen-testosterone implants with estrogen alone, the combination demonstrated either greater or comparable bone mineral density. One study demonstrated that the combination produced higher markers of bone formation and similar suppression of resorption. Adverse effects of testosterone include mild hirsutism, acne, and decreased high-density lipoprotein cholesterol.
The decline in testosterone levels has been associated in some studies with symptoms of decreased libido, decreased energy, decreased muscle strength, increased fat mass, and low bone mass. Testosterone replacement in men with low levels of testosterone has resulted in reports of modest increase in bone mass, gains in strength, decrease in body fat, and increase in lean body mass. The long-term effects of testosterone replacement are not fully known. Prostate-specific antigen levels increase very little in studies of up to 3 years’ duration, but the number of men included in clinical trials has been very small. To date, there, are no data to address whether androgens enhance the progression of preclinical to clinical prostate cancer. Nested case-control studies from two large population-based epidemiologic studies have revealed contradictory results regarding an association between baseline testosterone levels and subsequent risk of developing prostate cancer. Men receiving testosterone replacement should be monitored for changes in prostate examination or increases in prostate-specific antigen level. Additional adverse effects that should be monitored are increased hematocrit and precipitation of sleep apnea. Testosterone preparations that are aromatized to estrogen do not appear to affect lipid levels; the effects of testosterone on cardiovascular risk are not known. Testosterone may be given intramuscularly, via patch (scrotal or transdermal), or as a topical gel.
See Endocrine and Metabolic Disorders.
See Endocrine and Metabolic Disorders.
See Endocrine and Metabolic Disorders.
■ Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med. 2000;132(9):689–696.
This analysis of venous thromboembolic events from 2763 women with known coronary artery disease receiving estrogen with progesterone or placebo for 4 years revealed that women receiving the estrogen and progesterone combination were more likely to experience a thrombotic event (34 events versus 13 events in the placebo group; relative hazard 2.7). There was no trend for decreasing relative hazard over time for deep-vein thrombosis (in contrast to the suggestion that any thrombotic event from estrogen would occur in the first few months following the initiation of therapy), but there was decreasing trend for pulmonary emboli after the first 2 years. Baseline characteristics that predicted venous thrombosis in multiple regression analysis were advanced age and assignment to hormone therapy. During the study, risk for thrombosis increased among women with a lower-extremity fracture or cancer, and increased in the first 90 days following inpatient surgery or nonsurgical hospitalization and following myocardial infarction. Risk was substantially diminished in women using aspirin or statins. These findings are consistent with observational studies that suggest that estrogen therapy increases the risk of thrombotic events approximately two- to fourfold.
■ Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med. 2000;343(8):522–529.
Women with coronary artery disease (N = 309) were randomized to receive estrogen, estrogen plus medroxyprogesterone, or placebo for 3 years. Baseline and follow-up coronary angiograms were analyzed to assess changes in atherosclerosis measured by minimal coronary-artery diameter changes. Several secondary angiographic and cardiovascular events were evaluated. No significant differences could be found between active treatment and placebo for minimal coronary-artery diameter, rates of coronary artery revascularization, hospitalization for unstable angina, stroke, transient ischemic attack, or death. This study adds to the literature that demonstrates that estrogen has no beneficial effect on coronary artery disease in women in whom atherosclerosis is already present. It adds information that neither unopposed nor opposed estrogen have an effect. We continue to await the results of the Womens Health Initiative to answer questions about the ability of estrogen to prevent atherosclerotic disease.
■ Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280(7):605–613.
This randomized clinical trial was conducted to determine whether estrogen replacement therapy alters the risk of coronary events in women with established coronary disease. A total of 2763 women (mean age 67 years) were followed for 5 years and assessed for myocardial infarction, angina, or death. The final analysis found no difference between the placebo and treatment groups. The group receiving estrogen had more cardiac events in the first year after initiation of therapy than did the placebo group. Lipid levels and primary cardiac events and nonfatal myocardial infarction improved with estrogen treatment in years 2, 3, 4, and 5. The discussion points out that the mechanism by which estrogen increased risk for coronary disease in the first year would need to be determined so that the observed “benefit” in the subsequent years could be further evaluated. The trial did find that although all of these women had established coronary disease, 90% had elevated cholesterol levels and only 30% were receiving β-blocker therapy. This trial does not address the potential of estrogen replacement therapy for primary prevention.
■ Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA. 2000; 283(8):1007–1015.
This reports a randomized clinical trial of estrogen replacement (either 0.625 or 1.25 mg/dL) or placebo given to 120 women with mild to moderate Alzheimer’s disease. A battery of cognitive tests, functional assessments, and mood evaluations were performed. There was no benefit found in any area of cognition or performance in any group. The authors discuss why estrogen may in theory be useful as a preventive agent (the studies to assess this are still ongoing) but appears not to be beneficial in the treatment of Alzheimer’s disease in older women.
■ Tenover JL. Testosterone and the aging male. J Androl. 1997;18(2):103–106.
This is a review of the information available on the use of testosterone specifically in older men with the typical decline in testosterone that accompanies aging and comorbidity. It critically examines the data available and highlights the lack of uniformity of the populations examined to date. The review outlines testosterone replacement effects on changes in body composition, bone, sexual behavior, cognition, and mood, as well as the risk of testosterone to prostate, erythropoiesis, and serum cholesterol.
Anne M. Kenny, MD
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