Estrogen Replacement Therapy
Estrogens are used for the treatment of moderate to severe vasomotor symptoms and other symptoms, including vulvar and vaginal atrophy, associated with menopause and for the prevention and treatment of osteoporosis. When estrogens are used alone, such therapy is referred to as estrogen replacement therapy (ERT); when estrogens are used in combination with progestins, such therapy usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy. Another therapeutic option for postmenopausal women involves use of estrogens in combination with an estrogen agonist-antagonist (e.g., bazedoxifene); this combination is referred to as a tissue-selective estrogen complex (TSEC). Long-term therapy with estrogens is associated with an increased risk of endometrial hyperplasia and/or carcinoma in postmenopausal women; however, use of progestins in conjunction with estrogen therapy (HRT) substantially reduces the risk. Women with an intact uterus must receive progestin in addition to estrogen to avoid the increased risk of endometrial carcinoma; long-term use of estrogen alone in women with an intact uterus is not recommended. As an alternative to progestin therapy, the use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces the risk of endometrial hyperplasia. HRT is associated with increased risks of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli, and deep-vein thrombosis. ERT is associated with increased risks of stroke and deep-vein thrombosis. Because of the potential risks associated with HRT and ERT, the benefit to risk should be assessed for each patient, considering alternative therapies as part of this assessment. If ERT or HRT is used, it should be prescribed at the lowest effective dosage and for the shortest duration consistent with treatment goals and risks for the individual woman.
In the past, estrogens were used for prevention of cardiovascular disease in postmenopausal women; however, recent data indicate that use of ERT or HRT does not decrease the incidence of cardiovascular disease, and estrogen replacement therapy alone (ERT) or combined with progestins (HRT) should no longer be used for the prevention of cardiovascular disease.
While estrogen or estrogen/progestin therapy is effective for the management of certain menopausal symptoms and for the prevention and treatment of osteoporosis, results of a recent controlled study (Women's Health Initiative [WHI] study of estrogen plus progestin) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism. Results of the WHI study of estrogen alone indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis. Results of the WHI also showed that HRT had no clinically important effect on measures of depression, insomnia, sexual function, or cognition (i.e., health-related quality-of-life measures) in women without menopausal symptoms. Based on the WHI findings, recommendations on the appropriate use of hormone therapy have been revised. Because the risks of hormone therapy exceed the benefits for the prevention of chronic diseases in postmenopausal women, experts state that ERT or HRT should not be used for the prevention of chronic conditions in postmenopausal women. The American Heart Association (AHA), the American College of Obstetricians and Gynecologists (ACOG), FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention). ACOG, FDA, and the manufacturers also recommend that women receiving hormone therapy solely for the prevention of postmenopausal osteoporosis consider alternative therapy (e.g., alendronate, raloxifene, risedronate). Although these recommendations are based on results of the WHI study that evaluated one specific estrogen (conjugated estrogens 0.625 mg) and one estrogen/progestin preparation (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg), the risks should be assumed to be similar with other hormonal regimens, including different dosages of these drugs as well as other estrogen/progestin combinations not studied in WHI, in the absence of comparable data to the contrary.
While the risks of HRT are likely to exceed the benefits in most women receiving these agents for prevention of chronic diseases (e.g., cardiovascular disease, osteoporosis), the long-term safety of short-term use of HRT for the management of menopausal symptoms remains to be precisely established. Estrogen or estrogen/progestin therapy is the most effective therapy for the relief of vasomotor symptoms such as hot flushes (flashes) and sleep disturbances. The fixed combination of conjugated estrogens with bazedoxifene acetate also is used for the management of moderate to severe vasomotor symptoms associated with menopause. Estrogen or estrogen/progestin therapy also is effective in the treatment of genitourinary symptoms such as vaginal dryness; however, the use of topical vaginal preparations should be considered when only vulvar and vaginal symptoms are being treated. The decision to use estrogen or estrogen/progestin therapy for management of menopausal symptoms should be individualized taking into account the woman's preference, her risk for specific chronic diseases, and the presence and severity of menopausal symptoms. ACOG, FDA, and the manufacturers recommend that women who choose hormone therapy for the relief of menopausal symptoms receive such therapy for the shortest possible time and in the lowest effective dosage; women also should regularly consult their clinician and undergo regular breast cancer screenings. ACOG recommends against routine discontinuance of systemic estrogen therapy when a women reaches 65 years of age, since some women 65 years of age or older may continue to need systemic hormone therapy for management of vasomotor symptoms. Continuation of hormone therapy for management of vasomotor symptoms should be individualized taking into account the woman's symptoms and the risks and benefits of hormone therapy, regardless of age.
Regardless of a woman's age or duration of hormone therapy, discontinuance may be associated with recurrent vasomotor symptoms in approximately 50% of women. There is insufficient evidence to recommend one method of stopping hormone therapy (e.g., abrupt discontinuance, dosage tapering) over another to prevent recurrent symptoms.
Lifestyle modifications that may help reduce menopausal symptoms such as hot flushes include smoking cessation, dietary manipulation (avoid/limit spicy foods, caffeine, and alcohol), stress reduction, and loose or layered clothing. There is increasing evidence that drugs other than hormone preparations may alleviate certain menopausal symptoms. For women experiencing vasomotor symptoms, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), gabapentin, or clonidine has been used for treatment. SSRIs, SNRIs, and gabapentin have been shown to be effective for treatment of vasomotor symptoms in randomized, controlled trials, while evidence supporting the efficacy of clonidine is limited. For symptoms such as vaginal dryness, topical administration of estrogen alone usually is effective. Although only limited amounts of estrogen are systemically absorbed from vaginal tablets and rings, limited data are available regarding long-term safety of vaginally administered estrogen.
Estrogens also are used in the treatment of a variety of other conditions associated with a deficiency of estrogenic hormones, including female hypogonadism and castration and primary ovarian failure. In addition, estrogens also may be used in the treatment of abnormal uterine bleeding caused by hormonal imbalance not associated with organic pathology; however, progestins are usually preferred.
Prevention in Postmenopausal Women
Estrogen replacement therapy (ERT) is effective for the prevention of osteoporosis in women and has been shown to reduce bone resorption and retard or halt bone loss associated with estrogen deficiency in postmenopausal women. Oral estrogens (e.g., estradiol, estropipate, conjugated estrogens) and transdermal estrogens (e.g., estradiol) are used adjunctively with other therapeutic measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and the progression of osteoporosis in postmenopausal women. The fixed combination of conjugated estrogens with bazedoxifene acetate also is used for the prevention of osteoporosis.
In a placebo-controlled study in postmenopausal women, administration of estrogen replacement therapy (conjugated estrogens) with (HRT) or without (ERT) a progestin for 36 months was associated with a 1.7% increase in hip bone mineral density (BMD) and 3.5-5% increase in lumbar spine BMD compared with baseline, while placebo recipients lost an average of 1.7% in hip BMD and 1.8% in spinal BMD. Increases in BMD observed in women receiving estrogen replacement therapy without a progestin (ERT) generally have been essentially the same as those observed in women receiving combined estrogen/progestin therapy (HRT).
In case-controlled studies in Caucasian women, estrogen replacement therapy has been associated with a substantial (about 60%) reduction in the incidence of hip and wrist fractures in those in whom estrogen therapy was initiated within a few years of menopause; some studies suggest that estrogens may also reduce the incidence of vertebral fracture. In the WHI study, there was a 24% reduction in total fractures in postmenopausal women receiving HRT compared with those receiving placebo and a 30-39% reduction in total fractures in women receiving ERT compared with women receiving placebo. The number of cases of hip fracture per 10,000 patient-years of exposure was 10 or 15 in women receiving HRT or placebo, respectively. The number of cases of hip fracture per 10,000 patient-years of exposure was 11 or 17 in women receiving ERT or placebo, respectively. Estrogen replacement therapy reportedly prevents further estrogen deficiency-induced bone loss in postmenopausal women when started up to 6 years after menopause, but such therapy does not appear to restore bone mass to premenopausal levels. In addition, when estrogen therapy is discontinued, bone mass declines at a rate similar to that occurring in the immediate postmenopausal period. It has been suggested that optimum estrogen replacement therapy for the prevention of osteoporosis should be initiated within 5 years of menopause and be continued for long-term (exceeding 10 years); however, risks associated with such long-term use should be considered.
Caucasian or Asian women are at a higher risk for osteoporosis than black women. Other risk factors include premature ovarian failure; a family history of osteoporosis; a small, slim body frame; endocrine disorders such as thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, insulin-dependent diabetes mellitus (type 1, IDDM); cigarette smoking; drinking excessive amounts of alcohol; a sedentary lifestyle and/or lack of physical exercise; low body weight; and low dietary calcium intake. Premature ovarian failure (surgical or nonsurgical) hastens the onset of osteoporosis, and estrogen deficiency in premenopausal women (e.g., secondary to anorexia nervosa- or exercise-induced amenorrhea or to hyperprolactinemia) induces bone loss and may reduce peak bone mass.
While estrogen or estrogen/progestin therapy is effective for the prevention of osteoporosis in postmenopausal women, results of a recent controlled study (WHI study) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism. Results of the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis. Because the risks of hormone therapy exceed the benefits for the prevention of chronic diseases in postmenopausal women, experts state that ERT or HRT should not be used for the prevention of chronic conditions (e.g., osteoporosis) in postmenopausal women. ACOG, FDA, and the manufacturers recommend that women receiving hormone therapy solely for the prevention of postmenopausal osteoporosis consider alternative therapy. Alternative agents that can be used for the prevention of osteoporosis include alendronate, raloxifene, or risedronate. However, experience with these agents is not as extensive as with HRT. (See , , and .) In addition, alendronate and risedronate are associated with substantial adverse GI effects (e.g., esophagitis). (See Dosage and Administration: Administration, in and .)
Women being considered for estrogen replacement therapy should have no contraindications to estrogen therapy and should fully understand the risks associated with estrogen use and agree to regular medical examinations. The choice of estrogen replacement therapy, alendronate, raloxifene, or risedronate for the prevention of postmenopausal osteoporosis should be individualized, taking into account differences in tolerability and safety and individual preference. For all women, lifestyle modifications for healthy bones include a diet high in calcium (postmenopausal women should receive 1.2-1.5 g of calcium daily), adequate intake of vitamin D (as supplied by a multivitamin), and regular weight-bearing exercise such as walking or jogging. Whether additional preventive therapy generally should be offered to all women or just recommended for selected women at highest risk of developing osteoporosis remains to be established.
Although there is no biologic reason to suspect that the effects of estrogens would differ in nonwhite women, the efficacy of estrogen replacement therapy in preventing osteoporosis in nonwhite women has not been established to date.
Treatment in Postmenopausal Women
Estrogen replacement therapy has been effective in the treatment of osteoporosis in postmenopausal women and has been recommended as first-line therapy for women with osteoporosis. However, results of a recent controlled study (WHI study) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism. Results of the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis. Based on these findings, recommendations on the appropriate use of hormone therapy are being revised. The risks and benefits of long-term use of hormone therapy in the management of osteoporosis should be evaluated taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.
Estrogen replacement therapy produces the most marked benefits when begun soon (e.g., within 5 years) following menopause; such therapy also appears to be effective even when initiated many years after menopause in older women. Some clinicians suggest that prolonged therapy (e.g., at least 5 years) with estrogens is necessary since the beneficial effects of estrogen replacement therapy do not appear to persist after discontinuance of treatment.
Various estrogen-containing therapies (e.g., conjugated estrogens, estrogen/progestin combinations) have been used concomitantly with bisphosphonates (e.g., alendronate, etidronate) and calcium in the treatment of osteoporosis in postmenopausal women. In several clinical trials in postmenopausal women with osteoporosis, the combination of estrogen-containing therapy and alendronate resulted in a greater degree of suppression of bone turnover than either therapy given alone. In a placebo-controlled, 2-year clinical trial comparing monotherapy with alendronate (10 mg daily) or conjugated estrogens (0.625 mg daily) with the combination of these drugs at the same monotherapy dosages in postmenopausal women with osteoporosis not currently receiving antiresorptive therapy, combination therapy increased bone mineral density (BMD) (as determined by dual-energy radiographic absorption measurements) in the lumbar spine and femoral neck compared with either agent given alone or placebo (calcium 500 mg daily). A bone histology study in these patients indicated that the bone formed during therapy was of normal quality. Compared with calcium supplementation alone, bone turnover after 18 months was suppressed by 98% with combined alendronate-estrogen replacement therapy, 94% with alendronate therapy alone, and 78% with estrogen replacement therapy alone. In another comparative study in postmenopausal women who had osteoporosis despite hormone replacement therapy with estrogen (conjugated estrogens) or estrogen plus progestin (medroxyprogesterone) for at least 1 year (mean duration about 10 years), the addition of alendronate (10 mg daily) increased BMD (as determined by dual-energy radiographic absorption measurements) in the lumbar spine and hip trochanter compared with hormone replacement therapy alone at 12 months; all patients also received calcium and vitamin D supplementation. In both trials, the incidence of new fractures was similar across treatment groups. In these trials, sample size and study duration may have been inadequate to detect differences in fracture incidence with combination therapy, monotherapy with alendronate or estrogen, or placebo, and further studies are needed. The safety of combination therapy was similar to that with each antiresorptive agent alone.
Prevention in Women with Anorexia Nervosa
Estrogens have been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss and, thereby, reduce the risks of osteoporosis. However, results of various controlled and uncontrolled studies indicate that estrogens appear to benefit only a subset of low-weight (initial body weight less than 70% of ideal body weight) women with anorexia nervosa. Because data supporting use of estrogen therapy for the treatment or prevention of osteoporosis in female children, adolescents, or adults with anorexia nervosa are limited or lacking, the American Psychiatric Association (APA) concludes that therapy with estrogens alone does not appear to reverse osteoporosis or osteopenia, and unless there is weight gain, such therapy does not prevent further bone loss.Furthermore, many clinicians state that the decision to initiate estrogen therapy in these patients should be deferred until weight gain and normal menses have been restored, since artificially inducing menses carries the risk of supporting or reinforcing a patient's denial that she does not need to gain weight. For a complete discussion of diagnosis and treatment of anorexia nervosa and other eating disorders,
Cardiovascular Risk Reduction
While results from earlier observational studies indicated that estrogen replacement therapy or combined estrogen/progestin therapy was associated with cardiovascular benefit in postmenopausal women, results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) study indicate that use of estrogen replacement therapy (ERT) or combined estrogen/progestin replacement therapy (hormone replacement therapy, HRT) does not decrease the incidence of cardiovascular disease.
Substantial epidemiologic evidence has indicated that postmenopausal women receiving ERT may have a reduction of up to 50% in the risk of ischemic heart disease and a similar reduction in total mortality compared with women who have never received such therapy. In observational studies, the increase in life expectancy based on a reduced risk of coronary heart disease (CHD) in postmenopausal women receiving ERT has been estimated to be 2-3 years. While these studies generally enrolled healthy women, observational studies in women with preexisting coronary disease also suggest that ERT reduces the risk of reinfarction and CHD-related death. However, the conclusions of these studies have been criticized for methodological reasons.
Although some observational studies have shown a cardioprotective effect with estrogen alone or in combination with progestin, conflicting data have been reported in large prospective, randomized studies. In one of these studies (HERS), no overall cardiovascular benefit was reported with HRT in postmenopausal women with established coronary disease. In addition, results of the WHI study indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of cardiovascular disease and stroke in predominantly healthy postmenopausal women. Results from the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) does not affect the risk of CHD but is associated with a small increase in the risk of stroke in healthy postmenopausal women who have undergone a hysterectomy. In another randomized study, ERT (conjugated estrogens 0.625 mg daily) or HRT (conjugated estrogens 0.625 mg daily and medroxyprogesterone acetate 2.5 mg daily) was associated with reductions in LDL-cholesterol and increases in HDL-cholesterol concentrations but had no effect on progression of coronary atherosclerosis in women with established CHD.
In HERS, 2763 postmenopausal women with established CHD were randomized to receive HRT (conjugated estrogens 0.625 mg daily in conjunction with medroxyprogesterone acetate 2.5 mg daily) or placebo. After a follow-up averaging 6.8 years, HRT was not associated with an overall reduction in the rate of CHD events (e.g., nonfatal MI, CHD-related death). Based on year of randomization, women who received HRT experienced an increased incidence of CHD events during the first year and a lower incidence in the fourth year compared with women who received placebo. However, based on the entire 6.8 years of follow-up, a trend toward a lower or higher incidence of CHD over time was not evident. Analysis of data from 2 observational studies in postmenopausal women with cardiovascular disease (i.e., the Nurses' Health Study and a Group Health Cooperative study) indicate that the risk for a recurrent major coronary event in women with established coronary heart disease is increased early (up to 1 year) after initiation of HRT and decreases with long-term use. Women with CHD often have risk factors such as diabetes mellitus and obesity that influence the tendency to develop thrombosis, and any procoagulant effects of hormone therapy would be greatest in such women. Whether estrogen/progestin therapy (HRT) is associated in susceptible subgroups with immediate prothrombotic, proarrhythmic, or proischemic effects that are gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis (perhaps as a result of favorable effects on lipoproteins) requires further study.
The WHI was a long-term study sponsored by the National Institutes of Health (NIH) that focused on strategies that can potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women. One part of this initiative followed 16,608 predominantly healthy women (with an intact uterus) who were 50-79 years of age who received HRT (i.e., conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) or placebo. The goal of this 8.5-year study was to evaluate the relationship between HRT and CHD, stroke, pulmonary embolism, breast cancer, endometrial carcinoma, colorectal cancer, hip fracture, and death from other causes. The study was stopped early because health risks exceeded benefits over an average follow-up of 5.2 years. At the time the study was stopped, the increased number of cases of invasive breast cancer, CHD, stroke, and pulmonary embolism in the estrogen/progestin group relative to the placebo group was not counterbalanced by reductions in the number of cases of hip fracture and colorectal cancer. Estrogen/progestin therapy did not affect all-cause mortality.
In the WHI estrogen plus progestin study, there was a 29% increase in the incidence of heart disease in postmenopausal women receiving HRT compared with those receiving placebo. The number of CHD events (e.g., MI) per 10,000 patient-years of exposure was 37 or 30 in women receiving HRT or placebo, respectively. In addition, there was a 41% increase in the incidence of stroke in postmenopausal women receiving HRT compared with those receiving placebo. The number of cases of stroke per 10,000 patient-years of exposure was 29 or 20 in women receiving HRT or placebo, respectively.
Another part of the WHI initiative followed 10,739 predominately healthy women who were 50-79 years of age and had undergone a prior hysterectomy, and received ERT (conjugated estrogens 0.625 mg daily) or placebo. The goal of this study was to evaluate the relationship between ERT and CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fracture, and death from other causes. At the time the study was stopped (after nearly 7 years), results indicated that ERT did not affect the incidence of CHD or overall mortality but did increase the risk of stroke. There was a 39% increase in the incidence of stroke in women receiving ERT compared with those receiving placebo. Approximately 80% of all strokes were ischemic. The number of cases of stroke per 10,000 patient-years of exposure was 44 or 32 in women receiving ERT or placebo, respectively.
An ancillary substudy of the WHI examined the effect of ERT (conjugated estrogens 0.625 mg daily) or placebo on coronary-artery calcification in women 50-59 years of age at the time of randomization. Imaging of the coronary arteries 8.7 years after study start (7.4 years of treatment and 1.3 years after study completion) indicated that women who received estrogen had a lower prevalence and quantity of coronary-artery calcium than placebo-treated women. Intent-to-treat analysis showed that administration of estrogen reduced coronary calcification by 42%; in women with at least 80% adherence to study medication for 5 years, administration of estrogen reduced coronary calcification by 61%.
Based on the finding of no overall cardiovascular benefit observed in HERS and the WHI study and the lack of effect of ERT or HRT on angiographic progression of coronary artery disease, the AHA, ACOG, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).
If a woman with cardiovascular disease receiving long-term HRT experiences an acute cardiovascular event (e.g., MI) or is immobilized, discontinuance of HRT or administration of venous thrombosis prophylaxis during hospitalization should be considered to reduce the risk of thromboembolism. Decisions to resume HRT should be based on established noncoronary risks and benefits and patient preference.
Corticosteroid-induced Hypogonadism and Osteoporosis
Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the ovaries and testes, and such hypogonadism may be associated with bone loss. Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present.
Hormone replacement therapy (HRT, combined estrogen and progestin therapy) has been effective in increasing lumbar spine but not femoral neck bone mass density (BMD) in postmenopausal women with asthma or rheumatoid arthritis who were receiving chronic corticosteroid therapy. HRT in a control group of women receiving long-term low-dose corticosteroid therapy in one study appeared to prevent BMD loss at the lumbar spine, hip, and distal radius over the course of 1 year. While there currently are no well-designed studies establishing the preventive efficacy of HRT on corticosteroid-induced bone loss and radiographic vertebral fractures, data from existing studies suggest that HRT is adequate to prevent bone loss in postmenopausal women receiving low-to-moderate-dose corticosteroid therapy, and postmenopausal women receiving long-term corticosteroid therapy should be offered HRT if no contraindications exist. The protective efficacy of HRT in such women who are receiving moderate-to-high doses of corticosteroids remains to be established. Corticosteroid-treated women who develop fractures while receiving HRT or in whom HRT is not well tolerated should receive calcium and vitamin D supplementation along with bisphosphonate therapy (e.g., alendronate, risedronate) in an attempt to prevent bone loss and/or increase BMD as well as to prevent apoptosis of osteocytes and osteoblasts and reduce the risk of radiographic vertebral fractures.
There also currently are no controlled studies of HRT in premenopausal women receiving chronic corticosteroid therapy. However, observational studies in premenopausal female athletes with menstrual irregularities suggest that estrogen-progestin combination (e.g., oral contraceptive) use is associated with a higher adjusted bone mineral content and BMD relative to women who do not take estrogen-progestin combinations. Therefore, premenopausal women who develop menstrual irregularities (e.g., oligomenorrhea, amenorrhea) while receiving long-term corticosteroid therapy should be offered combined cyclic estrogen and progestin therapy (e.g., estrogen-progestin combination oral contraceptives) in an attempt to treat hypogonadism and possibly reduce the risk ofcorticosteroid-induced osteoporosis when contraindications to estrogen-progestin therapy are not present.
Some data from observational studies indicate that prior use of hormone replacement therapy (HRT), but not current HRT unless such use exceeds 10 years, is associated with reduced risk of Alzheimer's disease. Estrogens have not been shown to prevent progression of Alzheimer's disease, and the American Academy of Neurology (AAN) recommends that estrogens not be used for the treatment of Alzheimer's disease.
Findings from the Women' Health Initiative Memory study (WHIMS; an ancillary study of the Women's Health Initiative [WHI] study in women 65 years of age or older without dementia at study entry) indicate that use of ERT (conjugated estrogens 0.625 mg daily) or HRT (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) does not improve cognitive function relative to placebo in these women and may adversely affect cognition. In the WHIMS study, more women receiving ERT or HRT had substantial and clinically important declines in the Modified Mini-Mental State Examination total score compared with women receiving placebo, suggesting that some women receiving these hormonal therapies experience detrimental effects. In addition, the rate of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. Women with relatively low baseline cognitive function were at particularly high risk for adverse cognitive effects. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.
Metastatic Breast Carcinoma
Estrogens are used in the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in postmenopausal women and in men. Estrogens are one of several second-line agents that can be used in certain postmenopausal women with metastatic breast cancer.
In males, estrogens are used for the palliative treatment of advanced carcinoma of the prostate; however, the risk of adverse cardiovascular effects of the drugs must be considered.
Estrogens also are used in combination with progestins for ovulation control in the prevention of conception and for the treatment of moderate acne vulgaris; estrogen-progestin combinations also are used in short-course, high-dose regimens in women for the prevention of contraception after unprotected intercourse (postcoital contraception, ''morning-after pills'') as emergency contraceptives.
Although in the past estrogens have been used for the prevention of postpartum breast engorgement, FDA has withdrawn approval of estrogen-containing drugs for this indication since estrogens have not been shown to be safe for use in women with postpartum breast engorgement. Data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to appropriate analgesic or other supportive therapy.
Estrogens have not been shown to be effective for any purpose during pregnancy.
For information on the uses of specific estrogens, see the individual monographs in 68:16.04.