Estrogen prophylaxis

Date: Nov, 1990

Estrogen Prophylaxis

Burden of Suffering

An estimated 1.3 million osteoporosis-related fractures occur each year in the United States. [1] Most of these injuries occur in postmenopausal women. It has been estimated that about one-quarter of all women over age 60 have spinal compression fractures and about 15 percent of women sustain hip fractures during their lifetimes. [2,3]

Hip fractures are associated with significant pain and disability, decreased functional independence and high mortality. There is a15 to 20 percent reduction in expected survival in the first year following a hip francure. [4] Hip fractures cost the United States over $7 billion each year in direct and indirect costs. [5] Important risk factors for osteoporosis include advanced age, female sex, Caucasian or Asian race, slender build, bilateral oophorectomy prior to natural menopause, smoking and alcohol abuse.

Efficacy of Chemoprophylaxis

Retrospective studies [6-9] and clinical trials [10-17] provide good evidence that estrogen replacement can reduce the rate of bone loss in postmenopausal women. Although it is likely that this physiologic effect on bone mineral content can reduce the incidence of fractures and other clinical measures of osteoporosis, prospective evidence linking estrogen to fracture rates has been difficult to obtain because of the long interval between the onset of osteoporosis and the occurrence os symptoms. There is, however, a large body of evidence from retrospective studies, [6,8,9,18] cross-sectional studies, [19] cohort studies and nonrandomized clinical trials [20, 21] to suggest that estrogen replacement is associated with a decreased rate of fractures. These findings do not provide conclusive evidence of efficacy, because of the potential influence of selection bias, recall bias and confounding in many of these studies. It may be impractical, however, to carry out randomized controlled trials of sufficient duration to provide definitive evidence that estrogen replacement can lower fracture rates.

The sue of estrogen to prevent osteoporosis can also have other benefits. Estrogen can reduce the incidence of vasomotor flushes and vaginal atrophy. Perhaps the most important benefit of estrogen, however, is its ability to improve lipoprotein profiles> many studies in recent years have demonstrated an association between the use of estrogen and reduced mortality from coronary artery disease. [22-28] At the same time, potentially important side effects are associated with the long-term use of unopposed estrogen.

Prolonged use of unopposed conjucated estrogens increases the risk of endometrial hyperplasia and endometrial concer. [29-33] Although these tumors are usually at an early stage and minimally invasive at diagnosis, an increased risk of disseminated endometrial cancer has been documented. [29,30] combining estrogen with cycled progestins may reduce the risk of cancer, [34] but conclusive evidence of an effect on endometrial cancer mortality is lacking. [35] In addition, some women may dislike the menstrual bleeding produced by progestins and discontinue use of the drug. Evidence is inconstent regarding the reported association between estrogen therapy and such diseases as breast cancer and gallbaldder disease. [35-40]

Effectivenesses of Counseling

Few studies have examined the effectiveness of physician counseling on estrogen use. Evidence suggests, however, that compliance with estrogen therapy is generally poor among postmenopausal women, in part becasue of the perceived risk of developing cancer and the unpleasant side effects. One author, [41] citing personal communications from the investigators, reported that 20 to 30 percent of women in the Massachusetts Women's Health Survey never had their estrogen prescriptions filled, because thay were not convinced of the benefits and safety of therapy. Of those who began therapy, 20 percent discontinued the drug within nine months.

Compliance with estrogen replacement is often limited by the inconvenience associated with daily administration. The availability of transdermal estrogen and new dosage regimens may offer potential means of reducing the inconvenience, but the effectiveness of alternative routes of administration in enhancing long-term compliance has yet to be proved. [41]

Recommendations of Others

The American College of Obstetricians and Gynecologists recommends consideration of estrogen therapy in all hypoestrogenic (including postmenopausal) women. [42] A 1984 National Institutes of Health consensus development conference recommended that estrogen therapy after menopause should be considered in high-risk women who have no medical contra-indications and who are willing to adhere to a program of careful follow-up. [1] The Canadian Task Force on the Periodic Health Examination advises agains widespread use of estrogen to prevent osteoporosis, but recommends offering therapy to women who appear to be at increased risk on an individual basis. [43]


Although there is good evidence that estrogen therapy can reduce bone loss in postmenopausal women, the evidence is insufficient to recommend routine prescription of estrogen. Definitive evidence that estrogen replacement therapy can prevent bone fractures or other clinical measures of osteoporosis requires a lengthy, randomized, controlled trial that may be difficult to perform for logistic reasons.

In the absence of definitive evidence, it is difficult to determine with certainty whether the benefits of estrogen replacement (e.g., preservation of bone mass, improved lipoprotein profiles, cardiovascular mortality reduction, reduced menopausal symptoms) outweigh its potential risks (e.g., endometrial cancer) and inconvenience (e.g., vaginal bleeding, daily administration) in all postmenopausal women. In some asymptomatic women, however, such as those at increased risk and those with early indications of low peak bone mass, the benefit-risk ratio is lilely to be more favorable. It is especially important for such women to receive counseling about potential benefits and risks so that they can make an informed decision about therapy. The perimenopausal period is an important time of such decisions> the evidence is less clear regarding the benefits of beginning estrogen treatment at older ages. [44]

Clinical Intervention

Although estrogen replacement is not recommended all postmenopausal women, estrogen therapy should be considered in asymptomatic women who are at increased risk for osteoporosis (e.g., Caucasian or Asian women, women with low bone-mineral content, those with a slender build, those with a history of early menopause or bilateral oophorectomy prior to menopause) and who are without known contraindication (e.g., a history of undiagnosed vaginal bleeding, active liver disease, thromboembolic disorders, hormone-dependent cancer). These pateints should receive information on the risks and consequences of osteopptic fractures and the risks and benefits of hormonal theraphy. All women should receive information about potential alternatives for osteoporosis prevention, such a weight-bearing exercis and dietary calcium supplementation.

Women consenting to estrogen theraphy should be counseled about the various estrogen and progestin preparations and routes of administration that the available. One common regimen is 0.625 mg of conjugated equine estogen on days 1 to 25 (or daily), with the addition of 5 to 10 mg of medroxyprogesterone acetate on the last 12 days of the cycle. Dosages should be modified to reduced side effects such as nausea, headache, breakthrough bleeding, weight and breast tenderness.

NTE: See also the relevant Task Force background paper: Mann K. Wiese WH, Stachencko S. Preventing postmenopausal osteoporosis and related fractures. In: Goldbloom RB, Lawrence RS, eds. Preventing disease: beyond the rhetoric. New York: Springer-Velag, 1990.


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