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Estrogen Use and Postmenopausal Women

National Institutes of Health
Consensus Development Conference Statement
September 13-14, 1979

Confernce artwork, a smiling post-menopausal woman.

Please see more recent conference statement "NIH State-of-the-Science Conference on 
Management of Menopause-Related Symptoms
" published in 2005

This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/.

This statement was originally published as: Estrogen Use and Postmenopausal Women. NIH Consens Statement 1979 Sep 13-14;2(8):45-48.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Estrogen Use and Postmenopausal Women. NIH Consens Statement Online 1979 Sep 13-14 [cited year month day];2(8):45-48.

Introduction

A Consensus Development Conference on Estrogen Use and Postmenopausal Women was held at the National Institutes of Health September 13-14, 1979. The meeting was scheduled to explore the risks and benefits of estrogen use, which are of great interest to the nation's 31 million postmenopausal women and their physicians.

Among the subjects addressed were the benefits of estrogen use, including treatment for menopausal symptoms and possible prevention of osteoporosis; hazards of estrogen use; relative risks and benefits of various types of estrogen therapy; economic issues; and indications for and contraindications to estrogen use.

At NIH, consensus development conferences bring together biomedical research scientists, practicing physicians, consumers, and others as appropriate, in an effort to reach general agreement on the safety and efficacy of a medical technology. That technology may be a drug, device, or medical or surgical procedure.

This summary is based on the three position papers prepared for the conference, the response of the panel, and the general discussion by the audience, followed by an analysis by the panel and other invited conference participants. All conclusions presented below represent the general consensus that was reached.

In approaching the topic, the group first reviewed the evidence for the efficacy of estrogens in treating specific conditions associated with the menopause. It was accepted that estrogens are more effective than placebo in decreasing the frequency and/or severity of vasomotor symptoms (hot flashes and sweating). The questions that remain to be answered include whether vasomotor symptoms represent a homogeneous entity with a single cause and why some patients require much larger doses than average to control symptoms. There was general agreement that the decision of whether to initiate therapy should depend on the severity of symptoms and the patient's perceived need for relief and that the lowest effective dose should be utilized. The occurrence of hot flashes naturally declines over a period of time, and unnecessary prolongation of therapy should be avoided.

It is recognized that estrogens are effective in overcoming the atrophy of the vaginal epithelium (wall) and the associated symptoms, which may include dryness, burning, itching, and pain on intercourse. It was suggested that the possible relationship of urinary tract symptoms to estrogen lack be more thoroughly investigated. Attempts to avoid systemic effects by treating vaginal symptoms with local application of estrogen-containing creams have been common. However, evidence now exists that the estrogens in these creams may be absorbed rapidly into the bloodstream. The biological consequences of this absorption are undetermined and require study.

There is no evidence at present to justify the use of estrogens in treatment of primary psychological problems. Surveys have shown no established specific or temporal association of sleep patterns, mental performance, mood, or psychological state with menopause or estrogen deprivation. On the other hand, in preliminary intervention studies comparing estrogens to placebo, effects on sleep latency and REM sleep have been noted. Some improvement in mental well-being in women receiving estrogens may be secondary to alleviation of physical symptoms.

The group acknowledged the validity of three randomized trials indicating that exogenous estrogens can retard bone loss if given around the time of the menopause. Except for dietary calcium, which appears to decrease bone loss to a lesser extent, other substances have not been shown to have such an effect. It is inferred but not proven that this retardation of bone loss will prevent the ultimate development of osteoporosis and attendant fractures. Case-control studies not yet published but discussed at the meeting report an association of estrogen use with a decreased risk of osteoporosis-related fractures. However, more data are definitely needed before the efficacy of estrogens in preventing fractures can be established. An inconsistency was noted: namely, in the randomized trials, accelerated bone loss following discontinuation of estrogen use resulted in loss of any favorable effect on bone mass, whereas in the case-control studies, use of estrogens at any time in the past conferred some protection against fractures. Identification of patients at increased risk of osteoporosis would be desirable because of the strong possibility of successful prophylaxis. One high-risk group in which to investigate possible benefits of estrogens consists of patients who already have developed osteoporosis and sustained fractures. Estrogen administration represents a promising approach to prevention of the widespread problem of hip fracture.

There is no convincing evidence that estrogens in customary doses increase the risk of thromboembolic phenomena, stroke, or heart disease in women who have undergone natural menopause. Although it was once hoped that estrogens would protect against heart disease in aging women, this effect has not yet been demonstrated. One promising approach would be to devise a more physiological mechanism for estrogen replacement. Because oral therapy results in the delivery of supraphysiological concentrations of estrogens to the liver, it can exert an exaggerated effect on lipoprotein metabolism, blood coagulation, and other important processes.

The group then reviewed the evidence for adverse effects associated with postmenopausal estrogen use. In the absence of exogenous estrogens, the incidence rate of endometrial cancer is approximately 1 per 1,000 postmenopausal women per year. It was recognized that this rate increases several fold beginning after approximately 2 to 4 years of use of 0.625 or 1.25 mg of conjugated estrogens per day. Evidence was presented that the risk of endometrial cancer increases with the duration of use and declines after discontinuation. Estrogen use is most strongly associated with lesions of the lowest grade and earliest stage. Of interest is the temporal relationship of the number of estrogen prescriptions and the incidence of carcinoma of the endometrium; both rising steadily until 1976 and then declining in parallel. Although the incidence of carcinoma of the endometrium rose, mortality from the disease did not increase. A considerable part of this discrepancy may be attributable to early detection and the high cure rate.

Cystic hyperplasia of the endometrium, which is considered a premalignant condition, has been associated with unopposed estrogen, whether endogenous (as in anovulatory states) or exogenous. The cost effectiveness of sampling the endometrium in order to screen for endometrial hyperplasia and cancer in completely asymptomatic women currently or potentially receiving estrogens is uncertain at present. It was agreed that suction curettage is effective in evaluating the endometrium and that the cause of any bleeding must be determined. A report indicating that uterine bleeding may sometimes be absent early in the course of endometrial cancer was presented at the meeting. Hence, prudence would suggest that, even in the absence of bleeding, the endometrium should be sampled before and during estrogen therapy (on a yearly basis).

The use of progestins for several days of each estrogen treatment cycle has been demonstrated to decrease the occurrence of endometrial hyperplasia and might also reduce the associated risk of developing cancer of the endometrium. Before the application of combined therapy becomes established, risks of the various progestins must be adequately evaluated.

The association of estrogens and breast cancer in experimental animals is well known. Careful review of several well conducted case-control studies has not revealed such a relationship in humans. In two followup studies of estrogen users, varying associations were encountered. Compared to data on the general population, one showed an excess of cases in years 5 to 9, but the other only after 15 years, of estrogen use. Incidence rates of breast cancer have not changed in parallel with those of estrogen use, as have those of endometrial carcinoma. Because of the high incidence and relatively poor prognosis of breast cancer, any possible association with estrogen use remains a concern.

There are experimental data indicating that estrogens can induce the production of lithogenic bile, and in one study a 2.5-fold relative risk for the development of surgically confirmed gallbladder disease was observed.

One area of general agreement was that the patient should be given as much information as possible about the evidence for the effectiveness of estrogens in treating specific menopausal conditions and the risks that their use may entail. Patients must be kept continually informed of new findings as they arise. Given the current state of knowledge, no general recommendation, applicable to all postmenopausal women, can be made.

Some concern was expressed about women who have undergone menopause many years in advance of the normally expected age. Although most of the participants felt intuitively that approximation of the normal physiological state through hormone replacement therapy would be best, there are no carefully controlled studies comparing the risks and benefits in these circumstances. Support was voiced for conserving the ovaries of young women when possible.  

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