Author Affiliation: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena.
In July 2002, initial results from the Women’s Health Initiative (WHI) randomized trial of combined estrogen plus progestin hormone therapy (CEE + MPA)1 and follow-up data from the Heart Estrogen/progestin Replacement Study (HERS)2 were published within weeks of each other. The increased risks associated with CEE + MPA therapy for postmenopausal women drew wide attention not only among the clinical professions, but also among the media, including front-page articles in major newspapers, feature stories in major weekly news magazines, and coverage by virtually all major television news programs. Neither women taking hormones nor their physicians could escape the media message: postmenopausal hormone therapy is dangerous.
Many women taking hormones were urged by their physicians to stop taking these medications immediately or decided to stop taking them on their own. At the time, anecdote, not evidence, answered women’s question, “What can I expect?” In this issue of JAMA, Ockene et al3 report the results of a systematic collection of data on symptoms after discontinuing CEE + MPA or placebo pills from 8405 of the 9351 participants in WHI who were still taking their assigned study drug on the stop date of the intervention (July 8, 2002). The WHI data and safety monitoring board had concluded in May 2002 that the risks of CEE + MPA treatment outweighed the benefits and recommended early stopping of the study.1 These data should be of great interest both for counseling women currently taking hormones who may be reluctant to stop, and for providing information about symptoms commonly attributed to the decline in ovarian hormones that occurs with the menopausal transition.
After discontinuing use of CEE + MPA or placebo, women most commonly reported hot flashes or night sweats, pain and stiffness, and fatigue and difficulty sleeping, but nearly 36.7% of women reported neither moderate nor severe symptoms after they stopped taking CEE + MPA. Among women who did not have a history of vasomotor symptoms at baseline, only 6.4% reported symptoms after discontinuing use of CEE + MPA. Among the 63.3% of the WHI participants who reported at least 1 moderate or severe symptom after discontinuing use of CEE + MPA, a wide range of strategies—many of them lifestyle changes, such as drinking more fluids, starting or increasing exercise, practicing yoga, meditation or breathing exercises, and using fans or air conditioners—were perceived to be quite helpful in relieving or coping with symptoms.
So what can women who stop taking hormone therapy expect? Many will not experience unbearable symptoms, and those women whose symptoms are troubling may find relief with self-initiated, nonhormonal remedies.
Symptom reports from the women in the WHI study who stopped taking placebo were also relatively common. Prior studies have shown that women who are randomized to the placebo group of trials investigating a variety of treatments for menopausal symptoms often improve.4 This is true not only for hormone therapies but also for treatments that are classified as complementary or alternative.4 - 5
In the WHI study, 40.5% of women who had been assigned to the placebo group reported a moderate or severe symptom after ceasing placebo use. Among women who had the symptom at baseline, 21.3% reported vasomotor symptoms, and 38.3% reported pain or stiffness after they stopped taking the placebo.
This “placebo withdrawal effect”—combined with the data suggesting that simple lifestyle changes relieve some symptoms in at least some women—raises questions about the physiological basis of some of the symptoms that have always been associated with the estrogen-deficient state. Which of these are true consequences of cessation of estrogen production by the ovary? Accumulating evidence suggests many symptoms commonly attributed to estrogen deficiency are not. For example, in an examination of evidence for a causal association between ovarian aging and senescence and symptoms commonly attributed to menopause, including vasomotor symptoms (hot flashes and night sweats), vaginal dryness, sleep disturbances, mood symptoms (depression, anxiety, and irritability), cognitive disturbances, somatic symptoms (back pain, tiredness, stiff joints), urinary incontinence, and sexual dysfunction, a panel convened by the National Institutes of Health recently concluded that the evidence established causality only for vasomotor symptoms and vaginal dryness.6 The panel acknowledged some positive evidence for sleep disturbances.6
Despite their frequent attribution to menopause by perimenopausal and postmenopausal women, joint pain, general aches and pain, feeling tired, and low back pain are not generally recognized symptoms of menopause. They are common in both men and women at various times of life. The National Institutes of Health panel noted that the majority of observational studies showed no association between the prevalence of somatic symptoms, including back pain, tiredness, and stiff or painful joints, and menopausal status.7
Middle age is a time of change physically, psychologically, socially, and economically, and these changes affect the body and the mind. Aches, pains, fatigue, and some other symptoms that are reported frequently by middle-aged women may be a consequence of simple (or not so simple) aging. Delineation of which symptoms are truly due to ovarian aging and which are due to general aging would permit more specific symptom management strategies. Hormone therapy could be used for the symptoms resulting from a decline in natural hormone levels. Treatments that carry minimal risk, including self-management strategies and positive changes in lifestyle, could be recommended for women with other symptoms.
Most clinicians would agree with the American College of Obstetricians and Gynecologists that when symptoms of menopause necessitate hormone therapy, treatment should be prescribed at the lowest effective dose for the shortest possible time.7 The high frequency of symptoms reported by the WHI participants may be a result of the abrupt withdrawal from hormone (or placebo) therapy. Thus, when it is time to consider discontinuing hormone therapy, gradual tapering of the dose would be a logical clinical strategy arising from these new observations from the WHI.
As has been the experience with prior reports from the WHI, these latest results bring some surprises, some answers to important clinical concerns, and some new questions for future investigation.
Corresponding Author: Diana B. Petitti, MD, 393 E Walnut Ave, Pasadena, CA 91188 (Diana.b.Petitti@kp.org).
Financial Disclosures: None reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
Instructions
Comments are moderated and will appear on the site at the discretion of the Journal of American Medical Association editors. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest* Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Customize your page view by dragging & repositioning the boxes below.
Users' Guides to the Medical Literature Although the logic of prognostic balance is clear in comparing hospitalized patients with those...
Users' Guides to the Medical Literature What was the cause of bias in the HRT observational studies? Evidence suggests that women...
All results at JAMAevidence.com >
and access these and other features:
Register Now
Enter your username and email address. We'll send you a reminder to the email address on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.