On 23 and 24 October 2002, the National Institutes of Health (NIH) convened a Scientific Workshop on Menopausal Hormone Therapy. Dr. Ruth Kirschstein, Deputy Director, NIH, and Dr. Vivian Pinn, Director of the Office of Research on Women's Health, NIH, opened the conference, stating that the purposes of this scientific workshop were to place the WHI E + P clinical trial results and reasons for stopping the trial in the context of other federally funded studies (such as those evaluating the effect of HT on cognition and osteoporosis) and to help clinicians and their patients better understand the current information on the risks and benefits of short- and long-term use of combination HT.

The results from other combination HT trials were considered by the DSMBs of all NIH-funded clinical trials involving HT. Some of these studies were discontinued, and others were recommended for continuation. To provide the conference attendees with the necessary background about decision making in protecting participants in clinical trials, Dr. Diana Petitti of Kaiser Permanente in Southern California reviewed the purpose of a clinical trial and how DSMBs evaluate risks and benefits for study participants.

WHI: Results, Other Trials, and Ancillary Studies

Dr. Marcia Stefanick, WHI Steering Committee Chair from Stanford University, summarized the cardiovascular studies that led to the WHI trials. These included the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, which compared the effects of E alone, and E plus many progestin regimens, on CHD risk factors ( The Writing Group for the PEPI TrialEffects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-208. [Abstract/Free Full Text]). Although the results were positive, this trial could not directly test whether CHD would be prevented. The Heart and Estrogen/progestin Replacement Study (HERS) was a secondary prevention trial of E + P that showed no benefit for CHD; in fact, there were indications of early harm ( Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-13. [Abstract/Free Full Text]). Other WHI investigators presented the results from the E + P study (summarized in the Table) ( Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. [Abstract/Free Full Text]), stressing that the JAMA report does not provide the nuances that will be developed through subgroup analyses; WHI investigators plan to publish detailed analyses of the effects of E + P on the development of cardiovascular disease, cancer, osteoporosis, cholelithiasis, degenerative arthritis, sexual function, cognition and dementia, and quality of life. They will also analyze the effect of previous hormone use on the risk for breast cancer. All these analyses will use the complete, centrally adjudicated clinical outcomes and will include laboratory studies of risk markers.

The National Heart, Lung, and Blood Institute (NHLBI) has sponsored other studies to elucidate the effects of HT on cardiovascular disease, according to Dr. David Gordon from the NHLBI. For example, the Estrogen Replacement in Atherosclerosis (ERA) trial, involving 309 postmenopausal women with coronary artery disease, was published 2 years ago; the study showed no statistically significant differences in angiographic end points for women who received E + P, E-alone, or placebo ( Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-9. [Abstract/Free Full Text]). The published results of the Acute Hormone Therapy in Unstable Angina Study, which included 239 postmenopausal women with acute coronary syndrome, showed no differences in ischemia based on use of E + P, E-alone, or placebo ( Schulman SP, Thiemann DR, Ouyang P, Chandra NC, Schulman DS, Reis SE. Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. J Am Coll Cardiol. 2002;39:231-7. [Abstract/Free Full Text]).

The National Institute of Child Health and Human Development (NICHD) supported the Women's Contraceptive and Reproductive Experiences Study, a cancer case–control study conducted in five U.S. metropolitan areas for women 35 to 64 years of age. According to Dr. Robert Spirtas of NICHD, one part of this retrospective study examined the association between breast cancer risk and use of postmenopausal HT. Continuous combined HT was associated with increased risk for breast cancer among women who had been using HT for 5 years or longer. For former users of HT, breast cancer risk did not increase. Estrogen-alone therapy was not associated with increased risk for breast cancer at any disease stage, regardless of the duration or recency of use (Obstet Gynecol. [In press]).

Dr. Joan McGowan of the National Institute of Arthritis and Musculoskeletal and Skin Diseases described two studies on alternative therapies for osteoporosis. One trial to determine whether HT exacerbates disease symptoms in women with systemic lupus erythematosus was discontinued at the recommendation of the DSMB. A second, measuring bone mineral density, was continued because it is using a low-dose regimen of combination HT. Alternative strategies for preventing and treating osteoporosis are available, and more are being studied.

The National Institute on Aging (NIA) is supporting research to study estrogen effects on cognition. According to Dr. Judith A. Salerno from the NIA, that research is based on epidemiologic and small clinical studies that indicate a decreased risk for Alzheimer disease and cognition deficits in women who used estrogen therapy. However, this finding has not been consistent; some clinical studies had serious methodologic limitations, and some biological studies pointed to mechanisms for a protective effect. Of 24 treatment studies conducted from 1976 to 2001, 6 showed positive effects, 11 were equivocal, and 7 showed no effect. One NIA clinical trial is investigating the relation between memory and use of an estradiol patch and the patch plus oral medroxyprogesterone, while another is studying the use of Premarin and Prempro in normal women who have a first-degree relative with cognitive disease. The respective DSMBs recommended that both studies be continued, with notification and re-consent of enrolled research participants.

Two ancillary studies within the WHI are studying the effects of hormones on cognitive impairment, according to Dr. Sally Shumaker of Wake Forest University. The WHI Memory Study examines all phases of dementia in women age 65 years and older. The WHI Study of Cognitive Aging (WHISCA) is assessing whether HT protects against age-associated memory and cognitive decline in women older than 65 years. The E + P arms of both studies were discontinued in June 2002, and results from these studies will be published in early 2003.

Assessing and Communicating Risks and Benefits

In the past, women usually decided that they could benefit from combination HT. That certainty now has shifted, according to Dr. Deborah Grady of the University of California, San Francisco. Combination HT is not a generally effective preventive therapy, and each woman needs to decide whether the risks from combination HT outweigh benefits in relieving vasomotor and other menopausal symptoms.

Women who are most likely to benefit from combination HT are those at high risk for hip fracture, those who have previously had a vertebral fracture, or those at high risk for colon cancer. However, according to Dr. Grady, many of those women, including those with osteoporosis, will receive no net benefit from combination HT when the harms and benefits are calculated.

Although the WHI focused on prevention, not on symptom relief and other quality-of-life benefits, many members of the news media and the public did not understand that subtlety, according to Susan Dentzer from The NewsHour with Jim Lehrer on PBS. Although news stories were written in the context of prevention, the public was interested in stories related to quality of life and symptom relief. Neither the news organizations nor the public grasped the concepts of absolute risk and relative risk, and there was a tendency to focus mostly on sharp increases in relative risks, which were emphasized in press releases from the NIH and JAMA. Hence, the media emphasized one "side" of the story or the other—either the sharply increased relative risks or the lesser absolute risks. The differences between these two concepts are significant: Although the relative risk for breast cancer among women in the WHI study who used E + P increased 26% during the 5 years of the study, the absolute risk in an individual woman was small.

What women are really worrying about is disease risk versus the benefits of symptom relief and quality of life, according to Ms. Dentzer. Women also want more timely information about doses, drugs, supplements, and other therapies. This information is especially urgent since no other available therapeutic options are as effective in symptom relief as combination HT.

Future announcements of this type should be accompanied by more concerted efforts to brief the news media thoroughly, Ms. Dentzer recommended. Moreover, thoroughly briefing medical professional groups and clinicians before a major announcement would help them to provide more useful and timely information to their patients.

Food and Drug Administration Perspective

The U.S. Food and Drug Administration (FDA) has approved 5 combination estrogen–progestin hormone products (4 oral, 1 transdermal) for use in menopausal women, 15 estrogen-alone products (some administered orally and others by various other routes), and 6 progestin products (delivered orally, by injection, or as a gel). Dr. Janet Woodcock from the FDA's Center for Drug Evaluation and Research said that these hormone products are approved for managing menopausal symptoms such as vasomotor and genitourinary tract abnormalities and for preventing osteoporosis, not for preventing cardiovascular disease or as hormone replacement therapy.

Food and Drug Administration approvals of hormone products for treating menopausal symptoms are usually based on 3-month, placebo-controlled trials involving approximately 100 participants, with end points of clinical improvement of vasomotor or genitourinary tract symptoms. Approval for osteoporosis prevention is based on bone mineral density measurements in 2-year trials involving approximately 300 participants. Whereas several other types of products are approved by the FDA for increasing bone mass and preventing osteoporosis, no other FDA-approved products are available for treating menopausal symptoms.

Although the WHI risk findings regarding the E + P trial provide important information, it is not possible to extrapolate those findings and apply them to other doses and toxicities of related products, according to Dr. Woodcock. In the case of clinical trials evaluating preventive indications of products, such as the WHI's E + P trial, investigators carry a higher burden to prove a positive benefit–risk ratio. In this case, for example, it might be possible to improve that ratio by administering E + P to women with more recalcitrant menopausal symptoms or to women considered at especially high risk for osteoporosis. Meanwhile, the FDA believes that alternative hormonal treatments involving different doses and routes of administration are worth examining. The risks to users of such products can be communicated through product labels, patient education, and responsible advertising.

An Industry Perspective

Menopausal symptoms, which include vasomotor symptoms and vulvovaginal atrophy, significantly affect women's lives and their ability to function, stated Dr. Ginger Constantine from Wyeth Pharmaceuticals, and combination HT has been an important and effective therapy for treating menopausal symptoms.

Therapeutic decisions on the use of HT should be individualized. The WHI data have helped to quantify selected risks, including coronary heart disease, venous thromboembolic disease, stroke, and breast and endometrial cancer. The quantifiable absolute risk for these events was low and would be expected to be even lower in a younger, newly menopausal population. Combination HT should be used for the shortest duration that is consistent with treatment goals and risks to the individual woman. Treatment should be re-evaluated periodically; these re-evaluations are especially important when longer therapy (particularly >5 years) is being considered.

Current Considerations for Use of Combination HT

More than 40 million women take HT to relieve menopausal symptoms, according to Dr. James Liu of the American College of Obstetricians and Gynecologists (ACOG), and only 20% of those women stay on such regimens longer than 5 years. Considerations for combination HT could be divided into short-term use for relief of vasomotor symptoms and longer-term use for prevention of chronic disease.

Treating Vasomotor Symptoms of Menopause

The ACOG and the North American Menopause Society both recommend that taking combination HT to manage vasomotor symptoms should be limited to the shortest duration consistent with treatment goals and benefits versus risks for individual women, taking into account issues of quality of life. Alternative delivery methods such as vaginal creams, vaginal tablets, or a vaginal ring can be effective and do not appreciably increase systemic estrogen levels. However, there are few data to assess the long-term benefit–risk ratios of these alternatives. The North American Menopause Society noted that WHI data cannot be extrapolated directly to symptomatic perimenopausal women or to women experiencing early menopause (40 to 50 years of age) or premature menopause (age < 40 years).

According to Dr. Lorraine Anne Fitzpatrick from the Mayo Clinic and Foundation, the following substances do not work very well, if at all, for treating vasomotor symptoms such as hot flashes: vitamin E, evening primrose, soy isoflavones, dong quai, red clover, naloxone, propranolol, ginseng, yam cream, and Chinese medicinal herbs. Clonidine and methyldopa can reduce the frequency of hot flashes but cause dizziness and dry mouth. Of the antidepressants, venlafaxine is the best studied and has demonstrated efficacy. Other agents being considered but not yet well studied include selective estrogen receptor modulators, selective serotonin reuptake inhibitors, mirtazapine, gabapentin, black cohosh, and chasteberry.

Other modalities for patients and their health care providers to investigate include meditation, acupuncture, hypnosis, biofeedback, and deep breathing exercises. Dr. Fitzpatrick advised women to keep a diary to assess hot-flash triggers; increase exercise; stop smoking; avoid spicy food, caffeine, and alcohol; wear layered clothing; and maintain a low ambient temperature when possible.

Long-Term Use of Combination HT

The participants at the meeting agreed that combination HT has no role in the prevention of cardiovascular disease. Women who are taking combination HT for this purpose should discontinue using the drug. As noted in the presentation of the recommendations from the U.S. Preventive Services Task Force, evidence is insufficient to recommend for or against the use of unopposed estrogen for prevention of chronic conditions in postmenopausal women who have undergone a hysterectomy.

Postmenopausal women who are taking E + P to reduce bone loss should seek advice from their health care providers. The American Society for Bone and Mineral Research recommended that if combination HT was being administered to prevent or treat osteoporosis, changing to another agent, such as a bisphosphonate, should be considered. Assessment of bone density and other risk factors for fracture should help guide such decision making. Accelerated "catch-up" bone loss may occur when HT is stopped, so bone density should be monitored for several years.

The apparent reduction in risk for colorectal cancer is not sufficiently robust to recommend combination HT for preventing colorectal cancer.

Implications for Future Research

Dr. Claude Lenfant, Director of the NHLBI, introduced the areas in which research is continuing or will be developed. Ongoing studies in the WHI, described by Dr. Jacques Rossouw, Acting Director of the WHI, include a trial to assess the effect of calcium and vitamin D on osteoporotic fractures and a trial of a diet low in fat and high in fruits, vegetables, and cereals to prevent breast and colorectal cancer; these studies are in addition to the ongoing study of E-alone in postmenopausal women. Observational studies in the WHI will provide more information about the aging process in healthy women. Dr. Rossouw described in-progress biomarker studies to determine whether subsets of women with specific genotypes are at increased risk for adverse events with combination HT.

The risk for Alzheimer disease increases exponentially after age 65, and projections based on demographics suggest as much as a fivefold increase in the number of Americans with this disease by 2030. Observational studies suggest that postmenopausal women who receive estrogen have a 50% reduction in their risk for Alzheimer disease, according to Dr. Richard Hodes of the NIA, a finding supported by in vitro studies based on responses of neuronal cells to estrogen in cell culture. The NIA plans to explore these findings with a controlled clinical trial involving women at elevated risk for this disease, paying heed to their other estrogen-associated health risks.

The National Cancer Institute (NCI) is supporting several clinical trials exploring means to prevent breast cancer, including the WHI diet component, a tamoxifen trial, and a healthy lifestyle approach, according to Dr. Leslie Ford of the NCI. Although risk for colorectal cancer was reduced in women receiving combined HT in the WHI trial, the NCI does not consider that finding robust enough to outweigh other risks associated with such treatments.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) supports studies to evaluate alternative means for preserving bone mass, including nitric oxide, phytoestrogens, doxycycline, and outfitting individuals with hip protectors to prevent hip fractures. Dr. Stephen Katz, Director of the NIAMS, described investigations of several combination therapies, including low-dose estrogen hormones or combinations of parathyroid hormone with other bone-strengthening agents, as well as studies involving biophysical stimuli to strengthen bones.

Many Americans are using alternative therapies, according to Dr. Stephen Straus, Director of the National Center on Complementary and Alternative Medicine (NCCAM), even though many of these materials have not been proven safe or effective. The NCCAM is supporting several small-scale clinical trials to evaluate alternative materials, such as phytoestrogens, for health effects on women. Some of these studies will help to delineate quality-of-life issues for menopausal women and will also consider safety issues involving hormone-sensitive cancer.

There is a need to develop alternative HT dose levels, other routes of administering them, or other regimens for women using combination HT to alleviate vasomotor and genitourinary menopausal symptoms, according to Dr. Duane Alexander, Director of the National Institute of Child Health and Human Development.

An Important Take-Home Message for Women and Their Health Care Providers

Dr. Elias Zerhouni, Director of the NIH, stated that this scientific workshop provided an important primary message: Each woman must make a personal decision in consultation with her health care provider, considering current information about the appropriateness of beginning or continuing combination HT. The announcement about the decision to stop the combination HT arm of the WHI study, based on the reported results, has caused concern proportionate to the strength of the dogma being overturned by those findings. After this scientific meeting, the NIH will review its communication strategies to the public to determine what improvements can be made. Meanwhile, other ongoing or planned NIH-sponsored studies will examine and report on the health effects of hormones and HT.