The Women's Health Initiative is the largest, randomized intervention trial of postmenopausal hormone therapy ever conducted. The Estrogen Plus Progestin trial provided us the opportunity to study menopausal symptoms and the effects of hormone therapy on symptoms in women across the spectrum of postmenopausal ages.
Most previous reports of menopausal symptoms have been short-term studies limited to perimenopausal and younger menopausal women who are thought to be most likely to have these symptoms. In the Heart and Estrogen-Progestin Replacement Study (HERS) trial of older postmenopausal women, almost 20% of women aged 70–74 reported frequent or somewhat frequent hot flushes.11 A large, population-based study of symptoms suggested that approximately 50% of women experience vasomotor symptoms at cessation of menses and 20% are symptomatic 4 years postmenopause.19 At baseline, more than 60% of WHI E+P trial participants aged 50–54 and more than 10% of those aged 70–79 still experienced hot flushes, ranging from mild to severe. However, these data might underestimate the prevalence in the general population slightly because women with more severe vasomotor symptoms were excluded from the trial if they were taking hormones at baseline and were unable or unwilling to be randomized to placebo. Estimates from other studies suggest that up to 70% of naturally menopausal women experience vasomotor symptoms, with severe symptoms in 15–20%.2,3 Our data are consistent with these estimates, although they cannot be generalized to women undergoing surgical menopause.
Black and Hispanic women reported a higher prevalence of vasomotor symptoms than white women, and Asian women reported the lowest rates. These data are similar to other reports of ethnic differences in symptom prevalence20 although the reasons for these differences are not known.
At baseline, younger women more frequently reported hot flushes, night sweats, mood swings, and headaches or migraines than older women. Younger women and those closer to menopause also were more likely to have relief of vasomotor symptoms. This suggests that vasomotor symptoms in older women may have causes other than menopausal status and may not respond as well to hormone therapy. Older women more frequently reported joint pain or stiffness. Other pain symptoms, including general aches or pains and low back pain, were very common among all age groups, with remarkable stability across the age distribution. This is somewhat surprising because the prevalence of musculoskeletal symptoms overall would be expected to increase with age. These data suggest that pain symptoms, such as general aches and pains and low back pain, are already well established by midlife. Among women asymptomatic at baseline, there was a prophylactic effect of E+P on these symptoms at years 1 and 3. The beneficial effect of hormone therapy on joint symptoms and other musculoskeletal complaints has long been suspected and women anecdotally have reported improvement, but this has not been well documented in the literature. This benefit of E+P was seen in all age groups of women and persisted at year 3, although the benefit in the subsample was not statistically significant. Hays and colleagues12 reported a benefit in physical functioning and bodily pain in the E+P trial, consistent, in part, with the small, prophylactic effect of E+P on musculoskeletal symptoms seen among asymptomatic women in the current analysis. Smaller studies have demonstrated a beneficial effect of hormone therapy on quality of life in younger menopausal women.21
In WHI E+P trial participants, the rates of vaginal bleeding, a known treatment effect of combined hormone therapy, are similar to those reported in other studies of continuous, combined hormone therapy,22–25 although the range of bleeding reported in these studies is wide. Most prior studies reported short-term bleeding rates only. Our data suggest that bleeding persists in up to 12% of women at 5 or more years of use, which is important information for women considering combined hormone therapy for symptom relief. This is especially true for older women considering hormone therapy, because they were more likely to bleed than women closer to menopause. Most bleeding on combined hormone therapy in the E+P trial was classified as spotting and was associated with benign endometrial changes (ie, normal histology or atrophic/insufficient specimen).
Hysterectomy was slightly more common in women on active E+P, but the indications for the procedure did not differ between the groups. The most common indication, uterine prolapse or descensus, was not increased in women on active intervention.
Estrogen plus progestin improved vasomotor symptoms, vaginal or genital dryness, and all pain symptoms evaluated compared with placebo. In spite of a preponderance of mood swings in younger postmenopausal women, E+P did not have any effect on this symptom, bringing into question a direct relationship between hormonal status and mood. Other studies have shown that mood disorders are more common in symptomatic perimenopausal women, suggesting that some women have a heightened sensitivity to the effects of changing or declining estrogen levels than other women.26 It is not known whether estrogen-alone therapy will have a different effect on mood swings in symptomatic women. The decrease in prevalence of other subjective symptoms, such as difficulty concentrating, could be due to difference in perception of these age groups. In addition, this analysis looked primarily at moderate-to-severe symptoms, which may be more apparent to younger women. Although weight gain has been a concern of women considering hormone therapy, recent data suggest that they are not at greater risk for weight gain.27 The data from this study also confirm that combined hormone therapy has no adverse effect on weight in menopausal women.
Thinner women were more likely to experience relief from vasomotor symptoms, but were more prone to vaginal bleeding and breast tenderness. Older women and those further from menopause also were more likely to report breast tenderness, an anticipated adverse treatment effect of combined hormone therapy. Increases in mammographically defined breast density in response to hormone therapy are greater in women with lower breast density at the time hormone therapy is started.28,29 Although women remote from menopause might be expected to have lower breast density than younger women and be more susceptible to the effects of hormone therapy, a specific association between a change in breast density and breast tenderness has not been established.
Combined hormone therapy decreased the prevalence of vasomotor symptoms associated with menopause, especially in younger women. Estrogen plus progestin also decreased reports of vaginal or genital dryness and joint aches and pains. However, bleeding was common throughout therapy, especially in the first 6 months. Other treatment effects, such as vaginal discharge and irritation and breast tenderness, especially in older women, would limit the overall benefit on quality of life. Our results bridge earlier findings on the effect of E+P on health-related quality of life in this cohort, showing a beneficial effect for younger, symptomatic women only.12 Long-term health benefits of E+P are outweighed by health risks, supporting short-term hormone therapy for the treatment of moderate-to-severe menopausal symptoms, primarily in younger women. According to current prescribing guidelines, combined hormone therapy is indicated only for the treatment of moderate-to-severe vasomotor symptoms associated with menopause30 when the benefits of short-term therapy may outweigh the risks.
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Women's Health Initiative Investigators
Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD) Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan.
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Ronald Prineas, Michelle Naughton; (Medical Research Laboratories, Highland Heights, KY) Evan Stein, Peter Laskarzewski; (University of California at San Francisco, San Francisco, CA) Steven Cummings, Michael Nevitt, Maurice Dockrell; (University of Minnesota, Minneapolis, MN) Lisa Harnack; (McKesson BioServices, Rockville, MD) Frank Cammarata, Steve Lindenfelser; (University of Washington, Seattle, WA) Bruce Psaty, Susan Heckbert.
Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman; (Baylor College of Medicine, Houston, TX) Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, Paul Bray; (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn Manson, Julie Buring, Kathryn Rexrode, Claudia Chae, Caren Solomon; (Brown University, Providence, RI) Annlouise R. Assaf, Carol Wheeler, Charles Eaton, Michelle Cyr; (Emory University, Atlanta, GA) Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley A. A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Robyn Andersen; (George Washington University, Washington, DC) Judith Hsia, Nancy Gaba, Joao Ascensao; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski, Robert Detrano, Anita Nelson, Michele Geller; (Kaiser Permanente Center for Health Research, Portland, OR) Evelyn Whitlock, Patricia Elmer, Victor Stevens, Njeri Karanja; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan, Stephen Sidney, Geri Bailey, Jane Hirata; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard, Lucile Adams-Campbell, Lawrence Lessin, Monique Rainford, Gabriel Uwaifo; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, Carol Rosenberg; (Rush-Presbyterian St. Luke's Medical Center, Chicago, IL) Henry Black, Lynda Powell, Ellen Mason, Martha Gulati; (Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA) Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, Linda C. Giudice; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina; (The Ohio State University, Columbus, OH) Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, Michael Blumenfeld; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis, Albert Oberman, James M. Shikany, Monika Safford, Brian K. Britt; (University of Arizona, Tucson/Phoenix, AZ) Tamsen Bassford, Cyndi Thomson, Marcia Ko, Ana Maria Lopez; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, June Chang; (University of California at Davis, Sacramento, CA) John Robbins, S. Yasmeen; (University of California at Irvine, Orange, CA) Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk; (University of California at Los Angeles, Los Angeles, CA) Howard Judd, David Heber, Robert Elashoff; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. Elaine Hanson; (University of Cincinnati, Cincinnati, OH) Margery Gass, Suzanne Wernke, Nelson Watts; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson; (University of Hawaii, Honolulu, HI) David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Santosh Sharma; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Jennifer Robinson; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis; (University of Miami, Miami, FL) Mary Jo O'Sullivan, Linda Parker, R. Estape, Diann Fernandez; (University of Minnesota, Minneapolis, MN) Karen L. Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, Sarah Kempainen; (University of Nevada, Reno, NV) Robert Brunner, William Graettinger, Vicki Oujevolk; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller, Jane Cauley, N. Carole Milas; (University of Tennessee, Memphis, TN) Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Stephanie Connelly, Fran Tylavsky; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, Charles Mouton; (University of Wisconsin, Madison, WI) Gloria Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, Barbara Loevinger; (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds, Greg Burke, Robin Crouse, Mara Vitolins, Scott Washburn; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix, Michael Simon, Gene McNeeley.
Former Principal Investigators: Baylor College of Medicine, John Foreyt, phd; Emory University, Dallas Hall, md; George Washington University, Valery Miller, md; Kaiser, Oakland, Robert Hiatt, md; Kaiser, Portland, Barbara Valanis, drph; University of California, Irvine, Frank Meyskens Jr, md; University of Cincinnati, James Liu, md; University of Miami, Marianna Baum, phd; University of Minnesota, Richard Grimm, md; University of Nevada, Sandra Daugherty, md (deceased); University of North Carolina, Chapel Hill, David Sheps, md; University of Tennessee, Memphis, William Applegate, md; University of Wisconsin, Catherine Allen, phd (deceased).