Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials

Jo Ann E. Manson, Rowan T. Chlebowski, Marcia L. Stefanick, Aaron K. Aragaki, Jacques E. Rossouw, Ross L. Prentice, Garnet Anderson, Barbara V. Howard, Cynthia A. Thomson, Andrea Z. Lacroix, Jean Wactawski-Wende, Rebecca D. Jackson, Marian Limacher, Karen L. Margolis, Sylvia Wassertheil-Smoller, Shirley A. Beresford, Jane A. Cauley, Charles B. Eaton, Margery Gass, Judith Hsia & 13 others Karen Johnson, Charles Kooperberg, Lewis H. Kuller, Cora E. Lewis, Simin Liu, Lisa W. Martin, Judith K. Ockene, Mary Jo O'sullivan, Lynda H. Powell, Michael S. Simon, Linda Van Horn, Mara Z. Vitolins, Robert B. Wallace

Research output: Contribution to journalComment/debate

Abstract

The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone.Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11-1.48).During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index.Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed.These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms.

Original languageEnglish (US)
Pages (from-to)83-85
Number of pages3
JournalObstetrical and Gynecological Survey
Volume69
Issue number2
DOIs
StatePublished - Jan 1 2014

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Conjugated (USP) Estrogens
Women's Health
Hormones
Medroxyprogesterone Acetate
Health
Placebos
Therapeutics
Confidence Intervals
Breast Neoplasms
Coronary Disease
Hip Fractures
Pulmonary Embolism
Stroke
Gallbladder Diseases
Mortality

All Science Journal Classification (ASJC) codes

  • Obstetrics and Gynecology

Cite this

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials. / Manson, Jo Ann E.; Chlebowski, Rowan T.; Stefanick, Marcia L.; Aragaki, Aaron K.; Rossouw, Jacques E.; Prentice, Ross L.; Anderson, Garnet; Howard, Barbara V.; Thomson, Cynthia A.; Lacroix, Andrea Z.; Wactawski-Wende, Jean; Jackson, Rebecca D.; Limacher, Marian; Margolis, Karen L.; Wassertheil-Smoller, Sylvia; Beresford, Shirley A.; Cauley, Jane A.; Eaton, Charles B.; Gass, Margery; Hsia, Judith; Johnson, Karen; Kooperberg, Charles; Kuller, Lewis H.; Lewis, Cora E.; Liu, Simin; Martin, Lisa W.; Ockene, Judith K.; O'sullivan, Mary Jo; Powell, Lynda H.; Simon, Michael S.; Van Horn, Linda; Vitolins, Mara Z.; Wallace, Robert B.

In: Obstetrical and Gynecological Survey, Vol. 69, No. 2, 01.01.2014, p. 83-85.

Research output: Contribution to journalComment/debate

Manson, JAE, Chlebowski, RT, Stefanick, ML, Aragaki, AK, Rossouw, JE, Prentice, RL, Anderson, G, Howard, BV, Thomson, CA, Lacroix, AZ, Wactawski-Wende, J, Jackson, RD, Limacher, M, Margolis, KL, Wassertheil-Smoller, S, Beresford, SA, Cauley, JA, Eaton, CB, Gass, M, Hsia, J, Johnson, K, Kooperberg, C, Kuller, LH, Lewis, CE, Liu, S, Martin, LW, Ockene, JK, O'sullivan, MJ, Powell, LH, Simon, MS, Van Horn, L, Vitolins, MZ & Wallace, RB 2014, 'Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials', Obstetrical and Gynecological Survey, vol. 69, no. 2, pp. 83-85. https://doi.org/10.1097/01.ogx.0000444679.66386.38
Manson, Jo Ann E. ; Chlebowski, Rowan T. ; Stefanick, Marcia L. ; Aragaki, Aaron K. ; Rossouw, Jacques E. ; Prentice, Ross L. ; Anderson, Garnet ; Howard, Barbara V. ; Thomson, Cynthia A. ; Lacroix, Andrea Z. ; Wactawski-Wende, Jean ; Jackson, Rebecca D. ; Limacher, Marian ; Margolis, Karen L. ; Wassertheil-Smoller, Sylvia ; Beresford, Shirley A. ; Cauley, Jane A. ; Eaton, Charles B. ; Gass, Margery ; Hsia, Judith ; Johnson, Karen ; Kooperberg, Charles ; Kuller, Lewis H. ; Lewis, Cora E. ; Liu, Simin ; Martin, Lisa W. ; Ockene, Judith K. ; O'sullivan, Mary Jo ; Powell, Lynda H. ; Simon, Michael S. ; Van Horn, Linda ; Vitolins, Mara Z. ; Wallace, Robert B. / Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials. In: Obstetrical and Gynecological Survey. 2014 ; Vol. 69, No. 2. pp. 83-85.
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abstract = "The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone.Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95{\%} confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95{\%} CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95{\%} CI, 1.11-1.48).During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95{\%} CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95{\%} CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95{\%} CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index.Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed.These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms.",
author = "Manson, {Jo Ann E.} and Chlebowski, {Rowan T.} and Stefanick, {Marcia L.} and Aragaki, {Aaron K.} and Rossouw, {Jacques E.} and Prentice, {Ross L.} and Garnet Anderson and Howard, {Barbara V.} and Thomson, {Cynthia A.} and Lacroix, {Andrea Z.} and Jean Wactawski-Wende and Jackson, {Rebecca D.} and Marian Limacher and Margolis, {Karen L.} and Sylvia Wassertheil-Smoller and Beresford, {Shirley A.} and Cauley, {Jane A.} and Eaton, {Charles B.} and Margery Gass and Judith Hsia and Karen Johnson and Charles Kooperberg and Kuller, {Lewis H.} and Lewis, {Cora E.} and Simin Liu and Martin, {Lisa W.} and Ockene, {Judith K.} and O'sullivan, {Mary Jo} and Powell, {Lynda H.} and Simon, {Michael S.} and {Van Horn}, Linda and Vitolins, {Mara Z.} and Wallace, {Robert B.}",
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TY - JOUR

T1 - Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials

AU - Manson, Jo Ann E.

AU - Chlebowski, Rowan T.

AU - Stefanick, Marcia L.

AU - Aragaki, Aaron K.

AU - Rossouw, Jacques E.

AU - Prentice, Ross L.

AU - Anderson, Garnet

AU - Howard, Barbara V.

AU - Thomson, Cynthia A.

AU - Lacroix, Andrea Z.

AU - Wactawski-Wende, Jean

AU - Jackson, Rebecca D.

AU - Limacher, Marian

AU - Margolis, Karen L.

AU - Wassertheil-Smoller, Sylvia

AU - Beresford, Shirley A.

AU - Cauley, Jane A.

AU - Eaton, Charles B.

AU - Gass, Margery

AU - Hsia, Judith

AU - Johnson, Karen

AU - Kooperberg, Charles

AU - Kuller, Lewis H.

AU - Lewis, Cora E.

AU - Liu, Simin

AU - Martin, Lisa W.

AU - Ockene, Judith K.

AU - O'sullivan, Mary Jo

AU - Powell, Lynda H.

AU - Simon, Michael S.

AU - Van Horn, Linda

AU - Vitolins, Mara Z.

AU - Wallace, Robert B.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone.Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11-1.48).During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index.Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed.These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms.

AB - The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone.Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11-1.48).During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index.Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed.These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms.

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