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 HsiaKaren C. 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 journalArticle

545 Citations (Scopus)

Abstract

IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomeswere coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPAvs 323 for placebo; HR, 1.28 [95%CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR,0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR,0.79; 95%CI,0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomeswere similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, youngerwomen(aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Original languageEnglish (US)
Pages (from-to)1353-1368
Number of pages16
JournalJAMA - Journal of the American Medical Association
Volume310
Issue number13
DOIs
StatePublished - Oct 8 2013

Fingerprint

Women's Health
Hormones
Health
Placebos
Breast Neoplasms
Coronary Disease
Hip Fractures
Pulmonary Embolism
Therapeutics
Chronic Disease
Stroke
Gallbladder Diseases
Conjugated (USP) Estrogens
Medroxyprogesterone Acetate
Mortality
Urinary Incontinence
Endometrial Neoplasms
Hysterectomy
Uterus
Dementia

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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 C.; 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: JAMA - Journal of the American Medical Association, Vol. 310, No. 13, 08.10.2013, p. 1353-1368.

Research output: Contribution to journalArticle

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, KC, 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 2013, 'Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials', JAMA - Journal of the American Medical Association, vol. 310, no. 13, pp. 1353-1368. https://doi.org/10.1001/jama.2013.278040
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 C. ; 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: JAMA - Journal of the American Medical Association. 2013 ; Vol. 310, No. 13. pp. 1353-1368.
@article{c906792087924822ad52f5c30416971f,
title = "Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials",
abstract = "IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomeswere coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95{\%} CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95{\%} CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPAvs 323 for placebo; HR, 1.28 [95{\%}CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR,0.94; 95{\%} CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR,0.79; 95{\%}CI,0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95{\%} CI, 0.65-0.97). Results for other outcomeswere similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, youngerwomen(aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.",
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 Johnson, {Karen C.} 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.}",
year = "2013",
month = "10",
day = "8",
doi = "10.1001/jama.2013.278040",
language = "English (US)",
volume = "310",
pages = "1353--1368",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "13",

}

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 C.

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 - 2013/10/8

Y1 - 2013/10/8

N2 - IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomeswere coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPAvs 323 for placebo; HR, 1.28 [95%CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR,0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR,0.79; 95%CI,0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomeswere similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, youngerwomen(aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

AB - IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomeswere coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPAvs 323 for placebo; HR, 1.28 [95%CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR,0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR,0.79; 95%CI,0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomeswere similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, youngerwomen(aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

UR - http://www.scopus.com/inward/record.url?scp=84884917272&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884917272&partnerID=8YFLogxK

U2 - 10.1001/jama.2013.278040

DO - 10.1001/jama.2013.278040

M3 - Article

C2 - 24084921

AN - SCOPUS:84884917272

VL - 310

SP - 1353

EP - 1368

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 13

ER -