Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
BACKGROUND
Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.


OBJECTIVE
To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.


METHODS
A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.


METHODS
Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.


METHODS
The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.


RESULTS
In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.


CONCLUSIONS
The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.
Anderson
Garnet L
GL
Fred Hutchinson Cancer Research Center, Seattle, Wash 98109-1024, USA. garnet@whi.org
Limacher
Marian
M
Assaf
Annlouise R
AR
Bassford
Tamsen
T
Beresford
Shirley A A
SA
Black
Henry
H
Bonds
Denise
D
Brunner
Robert
R
Brzyski
Robert
R
Caan
Bette
B
Chlebowski
Rowan
R
Curb
David
D
Gass
Margery
M
Hays
Jennifer
J
Heiss
Gerardo
G
Hendrix
Susan
S
Howard
Barbara V
BV
Hsia
Judith
J
Hubbell
Allan
A
Jackson
Rebecca
R
Johnson
Karen C
KC
Judd
Howard
H
Kotchen
Jane Morley
JM
Kuller
Lewis
L
LaCroix
Andrea Z
AZ
Lane
Dorothy
D
Langer
Robert D
RD
Lasser
Norman
N
Lewis
Cora E
CE
Manson
JoAnn
J
Margolis
Karen
K
Ockene
Judith
J
O'Sullivan
Mary Jo
MJ
Phillips
Lawrence
L
Prentice
Ross L
RL
Ritenbaugh
Cheryl
C
Robbins
John
J
Rossouw
Jacques E
JE
Sarto
Gloria
G
Stefanick
Marcia L
ML
Van Horn
Linda
L
Wactawski-Wende
Jean
J
Wallace
Robert
R
Wassertheil-Smoller
Sylvia
S
D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology; D002423:Cause of Death; D015179:Colorectal Neoplasms / Q000453:epidemiology; D003327:Coronary Disease / Q000453:epidemiology; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000627:therapeutic use*; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use*; D005260:Female; D006620:Hip Fractures / Q000453:epidemiology; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D017698:Postmenopause; D016016:Proportional Hazards Models; D011655:Pulmonary Embolism / Q000453:epidemiology; D018570:Risk Assessment; D020521:Stroke / Q000453:epidemiology
D004967:Estrogens; D004966:Estrogens, Conjugated (USP)