Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative.
OBJECTIVE
To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women.


METHODS
Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50-79 (mean +/- standard deviation 63.3 +/- 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out.


RESULTS
Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40-5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04-3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90-3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24-1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08-1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59-5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44-5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27-1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08-1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001).


CONCLUSIONS
Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery.
Barnabei
Vanessa M
VM
Department of Obstetrics and Gynecology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. barnabei@mcw.edu
Cochrane
Barbara B
BB
Aragaki
Aaron K
AK
Nygaard
Ingrid
I
Williams
R Stan
RS
McGovern
Peter G
PG
Young
Ronald L
RL
Wells
Ellen C
EC
O'Sullivan
Mary Jo
MJ
Chen
Bertha
B
Schenken
Robert
R
Johnson
Susan R
SR
D000284:Administration, Oral; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects* / Q000502:physiology; D011336:Probability; D011788:Quality of Life; D012016:Reference Values; D018570:Risk Assessment; D016896:Treatment Outcome
D004338:Drug Combinations; D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate