Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial.
ABSTRACT The effects of continuous combined hormone therapy on gynecologic cancers have not been investigated previously in a randomized trial setting.
To determine the possible associations of estrogen plus progestin on gynecologic cancers and related diagnostic procedures.
Randomized, double-blind, placebo-controlled trial of 16 608 postmenopausal women, who had not had a hysterectomy at baseline and who had been recruited from 40 US clinical centers between September 1993 and October 1998 (average follow-up, 5.6 years).
One tablet per day containing 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).
Incident invasive cancer of the ovary and endometrium.
In 5.6 years of follow-up, there were 32 cases of invasive ovarian cancer, 58 cases of endometrial cancer, 1 case of nonendometrial uterine cancer, 13 cases of cervical cancer, and 7 cases of other gynecologic cancers. The hazard ratio (HR) for invasive ovarian cancer in women assigned to estrogen plus progestin compared with placebo was 1.58 (95% confidence interval [CI], 0.77-3.24). The HR for endometrial cancer was 0.81 (95% CI, 0.48-1.36). No appreciable differences were found in the distributions of tumor histology, stage, or grade for either cancer site. The incidence of other gynecologic cancers was low and did not differ by randomization assignment. More women taking estrogen plus progestin required endometrial biopsies (33% vs 6%; P<.001).
This randomized trial suggests that continuous combined estrogen plus progestin therapy may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo. The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen. These data provide additional support for caution in the use of continuous combined hormones.
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ABSTRACT: The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen plus progestin therapy after menopause. To examine the effect of long-term postmenopausal hormone therapy on common noncardiovascular disease outcomes. Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent open-label observational follow-up for 2.7 years (HERS II), carried out between 1993 and 2000 in outpatient and community settings at 20 US clinical centers. A total of 2763 postmenopausal women with coronary disease and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II. Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group and increased from 0% (year 1) to 8% (year 6) in the placebo group. Thromboembolic events, biliary tract surgery, cancer, fracture, and total mortality. Comparing women assigned to hormone therapy with those assigned to placebo, the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04) during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend =.08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of the 73 women with thromboembolism died within 30 days due to pulmonary embolism. The overall RH for biliary tract surgery was 1.48 (95% CI, 1.12-1.95); for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture, 1.04 (95% CI, 0.87-1.25). There were 261 deaths among those assigned to hormone therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjusted and as-treated analyses did not alter our conclusions. Treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery. Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations.JAMA The Journal of the American Medical Association 08/2002; 288(1):58-66. · 29.98 Impact Factor
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ABSTRACT: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.JNCI Journal of the National Cancer Institute 08/1999; 91(13):1131-7. · 14.34 Impact Factor
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ABSTRACT: Estrogen replacement therapy (ERT), which is mainly used to relieve climacteric symptoms, increases a woman's risk for uterine endometrial cancer and epithelial ovarian cancer (EOC). Estrogens are often combined with progestins in hormone replacement therapy (HRT) to reduce the risk of uterine endometrial cancer. Data on the association between HRT including progestins and EOC risk are limited. This nationwide case-control study examined EOC risk in relation to HRT regimens with sequentially added progestins (HRTsp) and continuously added progestins (HRTcp). Between 1993 and 1995, we enrolled 655 histologically verified incident case patients with EOC and 3899 randomly selected population controls, all 50-74 years of age. Data on HRT use were collected through mailed questionnaires. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the use of unconditional logistic regression. Risks of EOC were elevated among ever users as compared with never users of both ERT (OR = 1.43, 95% CI = 1.02 to 2.00) and HRTsp (OR = 1.54, 95% CI = 1.15 to 2.05); risks were elevated for serous, mucinous, and endometrioid subtypes. For all EOC types combined, the greatest risk increases were seen with hormone use exceeding 10 years. Ever use of HRTcp was not associated with increased EOC risk relative to HRTcp never use (OR = 1.02, 95% CI = 0.73 to 1.43). The risk of EOC was elevated among HRTsp ever users as compared with HRTcp ever users (OR = 1.78, 95% CI = 1.05 to 3.01). ORs for EOC after ever use of low-potency estrogens were 1.18 (95% CI = 0.89 to 1.55) for oral and 1.33 (95% CI = 1.03 to 1.72) for vaginal applications, but no relationship was seen between EOC risk and duration of use. Ever users of ERT and HRTsp but not HRTcp may be at increased risk of EOC.JNCI Journal of the National Cancer Institute 05/2002; 94(7):497-504. · 14.34 Impact Factor