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Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal Hormone Replacement Therapy: Scientific Review. JAMA. 2002;288(7):872–881. doi:10.1001/jama.288.7.872
Author Affiliations: Division of Medical Informatics and Outcomes Research and Evidence-based Practice Center, and Department of Medicine, Oregon Health and Science University, Portland (Drs Nelson and Humphrey and Ms Nygren) and Medical Service, Veterans Affairs Medical Center, Portland, Ore (Drs Nelson and Humphrey); Merck and Co Inc, West Point, Pa (Dr Teutsch); and School of Nursing, University of Texas Health Science Center, San Antonio (Dr Allan).
Scientific Review and Clinical Applications Section
Editor: Wendy Levinson, MD, Contributing Editor.
Context Although postmenopausal hormone replacement therapy (HRT) is widely
used in the United States, new evidence about its benefits and harms requires
reconsideration of its use for the primary prevention of chronic conditions.
Objective To assess the benefits and harms of HRT for the primary prevention of
cardiovascular disease, thromboembolism, osteoporosis, cancer, dementia, and
cholecystitis by reviewing the literature, conducting meta-analyses, and calculating
Data Sources All relevant English-language studies were identified in MEDLINE (1966-2001),
HealthSTAR (1975-2001), Cochrane Library databases, and reference lists of
key articles. Recent results of the Women's Health Initiative (WHI) and the
Heart and Estrogen/progestin Replacement Study (HERS) are included for reported
Study Selection and Data Extraction We used all published studies of HRT if they contained a comparison
group of HRT nonusers and reported data relating to HRT use and clinical outcomes
of interest. Studies were excluded if the population was selected according
to prior events or presence of conditions associated with higher risks for
Data Synthesis Meta-analyses of observational studies indicated summary relative risks
(RRs) for coronary heart disease (CHD) incidence and mortality that were significantly
reduced among current HRT users only, although risk for incidence was not
reduced when only studies that controlled for socioeconomic status were included.
The WHI reported increased CHD events (hazard ratio [HR], 1.29; 95% confidence
interval [CI], 1.02-1.63). Stroke incidence but not mortality was significantly
increased among HRT users in the meta-analysis and the WHI. The meta-analysis
indicated that risk was significantly elevated for thromboembolic stroke (RR,
1.20; 95% CI, 1.01-1.40) but not subarachnoid or intracerebral stroke. Risk
of venous thromboembolism among current HRT users was increased overall (RR,
2.14; 95% CI, 1.64-2.81) and was highest during the first year of use (RR,
3.49; 95% CI, 2.33-5.59) according to a meta-analysis of 12 studies. Protection
against osteoporotic fractures is supported by a meta-analysis of 22 estrogen
trials, cohort studies, results of the WHI, and trials with bone density outcomes.
Current estrogen users have an increased risk of breast cancer that increases
with duration of use. Endometrial cancer incidence, but not mortality, is
increased with unopposed estrogen use but not with estrogen with progestin.
A meta-analysis of 18 observational studies showed a 20% reduction in colon
cancer incidence among women who had ever used HRT (RR, 0.80; 95% CI, 0.74-0.86),
a finding supported by the WHI. Women symptomatic from menopause had improvement
in certain aspects of cognition. Current studies of estrogen and dementia
are not definitive. In a cohort study, current HRT users had an age-adjusted
RR for cholecystitis of 1.8 (95% CI, 1.6-2.0), increasing to 2.5 (95% CI,
2.0-2.9) after 5 years of use.
Conclusions Benefits of HRT include prevention of osteoporotic fractures and colorectal
cancer, while prevention of dementia is uncertain. Harms include CHD, stroke,
thromboembolic events, breast cancer with 5 or more years of use, and cholecystitis.
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