Menopausal hormone therapy and women's health: An umbrella review

Abstract

Background: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.

Methods and findings: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412).

Conclusions: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Fig 1. Flow chart for study selection process.

MHT, menopausal hormone therapy; OE, observational epidemiological study; RCT, randomized controlled trial.

Fig 2. Quality assessment by outcome presented as percentages across all included systematic reviews.

PI(E)CO, Population, Intervention or Exposure, Comparator, Outcome; RoB, risk of bias.

Fig 3. Consistent or highly suggestive evidence from meta-analyses of randomized controlled trials on menopausal hormone therapy and incidence of diseases and other health outcomes.

The average effects of any menopausal hormone therapy (ET or EPT) in perimenopausal or postmenopausal women, unless otherwise stated. All estimates are from our own analysis apart from diabetes mellitus. Subgroup analysis results by type of menopausal hormone therapy can be found in Tables F to K in S1 Text. The center of each square represents the summary average effect for each outcome, and the horizontal line represents the corresponding 95% CI. CI, confidence interval; EPT, estrogen plus progestin therapy; ET, estrogen-alone therapy; NA, not available or not applicable. ^aIn women who already have the outcome of interest. ^bThe effect measures for continuous outcomes were converted into the risk ratio scale for comparison; the results in original scale can be found in Tables F and I in S1 Text.

Fig 4. Consistent or highly suggestive evidence from meta-analyses of observational epidemiological studies on menopausal hormone therapy and incidence of diseases and other health outcomes.

The average effects of any menopausal hormone therapy (ET or EPT) in perimenopausal or postmenopausal women, unless otherwise stated. The estimates are for ever use of menopausal hormone therapy, unless otherwise stated. All estimates are from our own analysis. Subgroup analysis results by type and recency of menopausal hormone therapy use can be found in Tables L to Q in S1 Text. The center of each square represents the summary average effect for each outcome, and the horizontal line represents the corresponding 95% CI. Cc, case–control study; CI, confidence interval; Co, cohort study; EPT, estrogen plus progestin therapy; ET, estrogen-alone therapy; NA, not available or not applicable. ^aCurrent use of menopausal hormone therapy. ^bUse of menopausal hormone therapy before or after diagnosis of cancer. ^cUse of menopausal hormone therapy after diagnosis of cancer.