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.

Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study

“…One likely reason for this is that male patients tend to have more tobacco and alcohol consumption than female patients, both of which are clear risk factors of ESCC and EAC. Moreover, female hormones are reported to be preventive for ESCC and EAC in several previous studies [11][12][13]. Indeed, subgroup analysis according to age classes showed that the OR of male compared to female for EAC steadily decreased with ageing, while that for ESCC continuously increased (online suppl.…”

Abacavir antiretroviral therapy and indices of subclinical vascular disease in persons with HIV

“…Participants were excluded if they were treated with didanosine, an NRTI associated with increased risk of cardiovascular events [ 28 ]. In addition, women were excluded if pregnant, breast feeding, or postmenopausal, to minimize variability of endogenous sex hormones among participants and potential influence on cardiovascular function [ 29 ]. Similarly, persons on gender reaffirming hormone therapy in the previous year were also excluded.…”

Sex Disparities in Asthma Development and Clinical Outcomes: Implications for Treatment Strategies

“…An umbrella review including five prospective cohort studies with 163,161 women reported that MHT use was associated on average with a 1.41-fold (95% CI 1.09–1.81) increased risk of new-onset asthma compared to non-use. 65 Similarly, in a recent nested case-control study based on the Danish registers, 66 which included 34,533 women with asthma and 345,116 without asthma aged 40–65 years, use of MHT and its subtypes (estrogen-alone therapy and estrogen plus progestin therapy) was associated with an increased risk of developing asthma, with HRs ranging from 1.18 to 1.63. However, these results were contrasted by a UK national retrospective cohort study, 62 the largest longitudinal study on the topic to date, which included 353,173 women aged 46–70 years with 1,340,423 person-years of follow-up, and found that use of MHT and its subtypes was associated with a decreased risk of asthma, with HRs ranging from 0.78 to 0.89, and that longer duration of use was associated with a decreased asthma risk in a dose-response manner.…”

“… Hormonal contraceptives The evidence on hormonal contraceptives and asthma is mixed: the UK national cohort study 64 of 564,896 women and a German community-based cohort study 63 of 1191 women reported that use of hormonal contraceptives was associated with a decreased risk of new-onset asthma compared to non-use, and that longer duration of use was associated with a lower asthma risk than shorter duration 64 ; however, the Nurses’ Health Study 59 of 36,094 women found that use of hormonal contraceptives was associated with an increased asthma risk. Menopausal hormone therapy (MHT) The evidence on MHT and asthma is mixed: an umbrella review 65 including five cohort studies with 163,161 women and a Danish register-based nested case-control study 66 of 379,649 women reported that use of MHT was associated with an increased risk of new-onset asthma compared to non-use; however, the UK national cohort study 62 of 353,173 women found that use of MHT was associated with a decreased asthma risk, and that longer duration of use was associated with a lower asthma risk than shorter duration. Serum levels of sex hormones A cross-sectional study 67 reported that an elevated serum level of estradiol was associated with decreased odds of current asthma in both women and men.…”