Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition

Abstract

Introduction: Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial.

Methods: We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants.

Results: Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT.

Discussion: These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

Keywords: Alzheimer disease; HRT (hormone replacement therapy); cognition; menopause; meta-analysis.

Figure 1

PRIMSA Flow chart.

Figure 2

MHT effects on cognitive domains cores by initiation timing and formulation. Meta-analysis of randomized placebo-controlled trials investigating effects of systemic MHT on verbal memory, delayed verbal memory, visual memory and working memory domains. Values are standardized mean difference (SMD) and 95% confidence intervals (C.I.). ET, estrogen-only therapy; EPT, estrogen-progestogen therapy.

Figure 3

MHT effects on Mini Mental State Exam (MMSE), Trail Making Test-B, and FAS tests. Meta-analysis of randomized placebo-controlled trials investigating effects of systemic MHT on MMSE, TMT-B and FAS tests. Forest plots display individual and pooled estimates expressed as standardized mean difference (SMD) and 95% confidence intervals (C.I.). Studies are ordered by year of publication.

Figure 4

MHT effects on verbal memory tests. Meta-analysis of randomized placebo-controlled trials investigating effects of systemic MHT on paired associates immediate and delayed recall from the Wechsler memory scale, and California Verbal Learning Test (SVLT). Forest plots display individual and pooled estimates expressed as standardized mean difference (SMD) and 95% confidence intervals (C.I.). Studies are ordered by year of publication.

Figure 5

MHT effects on working memory tests. Meta-analysis of randomized placebo-controlled trials investigating effects of systemic MHT on digit span forward, backward, and total. Forest plots display individual and pooled estimates expressed as standardized mean difference (SMD) and 95% confidence intervals (C.I.). Studies are ordered by year of publication.