Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study

Abstract

BackgroundMenopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.Methods and FindingsKEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes.On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importa...

Evaluating the Role of Hormone Therapy in Postmenopausal Women with Alzheimer’s Disease

“…Also, a beneficial effect of norethisterone in combination with estradiol has been found in randomized clinical trial in healthy as well as in sAD postmenopausal women [95,96]. The KEEPS study used treatment with two types of estrogen (CEE orally and 17β-estradiol in a transdermal patch with or without micronized progesterone (MP)) and did not find any beneficial effects on cognition [13] (Table 4). However, in a group of ApoE ε4 carriers treated with low concentrations of estradiol (50µg), lower levels of Aβ deposit were found in comparison to non-carriers [97].…”

“…On one hand there is WHIMS, and the Women's Health Initiative Memory Study of cognitive aging (WHIMSCA) reporting a negative effect of HT on cognition. [11,15,16] On the other hand, the Women's Health Initiative Memory Study/young (WHIMS-Y) and KEEPS-Cog showed no beneficial effectn cognition (Table 4) [13,106] .…”

“…Additionally, a recent large randomised, double-blind study, KEEPS-Cog, showed no effect of estradiol and MP on cognition but rather beneficial effect of estradiol on amyloid deposits in ApoE ε4 carriers (Table 4) [13,97]. This study enrolled a large sample of recently postmenopausal women, aged 42 to 58 years, without high cardiovascular risk (normal blood pressure, mean body mass index 26.3, normal lipid levels), with a mean MMSE of 29.1 (cut off ˂23) and naturally occurring menopause.…”

“…This hormonal change has shown potential to additionally modulate neural processes and pathology linked to sporadic Alzheimer's disease (sAD) [2][3][4][5]. Some studies have shown that estrogen and progesterone depletion in postmenopausal women is a significant risk factor for development of sAD and that estrogen-based HT may reduce this risk [3,[6][7][8][9][10]; however, more recent data argue against this beneficial effect [11][12][13].…”

“…Recently, a new clinical trial has emerged, "Kronos Early Estrogen Prevention Study" (KEEPS), whose sub-study "Cognitive and Affective Study" (KEEPS-Cog) reported that there is no beneficial effect of HT on cognition [13]. The reasons for such inconsistency in results are not clear and the question of whether HT has a beneficial or detrimental effect on cognition is still open.…”