Menopause and cognitive impairment: A narrative review of current knowledge

Table 1 Observational studies on hormone therapy and cognition in women

Ref.	Study	Country	Design	n (%)	Age (yr)	Hormone therapy	Main findings
Carlson et al[77], 2001	Cache County Study	United States	Longitudinal	2073	≥ 65	ET or EPT	HT reduced cognitive decline
Seshadri et al[72], 2001		United Kingdom	Case-control	AD: 59. Controls: 221	Mean: 66.7	ET or EPT	HT was not associated with AD
Kang et al[76], 2004	Nurses’ Health Study	United States	Longitudinal	13807	≥ 70	ET or EPT	HT was not associated with relevant cognitive benefits
Henderson et al[82], 2005	Mirage Study	United States, Canada, Germany	Case-control	AD: 426. Controls: 545	Mean: 71.1	ET or EPT	HT reduced the AD risk by 30%
Ryan et al[69], 2009	Three City Study	France	Longitudinal	3130	≥ 65	ET or EPT	HT was not associated with dementia or AD, but current users had better cognitive performance in specific domains
Shao et al[79], 2012	Cache County Study extended	United States	Longitudinal	1768	≥ 65	ET or EPT	HT initiated within five years of menopause decreased the AD risk by 30%
Whitmer et al[80], 2011	Kaiser Permanente Medical Care Program of Northern California	United States	Longitudinal	5504	Mean in midlife: 48.7	ET or EPT	The use of HT only in midlife reduced the dementia risk. On the other hand, the use of HT in late-life increased this risk
Imtiaz et al[70], 2017	Kuopio Osteoporosis Risk Factor and Prevention study	Finland	Longitudinal	8195	46 a 56	ET or EPT	Long-term HT users (> 10 yr) exhibited a 47% reduction in the AD risk
Savolainen-Peltonen et al[83], 2019		Finland	Case-control	AD: 84739. Controls: 84739	Mean age at onset of systemic HT: 52	ET or EPT	HT increased the AD risk by 9%-17%, regardless of the age of onset of use and the type of HT

ET: Estrogen-only therapy; EPT: Estrogen-progestogen therapy; HT: Hormone therapy; AD: Alzheimer’s disease.

Table 2 Randomized clinical trials on hormone therapy and cognition in women

Ref.	Study	Country	n (%)	Age (yr)	Hormone therapy	Main findings
Shumaker et al[75], 2003	Women's Health Initiative Memory Study-WHIMS	United States	HT users: 2229. Placebo: 2303	≥ 65	CEE + MPA	HT increased the dementia risk
Shumaker et al[84], 2004	Women's Health Initiative Memory Study-WHIMS	United States	HT users: 1464. Placebo: 1483	65 to 79	CEE alone	Estrogen alone did not decrease the incidence of mild cognitive impairment or dementia
Greenspan et al[85], 2005		United States	HT users: 187. Placebo: 186	≥ 65	CEE with or without MPA	HT did not affect cognitive function
Yaffe et al[86], 2006		United States	HT users: 208. Placebo: 209	60 to 80	Ultra–low dose unopposed transdermal estradiol	Transdermal estradiol did not affect cognitive function
Espeland et al[87], 2010	Women's Health Initiative Study of Cognitive Aging-WHISCA	United States	HT users: 1125. Placebo: 1179	65 to 80	CEE with or without MPA	HT was associated with worsening global cognitive function and some specific cognitive domains. This worsening persisted after the interruption of HT
Espeland et al[73], 2013	Women’s Health Initiative Memory Study of Younger Women-WHIMSY	United States	HT users: 696. Placebo: 630	50 to 55	CEE with or without MPA	HT did not alter global cognitive function or specific cognitive domains
Gleason et al[74], 2015	Cognitive and Affective Study-KEEPS-Cog	United States	HT users: 431. Placebo: 262	Mean: 52.6	CEE + micronized progesterone ortransdermal estradiol + micronized progesterone	HT did not affect cognition
Henderson et al[92], 2016	Early vs Late Intervention Trial with Estradiol Cognitive endpoints-ELITE-Cog	United States	HT users: 284. Placebo: 283	Early postmenopause: 55.6. Late postmenopause: 64.9	Estradiol with or without micronized progesterone	HT did not affect verbal memory, executive function and global cognition, regardless of whether it was started < 6 yr or ≥ 10 yr after menopause
Espeland et al[91], 2017	WHIMSY extended + Women’s Health Initiative Memory Study of the Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO	United States	WHIMSY-HT users: 701. Placebo: 635. WHIMS-ECHO-HT users: 1402. Placebo: 1478	Two groups: 50 to 54; 65 to 79	CEE with or without MPA	HT prescribed to younger women had no significant effect on cognitive function in the long term. HT administered to older women produced decreased global cognitive function, executive function, and working memory

CEE: Conjugated equine estrogen; MPA: Medroxyprogesterone acetate; HT: Hormone therapy.