‘Brain fog’ refers to cognitive impairments experienced by some women during menopause. Between 11%-13% of women show clinically significant cognitive impairment, which can range from problems recalling words and numbers to symptoms associated with attention deficit hyperactivity disorder.¹

Maki and Jaff stress that ‘brain fog’ should not be confused with dementia, because the latter is rare <64-years. Yoon et al, caution that one in five women with mild cognitive impairments have an increased risk of progressing to Alzheimer’s disease (AD) or other forms of dementia.^1,4

Menopause societies endorse the use of HT to manage VMS and GSM. In fact, in their position statement issued last year, the North American Menopause Society (2022) states that HT is the most effective treatment for VMS and GSM (in women <60-years, or who are within 10 years of menopause onset and who have no contraindications), while the latest British Menopause Society guideline (2020) states that HT in women <60-years has a favourable benefit/risk profile (see article on page 38). ^2,3 

Can HT reduce the risk of cognitive impairment?

A number of studies investigated this question. Kantarci et al (2016) looked at whether HT in recently post-menopausal women (five to 36 months) modifies the risk of developing AD. Participants were part of the Kronos Early Estrogen Prevention Study (KEEPS), a randomised, double blinded placebo-controlled clinical trial.⁵

Participants in KEEPS were randomised to: 0.45mg/day oral conjugated equine oestrogens (CEE), 50μg/day transdermal 17β-oestradiol or placebo (pills and patch) for four years. Oral progesterone (200mg/day) was given to active treatment groups for 12 days each month.⁵

Kantarci et al used Pittsburgh compound B (PiB) PET scans to image β-amyloid deposits in the neuronal tissues - one of the hallmarks of AD – of participants.^5,6,7

The researchers found that participants randomised to transdermal 17β-oestradiol had lower PiB standard unit value ratio (SUVR) compared to placebo.⁵

Apolipoprotein E ε4 (APOE ɛ4) carriers have an increased risk of developing AD. The team showed that APOE ɛ4 carriers treated with transdermal 17β-oestradiol had lower PiB SUVR compared to either placebo, or the oral CEE treated group.^5,8

They concluded that transdermal 17β-oestradiol therapy in recently post-menopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in post-menopausal women.⁵

Yoon et al (2018) explored the therapeutic potential of HT in post-menopausal women with mild cognitive impairment. Participants were randomly assigned to either placebo or HT for 24 months to percutaneous oestradiol gel (0.1%, 2 mg/day) and oral micronised progesterone (100mg/day). All participants received donepezil, and APOE ɛ4 genotype was determined. The primary endpoint was general cognitive function. Cognitive assessments were performed every six months.⁴

The team found that progression rates to dementia were 52.9% in the placebo group and 44.4% in the HT group. Within-group analysis showed that all three tests significantly worsened during the trial in the placebo, but not the MHT groups. Analysis adjusted for APOE ɛ4 demonstrated that HT significantly reduced cognitive decline. The concluded that long-term HT using percutaneous oestradiol gel and oral micronised progesterone might attenuate cognitive decline in post-menopausal women with mild cognitive impairment.⁴

Matyi et al (2019) examined the effects of cumulative lifetime oestrogen exposure and late-life cognitive decline in 2114 older adult women who were dementia-free at baseline. Follow-up was 12 years.⁹

Lifetime oestrogen exposure was based on endogenous exposure (time of menarche to menopause), number of pregnancies, duration of breastfeeding, and HT use. HT variables included duration of use, HT type (unopposed, opposed), and time of HT initiation.⁹

Endogenous oestrogen exposure (EEE) was positively associated with cognitive status. In addition, longer duration of HT use was positively associated with cognitive status. Older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with higher Mini-Mental State Examination scores -  especially women who initiated HT within five years of menopause, compared with those initiating HT six or more years later.⁹

The authors concluded that their results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.⁹

What is the verdict?

According to the International Menopause Society (IMS) White Paper entitled Brain Fog in Menopause: A Healthcare Professional’s Guide for Decision-Making and Counseling on Cognition, current guidelines do not recommend HT at any age to treat cognitive concerns, or prevent cognitive decline and dementia, in women living with menopause.¹

The White Paper does state that the use of HT early in post-menopause appears safe for cognitive function, that the use of oestrogen therapy in women living with early menopause may be helpful in maintaining cognitive function and lower the risk of dementia, and the use of oestrogen even late in post-menopause appears to be safe for cognitive function.¹

The IMS cautions that use of HT late in post-menopause is risky if the formulation is CEE and medroxyprogesterone acetate but appears to be neutral if the formulation is oral oestradiol plus vaginal progesterone. There is currently no reliable guide on which to base treatment decisions about HT formulation or duration of use on dementia risk.¹

How can women reduce their risk of cognitive decline?

The IMS recommends a multi-pronged approach to optimise brain health. Recommendations include:

• Limiting alcohol intake
• Quitting smoking
• Assessing and treating hypertension, dyslipidaemia and diabetes, aiming for a blood pressure level of ≤120/80mmHg
• Maintaining an exercise regimen of at least 150 minutes of moderate-intensity aerobic physical activity weekly
• Maintaining a healthy BMI of 18.5-25 and following a balanced Mediterranean-type diet
• Challenging the brain - reading, learning a new language, volunteering, and learning a new skill to increase cognitive reserve (the capacity to deal with cognitive declines)
• Maintaining social engagement, especially if they have a history of depression.

REFERENCES

1. Maki PM, Jaff NG. Brain fog in menopause: a health-care professional’s guide for decision-making and counselling on cognition, Climacteric, 2022.
2. NAMS Position Statement. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause, 2022.
3. British Menopause Society. BMS & WHC’s 2020 recommendations on hormone replacement therapy in menopausal women. https://thebms.org.uk/publications/consensus-statements/bms-whcs-2020-recommendations-on-hormone-replacement-therapy-in-menopausal-women/
4. Yoon B-K, Chin J, Kim J-W, et al. Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial. Menopause, 2018.
5. Kantarci K, Lowe VJ, Lesnick TG, et al. Early Postmenopausal Transdermal17β-Estradiol Therapy and Amyloid-Deposition. Journal of Alzheimer’s Disease, 2016.
6. Klunk WE, Engler H, Nordberg A. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol, 2004.
7. Murphy MP, LeVine H. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis, 2010.
8. Nishita Y, Sala G, Shinohara M, et al. Effects of APOEɛ4 genotype on age-associated change in cognitive functions among Japanese middle-aged and older adults: A 20-year follow-up study. Experimental Gerontology, 2023.
9. Matyi JM, Rattinger GB, Schwartz S, et al. Lifetime estrogen exposure and cognition in late life: the Cache County Study. Menopause, 2019.