Does Hormone Replacement Therapy in Menopause Prevent Dementia?

The relationship between hormone therapy (HT) and dementia has been extensively investigated over the years, raising questions and new hypotheses with each published study. Initial studies suggested that estrogen replacement could reduce or delay the risk of Alzheimer's Disease (AD), especially if started early. However, the scenario changed as new data emerged, making the topic more complex and multifaceted.

The Concept of Limited Time Window

Research such as the Cache County Study indicated that HT use for at least 10 years was associated with a reduced risk of AD. This finding gave rise to the concept of "limited time window", which suggests that early initiation of therapy may be beneficial.

On the other hand, the Women's Health Initiative Memory Study (WHIMS) sub-study, conducted in 2003, presented contrary results. In a sample of more than 4,000 women aged ≥ 65 years, an increased risk of dementia was identified in HT users compared to placebo.

Age Factors and Duration of Use

A detailed analysis of WHIMS revealed that many participants were well beyond menopause when starting treatment. This raised the hypothesis that HT administered during menopausal transition could present a lower risk or even protective effects.

More recent studies showed conflicting results:

• Estrogen-only therapy: did not increase dementia risk
• Combination of estrogen and progestin: associated with a small increase in risk
• Exclusive vaginal estradiol use: did not influence AD risk

A Finnish retrospective study reinforced the complexity, demonstrating that route of administration (oral or transdermal) and hormonal combination may play distinct roles in dementia risk.

Current Guidelines for Hormone Therapy

According to the Menopause Society (2022) position statement, HT should be individualized, considering dose, formulation, route of administration, and duration of treatment. The guidelines recommend:

• Starting HT preferably before age 60 or within 10 years of menopause onset
• Evaluating risk-benefit ratio in women ≥ 60 years due to increased absolute risks, such as cardiovascular disease and dementia

Short-Duration Hormone Therapy and Early Initiation

A study with more than 60,000 women indicated that dementia risk increased with HT duration. Women who used therapy for 12 years had a 74% higher risk of dementia compared to non-users.

However, regimens containing only progestin or vaginal estrogen were not associated with this increased risk.

How to Interpret the Data?

Data from observational studies should be interpreted with caution, as they do not allow establishing causality. Additionally, other factors, such as severe vasomotor symptoms, may be associated with increased cerebral amyloid formation, a dementia risk marker.

On the other hand, recent studies with brain imaging biomarkers showed that women who started HT early presented:

• Better memory scores
• Larger hippocampal and entorhinal cortex volume

These benefits were observed mainly in APOE4 gene carriers.

Conclusions

The decision to start and maintain hormone therapy should be personalized. There is no evidence to justify arbitrary limitation of duration or prescription of minimal doses. For many women, adequate doses and well-adjusted therapies are essential for:

• Relieving symptoms
• Preventing bone loss
• Reducing fracture risk

Specialized medical follow-up is indispensable for individually evaluating benefits and risks, ensuring that therapy is conducted in the safest and most effective way possible.

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References

1. Kesslak, J.P. (2002). Can estrogen play a significant role in the prevention of Alzheimer's disease?. In: Jellinger, K.A., Schmidt, R., Windisch, M. (eds) Ageing and Dementia Current and Future Concepts. Journal of Neural Transmission. Supplementa, vol 62. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6139-5_21

2. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated Equine Estrogens and Global Cognitive Function in Postmenopausal Women: Women's Health Initiative Memory Study. JAMA. 2004;291(24):2959–2968. doi:10.1001/jama.291.24.2959

3. Vinogradova Y, Dening T, Hippisley-Cox J, Taylor L, Moore M, Coupland C et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases BMJ 2021; 374 :n2182 doi:10.1136/bmj.n2182

4. Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, Vattulainen P, Gissler M, Ylikorkala O, Mikkola TS. Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland: nationwide case-control study. BMJ. 2019 Mar 6;364:l665. doi: 10.1136/bmj.l665. PMID: 30842086; PMCID: PMC6402043.

5. "The 2022 Hormone Therapy Position Statement of The North American Menopause Society" Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 Jul 1;29(7):767-794. doi: 10.1097/GME.0000000000002028. PMID: 35797481.

6. Pourhadi N, Mørch L S, Holm E A, Torp-Pedersen C, Meaidi A. Menopausal hormone therapy and dementia: nationwide, nested case-control study BMJ 2023; 381 :e072770 doi:10.1136/bmj-2022-072770

7. Kantarci K, Manson J E. Menopausal hormone therapy and dementia BMJ 2023; 381 :p1404 doi:10.1136/bmj.p14

8. Saleh RNM, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort. Alzheimers Res Ther. 2023 Jan 9;15(1):10. doi: 10.1186/s13195-022-01121-5. PMID: 36624497; PMCID: PMC9830747.

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Authored by Dr. Francisco Tostes, Scientific Director of SottoPelle Brasil.