Evidence is reassuring for women using hormone therapy to treat menopausal symptoms
The case-control study by Vinogradova and colleagues reports reassuring findings on menopausal hormone therapy (commonly known as hormone replacement therapy in the UK) and risk of dementia. [1,2] An improved understanding of the risks and benefits of hormone therapy is needed to promote evidence based management of menopausal symptoms in women. Concern about the risk of dementia with menopausal hormone therapy stemmed from the Women’s Health Initiative Memory Study (WHIMS), which showed that incidence of all cause dementia doubled in women aged 65 years and older after treatment with conjugated equine oestrogens and medroxyprogesterone acetate for an average of four years.  A later article from that study found no increased risk of all cause dementia with conjugated equine oestrogens alone, whereas pooled analyses of both formulations showed a 76% increased risk.  WHIMS remains the only large scale randomised trial of hormone therapy for the primary prevention of dementia. Trials of hormone therapy and cognitive function among women in early menopause, however, showed neutral results. [3-5] Thus, key questions remain unanswered. Does oestrogen alone have greater cognitive safety than oestrogen and progestogen combined? Does timing or duration of use, or both, matter? Are the WHIMS findings generalisable to women in early menopause or to women using other hormone formulations?
The new large scale study of 615 917 women, including 118 501 cases of dementia, allowed for examination of key factors that could not be dealt with in WHIMS. A main finding was that the risk of dementia differed depending on the use of progestogens. Oestrogen alone was associated with a 15% decreased odds of dementia overall among women younger than 80 years who received treatment for at least 10 years, with a 1.1% decrease in risk for each year of treatment. Conversely, oestrogen and progestogen combined was associated with a 11% increased risk of Alzheimer’s disease dementia among women who had used hormone therapy for 5-9 years and a 19% increased risk among women treated for 10 years or more. Results were similar to an 18 year follow-up study of causes of mortality in 27 347 women enrolled in the Women’s Health Study randomised trial where treatment with conjugated equine oestrogens alone was associated with a 26% decreased risk of death from Alzheimer’s disease or other dementias, but this risk was not altered with use of conjugated equine oestrogens plus medroxyprogesterone acetate.  In the current study, risk of dementia with this combined treatment was similar to that with other progestogens. Of all combination formulations, oestrogen-dydrogesterone use for one to 11 years was associated with the lowest risk (adjusted odds ratio 0.88, 95% confidence interval 0.75 to 1.02). Micronised progesterone was not specifically examined. In earlier studies from these investigators, oestrogen-dydrogesterone was associated with the lowest risk for breast cancer and thromboembolic events compared with other formulations. [7,8]
Some previous cohort studies support the “timing hypothesis” that earlier initiation of hormone therapy might confer greater protection against Alzheimer’s disease compared with later use. [9,10] The current study could not address this important issue. In the study, the mean age of cases was 83.5 years and mean duration of treatment in the study period was 16 years, for an average age of 67.5 years at first captured prescription. Most women initiate hormone therapy for symptom relief earlier in the postmenopause period. Women classified as hormone therapy users in this study might have received treatment for several years before the study period, and women classified as non-users might have used hormone therapy earlier in their life but had no prescriptions listed. The authors argue that under-calculation of drug use was unlikely because the findings from a subgroup of women with a diagnosis of dementia when younger than 80 years—a group with more complete data on hormone therapy—were similar to findings overall. That subgroup, however, was the only group to show a statistically significantly lower risk of dementia with oestrogen alone. In this context, early initiation and use of progestogen might be important factors in conferring a decreased risk of dementia.
Observational studies of hormone therapy and dementia risk have other limitations. The potential for confounding by indication is a consideration, particularly for the period 1998-2002 when the view that hormone therapy might protect against dementia could have led to bias in prescribing treatment to women with cognitive concerns or frank dementia. Detection bias, particularly after publication of the WHIMS article in 2003, could have led to more routine or complete ascertainment of dementia in women who had regular medical visits and prescription refills, compared with women not seen regularly. 
Overall, these observations do not change the recommendation that menopausal hormone therapy should not be used to prevent dementia.  At the same time, it is helpful for providers to put dementia findings in context for patients. No increase in risk of dementia was observed with oestrogen alone in this case-control study, and, for oestrogen plus progestogen, the increased risk was five to seven extra cases per 10 000 woman years. The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason.
Pauline M Maki, professor, Department of Psychiatry, Psychology, and Obstetrics & Gynecology, University of Illinois at Chicago, Chicago, IL, USA.
JoAnn E Manson, professor, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA and Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MI, USA.
Competing interests: PMM has served as a paid consultant for AbbVie, Astellas, Balchem, Bayer, Johnson & Johnson, and Pfizer unrelated to the topic of this opinion.
Provenance and peer review: commissioned; not peer reviewed.
- Shumaker S, Legault C, Rapp S, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62.
- Shumaker S, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291:2947-58.
- Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS-Cognitive and Affective Study. PLoS medicine 2015;12(6):e1001833. doi: 10.1371/journal.pmed.1001833
- Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016;87(7):699-708. doi: 10.1212/WNL.0000000000002980
- Espeland MA, Shumaker SA, Leng I, et al. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 Years. JAMA Intern Med 2013:1-8. doi: 10.1001/jamainternmed.2013.7727
- Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative Randomized Trials. JAMA 2017;318(10):927-38. doi: 10.1001/jama.2017.11217
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019;364:k4810. doi: 10.1136/bmj.k4810
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873. doi: 10.1136/bmj.m3873
- Whitmer RA, Quesenberry CP, Zhou J, et al. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol 2011;69(1):163-9. doi: 10.1002/ana.22239
- Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 2012;79(18):1846-52. doi: 10.1212/WNL.0b013e318271f823
- The NHTPSAP. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 2017;24(7):728-53. doi: 10.1097/GME.0000000000000921
- Vinogradova Y, Dening T, Hippisley-Cox J, Taylor L, Moore M, Coupland C. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ 2021;374:n2182.