Slightly reduced risk of dementia with long-term estrogen use in women less than 80

Use of hormone replacement therapy (HRT) for the treatment of menopausal symptoms was not associated with an increased risk of dementia in women ≥55 years old, regardless of the type of hormones taken or the doses used, a large observational study found.

In fact, the risk of developing dementia among participants under the age of 80 who had been taking estrogen alone for at least 10 years was slightly less than it was for non-estrogen users, Yana Vinogradova, MD, University of Nottingham, Nottingham, United Kingdom, and colleagues reported in the BMJ.

On the other hand, there was a small increase in the risk of developing Alzheimer’s disease (AD) among women who took the combination of estrogen and progestogen, which increased over time, the same analysis showed.

“The clear take-home from our study is that at the generic level—and for vascular dementia (the only specific diagnosis other than AD for which there were sufficient cases to analyze)—we found no elevated risk association with use of HRT and with respect to AD, the elevated risk association was only for combined treatments and was very small,” Vinogradova told BreakingMED in an email.

“So, the one thing we can say for certain is that women suffering from severe menopausal symptoms should be cheered by our findings with respect to menopausal hormone therapy (MHT) and additional risks of dementia,” she added.

The two nested case-control studies analyzed included 118,501 women aged ≥55 years with a primary diagnosis of dementia obtained between 1998 and 2020. This group was matched by age and general practice to 497,416 females who had not been diagnosed with dementia and who served as controls.

The mean age of women at the time of a dementia diagnosis was 83.5 years, while the mean duration of HRT treatment was 16 years. Overall, the same percentage of women who had been diagnosed with dementia had used HRT for over 3 years (13.7% for cases and 13.8% for controls).

After adjusting for a range of potential confounders, there was no statistically significant overall association between use of HRT and risk of dementia either for estrogen-alone treatments (adjusted OR: 0.99; 95% CI, 0.96-1.02) or for combination HRT (OR: 1.00; 95% CI, 0.97-1.03), as Vinogradova and colleagues reported.

“This finding was independent of the length of exposure to hormone therapy and of the length of time after discontinuation of treatment,” the authors added. It was also consistent for all of the different types of hormones taken by the cohort overall.

Among women with dementia, slightly over one-quarter (27%) received the diagnosis before the age of 80.

Compared to women who were diagnosed with dementia at the age of ≥80 years, estrogen-alone HRT taken for more than 10 years was associated with a 15% lower risk of dementia (OR: 0.85; 95% CI, 0.76-0.94; P=0.003), or a 1.1% decrease for each year of HRT use, researchers noted.

Slightly over one-third of patients with dementia had a diagnosis of AD alone (34%), while 21% had a diagnosis of vascular dementia alone, with a small proportion of patients (3%) having a diagnosis of both.

For women on combination HRT, there was an 11% increased risk of being diagnosed with AD among those who took HRT for 5 to 9 years (OR: 1.11; 95% CI, 1.04-1.20)—an extra 4.5 cases (1.5-7.7 cases) compared to non-HRT users.

For those who took HRT for ≥10 years, the risk of developing AD was 19% higher (OR: 1.19; 95% CI, 1.06-1.33)—suggesting that the risk of developing AD increases by 1.2% for each year of HRT use—an extra 7.4 cases (2.5-12.9 cases) compared to non-HRT users, as the authors noted.

As Vinogradova emphasized, observational studies cannot point to causation but only to risk associations between different circumstances and specific outcomes.

However, some biological studies have suggested that estrogen possibly protects against dementia and that this protective effect might be reduced or eliminated by the concomitant use of progestogen.

Moreover, the largest randomized HRT trial ever done evaluating the potential association between HRT use and dementia risk—the Women’s Health Initiative Memory Study—showed an increased risk of dementia in women who took estrogen with or without medroxyprogesterone even though results were not statistically significant for those who took estrogen alone.

In an accompanying editorial, lead editorialist JoAnn Manson, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts and colleagues pointed out that the average age of women at the first captured prescription for HRT in the study was actually very old, at 67.5 years.

“Most women initiate hormone therapy for symptom relief earlier in the postmenopause period,” as they observed.

Thus, women deemed to be HRT users in the study may have received HRT treatment for several years before the study interval analyzed, while women classified as non-users might have actually used HRT earlier on in their menopause but had no prescriptions listed, as they argued.

Even while the authors themselves suggest that findings for the overall cohort were similar to those observed among women diagnosed with dementia under the age of 80—among whom there was more complete data on HRT use—”[t]hat subgroup…was the only group to show a statistically significantly lower risk of dementia with estrogen alone,” Manson and colleagues pointed out.

“In this context, early initiation and use of progestogen might be important factors in conferring a decreased risk of dementia,” they observed.

Overall, the editorialists stressed that observations from the study should not change current recommendations not to use HRT to prevent dementia.

“At the same time, it is helpful for providers to put dementia findings in context for patients,” Mason and colleagues suggested.

“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,” they concluded.

  1. HRT use did not increase risk of dementia regardless of the type of hormones or the dose taken in women 55 years of age and older.

  2. Results from this observational study are reassuring for women who need HRT for the treatment of menopausal symptoms.

Pam Harrison, Contributing Writer, BreakingMED™

Funding for the two databases initially analyzed was provided by the National Institute for Health Research School for Primary Care Research.

Neither Vinogradova nor Mason had any conflicts of interest to declare.

Cat ID: 334

Topic ID: 83,334,282,494,730,334,192,255,925