HRT & Age Management Medicine: March 2019

Hormone Replacement Therapy May Increase Risk for Alzheimer’s Disease

Amit Akirov, M.D.

March 13, 2019 (Endocrinology Advisor) – Patients should be informed of a possible risk for Alzheimer’s disease with prolonged use of hormone therapy, even though the absolute risk elevations are small.

Long-term use of systemic hormone replacement therapy (HRT) may slightly increase the risk of developing Alzheimer’s disease (AD), according to study results published in BMJ.

Previous studies have shown that AD is more common in women than men. Some experts pointed to estrogen deficiency in postmenopausal women as the reason for this gender difference, suggesting that estrogen treatment in early menopause may protect against AD. However, the data regarding the effect of HRT on the risk for AD is inconclusive. The goal of this study was to investigate the effect of HRT on the risk for AD.

In the nationwide case control study, the researchers investigated the use of HRT in 84,739 postmenopausal women in Finland diagnosed with AD between 1999 and 2013 and compared them with a similar number of postmenopausal women without AD matched by age and hospital district.

In almost all patients (99%) with AD, the diagnosis of AD was made at age ≥60 years, and most patients (56%) were older than 80 years at diagnosis.

Of the patients with AD, 19% were treated with systemic HRT, including estradiol only (7%), combination estradiol and progestogen (12%), or tibolone (0.3%). At the time of AD diagnosis, only 2305 women (15%) were still using hormone therapy. In addition, 10,188 women (65%) had stopped treatment >3 years before diagnosis.

The results indicated that the use of systemic HRT was more common in women with AD (18.6% vs 17.0%; P <.001), but the use of vaginal estradiol was more common in the control group (12.7% vs 13.2%; P =.005).

Systemic HRT that contained only estradiol was associated with a 9% increased risk for developing AD (odds ratio [OR], 1.09; 95% CI, 1.05-1.14). Furthermore, systemic HRT containing estrogen and progestin was associated with a 17% increased risk for AD (OR, 1.17; 95% CI, 1.13-1.21), and the risk was similar with different mixed progestogens. This increased risk suggests that for every 10,000 HRT-treated women between the age of 70 and 80 years, 9 to 18 women would develop AD every year.

The study showed no difference in the risk for AD based on the formulation of HRT, with a similar risk for patients treated with estrogen alone or with combinations of estrogen and progesterone.

In patients treated with vaginal estrogen only, there was no evidence of increased risk for AD.

The researchers reported that the study had several limitations, as is expected with an epidemiologic observational study design. In addition, they did not have information regarding potential important confounders, such as apolipoprotein E4 genotype.

“Hormone therapy users should be informed for a possible risk of the disease with prolonged use of [AD], even though the absolute risk elevations are small,” concluded the researchers.


Savolanian-Peltonen H, Rahkola-Soisalo P, Hoti F, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019;364:1665.

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