RESEARCH Use of postmenopausal hormone therapy and risk of Alzheimer’s BMJ: first published as 10.1136/bmj.l665 on 6 March 2019. Downloaded from disease in Finland: nationwide case-control study Hanna Savolainen-Peltonen,1,2 Päivi Rahkola-Soisalo,1 Fabian Hoti,3 Pia Vattulainen,3 Mika Gissler,4,5,6 Olavi Ylikorkala,1 Tomi S Mikkola1,2 1University of Helsinki and ABSTRACT ratio 1.09, 95% confidence interval 1.05 to 1.14) and Helsinki University Hospital, OBJECTIVES those of oestrogen-progestogen (1.17, 1.13 to 1.21). Obstetrics and Gynecology, To compare the use of hormone therapy between The risk increases in users of oestrogen-progestogen Haartmaninkatu 2, PO Box 140, FIN-00029 HUS, 00029 Finnish postmenopausal women with and without a therapy were not related to different progestogens Helsinki, Finland diagnosis for Alzheimer’s disease. (noreth isterone acetate, medroxyprogesterone 2 Folkhälsan Research Center, DESIGN acetate, or other progestogens); but in women Biomedicum, Helsinki, Finland younger than 60 at hormone therapy initiation, 3 Nationwide case-control study. EPID Research Oy, Espoo, these risk increases were associated with hormone Finland SETTING therapy exposure over 10 years. Furthermore, the 4National Institute for Health Finnish national population and drug register, age at initiation of systemic hormone therapy was and Welfare, Helsinki, Finland between 1999 and 2013. 5Karolinska Institute, not a decisive determinant for the increase in risk Department of Neurobiology, PARTICIPANTS of Alzheimer’s disease. The exclusive use of vaginal Care Sciences and Society, All postmenopausal women (n=84 739) in Finland estradiol did not affect the risk of the disease (0.99, Division of Family Medicine, who, between 1999 and 2013, received a diagnosis of 0.96 to 1.01). Huddinge, Sweden Alzheimer’s disease from a neurologist or geriatrician, 6 CONCLUSIONS University of Turku, Research and who were identified from a national drug register. Centre for Child Psychiatry, Long term use of systemic hormone therapy might Control women without a diagnosis (n=84 739), Turku, Finland be accompanied with an overall increased risk of matched by age and hospital district, were traced from Correspondence to: T S Mikkola Alzheimer’s disease, which is not related to the type [email protected] the Finnish national population register. (ORCID 0000-0003-2049-088X) of progestogen or the age at initiation of systemic INTERVENTIONS Additional material is published hormone therapy. By contrast, use of vaginal estradiol online only. To view please visit Data on hormone therapy use were obtained from the shows no such risk. Even though the absolute risk the journal online. Finnish national drug reimbursement register. increase for Alzheimer’s disease is small, our data http://www.bmj.com/ Cite this as: BMJ 2019;364:l665 MAIN OUTCOME MEASURES should be implemented into information for present http://dx.doi.org/10.1136/bmj.l665 Odds ratios and 95% confidence intervals for and future users of hormone therapy. Accepted: 1 February 2019 Alzheimer’s disease, calculated with conditional logistic regression analysis. Introduction RESULTS Alzheimer’s disease, the most common cause of In 83 688 (98.8%) women, a diagnosis for Alzheimer’s dementia, occurs more frequently in women than in disease was made at the age of 60 years or older, and men.1 This difference might be due to the longer life on 27 September 2021 by guest. Protected copyright. 47 239 (55.7%) women had been over 80 years of age expectancy of women, but sex specific differences in at diagnosis. Use of systemic hormone therapy was the incidence of Alzheimer’s disease might also exist.1-3 associated with a 9-17% increased risk of Alzheimer’s It is known that oestrogens exert neuroprotection in disease. The risk of the disease did not differ several animal studies.4-6 Also, oestrogen deficiency as significantly between users of estradiol only (odds a result of early menopause has been associated with an increased risk of Alzheimer’s disease.7 Therefore, WHAT IS ALREADY KNOWN ON THIS TOPIC prolonging the oestrogen supply with postmenopausal Data on the association between use of postmenopausal hormone therapy and hormone therapy could protect against Alzheimer’s risk of Alzheimer’s disease are conflicting disease. Several observational studies have indicated that hormone therapy might have a However, clinical data on the association between protective effect on the risk of Alzheimer’s disease, but this was not supported by hormone therapy and the disease have remained the placebo controlled Women’s Health Initiative Memory Study inconclusive. Despite several observational studies supporting the protective effect of hormone therapy These findings were later challenged by the timing hypothesis, which indicates on Alzheimer’s disease,8-13 a subsequent placebo that oestrogen could be neuroprotective only if it is started soon after the onset controlled trial (the Women’s Health Initiative Memory of menopause Study (WHIMS)) failed to confirm this benefit, and WHAT THIS STUDY ADDS in fact implied an increased risk of overall dementia 14 15 Use of postmenopausal systemic hormone therapy is accompanied with an in hormone therapy users. The conflicting data increase in the risk of Alzheimer’s disease in postmenopausal women, whereas could in part result from differences in the study the use of vaginal estradiol shows no such risk design, study populations, or hormone therapy regimens. Unlike clinical practice, hormone therapy Particularly long term exposure to hormone therapy is associated with an in the WHIMS trial was initiated in women aged 65 increased risk of Alzheimer’s disease, but the increase in risk is not dependent or older.14 15 Thus, one explanation might also be the on the age at treatment initiation timing hypothesis, which suggests that oestrogen the bmj | BMJ 2019;364:l665 | doi: 10.1136/bmj.l665 1 RESEARCH could be neuroprotective only if started soon after the opened) or later (that is, fresh starters: 65 102 cases onset of menopause.16 This hypothesis originates from and 65 102 controls), because this group’s detailed BMJ: first published as 10.1136/bmj.l665 on 6 March 2019. Downloaded from cardiovascular studies17 where the age at the start of history of treatment use was documented in the hormone therapy appears to predict the cardiovascular register. The findings in this subanalysis were fully in effects of hormone therapy. Treatment initiated before line with those in the whole study population, so the age 60 is protective, but if started at a later age, it is data of this subanalysis are not shown. detrimental towards the vasculature. Such a window The regimens of systemic hormone therapy in for hormone therapy use has also been suggested for Finland contain exclusively estradiol, which is given cognitive effects.16 either orally (90%) or transdermally (10%). The By using Finnish comprehensive nationwide regimens identified by trade names were transformed registers, we were able to conduct a case-control into doses of estradiol (oral or transdermal). Various comparison to investigate whether hormone therapy progestogens were used in combination with estradiol had an effect on the risk of Alzheimer’s disease, and (that is, oestrogen-progestogen therapy), of which whether this risk was associated with age of treatment norethisterone acetate and medroxyprogesterone initiation or duration of treatment use. acetate were the most common.20 According to the Finnish guidelines, only women who have had Methods hysterectomies can use estradiol without progestogen, In Finland, patients with Alzheimer’s disease and these women were studied as an estradiol only are entitled to 40% reimbursement for treatment group. Oral estradiol doses in Finland are usually 1-2 from national health insurance, but this requires a mg/day, and transdermal (gel or patch) estradiol is statement from a neurologist or geriatrician. They must used with equivalent doses (25-100 μg/day). However, base the diagnosis on symptoms consistent of mild owing to the switching of the use of hormone therapy or moderate Alzheimer’s disease, decrease in social from one route to another and to the relatively similar capacity for at least three months, cognitive tests, route independent levels of circulating oestrogen, we magnetic resonance imaging or computed tomography did no subanalyses according to the treatment route. scanning of the brain, and exclusion of alternative Sequential users of oestrogen-progestogen therapy diagnoses. The physician also must confirm whether were defined as women who used estradiol with 10- the patient has other dementia related diseases, such 14 days of progestogen courses each month, or at as Lewy body dementia or mixed dementia. For mixed intervals of one to three months. Women who used both http://www.bmj.com/ dementia, patients are entitled to reimbursement only estradiol and progestogen every day were considered if the symptoms and findings are caused mainly by as continuous users of oestrogen-progestogen therapy. Alzheimer’s disease. In total, 84 739 women with a Tibolone users were considered as a separate group. diagnosis for Alzheimer’s disease were entered into this Users of vaginal estradiol only (Vagifem, NovoNordisk, register in 1999-2013. During the same period of time, Copenhagen, Denmark; 25 μg twice a week) were control women without a diagnosis were identified analysed separately. from the Finnish National population register (one Exposure to hormone therapy (ever use) was on 27 September 2021 by guest. Protected copyright. control per case; n=84 739). Control women were considered to have started from the date of the matched with cases by age (within 1 month) and by first purchase, or from age 52 if systemic hormone hospital district according to the woman’s municipality therapy was used at the register opening or from of residence. Hospital districts were further divided age 65 years if vaginal estradiol was used at register into five university hospital districts.