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Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study the bmj | BMJ 2019;364:l665 | doi: 10.1136/bmj.l665 1 RESEARCH Use of postmenopausal hormone therapy and risk of Alzheimer’s 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 ABSTRACT OBJECTIVES To compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer’s disease. DESIGN Nationwide case-control study. SETTING Finnish national population and drug register, between 1999 and 2013. PARTICIPANTS All postmenopausal women (n=84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer’s disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n=84 739), matched by age and hospital district, were traced from the Finnish national population register. INTERVENTIONS Data on hormone therapy use were obtained from the Finnish national drug reimbursement register. MAIN OUTCOME MEASURES Odds ratios and 95% confidence intervals for Alzheimer’s disease, calculated with conditional logistic regression analysis. RESULTS In 83 688 (98.8%) women, a diagnosis for Alzheimer’s disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer’s disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (noreth isterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer’s disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01). CONCLUSIONS Long term use of systemic hormone therapy might be accompanied with an overall increased risk of Alzheimer’s disease, which is not related to the type of progestogen or the age at initiation of systemic hormone therapy. By contrast, use of vaginal estradiol shows no such risk. Even though the absolute risk increase for Alzheimer’s disease is small, our data should be implemented into information for present and future users of hormone therapy. Introduction Alzheimer’s disease, the most common cause of dementia, occurs more frequently in women than in men.1 This difference might be due to the longer life expectancy of women, but sex specific differences in the incidence of Alzheimer’s disease might also exist.1-3 It is known that oestrogens exert neuroprotection in several animal studies.4-6 Also, oestrogen deficiency as a result of early menopause has been associated with an increased risk of Alzheimer’s disease.7 Therefore, prolonging the oestrogen supply with postmenopausal hormone therapy could protect against Alzheimer’s disease. However, clinical data on the association between hormone therapy and the disease have remained inconclusive. Despite several observational studies supporting the protective effect of hormone therapy on Alzheimer’s disease,8-13 a subsequent placebo controlled trial (the Women’s Health Initiative Memory Study (WHIMS)) failed to confirm this benefit, and in fact implied an increased risk of overall dementia in hormone therapy users.14 15 The conflicting data could in part result from differences in the study design, study populations, or hormone therapy regimens. Unlike clinical practice, hormone therapy in the WHIMS trial was initiated in women aged 65 or older.14 15 Thus, one explanation might also be the timing hypothesis, which suggests that oestrogen WHAT IS ALREADY KNOWN ON THIS TOPIC Data on the association between use of postmenopausal hormone therapy and risk of Alzheimer’s disease are conflicting Several observational studies have indicated that hormone therapy might have a protective effect on the risk of Alzheimer’s disease, but this was not supported by the placebo controlled Women’s Health Initiative Memory Study These findings were later challenged by the timing hypothesis, which indicates that oestrogen could be neuroprotective only if it is started soon after the onset of menopause WHAT THIS STUDY ADDS Use of postmenopausal systemic hormone therapy is accompanied with an increase in the risk of Alzheimer’s disease in postmenopausal women, whereas the use of vaginal estradiol shows no such risk Particularly long term exposure to hormone therapy is associated with an increased risk of Alzheimer’s disease, but the increase in risk is not dependent on the age at treatment initiation 1University of Helsinki and Helsinki University Hospital, Obstetrics and Gynecology, Haartmaninkatu 2, PO Box 140, FIN-00029 HUS, 00029 Helsinki, Finland 2Folkhälsan Research Center, Biomedicum, Helsinki, Finland 3EPID Research Oy, Espoo, Finland 4National Institute for Health and Welfare, Helsinki, Finland 5Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Huddinge, Sweden 6University of Turku, Research Centre for Child Psychiatry, Turku, Finland Correspondence to: T S Mikkola
[email protected] (ORCID 0000-0003-2049-088X) Additional material is published online only. To view please visit the journal online. Cite this as: BMJ 2019;364:l665 http://dx.doi.org/10.1136/bmj.l665 Accepted: 1 February 2019 on 16 June 2021 by guest. P rotected by copyright. http://w w w .bm j.com / B M J: first published as 10.1136/bm j.l665 on 6 M arch 2019. D ow nloaded from mailto:
[email protected] http://orcid.org/0000-0003-2049-088X https://crossmark.crossref.org/dialog/?doi=10.1136/bmj.l665&domain=pdf&date_stamp=2019-03-04 http://www.bmj.com/ RESEARCH 2 doi: 10.1136/bmj.l665 | BMJ 2019;364:l665 | the bmj could be neuroprotective only if started soon after the onset of menopause.16 This hypothesis originates from cardiovascular studies17 where the age at the start of hormone therapy appears to predict the cardiovascular effects of hormone therapy. Treatment initiated before age 60 is protective, but if started at a later age, it is detrimental towards the vasculature. Such a window for hormone therapy use has also been suggested for cognitive effects.16 By using Finnish comprehensive nationwide registers, we were able to conduct a case-control comparison to investigate whether hormone therapy had an effect on the risk of Alzheimer’s disease, and whether this risk was associated with age of treatment initiation or duration of treatment use. Methods In Finland, patients with Alzheimer’s disease are entitled to 40% reimbursement for treatment from national health insurance, but this requires a statement from a neurologist or geriatrician. They must base the diagnosis on symptoms consistent of mild or moderate Alzheimer’s disease, decrease in social capacity for at least three months, cognitive tests, magnetic resonance imaging or computed tomography scanning of the brain, and exclusion of alternative diagnoses. The physician also must confirm whether the patient has other dementia related diseases, such as Lewy body dementia or mixed dementia. For mixed dementia, patients are entitled to reimbursement only if the symptoms and findings are caused mainly by Alzheimer’s disease. In total, 84 739 women with a diagnosis for Alzheimer’s disease were entered into this register in 1999-2013. During the same period of time, control women without a diagnosis were identified from the Finnish National population register (one control per case; n=84 739). Control women were matched with cases by age (within 1 month) and by hospital district according to the woman’s municipality of residence. Hospital districts were further divided into five university hospital districts. Finland has a reliable nationwide register that includes all hormone therapy users from year 1994. Use of the treatment in Finland is available only with a physician’s prescription, and regimens are partly (40-60%) reimbursed by the government. At each pharmacy visit, hormone therapy purchases are entered into the drug reimbursement register, confirming use of the prescribed regimen of hormone therapy. The register was initiated in 1994, so we could not differentiate whether a woman who bought the treatment in 1994 was a new user or was continuing her treatment initiated before 1994. Therefore, we assumed that all systemic users older than 52 years in 1994 had initiated the treatment at age 52 and vaginal users at age 65, which are the mean ages at systemic and vaginal initiation of hormone therapy in our study population, respectively.18 This approximation has been used in several previous studies. 19-21 However, we also analysed separately women who had started hormone therapy in 1995 (one year after the register opened) or later (that is, fresh starters: 65 102 cases and 65 102 controls), because this group’s detailed history of treatment use was documented in the register. The findings in this subanalysis were fully in line with those in the whole study population, so the data of this subanalysis are not shown. The regimens of systemic hormone therapy in Finland contain exclusively estradiol, which is given either orally (90%) or transdermally (10%). The regimens identified by trade names were transformed into doses of estradiol (oral or transdermal). Various progestogens were used in combination with estradiol (that is, oestrogen-progestogen therapy), of which norethisterone acetate and medroxyprogesterone acetate were the most common.20 According to the Finnish guidelines, only women who have had hysterectomies can use estradiol without progestogen, and these women were studied as an estradiol only group. Oral estradiol doses in Finland are usually 1-2 mg/day, and transdermal (gel or patch) estradiol is used with equivalent doses (25-100 μg/day). However, owing to the switching of the use of hormone therapy from one route to another and to the relatively similar route independent levels of circulating oestrogen, we did no subanalyses according to the treatment route. Sequential users of oestrogen-progestogen therapy were defined as women who used estradiol with 10- 14 days of progestogen courses each month, or at intervals of one to three months. Women who used both estradiol and progestogen every day were considered as continuous users of oestrogen-progestogen therapy. Tibolone users were considered as a separate group. Users of vaginal estradiol only