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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 (norethisterone 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.
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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 identied 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% condence 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 dier
signicantly between users of estradiol only (odds
ratio 1.09, 95% condence 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 dierent 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 aect 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 dierence might be due to the longer life
expectancy of women, but sex specific dierences 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 eect 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 dierences 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 eect on the risk of Alzheimer’s disease, but this was not supported by
the placebo controlled Women’s Health Initiative Memory Study
These ndings were later challenged by the timing hypothesis, which indicates
that oestrogen could be neuroprotective only if it is started soon aer 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
tomi.mikkola@hus.
(ORCID 0000-0003-2049-088X)
Additional material is published
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Cite this as: BMJ 2019;364:l665
http://dx.doi.org/10.1136/bmj.l665
Accepted: 1 February 2019
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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
eects 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 eects.16
By using Finnish comprehensive nationwide
registers, we were able to conduct a case-control
comparison to investigate whether hormone therapy
had an eect 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 dierentiate 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 (Vagifem, NovoNordisk,
Copenhagen, Denmark; 25 μg twice a week) were
analysed separately.
Exposure to hormone therapy (ever use) was
considered to have started from the date of the
first purchase, or from age 52 if systemic hormone
therapy was used at the register opening or from
age 65 years if vaginal estradiol was used at register
opening. Cumulative exposure to hormone therapy
was classified by duration (lasting ≤3 years, >3 to ≤5
years, >5 to ≤10 years, or >10 years). We assessed the
time period from treatment initiation to diagnosis for
Alzheimer’s disease. To address the potential critical
time window for oestrogen brain eect,16 we also
compared the risk of the disease in women who had
started hormone therapy aged under 60 versus those
aged 60 and over.
Statistical methods
We used a conditional logistic regression analysis to
estimate, by using odds ratios with 95% confidence
intervals, the relative risk of Alzheimer’s disease
associated with dierent regimens of hormone therapy.
The association between age at treatment initiation
and Alzheimer’s disease was also analysed with
conditional logistic regression, using both continuous
age and five years age classes as variables. We used
the χ2 test to test dierences between categorical
variables. Dierences between continuous variables
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2019;364:l665 | doi: 10.1136/bmj.l665 3
were evaluated with the student’s t test or two tailed
test of equal or given proportions. Significance was set
at P<0.05.
Patient and public involvement
No patients were involved in the setting of the
research question or the outcome measures, nor were
they involved in the developing plans for design or
implementation of the study. No patients were asked
to advise on interpretation or writing up of the results.
There are no plans to disseminate the results of the
research to study participants or the relevant patient
community.
Results
Overall, 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 (table 1). Time from initiation
of hormone therapy to diagnosis was shorter than five
years in 886 (5.6%) women, but longer than 10 years
in 11 805 (74.9%). At the time of diagnosis, only 2305
(14.6%) women were still using hormone therapy,
whereas 10 188 (64.6%) had stopped treatment more
than three years before diagnosis.
Patients with Alzheimer’s disease used systemic
hormone therapy more often (18.6% v 17.0%,
respectively, P<0.001) but used vaginal estradiol only
less often (12.7% v 13.2%, P=0.005) than controls (table
1). The mean exposure time to systemic hormone therapy
did not dier between patients with Alzheimer’s disease
and control women (table1). The relative proportions of
dierent progestogens users were similar in cases and
controls (table 1), but exposure to oestrogen-progestogen
therapy with other or mixed progestogens was longer in
patients with Alzheimer’s disease (P=0.02).
Overall, hormone therapy users with Alzheimer’s
disease (n=11 456, 73.7%) had started systemic
hormone therapy under age 60 years less often than
controls (n=10 662, 75.1%, P=0.006). The mean age
at initiation of estradiol only was similar for patients
with Alzheimer’s disease and controls (table 1), but
the mean age at initiation of oestrogen-progestogen
therapy was slightly higher for patients with
Alzheimer’s disease than for controls (56.1 (standard
deviation 7.8) v 55.8 (7.6), P=0.02).
Table1 | Characteristics of study population. Data are number (%) of women unless stated otherwise
Patients with Alzheimer’s disease (n=84 739) Controls (n=84 739) P
Start of follow-up (age at Alzheimer diagnosis (years) for cases)
<50 99 (0.1) 101 (0.1)
50-54 273 (0.3) 274 (0.3)
55-59 679 (0.8) 678 (0.8)
60-64 1373 (1.6) 1373 (1.6)
65-69 4028 (4.8) 4028 (4.7)
70-74 10 731 (12.7) 10 785 (12.7)
75-79 20 317 (24.0) 20 311 (24.0)
≥80 47 239 (55.7) 47 193 (55.7)
University healthcare district at the time of diagnosis
Northern (Oulu) 14 794 (17.5) 14 746 (17.4)
Eastern (Kuopio) 17 425 (20.6) 17 450 (20.6)
Southern (Helsinki) 24 053 (28.4) 23 956 (28.3)
Western (Turku) 10 856 (12.8) 10 873 (12.8)
Central Finland (Tampere) 17 574 (20.7) 17 624 (20.8)
Unknown 6 (0.01) 3 (0.0)
Abroad 31 (0.04) 87 (0.1)
Hormone therapy use
No use 58 186 (68.7) 59 175 (69.8) <0.001
Systemic use 15 768 (18.6) 14 394 (17.0)
Estradiol only 5606 (35.6) 5312 (36.9) 0.01
EPT 9941 (63.0) 8890 (61.9)
EPT with MPA 1955 (19.7) 1795 (20.1) 0.27
EPT with NETA 3080 (31.0) 2661 (29.8)
EPT with other* or mixed progestogens 4906 (49.4) 4434 (50.0)
Tibolone 221 (1.4) 192 (1.3) 0.17
Vaginal estradiol 10 785 (12.7) 11 170 (13.2) 0.005
Age at hormone therapy initiation (mean, SD)
Estradiol only 58.0 (9.3) 57.7 (9.0) 0.1
EPT 56.1 (7.8) 55.8 (7.6) 0.02
Exposure time (mean, SD)
Systemic use 11.4 (8.6) 11.5 (8.6) 0.19
Estradiol only 11.8 (9.3) 11.9 (9.4) 0.40
EPT 9.8 (7.7) 9.7 (7.7) 0.28
EPT with MPA 9.6 (7.9) 9.7 (7.7) 0.10
EPT with NETA 7.0 (7.4) 6.7 (7.3) 0.28
EPT with other* or mixed progestogens 11.6 (7.4) 11.3 (7.4) 0.02
Tibolone 1.6 (1.8) 1.6 (1.7) 0.93
EPT=oestrogen-progestogen therapy; NETA=norethisterone acetate; MPA=medroxyprogesterone acetate; SD=standard deviation.
*Other progestogens include levonorgestrel, progesterone, megestrol acetate, lynestrenol, drospirenone, and trimegestone.
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2019;364:l665 | thebmj
In the whole study population, the risk of Alzheimer’s
disease was increased but did not dier 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). Exclusive use of
vaginal estradiol was not related to risk of Alzheimer’s
disease (0.99, 0.96 to 1.01). In women younger than
60 at hormone therapy initiation, use of the dierent
oestrogen-progestogen therapies was associated with
an 8-17% increased risk of Alzheimer’s disease (table
2). We saw no significant dierences between the
dierent therapies with regards to Alzheimer’s disease
risk. Use of estradiol only was associated with a small
but significant increase in disease risk. The risk of
Alzheimer’s disease in estradiol only users (odds ratio
1.06, 95% confidence interval 1.01 to 1.12) and all
users of oestrogen-progestogen therapy (1.14, 1.09 to
1.19) did not dier significantly. The use of tibolone
carried no significant risk of Alzheimer’s disease in
this age group. The risk increases in users of estradiol
only and oestrogen-progestogen therapy were related
to 10 years of exposure or more, whereas shorter use of
hormone therapy was not associated with Alzheimer’s
disease risk (table 3).
In women aged 60 or older at the initiation of
hormone therapy, use of estradiol only, oestrogen-
progestogen therapy, or tibolone was associated with
similar increases in risk (15-38%) for Alzheimer’s
Table2 | Odds ratios for Alzheimer’s disease in women younger than 60 or aged 60 and older at treatment initiation of
estradiol only or various combined therapies
Age at initiation and type of hormone therapy Patients with Alzheimer’s disease (No) Controls (No) Odds ratio (95% CI) P
Age <60 years
No hormone therapy 48 331 48 925 1.00
Estradiol only 3125 3042 1.06 (1.01 to 1.12) 0.03
EPT 6330 5812 1.14 (1.09 to 1.19) <0.005
EPT with MPA 1296 1247 1.08 (1.00 to 1.17) 0.06
EPT with NETA 1419 1270 1.17 (1.08 to 1.26) <0.005
EPT with other* or mixed progestogens 3615 3295 1.15 (1.09 to 1.21) <0.005
Tibolone 83 90 0.97 (0.72 to 1.32) 0.86
Age ≥60 years
No hormone therapy 45 180 45 635 1.00
Estradiol only 1310 1157 1.15 (1.06 to 1.25) <0.005
EPT 1630 1352 1.23 (1.14 to 1.32) <0.005
EPT with MPA 269 227 1.21 (1.01 to 1.44) 0.04
EPT with NETA 963 792 1.23 (1.12 to 1.36) <0.005
EPT with other* or mixed progestogens 398 333 1.21 (1.05 to 1.41) 0.009
Tibolone 90 66 1.38 (1.00 to 1.89) 0.05
EPT=oestrogen-progestogen therapy; NETA=norethisterone acetate; MPA=medroxyprogesterone acetate.
*Other progestogens include levonorgestrel, progesterone, megestrol acetate, lynestrenol, drospirenone, and trimegestone.
Table3 | Odds ratios for Alzheimer’s disease in women younger than 60 or aged 60 and over at treatment initiation of
estradiol only or various combined therapies, stratied by duration of treatment
Type and duration of hormone therapy Patients with Alzheimer’s disease (No) Controls (No) Odds ratio (95% CI) P
Age <60 years at treatment initiation
Estradiol only
No hormone therapy 44 879 44 978 1.00
<3 years 126 140 0.89 (0.69 to 1.15) 0.38
3 to <5 years 78 60 1.31 (0.93 to 1.87) 0.13
5 to <10 years 254 286 0.88 (0.74 to 1.06) 0.18
≥10 years 1989 1862 1.07 (1.00 to 1.15) 0.04
Oestrogen-progestogen therapy
No hormone therapy 46 301 46 796 1.00
<3 years 845 854 1.02 (0.92 to 1.13) 0.67
3 to <5 years 401 416 1.00 (0.86 to 1.15) 0.98
5 to <10 years 1118 1063 1.10 (1.00 to 1.20) 0.05
≥10 years 3355 2891 1.20 (1.13 to 1.26) <0.005
Age ≥60 years at treatment initiation
Estradiol only
No hormone therapy 43 894 44 062 1.00
<3 years 905 804 1.13 (1.03 to 1.25) 0.01
3 to <5 years 160 119 1.35 (1.07 to 1.72) 0.01
5 to <10 years 164 139 1.19 (0.95 to 1.50) 0.13
≥10 years 28 27 1.04 (0.61 to 1.77) 0.88
Oestrogen-progestogen therapy
No hormone therapy 44 135 44 422 1.00
<3 years 1204 1015 1.20 (1.10 to 1.30) <0.005
3 to <5 years 233 179 1.32 (1.08 to 1.60) 0.006
5 to <10 years 198 147 1.36 (1.10 to 1.69) <0.005
≥10 years 17 24 0.73 (0.39 to 1.35) 0.31
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disease (table 2). In this age group, the increased risk
was already detectable after three to five years’ use
of estradiol only or oestrogen-progestogen therapy
(table 3). The increases in risk of Alzheimer’s disease
between women younger than 60 and those aged 60 or
older at treatment initiation did not dier significantly.
When the eect of age at treatment initiation on
risk of Alzheimer’s disease was analysed further in
five year intervals, no association emerged (fig 1).
Furthermore, age as a continuous variable was no
determinant for disease risk in users of estradiol only
(odds ratio 1.0, 95% confidence interval 0.98 to 1.02),
oestrogen-progestogen therapy (1.0, 0.99 to 1.01), or
any hormone therapy (1.0, 0.99 to 1.01). The disease
appeared earlier in women with a history of systemic
use of hormone therapy than in those with vaginal
estradiol use or without any prior use of the treatment
(fig 2).
Discussion
Principal ndings
In our large case-control study of 84 739 patients with
Alzheimer’s disease and a similar number of control
women, we showed that the systemic use of estradiol
only or oestrogen-progestogen therapy was associated
with an increased risk of Alzheimer’s disease, whereas
use of vaginal estradiol showed no such risk. The age
at initiation of hormone therapy did not appear to be a
determinant for risk of the disease, whereas in women
younger than 60 at treatment initiation, the risk
increases were associated with exposure to hormone
therapy for over 10 years.
Comparison with other studies
Most observational studies have reported a reduced
risk of Alzheimer’s disease and all cause dementia in
users of hormone therapy.8-13 22 These analyses can be
criticised, owing to the lack of a placebo arm and the
possible bias of healthy woman in hormone therapy
users. This criticism gained strong support from the
placebo controlled WHIMS trial, reporting an increased
risk of impaired cognition and probable dementia in
women who used conjugated equine oestrogens (CEE)
with and without medroxyprogesterone acetate.14 15
On the other hand, this study was also criticised
because, unlike in normal clinical practice, hormone
therapy was initiated for women older than 65, many
years after the onset of menopause. Moreover, the
WHIMS study did not dierentiate Alzheimer’s disease
from other dementia or cognitive decline, although
the pathophysiology of dementia includes multiple
dierent neurodegenerative and vascular processes,
which could respond dierently to oestrogen exposure.
Our epidemiological study, although large in size
and conducted in a case-control setting, can show
only associations between hormone therapy use and
the risk of Alzheimer’s disease. Moreover, the small
risk increases are vulnerable to bias from unsuspected
sources, which are unavoidable in all observational
studies.8-13 But if there is a causal relation, it seems
that estradiol could be primarily responsible for the
increased risk of Alzheimer’s disease, because use
of estradiol only was related to the increased risk.
However, progestogen could potentiate the eect of
estradiol on the risk of Alzheimer’s disease, because the
risk elevations tended to be higher in users of oestrogen-
progestogen therapy than users of estradiol only. This
notion accords with the WHIMS study finding14 15 that
the risk of all cause dementia was higher in users of CEE
and medroxyprogesterone acetate than in those using
CEE only. Progestogens, such as medroxyprogesterone
acetate or norethisterone acetate, dier in structure
and in their capacity to bind to progesterone and other
steroid hormone receptors23; therefore, the risk of
Alzheimer’s disease in users of the dierent oestrogen-
progestogen therapies could vary. Our data show
that norethisterone acetate, medroxyprogesterone
acetate, or other progestogens as components of
oestrogen-progestogen therapy do not dier in regard
to risk of Alzheimer’s disease. Tibolone, a synthetic
steroid hormone with oestrogenic, progestogenic,
and androgenic actions, has shown a neuroprotective
eect in preclinical studies.24 Our finding implies that
tibolone does not dierentiate significantly from other
forms of systemic hormone therapy with regard to the
risk of Alzheimer’s disease, but owing to the small
number of tibolone users, this conclusion must be
interpreted with caution.
The cause of Alzheimer’s disease is not yet fully
understood, but β amyloid plaques and neurofibrillary
tangles containing hyperphosphorylated τ protein
do accumulate in the brain. 25 26 Several risk factors,
such as genetic tendency, head trauma, smoking, and
low education could speed up the development of the
disease. Multiple full term pregnancies might also
predispose to the development of Alzheimer’s disease,
perhaps due to repeat oestrogen and progesterone
surges.27 Our present data imply that the prolongation
of estradiol exposure beyond the natural menopausal
age with the use of hormone therapy could stimulate
the progression of Alzheimer’s disease, and thus
increase its risk, especially if such exposure to estradiol
is continued for over 10 years. Our data do not allow
any detailed speculations for the possible biological
Age at
initiation
of any HT
75-79
70-74
65-69
60-64
55-59
<50-54
00.5 1.51.0
Odds ratio
(95% CI)
47/60
134/130
260/277
343/305
358/365
3570/3579
No of cases
/controls
Fig1 | Risk of Alzheimer’s disease in women initiating systemic hormone therapy (HT) at
dierent ages, as odds ratios and 95% condence intervals. Line at 1.0 denotes the risk
in the group of women who started systemic use younger than 55. Numbers of cases
and controls are given for ve years periods
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mechanism through which estradiol could have
caused this eect. Although estradiol might inhibit
the accumulation of β amyloid in animal models and
in early postmenopausal women,3 6 28 it has been
speculated that such an eect of oestrogen is lost
with advancing age. We sought thoroughly for such a
timing eect from our data, but we must conclude that
the age at initiation of hormone therapy is no decisive
determinant for the risk of Alzheimer’s disease in the
future.
We have previously shown that the systemic use of
estradiol based hormone therapy was associated with
a marked dierence in the death risk of dementia; the
risk of death for vascular dementia was profoundly
decreased (by 37-39%), whereas risk of death
for Alzheimer’s disease showed a much smaller
decrease or even lacked a decrease. 21 Furthermore,
in the extended follow-up of the Women’s Health
Initiative study,29 the mortality for Alzheimer’s
disease and other dementia was reduced in CEE
users, although the authors conclude that this finding
should be interpreted cautiously because of multiple
comparisons. It is possible that the use of hormone
therapy is accompanied, directly or indirectly, with a
decreased risk of the most severe forms of Alzheimer’s
disease, perhaps by improving cardiovascular health.
Yet, it is the incidence of and not mortality from
Alzheimer’s disease that determines the total burden
of the disease.
Strengths and limitations of the study
Our study had several limitations. Firstly, we did
not have baseline demographic data for known risk
factors for Alzheimer’s disease, either for the hormone
therapy users or controls. We would not expect this
omission to cause many errors in our study, because
several common dementia risk factors (hypertension,
hypercholesterolaemia, and smoking) were evenly
distributed between the two groups in another study
from the same population.30 Moreover, cardiovascular
mortality was reduced in the Finnish hormone
therapy users,18 20 implying that higher cardiovascular
morbidity could not explain the elevated disease risk
of hormone therapy users in our study. The ApoE
E4 allele frequency in Finland (at nearly 20%) is
among the highest in the world,31 32 and some studies
suggest that the eects of postmenopausal hormone
therapy on Alzheimer’s disease are modified by the
ApoE status.2 ApoE E4 is not screened in the Finnish
healthcare system, but it is unlikely that ApoE status
would have diered between the two study groups.
Furthermore, Finnish users of hormone therapy did
not dier in socioeconomic status or education from
the non-users,33 and healthcare services in Finland are
available for everyone, free of charge, or substantially
subsidised.
Secondly, due to the first signs of cognitive
impairment seven to eight years before the final
diagnosis,34 there is a possibility that such women
sought help from hormone therapy, and thus an
increased risk of Alzheimer’s disease was a cause for
its use and not its consequence. However, this seems
unlikely in our population, because the disease
diagnosed most often at over age 80 would have
caused symptoms at around age 72-7334; however,
most hormone therapy users (74%) started use under
age 60. Furthermore, only 14% of users were still on
hormone therapy at the time of diagnosis. Thirdly,
the duration of the pre-register use of hormone
therapy had to be estimated in a quarter of the total
study population. However, based on the previous
data,20 21 such an estimation for hormone therapy
use is accurate. Fourthly, controls were not screened
with magnetic resonance imaging of the brain or
neurological examination to exclude Alzheimer’s
disease, and thus some controls could have had
undiagnosed disease. This chance should not cause
any concern because the prevalence of Alzheimer’s
disease in Europe is 4.4%.35 Finally, although we could
reliably dierentiate between systemic and vaginal use
of estradiol, we were not able to compare the use of
oral and transdermal preparations with use of cyclic
and continuous oestrogen-progestogen therapy.
Our study also had several strengths. Firstly, this
study is one of the largest on the association between
hormone therapy and Alzheimer’s disease. Secondly,
it is vital that in a study on women with cognitive
decline, the use of hormone therapy was objectively
assessed from a reliable nationwide register controlled
by authorities, because self reporting is not reliable
in patients with poor cognitive performance. Thirdly,
Alzheimer’s disease was accurately diagnosed and
dierentiated from vascular dementia and other
forms of dementia or cognitive decline according to
internationally approved criteria.36 Finally, it has been
shown that 97% of Finnish patients with Alzheimer’s
disease actually use treatment37 and thus have been
included into the reimbursement register, which
confirms that we could reliably detect patients with
Alzheimer’s disease in Finland.
Conclusions and policy implications
The present study indicates that the use of systemic
hormone therapy, once claimed to be protective against
Alzheimer’s disease, is accompanied with a 9-17%
Age group
Proportion with diagnosis
of Alzheimer's disease (%)
0
20
30
40
10
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
≥100
No HT
Any HT
Vaginal use of estradiol
Fig2 | Proportion (%) of women with a diagnosis of Alzheimer’s disease in dierent
age groups according to systemic use of hormone therapy, vaginal use of estradiol, or
without any history of hormone therapy (HT) use
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2019;364:l665 | doi: 10.1136/bmj.l665 7
increase in the risk of the disease in postmenopausal
women, whereas the exclusive use of vaginal estradiol
shows no risk. In absolute terms, we estimate that nine
to 18 excess diagnoses of the disease per year will be
detected in 10 000 women aged 70-80 (incidence 105
per 10 000 women years in this age group), especially
in those who had used hormone therapy for over 10
years. The age at initiation of hormone therapy is no
decisive determinant for the future risk of Alzheimer’s
disease. Hormone therapy users should be informed
for a possible risk of the disease with prolonged use
of Alzheimer’s disease, even though the absolute risk
elevations are small.
Contributors: TSM and OY designed the study. FH, PV, and MG
analysed the data. HS-P draed the gure and the tables. HS-P, PR-S,
OY, and TSM draed the manuscript, and all the authors read, revised
the manuscript, and approved its nal version. TSM and HS-P are
responsible for the overall content as guarantors, and accept full
responsibility for the work and the conduct of the study, had access
to the data, and controlled the decision to publish. The corresponding
author attests that all listed authors meet authorship criteria and that
no others meeting the criteria have been omitted, had full access to all
the data in the study, and had nal responsibility for the decision to
submit for publication.
Funding: This study was supported by a Helsinki University Hospital
research grant and the Jane and Aatos Erkko Foundation. The funders
had no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; and in the decision
to submit the article for publication. We conrm that the researchers
were independent from funders and that all authors had full access
to all of the data (including statistical reports and tables) in the
study and can take responsibility for the integrity of the data and the
accuracy of the data analysis.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare:
support from Helsinki University Hospital and the Jane and Aatos
Erkko Foundation for the submitted work; speaker and consulting fees
for Mylan (HS-P, TSM) and Astellas (TSM); funding for congress trips
from Merck, Sharp, and Dohme (HS-P), Astellas (PR-S), and Olympus
(PR-S); FH and PV work for EPID Research, which performs nancially
supported studies for several pharmaceutical companies; no other
relationships or activities that could appear to have influenced the
submitted work.
Ethical approval: The research committee of the Helsinki University
Hospital approved our study plan. Approval from the ethics
committee was not needed in our register based study because we
did not contact any study patients or their care givers. Appropriate
approvals for the use of condential register data in scientic research
were obtained from the National Institute for Health and Welfare
(THL/1370/5.05.00/2010), Statistics Finland (TK-53-1560-10), and
the Social Insurance Institution of Finland (KELA 40/522/2010). All
data were pseudonymised before inclusion into the study database.
Data sharing: No additional data are available.
The lead author arms that the manuscript is an honest, accurate,
and transparent account of the study being reported; that no
important aspects of the study have been omitted; and that any
discrepancies from the study as originally planned (and, if relevant,
registered) have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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... Other epidemiological studies have addressed the role of exogenous estrogens and dementia risk. A reduced risk of dementia was reported in MHT users, another did not associate MHT and all-cause dementia and AD [19]. Transdermal 17-beta estradiol therapy was associated with a decrease in beta-amyloid deposition in neuroimaging studies, particularly in carriers of APOE, a plasma protein constituent of lipoproteins, which functions to maintain the structure and regulate the metabolism of several of them; it plays a central role in the metabolism of plasma lipoproteins and in the transport of lipids within tissues. ...
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During the menopausal transition, which begins 4 to 6 years prior to stopping menstruation, women at this stage experience progressive changes in ovarian activity and physiological impairment of hypothalamic-pituitary-ovarian axis function associated with fluctuations in levels. hormonal; where they can suffer symptoms related to menopause such as vasomotor symptoms, sleep disorders, mood changes, memory problems and genitourinary syndrome of menopause. Neurological symptoms such as sleep disturbance and mood swings are the most important discomfort in the transition to menopause, which impacts quality of life, productivity and physical health. A review of the associations between menopause and/or hormone levels with sleep problems, mood and reduced cognitive performance is performed. During the transition to menopause, women experience dramatic fluctuations in the levels of sex hormones such as estradiol, progesterone, and androgens, responsible for changes in behavior, cognition, mood, and sleep.
... The authors note that MHT use in Denmark decreased significantly after the WHI study results were published in 2002 [71]. Lastly, a nationwide Finnish case-control study of 84,739 women with dementia and an equal number of controls [72] reported a small AD risk increase with estradiol-only therapy among women who initiated MHT before age 60 [OR = 1.06, 1.01-1.12]. Combined therapy was also associated with increased AD risk, but only for estrogen with norethisterone acetate [OR = 1.17, 1.08-1. ...
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Purpose of Review To provide an updated integration of available data on the effects of menopause hormone therapy (MHT) on risk of Alzheimer’s disease (AD) and dementia. Recent Findings MHT’s impact on AD and dementia risk may be influenced by factors including timing of initiation, formulation, administration, and Apolipoprotein E epsilon 4 (APOE-4) status. Summary Randomized controlled trials of older postmenopausal women showed an increased risk of dementia with oral conjugated equine estrogen (CEEs) and medroxyprogesterone acetate (MPA) compared with placebo. In contrast, observational studies of midlife women tend to report more positive effects. This updated random effect meta-analysis of observational data indicates an 11.3% reduced risk of AD or dementia with overall MHT use [relative risk, RR = 0.887 (0.829-0.950), P = 0.006]. In meta-regression analysis, estrogen-only therapy, midlife use, and longer duration of use were associated with reduced dementia risk (P ≤ 0.004), while studies from Northern Europe were more likely to report an increased risk of dementia than other locations (P = 0.005). Sub-analyses showed an advantage of oral over transdermal estrogen, and non-significant associations of oral estrogen combined with progestogens. APOE-4 genotype influenced risk, with a 35.2% reduced risk of AD for non-carriers using MHT [RR = 0.648 (0.476-0.880), P = 0.006] and neutral effects for APOE-4 carriers [RR = 0.990 (0.751-1.305), P = 0.941]. These findings support evaluating precision MHT for AD risk reduction.
... 8 However, none of the two controlled for MHT formulation or delivery form, while in the latter, age at menopause was also not accounted for. Even though we did not find either MHT formulation or form to be associated with CSF biomarkers in the current analyses, certain formulations and delivery forms have been reported to be associated with increased risk of AD. 55 Further studies with larger sample sizes are required to clarify how timing of MHT initiation is associated with CSF biomarkers of AD, especially in APOE ε4 carriers and non-carriers. ...
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Full-text available
INTRODUCTION Menopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it. METHODS In an observational study of 136 cognitively unimpaired female participants (Mage = 66.0; standard deviation = 6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p‐tau), amyloid beta (Aβ)40, Aβ42, p‐tau/Aβ42, and Aβ42/40 ratios. RESULTS Significant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p‐tau/Aβ42 and Aβ42/40 ratios than all other users and non‐users. DISCUSSION The presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk. Highlights Significant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p‐tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios. APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non‐users and non‐carriers, both users and non‐users. Younger age at MHT initiation was associated with worse levels of the p‐tau/Aβ42 and Aβ42/40 ratios in carriers only. The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology. Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.
Chapter
Menopause marks the end of a woman’s reproductive years and significantly impacts various physiological systems, particularly the brain. In India, where the life expectancy of women has risen to 70 years, it is crucial to ensure quality of life post-menopause. Neurological symptoms during perimenopause, including cognitive decline, are linked to estrogen deficiency, which disrupts estrogen-regulated brain functions such as thermoregulation, sleep, and memory. Estrogen plays a critical role in brain health by protecting neurons, reducing amyloid levels, and enhancing synaptic growth. However, during the perimenopausal transition, the estrogen receptor network weakens, leading to a hypometabolic state that may increase the risk of neurodegenerative diseases. Clinical studies have shown mixed results regarding the effects of hormone replacement therapy (HRT) on cognition. While some studies suggest that HRT may reduce dementia risk, others, including the Women’s Health Initiative Memory Study (WHIMS), indicate that estrogen-progestin therapy may increase the risk of dementia in older postmenopausal women. Recent trials, such as the KEEPS-Cog, have found no significant cognitive benefits from hormone therapy, though small mood improvements were noted in some groups. The timing of HRT initiation appears to influence its effects on cognition, with some evidence supporting early initiation for potential cardiovascular and cognitive benefits. Furthermore, factors such as comorbidities, vasomotor symptoms, and psychological health also contribute to cognitive decline post-menopause. A multidomain approach to prevention, including lifestyle interventions, may offer a promising strategy to mitigate cognitive decline in postmenopausal women. Further large-scale studies are needed to clarify the long-term effects of HRT on brain health and cognition.
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Accumulating evidence suggests that the effects of menopausal hormone therapy (MHT) on risk of Alzheimer’s disease (AD) and all-cause dementia are influenced by timing of initiation relative to age and time-since-menopause and the type of formulation. Randomized clinical trials (RCTs) of MHT conducted in older postmenopausal women indicate an increased risk of dementia. While RCTs conducted in midlife are lacking, observational research has provided evidence for associations between midlife estrogen-only therapy (ET) use and a reduced risk of AD dementia, whereas estrogen-progestogen therapy (EPT) is associated with more variable outcomes. However, existing studies are heterogenous, and conventional endpoints might not adequately assess MHT’s potential for AD prevention. Herein, several approaches are being discussed, and the case is being made for utilizing AD biomarkers for assessment of early, AD-specific outcomes in relation to MHT use. From a clinical standpoint, findings that MHT may lower dementia risk warrant consideration as existing therapies like acetylcholinesterase inhibitors and memantine lack preventative efficacy, and vaccines for primary or secondary prevention are not yet available. MHT-associated risks, including breast cancer, stroke and venous thromboembolism, are generally considered rare (<10 events/10,000 women). Overall, the literature supports renewed interest in evaluating MHT as a sex-specific, time-sensitive approach for AD risk reduction, which is key to applying cumulated data in clinical decision making concerning AD prevention.
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Alzheimer's disease (AD), one of the most prevalent neurodegenerative disease responsible for 60%–80% dementia cases globally. The disease is more prevalent among elder females. Female reproductive hormones are found to be essential for cellular activities in brain. The physiological role of neurotrophins and sex hormones in hippocampal region during neurogenesis and neuron differentiation was studied as well. In addition to triggering cellular pathways, estrogen and progesterone carry out a number of biological processes that lead to neuroprotection. They might have an impact on learning and memory. One of estrogen's modest antioxidant properties is its direct scavenging of free radicals. The neurotrophic effect of estrogen and progesterone can be explained by their ability to rise the expression of the brain‐derived neurotrophic factor (BDNF) mRNA. Additionally, they have the ability to degrade beta‐amyloid and stop inflammation, apoptotic neuronal cell death, and tau protein phosphorylation. To enhance their neuroprotective action, various cross‐talking pathways in cells that are mediated by estrogen, progesterone, and BDNF receptors. This include signaling by mitogen‐activated protein kinase/extracellular regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B, and phospholipase/protein kinase C. Clinical research to establish the significance of these substances are fragmented, despite publications claiming a lower prevalence of AD when medication is started before menopause. This review article emphasizes an update on the role of estrogen, and progesterone in AD.
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Commentary on Nerattini M, Jett S, Andy C, et al. Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia. Front Aging Neurosci. 2023;15:1260427. Series Editor Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George’s,University of London, UK.
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Background: There is a continued debate on whether menopausal hormone therapy (MHT) protects women against Alzheimer's disease (AD). It is also unclear whether phytoestrogen could be an alternative treatment for AD. Objective: To investigate whether mixed study findings may be due to differences in age at initiation of MHT and duration of prescription of different types of MHT using meta-analyses. Methods: After a systematic literature search, meta-analyses were carried out using Cochrane Revman 5.4.1.software including data from large nationwide studies of registered medically diagnosed AD and prescribed MHT. These analyses were stratified for duration and type of treatment, by age at start of prescription of therapy. Insufficient quality data were available for phytoestrogen treatment and AD meta-analyses. Results: A total of 912,157 women were included from five registries, of whom 278,495 had developed AD during follow-up. Meta-analyses suggested a small increased AD risk after 5-10 years prescription of combination MHT regardless of age, and over 10 years only in women younger than 60 years of age. No association was seen for estrogen alone for women younger than 60 years of age, but AD risk did increase for women over 60 years of age for up to 5 years of MHT prescriptions. Conclusions: Combination MHT should probably be prescribed for less than 5 years after menopause to reduce risk for AD, while estrogen alone should not be prescribed to women over 60. For phytoestrogen, small treatment trials suggested some benefit of tempeh (fermented soy), which should be investigated further.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.
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Importance Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials. Design, Setting, and Participants Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration clinicaltrials.gov Identifier: NCT00000611
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Objective: To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD). Methods: Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47-56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999-2009). The study population included 8,195 women (227 cases of incident AD). Results: Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68-1.2, 0.99/0.75-1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31-0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome. Conclusions: Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use.
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Hormone replacement therapy (HRT) increases the risk of endometrial and breast cancer. A strategy to reduce this incidence is the use of tibolone (TIB). The aim of this paper was to address the effects of TIB on the central nervous system (CNS). For the present review, MEDLINE (via PubMed), LILACS (via BIREME), Ovid Global Health, SCOPUS, Scielo and PsycINFO (ProQuest Research Library) electronic databases were searched for the results of controlled clinical trials on peri-and postmenopausal women published from 1990 to September 2016. Also, this paper reviews experimental studies performed to analyze neuroprotective effects, cognitive deficits, neuroplasticity, oxidative stress and stroke using TIB. Although there are few studies on the effect of this hormone in the CNS, it has been reported that TIB decreases lipid peroxidation levels and improves memory and learning. TIB has important neuroprotective effects that could prevent the risk of neurodegenerative diseases in postmenopausal women as well as the benefits of HRT in counteracting hot flashes, improving mood and libido. Some reports have found that TIB delays cognitive impairment in various models of neuronal damage. It also modifies brain plasticity since it acts as an endocrine modulator regulating neurotransmitters, Tau phosphorylation, and decreasing neuronal death. Finally, its antioxidant effects have also been reported in different animal models.
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Men and women exhibit differences in the development and progression of Alzheimer's disease (AD). The factors underlying the sex differences in AD are not well understood. This Review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuating multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research.
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Objective: To investigate the effects of completed pregnancy with childbirth and incomplete pregnancy without childbirth on the late-life cognition and the risk of Alzheimer disease (AD) in women. Methods: Using the pooled data of 3,549 women provided by 2 population-based cohort studies, we conducted logistic regression analyses to examine retrospectively the associations of completed and incomplete pregnancy with the risks of mild cognitive impairment and AD. For women without dementia, we also conducted analyses of covariance to examine the associations of completed and incomplete pregnancy with Mini-Mental State Examination (MMSE) score. Results: Grand multiparous women who experienced ≥5 completed pregnancies showed an ≈1.7-fold higher risk of AD than those who experienced 1 to 4 completed pregnancies (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.04-2.72), while those who had incomplete pregnancies showed half the level of AD risk compared with those who never experienced an incomplete pregnancy (OR 0.43, 95% CI 0.24-0.76 for 1 incomplete pregnancy; OR 0.56, 95% CI 0.34-0.92 for ≥2 incomplete pregnancies). In women without dementia, the grand multiparous had worse MMSE scores than those with 1 to 4 completed pregnancies (p < 0.001), while those who experienced ≥1 incomplete pregnancies had better MMSE scores than those who never experienced an incomplete pregnancy (p = 0.008). Conclusions: Grand multiparity was associated with high risk of AD, while incomplete pregnancy was associated with low risk of AD in late life.
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Objective: To examine the association between postmenopausal hormone therapy (HT) and Alzheimer's disease (AD). Methods: Medicine and Alzheimer's disease (MEDALZ) is a nested case-control study of the entire Finnish population with clinically verified AD from 2005 to 2011 and up to 4 matched controls per case. This study comprises 230,580 women (46,117 cases and 184,463 controls). Data on HT use from 1995 to 2011 was extracted from the national prescription register using following ATC codes: G03C (estrogen), G03D (progestogen) and G03F (estrogen and progestogen in combination). Only systemic HT (oral or transdermal) was considered. Results: Use of systemic estrogen and progestogen was associated with an increased risk of AD, with ORs (95% CI) of 1.10 (1.06-1.12) and 1.13 (1.10-1.17) respectively, but use of systemic estrogen HT for >10years (OR, 95% CI: 0.91, 0.84-0.99) was protective against AD. Long-term (>10years) use of progestogen and combination HT was not related to AD risk (OR, 95% CI: 1.0, 0.90-1.2). Conclusion: Our findings do not suggest HT is an important determinant of AD risk.
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Context: There are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimer's disease (AD). Objective: We analyzed the mortality risk attributable to VD or AD in women with a history of HT use. Design, Patients, Interventions and Main Outcome Measures: A total of 489,105 Finnish women using systemic HT in 1994-2009 were identified from the nationwide drug reimbursement register. Of these women, 581 died of VD and 1057 of AD in 1998-2009. The observed deaths in HT users with <5 or ≥5 years of exposure were compared with those having occurred in the age-standardized female population. Furthermore, we compared the VD or AD death risk of women who had started the use of HT at <60 versus ≥60 years of age. Results: The risk of death caused by VD was reduced by 37-39% (<5 or ≥5 years of exposure) with the use of any systemic HT, and this reduction was not associated with the duration or type (estradiol-only or estradiol-progestin combination) of HT. The risk of death caused by AD was not reduced with systemic HT <5 years of use, but was slightly reduced (15%) if the HT exposure had exceeded 5 years. The age at systemic HT initiation of <60 versus ≥60 years did not affect the death risk reductions. Conclusion: Estradiol-based HT use is associated with a reduced risk of death both from VD and AD, but the risk reduction is larger and appears sooner in VD than AD.
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Alzheimer’s disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer’s disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer’s disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer’s disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer’s disease.
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Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS. Study design and main outcome measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses. Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk. Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS.
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Context: The "window of opportunity hypothesis" refers to data indicating that conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, if initiated before 60 years of age, protects the heart but endangers it if initiated later (Women's Health Initiative study). Less is known about the "window of opportunity hypothesis" with natural estradiol alone (ET) or with various progestins in combination with estradiol (EPT). Objective: We related the death risk from coronary heart disease (CHD) in users of ET or EPT to the age at the initiation of therapy and to the progestin component of EPT. Design, Patients, Interventions, and Main Outcome Measures: Altogether, 498ü105 women had used ET or EPT containing medroxyprogesterone, norethisterone acetate, dydrogesterone, other progestins, or tibolone during 3.7 million person-years during 1994-2009. Women were followed from the therapy initiation to death, or to the end of year 2009. The risk of CHD death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals. Results: Age younger than 60 rather than older than 60 years at the initiation of ET (standardized mortality ratio, 0.53; 95% confidence interval, 0.47-0.59 vs 0.76; 0.71-0.82), EPT with norethisterone acetate (0.45; 0.41-0.49 vs 0.74; 0.67-0.81), or tibolone (0.35; 0.26-0.47 vs 1.01; 0.67-1.46) therapy lasting for less than 5 years was associated with significantly greater decreases in the CHD death risk. A similar tendency was also seen for other EPT groups and for longer use. In all hormone users, the CHD death risk was smaller the earlier the use of ET or EPT had started (P < .05); this phenomenon was unrelated to the progestin component of EPT. Conclusions: Estradiol-based hormone therapies are accompanied with larger CHD mortality risk reductions the earlier the therapies are initiated. The progestin component of EPT does not modify this "timing effect."