Postmenopausal hormonal treatment and cerebrovacular morbidity

1. Cerebrovascular Comorbidity
Menopausal Hormonal Treatments
Tevfik Yoldemir MD. BSc. MA. PhD.
tyoldemir
profdrdryoldemir

2. Stroke risk factors
tients with special characteristics, such as atrial fibrilla-
tion (AF) and carotid stenosis, is also discussed.
Hypertension
Hypertension is the most prevalent and modifiable risk
2 G. R. de Freitas and J. Bogousslavsky
Table 1 Stroke risk factors
Non-modifiable Modifiable Emerging
Age Hypertension Fibrinogen
Gender Diabetes mellitus Homocysteine
Race Hypercholesterolemia Inflammation/infection
Heredity Cigarette smoking
Alcohol abuse
Diet
Oral contraceptive
Atrial fibrillation
European Journal of Neurology 2001, 8: 1-15
notyetclear whethercholesterol is arisk factor for stroke ]
the paradox is not yet resolved (Demchuk et al., 1999;
Landau,1999).
According to European recommendations (Wood et al.,
1998), natural statins should be prescribed for patients with
high cholesterol levels because of the benefits for CHD.The
valueofstatinsintheprimarypreventionofstrokeisstill un-
clear.
Cigarette smoking
Studies published in the 80s clearly established cigarette
smoking as a powerful risk factor for stroke, especially is-
chemic stroke and subarachnoid hemorrhage (Abbott
et al., 1986; Bonita et al., 1986; Colditz et al., 1988; Shin-
ton and Beevers, 1989). Although in the Honolulu Heart
Program an excess of `hemorrhagic stroke' was seen
among smokers, this mayhave resulted from the inclusion
of subarachnoid hemorrhage in this group of patients
(Abbott et al., 1986), and it is therefore not yet clear
whether a relationship exists between intracranial hemor-
rhage and cigarette smoking. The estimated overall rela-
tive risk of ischemic stroke for cigarette smoking was 1.92
(95% CI 1.71]2.16), whereas the risk of subarachnoid
hemorrhage was 2.93 (95% CI 2.48]3.46) (Shinton et al.,
1989). The mechanism by which smoking causes
considerably reduced, but was still higher than in those
who had never smoked (Wannamethee et al., 1995)
(Figure 2). Nevertheless, the early and huge risk
reduction of more than 50% compared with current
smokers warrants vigorous efforts to encourage subjects
to stop smoking.
Cigar and pipe smoking
Although many cigarette smokers switch to a pipe or ci-
ß 2001EFNS European Journal of Neurology 8,1]15
Figure 2 Effect ofgiving up smoking on subsequent stroke events.
Data fromWannamethee et al. (1995). [Reproduced with the
permission of the Journal ofthe American Medical Association,
Volume 274,1995, p. 158 (#1995, American Medical Association).]

3. Proportional stroke risk, by age and usual
diastolic blood pressure
cs, such as atrial fibrilla-
s also discussed.
alent and modifiable risk
dwith ischemic stroke, in-
ubarachnoid hemorrhage
avsky
Emerging
Fibrinogen
Homocysteine
mia Inflammation/infection
Figure 1 Proportional stroke risk, by age and usual diastolic blood
pressure. Floating absolute risk, adjusted for study, gender, total
European Journal of Neurology 2001, 8: 1-15

4. The 5- and 10-Year Risk of All Stroke Across Cohorts
pling. Follow-up phone contact was subsequently made
at 6-month intervals for surveillance of suspected stroke
events, with medical records for suspected events retrieved
and adjudicated by a panel of physicians. The study was
approved by the Institutional Review boards at all participat-
ing universities, and written informed consent was obtained
tinuous variables, whereas other risk factors were treated as
dichotomous variables. SBP was recorded as the mean of
2 physician-recorded measurements made on the left arm
of the seated subject with a mercury column sphygmoma-
nometer and a cuff of appropriate width. Baseline CVD was
recorded as present if coronary artery disease, congestive
Table 1. The 5- and 10-Year Risk of All Stroke Across Cohorts
Old FHS New FHS REGARDS REGARDS White REGARDS Black New FHS 3C
Men
Sample size, n 2114 2291 10808 7245 3563 1198 2949
Age range, y ≥55 ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 62 309 200 109 45 75
Kaplan-Meier risk
(5-y probability)
0.029 0.031 0.030 0.034 0.041 0.028
10-y Follow-up
Cases, n 150 133 97 124
Kaplan-Meier risk
(10-y probability)
0.084 0.075 0.113 0.054
Women
Sample size, n 2979 2781 12883 7015 5868 1580 4652
Age range, y ≥55 ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 60 320 155 165 53 69
Kaplan-Meier risk
(5-y probability)
0.022 0.027 0.024 0.031 0.035 0.0167
10-y Follow-up
Cases, n 196 144 126 138
Kaplan-Meier risk
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5-y Follow-up
Cases, n 62 309 200 109 45 75
Kaplan-Meier risk
(5-y probability)
0.029 0.031 0.030 0.034 0.041 0.028
10-y Follow-up
Cases, n 150 133 97 124
Kaplan-Meier risk
(10-y probability)
0.084 0.075 0.113 0.054
Women
Sample size, n 2979 2781 12883 7015 5868 1580 4652
Age range, y ≥55 ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 60 320 155 165 53 69
Kaplan-Meier risk
(5-y probability)
0.022 0.027 0.024 0.031 0.035 0.0167
10-y Follow-up
Cases, n 196 144 126 138
Kaplan-Meier risk
(10-y probability)
0.072 0.065 0.104 0.041
FHS indicates Framingham Heart Study; REGARDS, Reasons for Geographic and Racial Differences in Stroke Study; and 3C, 3 Cities Study.
mhttp://ahajournals.orgbyonDecember23,2018

5. The 5- and 10-Year Risk of Ischemic Stroke Across Cohorts
surements obtained by a health professional. Nonstroke events
were based only on the history and review of study ECG; thus,
heart disease was defined as self-report of myocardial infarc-
tion, coronary artery bypass surgery, angioplasty, or stenting
or ECG evidence of myocardial infarction. Determination of AF
was by self-report of a physician diagnosis or ECG evidence at
baseline. ECG-LVH was determined as in FHS in two thirds of
the participants. However, in a third of the participants (those
not extracted.
Definition of Stroke
In FHS
Details of stroke surveillance and the protocol for determin-
ing the diagnosis and type of stroke have been published
previously.1,22
Stroke was defined as an acute-onset focal
Table 2. The 5- and 10-Year Risk of Ischemic Stroke Across Cohorts
New FHS REGARDS REGARDS White REGARDS Black New FHS 3C
Men
Sample size, n 2291 10808 7245 3564 1198 2949
Age range, y ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 55 253 163 90 40 55
Kaplan-Meier risk
(5-y probability)
0.025 0.026 0.025 0.028 0.036 0.020
10-y Follow-up
Cases, n 118 85 95
Kaplan-Meier risk
(10-y probability)
0.066 0.100 0.042
Women
Sample size, n 2781 12883 7015 5868 1580 4652
Age range, y ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 54 267 136 131 48 57
Kaplan-Meier risk
(5-y probability)
0.020 0.023 0.021 0.025 0.032 0.013
10-y Follow-up
Cases, n 129 114 112
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Age range, y ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 55 253 163 90 40 55
Kaplan-Meier risk
(5-y probability)
0.025 0.026 0.025 0.028 0.036 0.020
10-y Follow-up
Cases, n 118 85 95
Kaplan-Meier risk
(10-y probability)
0.066 0.100 0.042
Women
Sample size, n 2781 12883 7015 5868 1580 4652
Age range, y ≥55 ≥55 ≥55 ≥55 ≥65 ≥65
5-y Follow-up
Cases, n 54 267 136 131 48 57
Kaplan-Meier risk
(5-y probability)
0.020 0.023 0.021 0.025 0.032 0.013
10-y Follow-up
Cases, n 129 114 112
Kaplan-Meier risk
(10-y probability)
0.058 0.095 0.030
FHS indicates Framingham Heart Study; REGARDS, Reasons for Geographic and Racial Differences in Stroke Study; and 3C, 3 Cities Study.
dfromhttp://ahajournals.orgbyonDecember23,2018
Circulation. 2017;135:1145–1159.

6. Impact of Stroke Risk Factors at Baseline Examination on 10-
Year Risks of All Stroke in Each Cohort
Dufouil et al
Table 4. Impact of Stroke Risk Factors at Baseline Examination on 10-Year Risks of All Stroke in Each Cohort
HR (95% CI)
Old FHS New FHS REGARDS
REGARDS
White
REGARDS
Black 3C
Men
Baseline age (10 y) 1.63 (1.33–1.99) 1.64 (1.14–2.38) 1.72 (1.40–2.11) 1.87 (1.70–2.38) 1.38 (0.93–2.05) 2.14 (1.48–3.11)
Currently smoking 1.69 (1.27–2.23) 1.60 (0.97–2.67) 2.00 (1.55–2.59) 1.88 (1.32–2.28) 2.07 (1.40–3.08) 1.41 (0.78–2.57)
Prevalent CVD 1.73 (1.68–1.78) 1.57 (1.05–2.35) 1.31 (1.06–1.62) 1.14 (0.88–1.47) 1.74 (1.19–2.55) 1.22 (0.73–2.03)
AF 1.82 (1.01–3.29) 1.08 (0.61–1.94) 1.62 (1.23–2.14) 1.87 (1.38–2.55) 0.97 -0.50–1.86) 2.47 (1.36–4.50)
Age ≥ 65 y 1.58 (0.79–3.14) 1.34 (0.92–1.96) 1.51 (0.95–2.40) 1.18 (0.61–2.27)
DM 1.41 (0.97–2.04)
DM if <65 y 3.87 (1.97–7.61) 1.94 (1.31–2.87) 2.28 (1.33–3.91) 1.51 (0.85–2.68)
DM if ≥65 y 1.41 (0.87–2.30) 1.15 (0.89–1.49) 1.17 (0.84–1.62) 1.24 (0.80–1.93) 0.98 (0.59–1.65)
Antihypertensive
treatment
2.28 (1.32–3.94) 1.26 (0.99–1.60) 1.41 (1.07–1.86) 0.97 (0.61–1.55) 1.39 (0.80–2.41)
SBP 1.16 (1.10–1.24)
SBP in nontreated
hypertensives
1.31 (1.15–1.50) 1.09 (1.00–1.19) 1.07 (0.96–1.20) 1.12 (0.97–1.30) 1.10 (0.97–1.26)
SBP in treated
hypertensives
1.10 (0.99–1.23) 1.05 (1.97–1.29) 1.00 (0.90–1.10) 1.14 (1.01–1.28) 1.11 (1.00–1.23)
LVH 2.20 (1.26–3.84)
(SBP−110)*(200−SBP)* 1.0002
(1.0000–1.0004)
Antihypertensive
treatment
2.28 (1.32–3.94) 1.26 (0.99–1.60) 1.41 (1.07–1.86) 0.97 (0.61–1.55) 1.39 (0.80–2.41)
SBP 1.16 (1.10–1.24)
SBP in nontreated
hypertensives
1.31 (1.15–1.50) 1.09 (1.00–1.19) 1.07 (0.96–1.20) 1.12 (0.97–1.30) 1.10 (0.97–1.26)
SBP in treated
hypertensives
1.10 (0.99–1.23) 1.05 (1.97–1.29) 1.00 (0.90–1.10) 1.14 (1.01–1.28) 1.11 (1.00–1.23)
LVH 2.20 (1.26–3.84)
(SBP−110)*(200−SBP)* 1.0002
(1.0000–1.0004)
Women
Baseline age (10 y) 2.01 (1.69–2.40) 2.41 (1.72–3.38) 1.83 (1.49–2.24) 2.32 (1.73–3.09) 1.43 (1.05–1.93) 2.94 (2.06–4.21)
Currently smoking 1.72 (1.29–2.29) 1.67 (1.01–2.75) 1.77 (1.35–2.32) 2.21 (1.52–3.22) 1.39 (0.94–2.06) 0.77 (0.24–2.43)
Prevalent CVD 1.55 (1.17–2.07) 0.97 (0.61–1.56) 1.52 (1.18–1.94) 1.62 (1.15–2.28) 1.43 (0.99–2.06) 0.78 (0.28–2.10)
AF 3.06 (1.95–4.80) 3.34 (1.92–5.81) 1.57 (1.17–2.10) 1.86 (1.28–2.70) 1.26 (0.78–2.01) 2.66 (1.34–5.27)
Age ≥ 65 y 1.49 (0.69–3.22) 1.44 (0.97–2.14) 1.06 (0.61–1.86) 2.00 (1.14–3.51)
DM 1.75 (1.25–2.45)
DM if <65 y 2.92 (0.95–8.98) 1.66 (1.07–2.59) 2.03 (0.99–4.16) 1.44 (0.82–2.56)
DM if ≥65 y 1.07 (0.58–1.96) 1.11 (0.84–1.45) 1.22 (0.80–1.87) 0.98 (0.69–1.40) 1.57 (0.94–2.64)
Antihypertensive
treatment
1.14 (0.67–1.93) 1.19 (0.93–1.54 0.91 (0.64–1.27) 1.58 (1.03–2.43) 1.31 (0.82–2.08)
SBP 1.17 (1.12–1.23) -
SBP in nontreated
hypertensives
1.12 (0.98–1.28) 1.16 (1.06–1.26) 1.15 (1.05–1.27) 1.15 (0.97–1.36) 1.14 (1.00–1.29)
SBP in treated
hypertensives
1.19 (1.08–1.30) 1.18 (1.10–1.26( 1.24 (1.12–1.38) 1.13 (1.04–1.23) 1.12 (1.01–1.23)
LVH 2.24 (1.39–3.60)
(SBP−110)*(200−S
BP)*
1.0003
(1.0001–1.0004)
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Circulation. 2017;135:1145–1159.
The old Framingham Stroke Risk
Profile (FSRP) uses the
previously published means of
the risk factors, HRs, and
estimates of incident stroke.
The new Framingham Stroke
Risk Profile (FSRP) updates the
means of the risk factors to
reflect current prevalence,
updates the estimate of incident
stroke to reflect current rates,
and updates the HRs to reflect
current associations.

7. Associations between various exposures and risk of stroke in the
Women’s Health Initiative- Observational Study (WHI-OS)Table 2 Summary of findings examining associations between various exposures and risk of stroke in the Women’s Health Initiative-
Observational Study (WHI-OS) and ancillary studies
First author and year
(reference No.)
Exposure measure(s) WHI-OS or ancillary study
(N)
Principal findings
Kaplan et al (2008)20
Seven inflammatory and
hemostatic biomarkersa
HaBPS
(N ¼ 972 cases, 972
controls)
Threefold increase in odds of ischemic stroke with five or
more inflammatory/hemostatic biomarkers, independent
of CVD risk factors
Berger et al (2012)21
Panel of lipid and lipoprotein
biomarkersb
HaBPS
(N ¼ 972 cases, 972
controls)
Triglycerides, VLDL,b
and IDLb
were significant independent
predictors of ischemic stroke (adjusted ORs for highest vs.
lowest quartile ranged from 1.46 to 1.59, all p < 0.05)
Wassertheil-Smoller et al
(2008)22
LP-PLA2 HaBPS
(N ¼ 972 cases, 972
controls)
55% increase in odds of ischemic stroke in nonusers of HT
comparing highest to lowest quartile, independent of CVD
risk factors
Wassertheil-Smoller et al
(2008)23
CRP and LP-PLA2 HaBPS
(N ¼ 972 cases, 972
controls)
Addition of CRP and LP-PLA2 to Framingham risk models
significantly improved prediction of cardioembolic and
large artery strokes, respectively
Rajpathak et al (2011)24
Circulating levels of
adiponectin, leptin, resistin
HaBPS
(N ¼ 972 cases, 972
controls)
Resistin was an independent predictor of ischemic stroke
(adjusted OR comparing highest to lowest quartile ¼ 1.39;
95% CI, 1.01–1.09)
Kooperberg et al (2007)14
Panel of lipid, inflammatory,
and coagulation biomarkers
Nested CC within clinical
trial of HT
Biomarkers of inflammation, lipids, and coagulation did not
explain adverse effects of HT on stroke
Roussow et al (2012)25
Plasma TFPI and nAPCsr Nested CC within clinical
trial of HT
TFPI was associated with ischemic stroke (adjusted OR for 1
SD increase ¼ 1.17, 95% CI ¼ 1.01–1.37). Neither TFPI nor
nAPCsr explained increased stroke risk with HT
Stroke Findings in the Women’s Health Initiative Wassertheil-Smoller et al. 443
Semin Reprod Med 2014;32:438–446
Lp-PLA2, or lipoprotein-associated phospholipase-A2, measures disease activity within the artery wall below the
collagen or calcified cap due to the activation of macrophages.
Hormones and Biomarkers Predicting Stroke (HaBPS) Study
IDL, intermediate-density lipoprotein particle number

8. Associations between various exposures and risk of stroke in
the Women’s Health Initiative- Observational Study (WHI-OS)
(2008)22
2
(N ¼ 972 cases, 972
controls)
comparing highest to lowest quartile, independent of CVD
risk factors
Wassertheil-Smoller et al
(2008)23
CRP and LP-PLA2 HaBPS
(N ¼ 972 cases, 972
controls)
Addition of CRP and LP-PLA2 to Framingham risk models
significantly improved prediction of cardioembolic and
large artery strokes, respectively
Rajpathak et al (2011)24
Circulating levels of
adiponectin, leptin, resistin
HaBPS
(N ¼ 972 cases, 972
controls)
Resistin was an independent predictor of ischemic stroke
(adjusted OR comparing highest to lowest quartile ¼ 1.39;
95% CI, 1.01–1.09)
Kooperberg et al (2007)14
Panel of lipid, inflammatory,
and coagulation biomarkers
Nested CC within clinical
trial of HT
Biomarkers of inflammation, lipids, and coagulation did not
explain adverse effects of HT on stroke
Roussow et al (2012)25
Plasma TFPI and nAPCsr Nested CC within clinical
trial of HT
TFPI was associated with ischemic stroke (adjusted OR for 1
SD increase ¼ 1.17, 95% CI ¼ 1.01–1.37). Neither TFPI nor
nAPCsr explained increased stroke risk with HT
Smoller et al (2007)27
Panic attacks MIMS (N ¼ 3,369) Panic attacks were associated with increased risk of CHD or
stroke (adjusted OR ¼ 3.08; 95%:CI, 1.60–2.59), and
twofold increase in fatal or nonfatal stroke, which did not
reach statistical significance
Wassertheil-Smoller et al
(2004)28
Depressive symptoms on
CES-D scale
WHI-OS (N ¼ 93,676) 60% increase in odds of fatal or nonfatal stroke comparing
current vs. no depression
Smoller et al (2009)29
Antidepressant use WHI-OS and CT
(N ¼ 136,293)
SSRIs associated with increased risk of hemorrhagic stroke
(adjusted HR ¼ 2.12, 95% CI: 1.10–4.07) but not ischemic
stroke
McGinn et al (2008)30
Walking speed WHI-OS (N ¼ 13,048) 69% increase in risk of ischemic stroke comparing slowest
vs. fastest walking speed tertile
Shimbo et al (2012)31
Visit-to-visit blood pressure
variability (VVV)
WHI-OS and CT
(N ¼ 161,808)
Greater VVV associated with increasing risk of hemorrhagic
and ischemic stroke (adjusted HR ¼ 1.72; 95% CI,
1.28–2.32, comparing highest vs. lowest quartile)
Chen et al (2008)32
Sleep duration WHI-OS (N ¼ 93,175) U- or J-shaped relationship between sleep duration and
ischemic stroke (adjusted HR9 vs. 7 h ¼ 1.71; 95% CI,
1.33–2.21 and adjusted HR 6 vs. 7 h ¼ 1.16; 95% CI,
1.00–1.36)
Semin Reprod Med 2014;32:438–446
Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa (Xa).
While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex.
Higher normalized activated protein C sensitivity ratio (nAPCsr) values indicate increasing APC resistance.
Women’s Health Initiative Observational Study (WHI-OS)

9. Associations between various exposures and risk of stroke in
the Women’s Health Initiative- Observational Study (WHI-OS)
reach statistical significance
Wassertheil-Smoller et al
(2004)28
Depressive symptoms on
CES-D scale
WHI-OS (N ¼ 93,676) 60% increase in odds of fatal or nonfatal stroke comparing
current vs. no depression
Smoller et al (2009)29
Antidepressant use WHI-OS and CT
(N ¼ 136,293)
SSRIs associated with increased risk of hemorrhagic stroke
(adjusted HR ¼ 2.12, 95% CI: 1.10–4.07) but not ischemic
stroke
McGinn et al (2008)30
Walking speed WHI-OS (N ¼ 13,048) 69% increase in risk of ischemic stroke comparing slowest
vs. fastest walking speed tertile
Shimbo et al (2012)31
Visit-to-visit blood pressure
variability (VVV)
WHI-OS and CT
(N ¼ 161,808)
Greater VVV associated with increasing risk of hemorrhagic
and ischemic stroke (adjusted HR ¼ 1.72; 95% CI,
1.28–2.32, comparing highest vs. lowest quartile)
Chen et al (2008)32
Sleep duration WHI-OS (N ¼ 93,175) U- or J-shaped relationship between sleep duration and
ischemic stroke (adjusted HR9 vs. 7 h ¼ 1.71; 95% CI,
1.33–2.21 and adjusted HR 6 vs. 7 h ¼ 1.16; 95% CI,
1.00–1.36)
Yaemsiri et al (2012)33
Trans fat intake WHI-OS (N ¼ 87,025) Trans fat intake associated with overall increased risk of
ischemic stroke (highest vs. lowest adjusted HR ¼ 1.39;
95% CI, 1.08–1.79). The association was stronger in aspirin
users than nonusers (p-interaction ¼ 0.02)
Huang et al (2012)34
392 SNPs from candidate
gene studies and 2,371 SNPs
associated with changes in
blood protein concentrations
after HT use
WHI-OS and CT
(N ¼ 2,045)
Significant interactions between HT and stroke risk with
SNPs on genomic regions F13A1 and PCSK9, encoding
coagulation factor XIII subunit A and proprotein convertase
subtilisin kexin 9, respectively
Abbreviations: CC, case–control study; CES-D, center for epidemiologic studies depression scale; CHD, coronary heart disease; CRP, C-reactive protein;
CT, clinical trial; HaBPS, hormones and biomarkers predicting stroke; HR, hazard ratio; HT, hormone therapy; Lp-PLA2, lipoprotein-associated
phospholipase A2; MIMS, Myocardial Ischemia and Migraine Study; nAPCsr, normalized activated protein C resistance ratio; OR, odds ratio; SNP, single
nucleotide polymorphism; SSRIs, selective serotonin reuptake inhibitors; TFPI, tissue factor pathway inhibitor; WHI-OS, Women’s Health Initiative-
Observational Study.
a
CRP, IL-6, tPA, D-dimer, WBC, neopterin, and homocysteine combined in a multiple biomarker index.
Semin Reprod Med 2014;32:438–446

10. Framingham Stroke Score
s-risk-functions/stroke/ 5/7
insu ciency, intermittent ciaudication, or congestive heart
failure; AF, history of atrial brillation; LVH, left ventricular
hypertrophy on electrocardiogram.
Women: Probability of Stroke Within 10 Years
Points
0 +1 +2 +3 +4 +5
Age,y 54-
56
57-
59
60-
62
63-
64
65-
67
68-
70
Untreated SBP,
mmHg
95-
106
107-
118
119-
130
131-
143
144-
155
Treated SBP,
mmHg
95-
106
107-
113
114-
119
120-
125
126-
131
Diabetes No Yes
Cigs No Yes
CVD No Yes
AF No
LVH No Yes Yes
12/24/2018 Framingham Heart Study
Points
+6 +7 +8 +9 +10
Age,y 71-73 74-76 77-78 79-81 82-84
Untreated SBP,
mmHg
156-
167
168-
180
181-
192
193-
204
205-
216
Treated SBP,
mmHg
132-
139
140-
148
149-
160
161-
204
205-
216
Diabetes
Cigs
CVD
AF Yes
LVH
www.framinghamheartstudy.org/fhs-risk-functions/stroke/

11. Framingham Stroke
Score
https://www.framinghamheartstudy.org/fhs-risk-functions/stroke/
Points 10-Year
Probability,
%
Points 10-Year
Probability,
%
Points 10-Ye
Probab
%
1 1 11 8 21 43
2 1 12 9 22 50
12/24/2018 Framingham Heart Study
3 2 13 11 23 57
4 2 14 13 24 64
5 2 15 16 25 71
6 3 16 19 26 78
7 4 17 23 27 84
8 4 18 27
9 5 19 32
10 6 20 37
www.framinghamheartstudy.org/fhs-risk-functions/stroke/

12. Framingham Stroke Score
postmenopausal hormone therapy.
art.
Assess CHD risk and years since last menstrual period
Yes
Significant symptoms of menopause (moderate-to-severe hot
flashes, night sweats)?
Free of contraindications to HT and no h/o CHD, stroke, or TIA?
AND
No increased risk of stroke (10% by Framingham Stroke Score)?
No
No HT
No HT
Yes No
anson J. Harrison’s Principles of Internal Medicine 2008].
Framingham Stroke Score can be found at
http://www.zunis.org/Framingham%20Risk%20of%20CHD2.htm
Adapted from Manson J. Harrison’s Principles of Internal Medicine 2008

13. Framingham CHD Risk Score
severe menopausal symptoms, concern about CHD
risk from hormone therapy should not be a major
with more information o
postmenopausal hormone t
Figure 2. Hormone Therapy (HT) Decision-Making Flowchart.
Years Since Last Menstrual Period
5 Years 6 to 10 Years 10 Years
Very low (5%) HT OK HT OK No HT
Low (5% to 10%) HT OK HT OK
(Choose transdermal)
No HT
Moderate (10% to 20%)
HT OK
(Choose transdermal)
No HT No HT
High (more than 20%) No HT No HT No HT
CHDRiskOver10Years
(FraminghamCHDRiskScore)
DECISION ABOUT DURATION OF USE: ontinued moderate-to-severe symptoms;
patient preference; weigh baseline risks of breast cancer versus osteoporosis
Assess CHD risk and years since last m
Significant symptoms of menopause (
flashes, night swea
Free of contraindic
No increased risk
No
No HT
Yes
CHD=coronary heart disease, TIA=transient ischemic attack [Adapted from Manson J. Harrison’s Principles of Inter
Reproduced with permission from J. Manson, MD, DrPH.
Adapted from Manson J. Harrison’s Principles of Internal Medicine 2008

14. Risk of Cerebrovascular Disease Events in HERS
ther
e no
hor-
tion
sim-
nefi-
k of
usal
4.1
1000
5 to
rate.
and
arly
roup
clinical trial to examine the effect of hormone therapy on risk
of strokes, a predesignated secondary outcome of interest.
Our findings concur with many recent observational studies
that reported no significant association between postmeno-
TABLE 2. Risk of Cerebrovascular Disease Events in HERS
Outcome
Number of Women With Event*
RH (95% CI)Placebo EstrogenϩProgestin
Fatal stroke 10 16 1.61 (0.73–3.55)
Nonfatal stroke 60 70 1.18 (0.83–1.66)
TIA 44 35 0.90 (0.57–1.42)
Hemorrhagic stroke 5 8 1.65 (0.47–5.72)
Ischemic stroke 59 69 1.18 (0.83–1.67)
Any stroke 67 82 1.23 (0.89–1.70)
Any stroke or TIA 103 112 1.09 (0.84–1.43)
*A total of 4 fatal and 6 nonfatal strokes could not be classified as ischemic
or hemorrhagic, and 7 participants were censored after their initial nonfatal
stroke event.
Circulation. 2001;103:638-642
Kaplan-Meier estimate of cumulative incidence of stroke events
Number of women observed at each year of follow-up and still
free from stroke events is provided in parentheses; lines
Simon et a

15. Predictors of Incident Stroke in HERS
ension, diabetes, and cigarette smoking were
ndependent risk factors for stroke events.21–24
en in HERS experienced an increased risk for
s, even after controlling for other factors. These
decreased risk among heavier women.
There were a number of limitations to our study. HERS
was restricted to postmenopausal women with CHD, and
therefore our findings may not be generalizable to other
TABLE 3. Predictors of Incident Stroke in HERS
Variable
RH (95% CI)*
Simple Model Multivariate Model†
Age (10 y) 1.83 (1.41–2.38) 1.93 (1.45–2.55)
Race (black vs white) 1.86 (1.16–2.98) 1.91 (1.18–3.10)
Hypertension (yes vs no) 1.97 (1.32–2.96) 1.67 (1.10–2.53)
History of diabetes mellitus (yes vs no) 2.57 (1.85–3.56) 3.03 (2.12–4.32)
Cigarette smoking (current vs never) 1.45 (0.95–2.22) 2.01 (1.28–3.15)
Atrial fibrillation (yes vs no) 7.18 (3.66–14.09) 6.45 (3.25–12.82)
Body mass index (kg/m2
) 0.98 (0.95–1.01) 0.96 (0.93–0.99)
*All RH estimates are adjusted for treatment assignment.
†Stepwise regression was used to adjust for variables nominally associated with stroke at a P value
of Յ0.20. In addition to the variables noted in Table 3, marital status, level of education, alcohol
consumption, cigarette smoking (past vs never), aspirin use, warfarin use, use of lipid-lowering
medication, and level of lipoprotein(a) were also entered into the multivariate model. Only variables
associated with stroke at a P value of Յ0.05 were retained.
Circulation. 2001;103:638-642

16. Risk of cerebrovascular events by type and use of hormone
therapy by duration, regimen, route of administration, and dose
When we analyzed separately the risk of TIA,
we found that current use of HT was associated
with an increased risk (OR 1.48; 95% CI, 1.17-1.87)
(Table 2). The estimate associated with current HT
use was slightly larger during the first year of use
(OR 1.94; 95% CI, 1.34-2.74). The OR associated
with medium dose was 1.48 (95% CI, 1.12-1.96) and
1.96 (95% CI, 1.34-2.87) with a high dose. HT use
TABLE 2. Risk of cerebrovascular events by type and use of hormone therapy by duration, regimen, route of administration,
and dose
Ischemic CVA Hemorrhagic CVA TIA
HT use
Cases/
controls
Multivariatea
OR
CI
LL
CI
UL
Cases/
controls
Multivariatea
OR
CI
LL
CI
UL
Cases/
controls
Multivariatea
OR
CI
LL
CI
UL
Nonuse 187/7,186 1.0 88/7,186 1.0 361/7,186 1.0
Past 14/633 0.86 0.48 1.54 5/633 0.58 0.23 1.49 30/633 1.02 0.68 1.53
Recent 7/176 1.80 0.81 4.01 2/176 0.80 0.19 3.38 11/176 1.53 0.81 2.89
Current 51/2,005 1.12 0.78 1.59 30/2,005 1.21 0.76 1.93 134/2,005 1.48 1.17 1.87
By duration
e1 y 14/534 1.23 0.69 2.19 6/534 0.92 0.39 2.18 45/534 1.94 1.38 2.74
1 y 37/1,471 1.11 0.75 1.64 24/1,471 1.25 0.76 2.05 89/1,471 1.34 1.03 1.75
By estrogen doseb
Low 7/178 1.65 0.75 3.64 1/178 0.45 0.06 3.29 7/178 0.82 0.38 1.78
Medium 29/1,195 1.09 0.71 1.67 16/1,195 1.06 0.60 1.89 77/1,195 1.48 1.12 1.96
High 11/422 1.16 0.61 2.23 11/422 1.87 0.94 3.69 36/422 1.96 1.34 2.87
By regimen
Unopposed 10/521 0.79 0.40 1.54 10/521 1.54 0.76 3.12 33/521 1.36 0.92 2.01
Opposed 23/701 1.54 0.95 2.47 11/701 1.22 0.63 2.39 41/701 1.34 0.94 1.91
OR, odds ratio; CI LL, 95% confidence interval lower limit; CI UL, 95% confidence interval upper limit; HT, hormone therapy.
a
Individual models for each variable adjusted for age, past use of HT, history of smoking, hypertension, diabetes, obesity, hypercholesterolemia,
family history of cardiovascular disease, surgical menopause, lipid-lowering drug use, anticoagulant drug use, and cardioprophylactic use of aspirin.
b
Dose: low: less than 0.625 mg for oral estrogens and 25 Kg for transdermal estradiol; medium: 0.625 to 1.24 mg for oral estrogens and 50 Kg for
transdermal estradiol; high: 1.25 mg or higher for oral estrogens and 100 Kg for transdermal estradiol.
Menopause: 2006 Vol. 13, No. 5, pp. 730-736
Dose: low: less than 0.625 mg for oral estrogens and 25 µg for transdermal estradiol;
medium: 0.625 to 1.24 mg for oral estrogens and 50 µg for transdermal estradiol;
high: 1.25 mg or higher for oral estrogens and 100 µg for transdermal estradiol.

17. Risk of stroke from observational studies of MHTTable 1. Risk of stroke from observational studies of HRT.
Authors Cohort Study design Study size (n) HRT type Stroke type Number of stroke events (n) RR 95% CI
Løkkegaard et al. [16] Danish Nurse Study Cohort Total = 13 122 Estrogen (alone or combined) IS (fatal and non-fatal) Non-users = 53 Non-users = 1.00 0.98–2.70
HRT users = 3674 HRT users = 26 HRT users = 1.63
Petitti et al. [17] Northern California Case–control Cases = 349 Estrogen (alone or combined) Non-fatal IS 349 1.03 0.65–1.65
Kaiser Facility Controls = 349
Sourander et al. [18] Turku, Finland Cohort Total = 7944 Estrogen Non-fatal IS Non-users = 89 0.86 0.42–1.75
HRT users = 988 Current users = 10
Pfeffer et al. [19] CA, USA retirement Case–control Total = 1278 All estrogens Any stroke Non-users = 62 1.12 0.79–1.57
community HRT users = 148
Pederson et al. [20] Danish National Case–control Total = 4593 Estrogen (alone or combined) IS (fatal and non-fatal) Estrogen alone users = 73 1.24 0.91–1.70
Patient Register Non-users = 235
Combined HRT users = 133 1.27 1.00–1.62
Non-users = 435
Wilson et al. [21] Framingham Case–control Total = 1234 Estrogen (alone or combined) CVD and IS CVD = 45 CVD = 2.27 n/a
Heart Study HRT users = 302 IS = 21 IS = 2.6
Fung et al. [22] Rancho Bernardo, Cohort Total = 1031 Estrogen plus progestin Stroke Non-fatal stroke: 3.02 0.70–13.08
CA, USA HRT users = 278 (fatal and non-fatal) HRT users = 8
Non-users = 2
Fatal stroke:
HRT users = 7 0.92 0.34–2.49
Non-users = 20
Falkeborn et al. [23] Uppsala, Sweden Cohort Total cohort = 2179174 Estrogen (alone or combined) IS (fatal and non-fatal) Estrogen alone = 58 0.78 0.59–1.01
person-years
Total HRT users = 23088 All HRT types= 9 0.91 0.76–1.09
person-years
Rosenberg et al. [24] Northern California Case–control Total cohort = 594 Estrogen (alone or combined) IS (fatal and non-fatal) Cases = 41 1.16 0.75–1.77
Kaiser Facility Cases = 198 Controls = 73
Controls = 396
Lemaitre et al. [25] Group Health, Seattle, Case–control Total cohort = 3251 Estrogen plus progestin IS (fatal and non-fatal) Current HRT users (Cases) = 59 0.97 0.69–1.37
WA, USA IS Cases = 726 Current HRT users (Controls) = 290
Controls = 2525
Grodstein et al. [26] Nurses’ Health Study Cohort Non-users = Estrogen (alone or combined) IS (fatal and non-fatal) Any HRT = 142 1.26 1.00–1.61
358 125 person-years Non-users = 170
Current Medical Literature: Gynecology Obstetrics
2007, Vol. 12 Issue 4, p93-99

18. Risk of stroke from observational studies of MHT
Wilson et al. [21] Framingham Case–control Total = 1234 Estrogen (alone or combined) CVD and IS CVD = 45 CVD = 2.27 n/a
Heart Study HRT users = 302 IS = 21 IS = 2.6
Fung et al. [22] Rancho Bernardo, Cohort Total = 1031 Estrogen plus progestin Stroke Non-fatal stroke: 3.02 0.70–13.08
CA, USA HRT users = 278 (fatal and non-fatal) HRT users = 8
Non-users = 2
Fatal stroke:
HRT users = 7 0.92 0.34–2.49
Non-users = 20
Falkeborn et al. [23] Uppsala, Sweden Cohort Total cohort = 2179174 Estrogen (alone or combined) IS (fatal and non-fatal) Estrogen alone = 58 0.78 0.59–1.01
person-years
Total HRT users = 23088 All HRT types= 9 0.91 0.76–1.09
person-years
Rosenberg et al. [24] Northern California Case–control Total cohort = 594 Estrogen (alone or combined) IS (fatal and non-fatal) Cases = 41 1.16 0.75–1.77
Kaiser Facility Cases = 198 Controls = 73
Controls = 396
Lemaitre et al. [25] Group Health, Seattle, Case–control Total cohort = 3251 Estrogen plus progestin IS (fatal and non-fatal) Current HRT users (Cases) = 59 0.97 0.69–1.37
WA, USA IS Cases = 726 Current HRT users (Controls) = 290
Controls = 2525
Grodstein et al. [26] Nurses’ Health Study Cohort Non-users = Estrogen (alone or combined) IS (fatal and non-fatal) Any HRT = 142 1.26 1.00–1.61
358 125 person-years Non-users = 170
HRT users =
265 203 person-years
Finucane et al. [27] National Health and Cohort Total = 1910 HRT Any stroke Non-fatal stroke: 0.68 0.47–0.98
Nutrition Exam Survey HRT users = 397 (fatal and non-fatal) HRT users = 33
Non-users = 1513 Non-users = 217
Fatal stroke: HRT users = 5 0.41 0.17–1.03
Non-users = 59
Lindenstrom et al. [28] Copenhagen City Cohort Total = 4716 HRT Any stroke HRT and smokers = 11 0.57 0.29–1.13
Heart Study (stroke events = 238)
HRT and non-smokers = 13 1.01 0.55–1.84
Angeja et al. [29] National Registry of Cohort Total = 114 724 HRT IS (fatal and non-fatal) HRT users = 56 0.89 0.66–1.18
Myocardial Infarction-3, HRT users = 7353 Non-users = 961
CA, USA Non-users = 107 371
CI: confidence interval; CVD: cardiovascular disease; HRT: hormone replacement therapy; IS: ischemic stroke; n/a: not available; RR: relative risk.
Current Medical Literature: Gynecology Obstetrics
2007, Vol. 12 Issue 4, p93-99

19. Risk of stroke from randomized controlled trials of MHT
96 Cheryl D Bushnell and Larry B Goldstein
Table 2. Risk of stroke from randomized controlled trials of HRT.
Authors Cohort Study size (n) HRT type Stroke type Number of stroke RR 95% CI
events (n)
Simon et al. [30] Heart HRT = 1380 CEE/MPA IS HRT = 69 1.18 0.83–1.67
Estrogen-Progestin Placebo = 1383 Placebo = 59
Replacement Study
Fatal HRT = 10 1.61 0.73–3.55
stroke Placebo = 70
Non-fatal HRT = 70 1.18 0.83–1.66
stroke Placebo = 60
Viscoli et al. [31] Women’s Estrogen Estrogen = 337 17-β estradiol Stroke or Estrogen = 99 1.10 0.80–1.40
Stroke Trial Placebo = 327 death Placebo = 93
Non-fatal Estrogen = 51 1.00 0.70–1.40
stroke Placebo = 52
IS Estrogen = 9 4.4 0.90–20.2
Placebo = 2
Fatal Estrogen = 12 2.90 0.90–9.00
stroke Placebo = 4
Wassertheil- Women’s Health HRT = 8506 CEE/MPA IS HRT = 125 1.44 1.09–1.90
Smoller et al. [14] Initiative Placebo = 8102 Placebo = 81
Fatal HRT = 12 1.20 0.58–2.50
stroke Placebo = 11
Hendrix et al. [15] Women’s Health CEE = 5310 CEE All stroke CEE = 168 1.37 1.09–1.73
Initiative Placebo = 5429 Placebo = 127
IS CEE = 142 1.55 1.19–2.01
Placebo = 95
CEE: conjugated equine estrogen 0.625 mg; CI: confidence interval; HRT: hormone replacement therapy; IS: ischemic stroke;
MPA: medroxyprogesterone acetate 2.5 mg; RR: relative risk. Current Medical Literature: Gynecology Obstetrics
2007, Vol. 12 Issue 4, p93-99
+9 per 1000
+5 per 1000
+8 per 1000

20. Cerebrovascular events (including stroke and TIA)
Seventeen trials that examined combined oestrogen and pro-
gesterone therapy and seven trials that examined oestrogen mono-
therapy (see Supplementary material online, Table S1) were
to vascular risk. It also includes the most recent study, the
‘Women’s International Study of Long Duration Oestrogen after
the Menopause’ (WISDOM) trial.29
In essence, HRT is associated
European Heart Journal (2008) 29, 2031–2041
+3 per 1000

21. Effect of hormone replacement therapy on
arterial and venous events
...............................................................................................................................................................................
...............................................................................................................................................................................
...............................................................................................................................................................................
Table 1 Effect of hormone replacement therapy on arterial and venous events (cerebrovascular disease, coronary heart
disease and venous thromboembolism and their constituent parts); with odds ratio (95% confidence intervals) using
random effects model
Trials Subjects Events Control event rate
(events per person/year)
Odds ratio (95%
confidence interval)
P-value Heterogeneity
P
Cerebrovascular
disease
26 43 549 1034 0.02 1.24 (1.09–1.41) 0.001 0.53
Stroke 18 36 523 741 0.02 1.32 (1.14–1.53) ,0.0001 0.87
Transient ischaemic
attack
7 6035 153 0.03 1.05 (0.76–1.45) 0.78 0.53
Fatal stroke 11 32 935 105 0.003 1.35 (0.89–2.03) 0.16 0.39
Non-fatal stroke 10 32 680 581 0.02 1.28 (1.08–1.52) 0.004 0.58
Coronary heart
disease
25 43 159 1636 0.04 1.00 (0.90–1.11) 0.97 0.56
Myocardial
infarction
(MI)
21 41 849 1238 0.03 1.02 (0.91–1.15) 0.70 0.78
Fatal MI 15 40 319 396 0.01 1.03 (0.84–1.26) 0.77 0.49
Non-fatal MI 15 40 319 846 0.02 1.02 (0.88–1.18) 0.77 0.41
Unstable angina 5 9413 360 0.04 0.97 (0.71–1.40) 0.98 0.23
Association between HRT and subsequent arterial and venous vascular events 2037
European Heart Journal (2008) 29, 2031–2041
+3 per 1000
+3 per 1000

22. Indirect comparison of dual (combined oestrogen and
progesterone) vs. mono (oestrogen only) hormone therapy
on arterial and venous events
(not seen with oestradiol);36
oral vs. transdermal administration;36
and detrimental effects of some forms of progesterone.37,38
In the
present analysis of these hypotheses have, where possible, been
addressed using subgroup analysis.
Of note, CHD events were not significantly reduced in younger
women (OR 0.63, 95% CI 0.23–1.77, P ¼ 0.38) in contrast to a
previous analysis (reported OR 0.68, 95% CI 0.48–0.94 in
women ,60 years).12
Although the point estimates are similar,
CHD in both younger women, and with reduced time from meno-
pause. Taking this data into account in our analysis (and noting dif-
fering definitions of CHD) the risk of CHD in patients (60 years
remains non-significant, with a point estimate nearer neutral, OR
0.90 (CI 0.64–1.27). Thirdly, they defined CHD events as MI and
cardiac causes of death which may have included heart failure, an
outcome that is unlikely to be influenced by HRT and less likely
to occur in younger women, and one not counted in the
Four-level coronary heart disease (fatal MI/non-fatal
MI/unstable angina/no MI)
5 7765 140/248/360/7017 1.00 0.85–1.17 0.96
Three-level pulmonary embolism (fatal PE/non-fatal
PE/no PE)
3 7527 4/13/7510 2.57 0.73–9.01 0.14
...............................................................................................................................................................................
Table 3 Indirect comparison of dual (combined oestrogen and progesterone) vs. mono (oestrogen only) hormone
therapy on arterial and venous events (odds ratios shown represent the contribution of progesterone to the risk of
cerebrovascular disease, coronary heart disease and venous thromboembolism in addition to oestrogen therapy)
Outcome Trials oestrogen/oestrogen 1 progesterone Odds ratio 95% Confidence interval
Cerebrovascular disease 8/14 0.93 0.70–1.22
Coronary heart disease 7/16 1.16 0.85–1.53
Venous thromboembolism 6/12 2.02 1.39–2.92
European Heart Journal (2008) 29, 2031–2041

23. Crude and adjusted rate ratios of stroke associated
with current use of hormone replacement therapy
by drug type and route of administrationTable 2 | Crude and adjusted rate ratios of stroke associated with current use of hormone replacement therapy (HRT) by drug
type and route of administration (values are percentages (numbers) unless stated otherwise)
Type of HRT Cases* (n=15 710) Controls* (n=59 958)
Rate ratio (95% CI)
Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Transdermal route: 0.66 (103) 0.74 (441) 0.92 (0.74 to 1.14) 0.95 (0.75 to 1.20)
Oestrogen only 0.52 (81) 0.53 (317) 1.00 (0.78 to 1.28) 1.02 (0.78 to 1.34)
Oestrogen-progestogen 0.14 (22) 0.21 (124) 0.70 (0.45 to 1.11) 0.76 (0.47 to 1.22)
Oral route: 3.93 (618) 3.38 (2025) 1.20 (1.09 to 1.33) 1.28 (1.15 to 1.42)
Oestrogen only 1.67 (262) 1.34 (802) 1.28 (1.11 to 1.48) 1.35 (1.16 to 1.58)
Oestrogen-progestogen 2.27 (356) 2.04 (1223) 1.15 (1.02 to 1.31) 1.24 (1.08 to 1.41)
*One case and 7 controls were exposed to tibolone in combination with oestrogen-progestogen, 4 cases and 9 controls were exposed to progestogen
only, and 72 cases and 266 controls were exposed to tibolone. These 3 HRT categories were included in the model. Former users of HRT (416 cases
and 1376 controls) were also included in the model.
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy
‡Reference category, defined as no prescription of HRT in the 12 months before index date.
BMJ 2010;340:c2519
+3per1000
+2per1000

24. Crude and adjusted rate ratios of stroke associated
with current use of hormone replacement therapy
by drug dose and route of administrationTable 3 | Crude and adjusted rate ratios of stroke associated with current use of hormone replacement therapy (HRT) by drug
dose and route of administration (values are percentages (numbers) unless stated otherwise)
Type of HRT Cases* (n=15 710) Controls* (n=59 958)
Rate ratio (95% CI)
Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Transdermal route: 0.66 (103) 0.74 (441) 0.92 (0.74 to 1.14) 0.95 (0.75 to 1.20)
Low dose (≤50 μg) 0.48 (76) 0.64 (384) 0.78 (0.61 to 1.00) 0.81 (0.62 to 1.05)
High dose (50 μg) 0.17 (27) 0.10 (57) 1.87 (1.17 to 2.98) 1.89 (1.15 to 3.11)
Oral route: 3.93 (618) 3.38 (2025) 1.20 (1.09 to 1.33) 1.28 (1.15 to 1.42)
Low dose § 3.28 (515) 2.92 (1753) 1.16 (1.04 to 1.29) 1.25 (1.12 to 1.40)
High dose § 0.66 (103) 0.45 (272) 1.51 (1.20 to 1.90) 1.48 (1.16 to 1.90)
*The model also included current users of tibolone, tibolone in combination with oestrogen-progestogen, and progestogen as well as former users of
HRT (see table 2 for details).
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy.
‡Reference category, defined as no prescription of HRT in the 12 months before index date.
§ Low dose of oral HRT defined by ≤0.625 mg of equine oestrogen or ≤2 mg of estradiol and high dose of oral HRT defined by 0.625 mg of equine
oestrogen or 2 mg of estradiol.
RESEARCH
BMJ 2010;340:c2519
+7
per 1000
+3 per 1000
+2per1000

25. Crude and adjusted rate ratios of stroke associated with
current use of oestrogen (alone or in combination) by
duration of use and route of administration in women not
previously exposed to other hormone replacement therapy
Table 4 | Crude and adjusted rate ratios of stroke associated with current use of oestrogen (alone or in combination) by
duration of use and route of administration in women not previously exposed to other hormone replacement therapy (HRT)*
(values are percentages (numbers) unless stated otherwise)
Type of HRT Cases* (n=15 710) Controls* (n=59 958)
Rate ratio (95% CI)
Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Exclusive transdermal route: 0.46 (72) 0.44 (266) 1.05 (0.80 to 1.36) 1.10 (0.83 to 1.46)
For ≤1 year 0.08 (12) 0.08 (47) 0.95 (0.50 to 1.80) 0.98 (0.50 to 1.91)
For 1 year 0.38 (60) 0.37 (219) 1.07 (0.80 to 1.43) 1.13 (0.83 to 1.54)
Exclusive oral route: 3.28 (516) 2.79 (1675) 1.21 (1.09 to 1.34) 1.30 (1.16 to 1.45)
For ≤1 year 0.38 (59) 0.38 (230) 0.92 (0.69 to 1.23) 1.02 (0.75 to 1.38)
For 1 year 2.91 (457) 2.41 (1445) 1.26 (1.13 to 1.41) 1.35 (1.20 to 1.52)
*The model also included current users of tibolone, tibolone in combination with oestrogen-progestogen, and progestogen; former users of HRT; as
well as current oestrogen users (alone or in combination) who switched from another formulation or HRT product.
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy.
‡Reference category, defined as no prescription of HRT in the 12 months before index date.
BMJ 2010;340:c2519
+5 per 1000

26. Stroke risk in large randomized, placebo-controlled
trials of hormone therapy in postmenopausal women
trials, both focused on women with established vascular dis-
ease. The Heart and Estrogen/progestin Replacement Study
enrolled postmenopausal women with established coronary
disease14. Women, who were randomly assigned to daily
tomy status17. The dual clinical trial used a partial factorial
design, with three randomized interventions: low-fat diet, hor-
mone therapy (conjugated estrogens with or without medroxy-
progesterone acetate, depending on hysterectomy status), and
Table 1 Stroke risk in large randomized, placebo-controlled trials of hormone therapy or raloxifene in postmenopausal women*
Trial, year
Clinical population
(hysterectomy status)
Number
contributing
to analysis
Active
intervention
Type of
stroke
Number of events
Hazard ratio (95%
confi dence interval)
Active
group
Placebo
group
Hormone therapy
HERS, 200114 coronary heart disease (uterus) 2763 CEϩMPA any 82 67 1.2 (0.9–1.7)
ischemic 69 59 1.2 (0.8–1.7)
fatal 16 10 1.6 (0.7–3.6)
WEST, 200116 recent stroke or transient ischemic
attack (uterus or no uterus)
664 estradiol† any 63 56 1.1 (0.8–1.6)
ischemic 56 51 1.1 (0.8–1.5)‡
fatal 12 4 2.9 (0.9–9.0)
WHI, 200320 generally healthy (uterus) 16608 CEϩMPA any 151 107 1.3 (1.0–1.7)
ischemic 125 81 1.4 (1.1–1.9)
fatal 12 11 1.0 (0.5–2.6)‡
WHI, 200621 generally healthy (no uterus) 10739 CE any 168 127 1.4 (1.1–1.7)
ischemic 142 95 1.6 (1.2–2.0)
fatal 17 15 1.2 (0.6–2.3)‡
Raloxifene
MORE, 200233 osteoporosis 5133 raloxifene** any 22 32 0.7 (0.4–1.2)
fatal 3 6 0.5 (0.1–2.0)
RUTH, 200634 coronary heart disease or 10101 raloxifene** any 249 224 1.1 (0.9–1.3)
CLIMACTERIC 2012;15:229–234
+5 per 1000
+9 per 1000

27. Studies reporting stroke rates in women aged 45–54 years
Lancet Neurol 2012; 11: 82–91

28. Kaplan-Meier event curve for stroke risk associated with age
at menopause in the Framingham cohort
Lancet Neurol 2012; 11: 82–91

29. The Women’s Health Initiative Observational
Study (WHI-OS)
Menopause. 2014 March ; 21(3): 260–266
93,676 postmenopausal women, aged 50-79 years at study entry
and recruited September 1994 - December 1998, with annual
follow-up through August 14, 2009
Cases per 10,000 person-years
during the first 5 years of follow-up

30. Direct Comparison of Transdermal HT and Oral Low-
Dose CEE versus Conventional Dose CEE
Table 2
Direct Comparison of Transdermal HT and Oral Low-Dose CEE versus Conventional Dose CEE, updating
HT use during follow-up
Outcome Transdermal HT vs. Oral Conventional-dose CEE Oral Low dose CEE vs. Oral Conventional-dose CEE
# cases by baseline HT HR (95% CI)1,2 # cases by baseline HT HR (95% CI)1,2
Transdermal
Conv. dose
CEE
Low dose CEE
Conv.
dose CEE
Major CHD 18 324 0.63 (0.37, 1.06) 22 324 0.82 (0.57, 1.19)
Stroke 17 297 0.87 (0.55, 1.38) 36 297 1.07 (0.76, 1.49)
Total CVD 36 634 0.82 (0.59, 1.14) 59 634 0.86 (0.67, 1.12)
CVD Mortality 9 188 0.94 (0.50, 1.74) 19 188 0.87 (0.54, 1.42)
All-Cause Mortality 44 654 1.06 (0.78, 1.44) 65 654 0.98 (0.75, 1.28)
Major CHD = nonfatal MI and CHD mortality, Total CVD =major CHD, stroke and CVD mortality, Major CHD = nonfatal MI and CHD
mortality, CEE denotes conjugated equine estrogens. Low-dose CEE is defined as 0.625 mg/d. Conventional-dose CEE is defined as 0.625 mg/d.
1
All HR are from a Cox proportional hazard model stratified by baseline 5-year age intervals and history of CVD, and adjusted for age (linear),
race/ethnicity (White, Black, Hispanic, Asian/Pacific Islander, Other), smoking (never, former, current), quartiles of total recreational physical
activity, BMI categories (25, 25-30, ≥30), BMI (linear), hypertension (never, untreated, treated), treated diabetes (no,yes), high cholesterol
Menopause. 2014 March ; 21(3): 260–266
NIH-PAAuthorM
Shufelt et al.
Table 1
Demographic Characteristics by Hormone Therapy Dose and Formulation
Dose Formu
Low-dose
CEE*
(n=2,149)
Conventional-dose
CEE+
(n=24,399)
High-dose
CEE#
(n=3,396)
Oral E+P**
(n=13,208)
Oral CEE-
alone
(n=16,508)
Es
(n=
N (%) N (%) N (%) N (%) N (%)
Age at screening, mean
Page 10
Formulation
e Formulation Route
e
#
)
Oral E+P**
(n=13,208)
Oral CEE-
alone
(n=16,508)
Oral
Estradiol
(n=3,024)
Transdermal
Estradiol
(n=2,187)
) N (%) N (%) N (%) N (%)

31. Direct Comparison of Oral Estradiol and Oral
E+P versus Oral Conventional-Dose CEE
Table 3
Direct Comparison of Oral Estradiol and Oral E+P versus Oral Conventional-Dose CEE, updating HT use
during follow-up
Outcome Oral Estradiol vs. Oral Conventional-dose CEE Oral E+P vs. Oral Conventional-dose CEE alone
# cases by baseline HT HR (95% CI)1,2 # cases by baseline HT HR (95% CI)1
Estradiol Conv. CEE
Oral
E+P
Conv.
CEE alone
Major CHD 40 324 1.13 (0.79, 1.61) 138 258 1.02 (0.80, 1.31)
Stroke 21 297 0.64 (0.40, 1.02) 110 265 0.97 (0.75, 1.26)
Total CVD 65 634 0.93 (0.71, 1.23) 259 531 1.01 (0.85, 1.21)
CVD Mortality 23 188 1.33 (0.84, 2.12) 77 159 0.97 (0.69, 1.37)
All-Cause Mortality 81 654 1.09 (0.83, 1.43) 314 511 1.14 (0.95, 1.37)
Total CVD = total CHD, stroke and CVD mortality, Major CHD = nonfatal MI and CHD mortality, CEE denotes conjugated equine estrogens
Conventional-dose CEE is defined as 0.625 mg/d. Oral E+P is includes the formulations of both oral CEE and oral estradiol with a progestin o
progesterone
1
All HR are from a Cox proportional hazard model stratified by baseline 5-year age intervals and history of CVD, and adjusted for age (linear
Menopause. 2014 March ; 21(3): 260–266
Page 10
Table 1
y Hormone Therapy Dose and Formulation
Dose Formulation Route
se
E*
9)
Conventional-dose
CEE+
(n=24,399)
High-dose
CEE#
(n=3,396)
Oral E+P**
(n=13,208)
Oral CEE-
alone
(n=16,508)
Oral
Estradiol
(n=3,024)
Transdermal
Estradiol
(n=2,187)
%) N (%) N (%) N (%) N (%) N (%) N (%)

32. Odds Ratios of Ischemic Stroke in Relation to Current HT Use by
Route of Estrogen Administration and Pharmacological Classes
of Progestogens
tively, for older women (1427 cases and 5476 controls; P for
interaction=0.62). On the contrary, presence of cardiovascular
risk factors did not affect the association of oral and trans-
dermal estrogens with IS risk (Figure 3). Finally, associa-
tions of IS with oral and transdermal estrogens were similar
The dose-dependent association of oral estrogens with
stroke risk has been less often investigated. One early study
found no association of estrogens with stroke, with dose not
having any effect. However, these data cannot be extrapo-
lated to ours because the authors compared ever to never HT
Table 2. Odds Ratios of Ischemic Stroke in Relation to Current HT Use by Route of Estrogen Administration and
Pharmacological Classes of Progestogens
Characteristics Cases (n=3144) Controls (n=12158) Crude OR (95% CI) Adjusted OR (95% CI)*
Nonusers 2950 (93.8) 11331 (93.2) 1 (reference) 1 (reference)
Current users of oral estrogens 90 (2.9) 243 (2.0) 1.35 (0.89–2.01) 1.58 (1.01–2.49)
Current users of transdermal estrogens 104 (3.3) 584 (4.8) 0.73 (0.50–1.06) 0.83 (0.56–1.24)
No progestogens 42 (1.5) 177 (1.4) NA NA
Current users of progesterone 60 (1.9) 380 (3.1) 0.79 (0.50–1.24) 0.78 (0.49–1.26)
Current users of pregnane derivatives 58 (1.8) 197 (1.6) 0.98 (0.61–1.58) 1.00 (0.60–1.66)
Current users of norpregnane derivatives† 17 (0.5) 27 (0.2) 2.72 (1.34–5.49) 2.25 (1.05–4.81)
Current users of nortestosterone derivatives 17 (0.5) 46 (0.4) 1.22 (0.62–2.39) 1.26 (0.62–2.58)
P for homogeneity between oral estrogens use and transdermal estrogens use is significant (P0.01). P for homogeneity between pharmacological
classes of progestogens is significant (P=0.03). CI indicates confidence intervals; HT, hormone therapy; NA, not applicable; and OR, and odds ratio.
*Adjusted for antidiabetic medication, antihypertensive medication, antidyslipidemia medication, and long-term chronic disease.
†85% of the subjects used nomegestrol acetate. Stroke.2016;47:1734-1741

33. Different progestogens

34. Odds ratios of ischemic stroke according to estrogen
dose by route of administration
Stroke July 2016
2. Odds ratios of ischemic stroke according to estrogen dose by route of administration. Dotted lines represent overaStroke.2016;47:1734-1741

35. Associations between multivariable-adjusted stroke-free and
haemorrhagic stroke-free periods (early initiation)
PLOS Medicine |November 17, 2017
https://doi.org/10.1371/journal.pmed.1002445
Never use= 35,716
Early initiation= 19,571

36. Associations between multivariable-adjusted stroke-free and
haemorrhagic stroke-free periods (late initiation)
PLOS Medicine |November 17, 2017
https://doi.org/10.1371/journal.pmed.1002445
Never use= 35,716
Late initiation= 7,189

37. • HT was associated with a reduced or null risk of future stroke if initiated
relatively soon after the onset of menopause, regardless of regimen (type,
active ingredient, and route of administration) and duration.
• This finding was extended to haemorrhagic stroke, except the use of CEEs as
single therapy.
• However, when HT was initiated late with regard to menopause onset, an
increased risk was observed for stroke and haemorrhagic stroke when CEEs
were used as single therapy.
• Combined therapy initiated late was associated with increased risk of
haemorrhagic stroke only.
• The current results suggest that the initiation of HT 0–5 years after
menopause onset, as compared to never use, is associated with a
decreased risk of stroke and haemorrhagic stroke.
PLOS Medicine |November 17, 2017
https://doi.org/10.1371/journal.pmed.1002445

38. Low dose HT
Maturitas 56 (2007) 231–248

39. Low dose regimes – uterine bleeding
Maturitas 56 (2007) 231–248

40. Low dose regimes – uterine bleeding
Maturitas 56 (2007) 231–248

41. Low dose regimes – endometrial safety
Maturitas 56 (2007) 231–248

42. Low dose regimes – endometrial safety
Maturitas 56 (2007) 231–248
In this survey, no oestrogen alone group was included and so a direct comparison of effects was not possible.
Moreover, long-term head-to-head comparisons of different cc-HT formulations are lacking.
In this survey, no evidence for an increased risk of cardiovascular or cerebrovascular disease or cancer
incidence was reported.

43. Prescribable alternatives to HRT
• Gabapentin reduces hot flushes at a dose of 900mg per day in about
50% of patients.
• Pregabalin Dosage 50-300mg in divided doses
• Clonidine Dosage 25-50 micrograms bd up to a maximum of 75
micrograms bd or 50mcg tds.
• Paroxetine Dosage 10-20mg – baseline improvement50-60%
• Fluoxetine Dosage 20mg – baseline effectiveness 10-20%
• Citalopram (Escitalopram) Dosage 20mg - baseline effectiveness 40-50%
• SNRI SSRI Venlafaxine Dosage 37.5mg – 150mg sustained release
preparations recommended. Baseline benefit quoted 20-66%.
BRITISH MENOPAUSE SOCIETY Tool for clinicians

44. Take away notes
• Stroke risk is not modified by age of hormone initiation or use, or
by temporal proximity to menopause
• Stroke risks are similar for estrogen+progestogen and for
unopposed estrogen
• Limited evidence suggests that lower doses of transdermal
estradiol (50 μg/day) or low-dose oral conjugated estrogens (0.3
mg/day) may not alter stroke risk
• For women aged 60 years, the absolute risk of stroke from
standard-dose oral hormone therapy is about two additional strokes
per 10,000 person-years, equivalent to one additional stroke among
1000 women using hormone therapy for 5 years.
• The risk is considerably greater for older women
CLIMACTERIC 2012;15:229–234

45. Thank you for your attention.
Tevfik Yoldemir MD. BSc. MA. PhD.
tevfik.yoldemir@marmara.edu.tr

46. Example of a written informed consent for the use
of selected hormone replacement therapy
uncommon near
nitiate HRT after
difficult decision,
, as there are few
e cerebrovascular
udy suggests that
o increase the risk
be the preferred
all other medical
versely by HRT.
icose veins, bowel
is are not contra-
s a thromboembo-
nd, where active
Table 7 Example of a written informed consent for the use of
selected hormone replacement therapy in the presence of a personal
history of breast cancer/thrombosis/or other traditional
contraindications
The currently known risks and benefits of hormone replacement
therapy in my particular circumstances have been explained to me
by Dr . . . . . . . . . . I understand that it is theoretically possible that
such therapy could exacerbate or promote a recurrence of my . . . .
. . . . . . . . . . . . . . . . . . . (Specify the disorder/disease).
However, in view of the potential benefits for me, I wish to have a trial
of hormone replacement therapy as agreed between myself and my
doctor. I believe that the balance of potential benefits and risks is in
favor of starting such therapy and I take full responsibility for this
decision. I understand that I should have regular review of this
therapy by my medical team.
Dated, signed and printed name
Dated, signed and printed name of witness (preferably not the
advising doctor)
CLIMACTERIC 2011;14:409–417

47. Risk of stroke death in women discontinuing HT in relation
to HT exposure duration and age at the HT discontinuation,
as compared to age-matched background population
not considered to have discontinued HT.
A total of 432,775 women discontinued systemic HT
between 1994 and 2013. According to the Hospital Discharge
Register, 6,112 HT discontinuers had suffered a myocardial
infarction or other serious cardiac event (International Clas-
sification of Diseases, ICD: Ninth revision codes 410-414 in
1995 and Tenth revision codes I20-I25 since 1996) and 2,834
had suffered a stroke (ICD: Ninth revision codes 433-434 in
1995 and Tenth revision codes I63 since 1996) within 1 year
before the discontinuation of HT. These women (altogether
n ¼ 8,711) were excluded from the primary study population.
After this exclusion and due to the fact that the September 30,
2013 was the last possible date of discontinuation, 402,573
women were left to be followed for cardiac and stroke deaths
after discontinuation of HT (Fig. 1).
The duration of HT exposure was categorized as dura-
tion of 5 years or 5 years. In view of the timing
death risks were expressed as standardized mortality ratios
(SMRs). P values and 95% CIs were obtained from Poisson
distributions. Two-sided P values less than 0.05 were consid-
ered statistically significant.
The study plan was approved by the research committee at
the Helsinki University Hospital before the initiation of the
study. Subsequently, permissions and approvals to use the
confidential register data in scientific research were obtained
from the National Institute for Health and Welfare (THL/
1370/5.05.00/2010), Statistics Finland (TK-53-1560-10), and
Social Insurance Institution of Finland (KELA 40/522/2010,
3/522/2014).
RESULTS
Of the 402,573 followed women, 5,204 died of a cardiac
event and 3,434 died of a stroke (Fig. 1). The exposure time
(mean Æ SD) to HT had been 6.6 Æ 6.0 years, and the mean
3060 stroke deaths 1 year
after discontinuation
3 434 stroke deaths5 204 cardiac deaths
374 stroke deaths ≤ 1 year
after HT discontinuation
4 703 cardiac deaths 1 year
after HT discontinuation
501 cardiac deaths ≤ 1 year
after HT discontinuation
Follow-up of women who discontinued
postmenopausal HT between 1994-2013
n = 402 573 (3 232 992 woman years)
Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
cardiac and stroke deaths. The risks reduced with the pro-
longation of the follow-up, but remained elevated when
postdiscontinuation follow-up was extended to more than
one year.
effects of estrogen suddenly cease.20,21
Declining estrogen
may also modulate cardiac rhythm, perhaps via calcium ion
channels22
or by preventing long QT interval,23
and indeed
hypoestrogenic postmenopausal women with congenital long-
TABLE 2. Risk of stroke death in women discontinuing HT in relation to HT exposure duration and age at the HT discontinuation, as
compared with age-matched background population
HT exposure 5 y HT exposure 5 y
Age at
discontinuation (y)
Time since
last HT use (y)
Observed
deaths
Expected
deaths
SMR
(95% CI)
Observed
deaths
Expected
deaths
SMR
(95% CI)
60 1 77 29 2.62 (2.07-3.28) 39 12 3.22 (2.29-4.40)
1 430 397 1.08 (0.98-1.19) 140 143 0.98 (0.82-1.15)
!60 1 52 64 0.82 (0.61-1.07) 206 169 1.22 (1.06-1.40)
1 864 930 0.93 (0.87-0.99) 1,626 1,756 0.93 (0.88-0.97)
The data are expressed as standardized mortality ratio (SMR) with 95% CIs. Statistically significant values have been written in italic.
Menopause, Vol. 25, No. 4, 2018 377
Menopause: 2017
Vol. 25, No. 4, pp. 375-379

48. Risk of stroke death in women discontinuing HT in relation
to HT exposure duration and age at the HT discontinuation,
as compared to age-matched HT users
Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
the reduced death risks in older women observed in some of
the comparisons in this study when the post-HT follow-up
lasted for more than 1 year.
We acknowledge a number of limitations in our study.
First, we had no data on cardiovascular risk profiles of the
HT were included into the background comparator group,
which may have slightly diluted the observed changes in the
death risks.
Our study has several strengths. First, our national study
with comprehensive, reliable registers15,35,36
is certainly the
TABLE 4. Risk of stroke death in women discontinuing HT in relation to HT exposure duration and age at the HT discontinuation, as
compared with age-matched HT users
HT exposure 5 y HT exposure 5 y
Age at
discontinuation (y)
Time since
last HT use (y)
Observed
deaths
Expected
deaths
SMR
(95% CI)
Observed
deaths
Expected
deaths
SMR
(95% CI)
60 1 77 23 3.39 (2.67-4.24) 39 9 4.18 (2.97-5.71)
1 430 334 1.29 (1.17-1.42) 140 121 1.15 (0.97-1.36)
! 60 1 52 41 1.27 (0.95-1.66) 206 123 1.68 (1.46-1.92)
1 864 807 1.07 (1.00-1.14) 1,626 1,556 1.05 (1.00-1.10)
The data are expressed as standardized mortality ratio (SMR) with 95% CIs. Statistically significant values have been written in italic.
378 Menopause, Vol. 25, No. 4, 2018 ß 2017 The North American Menopause Society
Menopause: 2017
Vol. 25, No. 4, pp. 375-379
Discontinuation of postmenopausal HT may be associated with increased risk of cardiac and stroke
death during the first posttreatment year, particularly in women who discontinue
HT before the age of 60 years.