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Effects of post-menopausal hormone therapy on arterial stiffness in the ELITE trial

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Effects of post-menopausal hormone therapy on arterial stiffness in the ELITE trial

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EFFECTS OF POST-MENOPAUSAL HORMONE THERAPY ON ARTERIAL STIFFNESS
IN THE ELITE TRIAL
by
KANIKA BHALLA

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLGY)

May 2021

Copyright 2021 Kanika Bhalla

ii
DEDICATION

I started and ended working on this thesis during the unprecedented time of the COVID-
19 pandemic. Being 10,000 miles away from home and family with very little social
interaction possible, and being in a lockdown for almost a year, this has been
undoubtedly quite challenging. I dedicate this work to my parents, my brother, and my
partner Shalin for being my strongest support system and for always being there.

iii
ACKNOWLEDGEMENTS
I would like to thank my advisor Dr. Wendy Mack for letting me become a part of her
research and for guiding me through this process. I would also like to thank my
committee members Dr. Howard Hodis and Dr. Roksana Karim for their expertise and
helpful feedback.

iv
TABLE OF CONTENTS
Dedication………………………………………………………………………………………..ii
Acknowledgements……………………………………………………………………………..iii
List of Tables…………………………………………………………………………………….v
Abstract………………………………………………………………………………………….vi
Introduction………………………………………………………………………………………1
Methods…………………………………………………………………………………………10
Results………………………………………………………………………………………….14
Discussion………………………………………………………………………………………17
Conclusion……………………………………………………………………………………...21
References……………………………………………………………………………………..22
Tables…………………………………………………………………………………………...26

v
LIST OF TABLES
Table 1: Baseline Demographic, Clinical, and Laboratory Characteristics
Table 2: Carotid Artery Stiffness (CAS) measures
Table 3: Carotid Artery Stiffness (CAS) measures in the early
post-menopause strata only

Table 4: Change in CAS measures from baseline to one year by treatment
groups

vi
ABSTRACT
Background: The incidence of cardiovascular disease (CVD) is higher in men as
compared to women of the same age, but that gap narrows with increasing age and after
menopause women approximate the male incidence of CVD. This led to the hypothesis
that postmenopausal women are at a higher risk of CVD as compared to premenopausal
women. It was noted in preclinical studies that hormone therapy started closer to
menopause as opposed to starting treatment much later after menopause could be
beneficial in reducing the risk of developing coronary disease . We tested this timing
hypothesis in the Early Versus Late Intervention Trial with Estradiol (ELITE). The aim of
our study was to examine the effects of menopausal hormone therapy (MHT) on the
vascular health of healthy post-menopausal women, measured by carotid artery
measures of distensibility and compliance.
Methods: This study included a total of 220 healthy post-menopausal women without
pre-existing diabetes or any clinical signs of CVD who were stratified according to time
since menopause [6 years or less (early post-menopause) or  10 years (late post-
menopause)]. They were randomly assigned to receive either oral 17-  estradiol (1
mg/day with 4% vaginal progesterone gel [45 mg/day] for 10 days each month for women
with a uterus) or a double matched placebo. Women without a uterus received either 17-
 estradiol 1 mg/day alone or placebo. The primary outcome was the rate of change in
carotid artery stiffness (CAS) measures, including arterial distensibility, arterial
compliance, and total percent dilation. Mixed effect linear models were used to evaluate
this change.

vii
Results: The effect of estradiol with or without progesterone on CAS measures did not
significantly differ between the early and the late post menopause strata. While not
statistically significant, women in the early post-menopause stratum who received
estradiol showed a greater decrease in arterial distensibility as compared to women in
the placebo group (p=0.31). In the late post-menopause stratum, arterial distensibility
increased in the estradiol group and decreased in the placebo group (p=0.90). Arterial
compliance decreased in women who received estradiol as compared to placebo in the
early post menopause stratum (p=0.09) and in the late post menopause stratum, women
on placebo showed a greater increase in arterial compliance as compared to women who
received estradiol (p=0.93). Percent dilation of carotid artery decreased in both treatment
groups in the early post menopause strata with women on estradiol showing a greater
decrease as compared to placebo (p=0.24). In the late post menopause stratum, women
on placebo showed a greater increase in percent dilation as compared to women in the
estradiol group (p=0.69).
Conclusion: No significant differences were found in the annual rate of change in the
physiologic measures of arterial distensibility, arterial compliance and total percent
dilation between treatment groups in either postmenopausal stratum. Given that the
estradiol intervention in ELITE showed a highly significant benefit on early post
menopause on anatomical measures of atherosclerosis, further research should address
possible reasons for the discrepancy in these findings.

1
INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of mortality in the United States
(US), and globally. In the US, about 655,000 people succumb to CVD every year,
representing 1 in 4 deaths.
1,2
Many behavioral and environmental factors have been
associated with the risk of developing CVD. Urbanization and economic improvement
have led to major changes in diet, physical activity, and personal habits like smoking and
alcohol consumption. CVD rates differ between developing and developed countries.
Since developing countries account for the majority of the world’s population, global CVD
rates are driven by rates in these countries. Tobacco is one of the established risk factors
for CVD. Although overall cigarette smoking has declined in the US, cigarette smoking
among young men and women has increased
3
. Consumption of dietary fat especially
animal fat, another risk factor for CVD, increases with per capita income
3
. With
industrialization and wide-spread mechanization, physical activity has decreased
substantially, which in turn contributes to CVD.
3

Men have long been considered at higher risk for CVD than women. Although men
have a higher incidence of CVD at younger ages, women have a higher mortality rate and
poorer prognosis after an acute CVD event.
4
The incidence of CVD is higher in men as
compared to women of the same age, but that gap narrows with increasing age and after
menopause women approximate the male incidence of CVD.
Atherosclerotic coronary heart disease (CHD) is one form of CVD that affects the
blood vessels supplying blood to heart muscle. Atherosclerosis is the pathological
process by which the coronary arteries narrow due to plaque build-up within the lining of
the arteries.
5
Atherosclerosis is an early indicator of CVD and CHD ischemic events.
6

2
Structural and functional changes due to atherosclerosis in the vessel wall lead to loss of
elasticity and reduction in arterial compliance.
7

Atherosclerosis: Pathophysiology and risk factors
Atherosclerosis is a chronic inflammatory aging process characterized by plaque
build-up within the blood vessel wall that can compromise the lumen of the vessel
restricting blood flow to the heart leading to ischemic heart disease.
8
Atherosclerosis
develops gradually over years with accumulation of cholesterol and other lipids in the
arterial wall with an accompanying inflammatory response. High level of circulating lipids,
tobacco smoking, obesity, hypertension, diabetes mellitus and genetic predisposition
have been identified as important risk factors for atherogenesis.
The process of plaque build-up begins in childhood and early adolescence. The
earliest visible form of the lesion is fatty streak, an accumulation of lipid filled
macrophages in the intima of the arterial wall.
9
Cholesterol particles from the blood are
deposited on the endothelial layer of the vessel wall and as they accumulate they slowly
injure the endothelial layer resulting in its discontinuity. This layer of endothelial cells acts
as a barrier between the blood and the other layers of the vessel wall and allows the blood
to flow smoothly.
With disruption of the endothelial layer, lipids are exposed to the underlying smooth
muscle cells. Inflammation begins with activation of endothelial cells and secretion of
chemokines from the smooth muscle cells which activate the innate immune system. As
a result, white blood cells, predominantly monocytes are attracted to the site of injury.
Through diapedesis, monocytes transmigrate though the endothelial cell gap junctions

3
with the assistance of intracellular adhesion molecules transforming into macrophages
that engulf lipids engorging to become lipid-laden macrophages or foam cells that
coalesce to form fatty streaks. Factors promote apoptosis of macrophages and smooth
muscle cells; this necrotic debris results in further inflammation forming the necrotic core
of atherosclerotic plaque. As a result of the inflammatory process and healing, a fibrous
cap forms over the lipid filled necrotic core of the plaque.
10

Initially, the arterial wall remodels (outward remodeling toward the tunica
adventitia) to compensate for plaque build-up while the lumen of the artery remains
sufficiently patent. However, remodeling is limited. When the plaque occludes more than
40% of the vessel diameter, plaque growth exceeds vessel capacity to dilate and the
lumen of the artery narrows. Some plaques are stable, characterized by slow
accumulation of fibrous tissue, and such plaques are less prone to sudden changes or
disruption. Plaques can also be unstable and undergo sudden plaque rupture that leads
to thrombus formation within the lumen of the vessel. Thrombus formation narrows lumen
diameter and can lead to severe adverse clinical events such as stroke or sudden cardiac
death.
9

Arterial Distensibility and Arterial Compliance
Arterial distensibility and arterial compliance are important functional properties of
the large arteries and indicators of vascular health.
11
Arterial distensibility represents
elasticity of a vessel and its ability to expand and contract with the changes in blood flow
and blood pressure. Arterial distensibility is defined as relative change in volume per unit
of pressure ([ V/V]/ P).
12
Reduced arterial distensibility indicates increase in arterial

4
stiffness and is a risk factor for CVD.
13
This association has been investigated in multiple
studies such as the Atherosclerosis Risk in Communities (ARIC), Second Manifestations
of ARTerial disease (SMART), Baltimore Longitudinal Study of Aging (BLSA), and the
Multiethnic Study of Atherosclerosis (MESA).
14-17

Arterial compliance is the buffering capacity of the vessel that is associated with
distensibility and the diameter of the vessel. Arterial compliance is defined as change in
volume per unit of pressure [ V/ P].
12
During cardiac systole, the heart contracts and
pumps blood through the ventricles to the large arteries. In response to this, there is a
temporary increase in the volume of these arteries to buffer the variations in blood flow
and pressure caused by the intermittent left ventricular contraction. This buffering
capacity of the arteries depends on their compliance.
The buffering function of large elastic arteries helps to provide a smooth and a
constant flow of blood and oxygen to all tissues. Normally, the pulse wave is formed by
the overlapping of the forward wave that travels from heart to periphery and the reflected
wave travelling from periphery to heart. With decrease in arterial compliance, the reflected
wave returns earlier in systole instead of diastole and this leads to a higher increase of
systolic blood pressure as compared to diastolic pressure. This increases the workload
on the cardiac system and makes it vulnerable to the risks of cardiovascular events.
6

Menopause and Cardiovascular Disease
Women undergo menopause in midlife, usually between 45 – 55 years of age. The
average age of menopause in the US is 51 years.
18
Incidence of CVD in women increases
in later years of life and this led to the hypothesis that postmenopausal women are at a

5
higher risk of CVD as compared to the premenopausal women. This hypothesis was
investigated in the Framingham Heart Study, where the rate of CVD was found to be
higher at any age in postmenopausal women than in premenopausal women in age-
specific analyses.
19

Menopause is accompanied by physiological changes in the body that tend to
increase the risk for developing CVD. These changes include: a change in body fat
distribution from the gynoid pattern to an android pattern, increase in blood pressure,
reduced glucose tolerance, endothelial dysfunction, abnormal lipid pattern and vascular
inflammation. Female sex hormones, in particular estrogen, have been considered to
exert a protective effect against CVD risk. Proposed mechanisms of the cardioprotective
property of estrogen are known positive effects on the plasma lipid profile, anti-oxidant
effects and anti-platelet effects.
20

After menopause, estrogen withdrawal has a detrimental effect on cardiovascular
function and metabolism.
21
During the menopause transition, estrogen deficiency causes
certain symptoms that may differ in frequency and severity in each woman. The most
frequently observed symptoms are vasomotor changes (hot flashes), vaginal atrophy and
dryness, disturbed sleep, mood disorder and gradual decline of cognitive function.
22

These symptoms are usually treated with menopausal hormone treatment (MHT),
estrogen alone for women who have no uterus and estrogen plus progestogen for women
with an intact uterus.
Many observational studies have shown that postmenopausal hormone therapy
reduces CHD. In the Nurses’ Health Study, 59,337 postmenopausal women were
observed with a significant reduction in the risk of CHD in women who took estrogen or

6
estrogen plus progestogen as compared with women who did not take hormones.
23,24

Langer’s review of 10 observational studies
25
and other observational studies
26,27
showed
similar cardioprotective effects of hormone replacement therapy in healthy post-
menopausal women.
However, randomized controlled trials have had contradictory results. The Heart
and Estrogen/Progestin Replacement Study (HERS) was a randomized, double-blinded,
placebo-controlled secondary prevention trial carried out in 1998 in 2763 postmenopausal
women to determine the effect of conjugated equine estrogen (CEE) plus
medroxyprogesterone acetate (MPA) in preventing coronary events in women with pre-
existing CVD.
28
This trial did not show benefit of CEE plus MPA regimen as compared to
placebo in preventing secondary coronary events. In another randomized controlled trial,
the Estrogen Replacement and Atherosclerosis (ERA) trial, 309 postmenopausal women
with angiographically-verified coronary artery disease were studied to determine the
effect of CEE plus MPA and unopposed CEE as compared to placebo on coronary artery
diease.
29
The end point for this trial was serial coronary angiography to assess vessel
measures of coronary artery disease. This trial did not show any significant benefit of
estrogen replacement therapy or HRT on coronary angiographic outcomes.

Explanations for these differing results between the observational studies and
clinical trials is that the participants in the observational studies were women without
established CVD who were much younger (<55 years) and closer to menopause as
compared to the women in the clinical trials. In HERS, all participants had clinical CVD
and hormone treatment began at an average age of 66.7 years. Similarly, in ERA
participants had established coronary artery disease and were on average 65.7 years old.

7
In the Estrogen plus Progestin trial of the Women’s Health Initiative (WHI) study,
initial results showed a non-significant increase in coronary events in the active arm of
the trial as compared to placebo.
30,31
These negative results of postmenopausal hormone
therapy in WHI, one of the largest studies that focused on women’s health, resulted in a
major shift in routine treatment of post-menopausal women and use of menopausal
hormone therapy declined significantly. However, analysis of the WHI data stratified by
age and time since menopause shed light on the critical design flaw of the trial that led to
the initial negative results. The study population in WHI was overall older and hence more
years past menopause than the women in observational studies. Women recruited to WHI
were aged 50-79 years; average age of women who were given hormone therapy being
63 years and on average 12 years past menopause. Stratified analysis showed that in
younger women (50-59 years) who were <10 years past menopause, CEE alone reduced
the risk of developing CHD.
32,33

Two sister trials were conducted to test the MHT effect on primary and secondary
prevention of CVD. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT)
enrolled healthy post-menopausal women (free of diabetes and cardiovascular disease)
and found 17-  estradiol to be beneficial in slowing the progression of atherosclerosis
(measured by carotid artery intima-media thickness) as compared to placebo.
34
The
Women’s Estrogen Lipid Lowering Hormone Atherosclerosis Regression (WELL-HART)
trial enrolled post-menopausal women with at least one angiographically confirmed
coronary artery lesion. The results of this trial showed no beneficial effect of either 17- 
estradiol alone or 17-  estradiol with MPA on regression of coronary angiographic
measures of atherosclerosis.
35
These trials supported the hormone timing hypothesis that

8
the cardioprotective effect of MHT depends on the age and in turn on the health of the
underlying vascular tissue.

Hormone Timing Hypothesis
A pre-clinical study on cynomolgus monkeys by Thomas Clarkson played an
important part in providing the early basis for the timing hypothesis.
36
He surgically
removed the ovaries of 88 of these monkeys and fed them with an atherogenic diet for 24
months. Following this, the monkeys were allocated to either receive a lipid lowering diet,
lipid lowering diet with CEE, lipid lowering diet with CEE plus medroxyprogesterone or no
treatment (baseline group). The treatment phase lasted for 30 months. He observed that
monkeys receiving the lipid lowering diet alone showed coronary artery remodeling and
lumen enlargement as compared to the baseline group. However, monkeys who received
hormone treatment along with the lipid lowering diet did not show any further structural
improvement of the coronary artery as compared to monkeys receiving only the modified
diet. In this study, hormone therapy which was delayed for 2 years did not show any
regression of an established atherosclerotic plaque. This formed the early foundation for
the timing hypothesis that late treatment with estrogen does not provide cardioprotective
effects but early treatment started closer to menopause may be beneficial in reducing the
risk of developing coronary disease.
36

The Early Versus Late Intervention Trial with Estradiol (ELITE) was the first
randomized controlled trial specifically designed to test this timing hypothesis in humans.
It enrolled healthy post-menopausal women without pre-existing diabetes or clinical signs
of CVD. Participants were stratified according to the time since menopause [6 years or

9
less (early post-menopause) or  10 years (late post-menopause)] and were randomized
to receive either oral 17-  estradiol for women without a uterus or 17-  estradiol with
vaginal progesterone for women with an intact uterus. The primary outcome of this trial
was the annualized rate of change in carotid artery intima-media thickness (CIMT). In
women in the early post-menopause stratum, estradiol therapy slowed the progression of
subclinical atherosclerosis as compared to placebo. However, this beneficial effect was
not observed in the women in the late post-menopause stratum. In that stratum, there
was no significant difference between the estradiol treatment and placebo arm in
progression of subclinical atherosclerosis.
37
This current study is a secondary analysis of the ELITE trial. The aim of our study
was to examine the effects of MHT on the vascular health of healthy post-menopausal
women, measured by carotid artery measures of distensibility and compliance.
Previously published studies have had conflicting results on the effects of hormone
replacement therapy (HRT) on arterial stiffness measures like arterial distensibility and
arterial compliance. Cross sectional studies have found beneficial effects of HRT on
arterial stiffness in post-menopausal women.
38-40
Teede et al studied the effects of HRT
on arterial stiffness measures in post-menopausal women stratified by smoking status.
41

They found that smokers on HRT had better stiffness measures – systemic arterial
compliance and carotid intima-media thickness as compared to smokers not on HRT. In
non-smokers, they did not find significant differences in arterial stiffness measures
between women who were HRT users compared to non-users.
Prospective trials have not shown consistent beneficial effects of HRT on arterial
stiffness. Angere et al carried out a randomized controlled trial in post-menopausal

10
women with sub-clinical atherosclerosis to study the effects of HRT on the elastic
properties of the carotid artery.
42
They did not find any substantial influence of HRT on
the distensibility of central arteries. In another randomized placebo-controlled trial in peri-
menopausal women, carried out to assess the 2-year effects of HRT compared to placebo
on arterial distensibility and arterial compliance found no significant differences in these
stiffness measures between HRT users and non-users.
43

METHODS
Study Design
ELITE was a randomized, double-blinded, placebo-controlled trial conducted at the
Atherosclerosis Research Unit, University of Southern California. To test the hormone
timing hypothesis, recruitment was stratified according to time since menopause [6 years
or less (early post-menopause) or  10 years (late post-menopause)]. Additional
randomization stratification factors were hysterectomy status (yes or no) and baseline
CIMT (<0.75 mm or  0.75 mm). When started, the trial was planned for a 5-year period
(3 year recruitment and 2-5 year randomized treatment) and recruitment was based on
this timeline. The trial was extended to an additional 2.5 years of randomized intervention.

Inclusion Criteria
To be included in the study, participants had to be healthy post-menopausal
women without pre-existing diabetes or any clinical signs of CVD with a serum estradiol
level less than 25 pg/mL, and cessation of regular menses for at least 6 months in women

11
in the early post-menopause stratum or for 10 or more years in women in the late post-
menopause stratum.

Exclusion Criteria
Women were excluded from the study for the following reasons; if the time since
menopause could not be assessed, diagnosis of diabetes mellitus or fasting serum
glucose level higher than 140 mg/dL, serum creatinine level higher than 2.0 mg/dL, fasting
plasma triglyceride level higher than 500 mg/dL, uncontrolled hypertension (systolic blood
pressure/diastolic blood pressure > 160/110 mm Hg), any life threatening disease with a
prognosis of less than 5 years, untreated thyroid disease, a history of deep vein
thrombosis, pulmonary embolism, or breast cancer, and current MHT (within 1 month of
screening).

Randomization and Treatment
The women were randomized using stratified blocked randomization in a 1:1 ratio
to receive either active hormone therapy or placebo. Women with an intact uterus were
given either oral micronized 17-  estradiol 1 mg/day with 4% vaginal micronized
progesterone gel 45 mg/day for 10 days each month or a double matched placebo.
Women without a uterus were given either 17-  estradiol 1 mg/day alone or placebo.
Randomization was carried out according to the randomization list prepared before the
trial began. The study product given to each participant was prepared according to each
of the 8 strata which based on time since menopause, hysterectomy status, and baseline

12
CIMT. All study personnel including the investigator, participant, and data monitors were
blinded to the treatment assignment.

Assessment of Outcome and Baseline Measures
Primary outcome
This study focused on the assessment of subclinical atherosclerosis progression
assessed by carotid artery stiffness (CAS) measures. The primary outcome was the rate
of change in CAS measured as arterial distensibility, arterial compliance and total percent
dilation of the right distal common carotid artery. Carotid artery lumen diameter measures
at systole and diastole and systolic and diastolic blood pressure measurements were
used to calculate the CAS measures. The following equations were used to calculate
CAS.
Arterial distensibility = [[2(DS – DD)/DD]/PP] *7.6*1000*10
-6
N
-1
m
2

Arterial compliance = [(𝐷 𝑆
2
- 𝐷 𝐷
2
)/PP] *7.6 mm
2
/kPa
Percent dilation = (DS – DD)/DD *100
DS and DD represent the carotid artery lumen measures at systole and diastole and PP
represents the pulse pressure which is the difference between the systolic and diastolic
pressure. CAS was measured at the right distal common carotid artery using high
resolution B-mode ultrasonograms. These measurements were taken from carotid artery
ultrasounds obtained twice at baseline (at screening and at randomization visits) and then
every 6 months in the post randomization follow-up period. The measurements were
taken using technology specifically developed for longitudinal measurements of

13
atherosclerosis. Coefficients of variation using the two baseline ultrasound
measurements were 12.85% for arterial distensibility and 12.23% for arterial compliance.

Baseline measures
Blood pressure, pulse rate, and weight were measured at baseline and then at
each follow-up visit. Height was measured at baseline and hip and waist circumference
were measured every 6 months. Questionnaires were administered every 6 months to
obtain information about medical history, angina, claudication, physical activity, smoking
and alcohol use. Reproductive history was also obtained at baseline. All baseline
measurements were conducted before randomization. Cholesterol and triglyceride levels
were measured every 6 months using fasting blood samples.

Statistical Analyses
All participants who had carotid artery lumen diameter measurements at systole
and diastole were included in the analyses. A total of 220 participants were included in
the final analyses. Descriptive analysis for all baseline characteristics included frequency
and distribution of categorical variables using simple frequency tables and for continuous
variables, median and the interquartile range (IQR) was calculated. These results were
reported by time since menopause strata and by randomized treatment group.
Overall, we compared study groups (estradiol and placebo) within each time since
menopause strata (<6 and 10 years) for rate of change in CAS measurements. Mixed
effect models were used to evaluate this change. Dependent variable was CAS measured
at each trial timepoint. Independent variables were a continuous variable for time of

14
assessment (measured in years since randomization), and indicator variables for
randomized group, time since menopause stratum, and the randomization stratification
factors (hysterectomy status and baseline CIMT). Participant-level random effects for the
model intercept (mean CAS at randomization) and slope (annual rate of change in CAS)
were specified. The overall difference in the CAS measures between the strata (early and
late post-menopause) was estimated using a two-way interaction between years in the
study and the stratum variable. We also estimated the difference in the rate of change in
CAS measures between each study group (estradiol and placebo) using a two-way
interaction between years in the study and the treatment assignment variable. A three-
way interaction of years in study, stratum variable and treatment assignment was used to
test whether the effect of MHT on rate of change in CAS differed in early vs. late post-
menopause.

RESULTS

Of the 220 women in our study, 200 were in the early post menopause stratum
and 20 were in the late post-menopause stratum. In the early post menopause stratum
98 women were randomly assigned to receive placebo and 102 women were randomly
assigned to receive estradiol. In the late post menopause stratum 13 women were
randomly assigned to receive placebo and 7 women were randomly assigned to receive
estradiol. Baseline characteristics of participants are shown in Table 1. The median age
at randomization in the early post menopause stratum was 55.4 years and 63.1 years in
the late post-menopause stratum. Median time since menopause in the early post-
menopause stratum was 3.5 years and in the late post menopause stratum was 14 years.

15
Majority of women in both strata were non-Hispanic white (66% in early and 85% in late
post menopause stratum) followed by Hispanics (14.5% in early and 10% in late post
menopause stratum), Asians (12% in early and 5% in late post-menopause stratum) and
Blacks (7.5% in early and 0% in late post-menopause stratum). Median systolic blood
pressure in the early post-menopause stratum was 115.7 mmHg and 116.4 mmHg in the
late post-menopause stratum. Median diastolic blood pressure in the early post
menopause stratum was 76 mm Hg and 75 mm Hg in the late post-menopause stratum.

Carotid Artery Stiffness measures
Stiffness measurements used in our analysis are for three years of treatment with
either oral estradiol or placebo. The rate of change in the CAS measures for all
participants is shown in Table 2. We also carried out this analysis restricting our dataset
to women in only the early post-menopause group (Table 3). We did this because the
majority of our sample was from the early post-menopause stratum. We studied the rates
of change in arterial distensibility, arterial compliance and percent dilation of the right
carotid artery.

Rate of change in arterial distensibility
Women in the early post-menopause stratum who were randomly assigned to the
estradiol group showed a greater decrease in arterial distensibility -0.4043/year (95% CI=
-0.7848 – -0.0237) as compared to the women in the placebo group -0.1237/year (95%
CI= -0.5170 – 0.2696). However, this result was not statistically significant (p=0.31). In

16
the late post-menopause stratum, arterial distensibility increased in the estradiol group
0.0422/year (95% CI= -1.4627 – 1.5470) and decreased in the placebo group -
0.0759/year (95% CI= -1.1286 – 0.9769). The difference between groups was also not
statistically significant (p=0.90).

Rate of change in arterial compliance
In the early post-menopause stratum, women assigned to receive estradiol
showed a decrease in arterial compliance -0.0214/year (95% CI= -0.0391 – -0.0037) and
those assigned to receive placebo had a slight increase in arterial compliance
0.0003/year (95% CI= -0.0180 – 0.0186). Similarly in the late post menopause stratum,
those who received placebo showed a greater increase in arterial compliance 0.0057/year
(95% CI= -0.0432 – 0.0545) as compared to those who received estradiol 0.0020/year
(95% CI= -0.0680 – 0.0721). The treatment group differences were not statistically
significant in either post-menopause stratum.

Rate of change in percent dilation
In the early post-menopause stratum, participants in both treatment arms showed
a decrease in percent dilation of the carotid artery. Those in the estradiol group had a
greater decrease -0.1056/year (95% CI= -0.2037 – -0.0074) as compared to those in the
placebo group -0.0208/year (95% CI= -0.1222 – 0.0806). In the late menopause stratum,
both treatment groups showed an increase in percent dilation. However, this increase
was greater in the placebo group 0.1036/year (95% CI=-0.1681 – 0.3753) as compared

17
to the estradiol group 0.0082/year (95% CI= -0.3794 – 0.3958). None of these results
reached statistical significance.

Participants in the early post-menopause stratum only
When we restricted our analyses to women in the early post-menopause stratum,
the rate of change in CAS measures was similar to the analysis with all participants.
Women who were randomly assigned to the active arm of the study (estradiol group)
showed a greater decrease in arterial distensibility, arterial compliance, and percent
dilation of the carotid artery as compared to the women who received placebo. The
treatment group differences were not significant (all p>0.05, Table 3).

Change in CAS measures from baseline to one year
Table 4 shows the change in CAS measures in women who received estradiol
compared to women who were on placebo from baseline to one year. There was a
decrease in arterial distensibility, arterial compliance, and percent dilation after one year
from baseline in both treatment groups. There was a greater decrease in arterial
distensibility in women on placebo as compared to estradiol. For arterial compliance and
percent dilation, a greater decrease was observed in women who received estradiol as
compared to placebo. None of these results were significant (all p>0.05).

DISCUSSION
In this study we assessed subclinical atherosclerosis progression using carotid
artery stiffness measurements, including arterial distensibility, arterial compliance and

18
total percent dilation of the carotid artery in healthy post-menopausal women. This
analysis was based on 220 healthy post-menopausal women who were randomized to
receive either oral estradiol or placebo. No significant differences in arterial stiffness
measurements were evident between estradiol and placebo groups in either
postmenopausal stratum. Measurements in this analysis are for three years of
randomized treatment.
These results differ from the primary analysis of this trial where estradiol had a
significant beneficial effect on CIMT as compared to placebo in women in the early
postmenopausal stratum.
37
CIMT is an anatomic parameter that was measured
longitudinally to assess atherosclerosis progression by measuring thickness of the carotid
artery. Arterial stiffness measurements on the other hand are physiological
measurements that assess the degree to which the artery expands and contracts.
Normally with age, major arteries of the body become stiffer. This is due to the changes
in the physical structure and composition of the arterial wall such as collagen and
elastin.
44

Previous observational studies have shown a positive effect of HRT on arterial
stiffness and a cross sectional found no difference in the arterial stiffness of HRT users
compared to non-users. Miura et al studied the effects of HRT on arterial compliance in
normotensive post-menopausal women by assessing the differences in pulse wave
velocity (PWV) between women taking HRT compared to those who did not.
45
These
women were prescribed HRT for several months to 6 years. PWV was used to determine
changes in arterial stiffness. With increase in arterial stiffness, the value for PWV also
increases. In this study, PWV values were significantly lower for women on HRT

19
compared to those not taking HRT. However, this was a small non-randomized study with
56 postmenopausal women of whom 27 were on HRT and were age-matched to 29
women not on HRT.
In a similar study, Rajkumar, et al. assessed systemic arterial compliance (SAC)
and PWV in healthy pre-menopausal and post-menopausal women.
46
Among the
postmenopausal women, differences in SAC and PWV between women taking HRT and
women not taking HRT were observed. Postmenopausal women on HRT had significantly
higher SAC and significantly lower PWV than those not on HRT. Mean duration of therapy
in this study was 6.7  1 years. This was a small non-randomized study with 26
premenopausal and 52 postmenopausal women. Among the latter, 26 women were
taking HRT.
In another cross-sectional study, it was shown that there was no difference in PWV
measurements in healthy postmenopausal women between HRT users and non-users.
47

Users were on HRT for about 6.8  0.9 years. This study also looked at a very small
sample of 36 women, 18 users and 16 non-users of HRT.
Our study had a much larger sample size of 220 women as compared to previous
studies. Hence, the non-significant results in our study are not likely due to insufficient
statistical power to detect true associations. Also, none of these studies were randomized
clinical trials unlike ELITE.
One explanation for our results could be that MHT may not have significant effects
on the physiological characteristics (arterial stiffness measures) that determine
atherosclerosis progression. MHT did however, show significant positive effects on the

20
anatomical characteristics of atherosclerosis progression like the CIMT measurements in
the primary analyses of this trial. The reason for this difference in not clear.
Another explanation may be related to the duration of treatment. The
measurements in this analysis were for three years of HRT. In previous observational
studies, duration of therapy was on average about 6 years. Perhaps longer duration of
treatment is required to be able to detect differences in arterial stiffness measures
between women taking MHT and women not taking HRT.

21
CONCLUSION
This clinical trial was specifically designed to test the timing hypothesis of effects
of MHT in healthy post-menopausal women in early and late post-menopausal strata (<6
years or 10 years). Treatment effects on arterial stiffness measures of oral 17-  estradiol
and progesterone in women with an intact uterus and only 17-  estradiol in women without
a uterus was compared to placebo. No significant differences were found in the annual
rate of change in arterial distensibility, arterial compliance and total percent dilation
between treatment groups in either postmenopausal stratum. Further research is needed
to establish whether these findings hold for longer durations of HRT.

22
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26
TABLES

Table 1: Baseline Demographic, Clinical, and Laboratory Characteristics

Early Post-menopause Late Post-menopause
Stratum Stratum
(N=200) (N=20)
Placebo Estradiol
(n=98) (n=102)
Placebo Estradiol
(n=13) (n=7)
Median time since menopause –yr
(IQR)
3.5
(1.9-5.0)
3.5
(1.9-5.2)
11.8
(11.1-14.3)
16.2
(11.4-18.1)
Median age at randomization –yr
(IQR)
55.4
(53.0-57.8)
55.3
(53.3-57.7)
61.9
(60.5-66.5)
64.3
(60.2-68.4)
Race/Ethnicity – n (%)
White, Non-Hispanic
Black, Non-Hispanic
Hispanic
Asian

59 (60.2)
10 (10.2)
16 (16.3)
13 (13.3)

73 (71.6)
5 (4.9)
13 (12.8)
11 (10.8)

11 (84.6)
0 (0.0)
2 (15.4)
0 (0.0)

6 (85.7)
0 (0.0)
0 (0.0)
1 (14.3)
Education – n (%)
Less than high school
High school or some college
College graduate

0 (0.0)
29(29.6)
69 (70.4)

1 (1.0)
20 (19.6)
81 (79.4)

0 (0.0)
5 (38.5)
8 (61.5)

0 (0.0)
4 (57.1)
3 (42.9)
Smoking history – n (%)
Current smoker
Former smoker
Never smoked

3 (3.1)
39 (39.8)
56 (57.1)

4 (3.9)
30 (29.4)
68 (66.7)

1 (7.7)
3 (23.1)
9 (69.2)

0 (0.0)
4 (57.1)
3 (42.9)
Antihypertension medications – n (%) 19 (19.4) 16 (15.7) 3 (23.1) 2 (28.6)
Cholesterol lowering medication – n
(%)
18 (18.4) 14 (13.7) 4 (30.8) 0 (0.0)
Type of Menopause – n (%)
Natural
Surgical

95 (96.9)
3 (3.1)

98 (96.1)
4 (3.9)

11 (84.6)
2 (15.4)

4 (57.1)
3 (42.9)
Median arterial distensibility - 20.09 21.74 14.96 18.82
10
-6
N
-1
m
2
(IQR) (16.93-25.26) (17.49-26.45) (11.92-21.11) (15.54-19.25)
Median arterial compliance- 1.01 1.11 0.76 0.79
mm
2
/kPa (IQR) (0.79-1.29) (0.86-1.26) (0.61-0.96) (0.66-0.97)
Median percent dilation (IQR) 5.96 6.25 5.86 5.01
(4.83-7.17) (5.21-7.35) (3.83-6.80) (4.53-6.24)
Median body-mass index (IQR) 26.0
(23.4-29.9)
26.1
(23.4-30.4)
26.8
(22.7-28.6)
25.3
(21.4-31.4)
Median blood pressure mm Hg –
(IQR)
Systolic

Diastolic

116.7
(106.3-125)

77 (71-81)

114.7
(106.7-122.7)

75 (70-80)

120.7
(118.7-135)

79 (69-80)

112
(107.3-121.3)

71 (68-78)
Median lipid levels – mg/dl 9IQR)
Cholesterol 221.3 (198-244) 225 (207-244) 221 (208-231.5) 216.5 (203.5-236)

Triglycerides 90.8 (76.5-131.5) 93.8 (65-115.5) 109 (65.166.5) 92 (73.5-128.5)

HDL cholesterol 62.8 (50.5-75) 64 (54-76.5) 64 (48.5-75) 52 (44.5-77.5)

LDL cholesterol 133.6 (117.8-159.1) 140 (119-161) 131.7 (106.5-139.7) 137.7 (118.6-172.3)
Estradiol level – pg/ml (IQR) 7.7 (5.6-10.1) 8.7 (6.4-13.2) 7.9 (6.5-11.1) 7.7 (4.1-11)
Previous hormone use – n (%) 48 (49.0) 50 (49.0) 9 (69.2) 7 (100.0)
Current hormone use requiring 1
month washout period – n (%)

5 (5.1)

8 (7.8)

2 (15.4)

1 (14.3)

27

Table 2: Carotid Artery Stiffness (CAS) measures (N=220)

*The P values and 95% CI are for the difference between placebo and estradiol within a
given post-menopause stratum

Measure and Post-menopause Placebo Estradiol
Stratum (N=111) (N=109)

P Value* (95% CI)

Annual rate of change in
arterial distensibility 10
-6
N
-1
m
2

Early post-menopause (n=200) -0.1237 (-0.5170 – 0.2696) -0.4043 (-0.7848 – -0.0237) 0.31 (-0.27 – 0.83)
Late post-menopause (n=20) -0.0759 (-1.1286 – 0.9769) 0.0422 (-1.4627 – 1.5470) 0.90 (-1.95 – 1.72)

Annual rate of change in
arterial compliance mm
2
/kPa

Early post-menopause (n=200) 0.0003 (-0.0180 – 0.0186) -0.0214 (-0.0391 – -0.0037) 0.09 (-0.003 – 0.05)
Late post-menopause (n=20) 0.0057 (-0.0432 – 0.0545) 0.0020 (-0.0680 – 0.0721) 0.93 (-0.08 – 0.09)

Annual rate of change in
percent dilation

Early post-menopause (n=200) -0.0208 (-0.1222 – 0.0806) -0.1056 (-0.2037 – -0.0074) 0.24 (-0.06 – 0.23)
Late post-menopause (n=20) 0.1036 (-0.1681 – 0.3753) 0.0082 (-0.3794 – 0.3958) 0.69 (-0.38 – 0.57)

28
Table 3: Carotid Artery Stiffness (CAS) measures in the early post-menopause strata
only (N=200)

Arterial Stiffness Measure

Placebo
(N= 98)

Estradiol
(N=102)

P Value* (95% CI)

Annual rate of change in -0.1239 (-0.5289 – 0.2810) -0.4041 (-0.7961 - -0.0122) 0.33 (-0.28 - 0.843)
arterial distensibility 10
-6
N
-1
m
2

Annual rate of change in 0.0003 (-0.0185 – 0.0191) -0.0214 (-0.0396 - -0.0032) 0.10 (-0.01 – 0.05)
arterial compliance mm
2
/kPa

Annual rate of change in -0.0208 (-0.1256 – 0.0841) -0.1056 (-0.2072 - -0.0041) 0.25(-0.06 – 0.23)
percent dilation

*The P values are for the difference between placebo and estradiol within a given post-
menopause stratum

29
Table 4: Change in CAS measures from baseline to one year by treatment groups
(measure at 12 month visit - measure at baseline) (N=220)

CAS Measure Placebo Estradiol P Value* (95%
CI)
(N=111) (N=109)

Change in arterial distensibility -0.5565 (-1.6184 – 0.5053) -0.3376 (-1.3836 – 0.7083) 0.77 (-1.27 – 1.71)
10
-6
N
-1
m
2

Change in arterial compliance -0.0221 (-0.0739 – 0.0297) -0.0354 (-0.0864 – 0.0156) 0.72 (-0..09 – 0.06)
mm
2
/kPa

Change in percent dilation -0.0201 (-0.2836 – 0.2434) -0.1050 (-0.3646 – 0.1545) 0.65 (-0.45 – 0.29)

*The P values are for the difference between both treatment groups

Abstract (if available)

Abstract Background: The incidence of cardiovascular disease (CVD) is higher in men as compared to women of the same age, but that gap narrows with increasing age and after menopause women approximate the male incidence of CVD. This led to the hypothesis that postmenopausal women are at a higher risk of CVD as compared to premenopausal women. It was noted in preclinical studies that hormone therapy started closer to menopause as opposed to starting treatment much later after menopause could be beneficial in reducing the risk of developing coronary disease. We tested this timing hypothesis in the Early Versus Late Intervention Trial with Estradiol (ELITE). The aim of our study was to examine the effects of menopausal hormone therapy (MHT) on the vascular health of healthy post-menopausal women, measured by carotid artery measures of distensibility and compliance. ❧ Methods: This study included a total of 220 healthy post-menopausal women without pre-existing diabetes or any clinical signs of CVD who were stratified according to time since menopause [6 years or less (early post-menopause) or ≥ = 10 years (late post-menopause)]. They were randomly assigned to receive either oral 17-β estradiol (1 mg/day with 4% vaginal progesterone gel [45 mg/day] for 10 days each month for women with a uterus) or a double matched placebo. Women without a uterus received either 17-β estradiol 1 mg/day alone or placebo. The primary outcome was the rate of change in carotid artery stiffness (CAS) measures, including arterial distensibility, arterial compliance, and total percent dilation. Mixed effect linear models were used to evaluate this change. ❧ Results: The effect of estradiol with or without progesterone on CAS measures did not significantly differ between the early and the late post menopause strata. While not statistically significant, women in the early post-menopause stratum who received estradiol showed a greater decrease in arterial distensibility as compared to women in the placebo group (p=0.31). In the late post-menopause stratum, arterial distensibility increased in the estradiol group and decreased in the placebo group (p=0.90). Arterial compliance decreased in women who received estradiol as compared to placebo in the early post menopause stratum (p=0.09) and in the late post menopause stratum, women on placebo showed a greater increase in arterial compliance as compared to women who received estradiol (p=0.93). Percent dilation of carotid artery decreased in both treatment groups in the early post menopause strata with women on estradiol showing a greater decrease as compared to placebo (p=0.24). In the late post menopause stratum, women on placebo showed a greater increase in percent dilation as compared to women in the estradiol group (p=0.69). ❧ Conclusion: No significant differences were found in the annual rate of change in the physiologic measures of arterial distensibility, arterial compliance and total percent dilation between treatment groups in either postmenopausal stratum. Given that the estradiol intervention in ELITE showed a highly significant benefit on early post menopause on anatomical measures of atherosclerosis, further research should address possible reasons for the discrepancy in these findings.

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Asset Metadata

Creator Bhalla, Kanika (author)

Core Title Effects of post-menopausal hormone therapy on arterial stiffness in the ELITE trial

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 04/22/2021

Defense Date 04/20/2021

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag arterial stiffness,estadiol,hormone therapy,OAI-PMH Harvest,post-menopause,randomized controlled trial,timing hypothesis

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Mack, Wendy (committee chair), Hodis, Howard (committee member), Karim, Roksana (committee member)

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