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Effect of menopausal hormone replacement therapy on lipoprotein particle fractions and association with carotid artery intima-media thickness and grey-scale median, independent measurements of su...

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Effect of Menopausal Hormone Replacement Therapy on
Lipoprotein Particle Fractions and Association with Carotid
Artery Intima-Media Thickness and Grey-Scale Median,
Independent Measurements of Subclinical Atherosclerosis

By
Stephanie S Kim

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 of
MASTER OF SCIENCE
BIOSTATISTICS
May 2020

Copyright 2020 Stephanie S Kim

ii
Table of Contents
Acknowledgements ................................................................................................................ iii
List of Tables ........................................................................................................................... iv
List of Figures ........................................................................................................................... v
Abstract .................................................................................................................................... vi
Introduction .............................................................................................................................. 1
Methods ..................................................................................................................................... 2
Trial Design ........................................................................................................................................ 2
Measurements .................................................................................................................................... 2
Atherosclerosis outcomes ............................................................................................................................. 2
LP subclasses ................................................................................................................................................. 3
Study Population ............................................................................................................................... 3
Trial Follow-up .................................................................................................................................. 3
Other data .......................................................................................................................................... 4
Statistical analysis.............................................................................................................................. 4
Results ....................................................................................................................................... 5
Baseline Characteristics of Participant Population ....................................................................... 5
Baseline Atherosclerosis-LP associations ........................................................................................ 8
Baseline Atherosclerosis-LP associations, by time since postmenopausal. ................... 9
LP measure associations with CIMT .......................................................................................................... 9
LP measure associations with GSM .......................................................................................................... 10
HT effects on LP measures ............................................................................................................. 11
HT effects on LP measures: Total sample ................................................................................................ 12
HT effects on LP measures: Effects by time since postmenopausal ...................................................... 15
Discussion................................................................................................................................ 19
Conclusion .............................................................................................................................. 22
References ............................................................................................................................... 23

iii
Acknowledgements
I would like to thank my advisor Dr. Wendy Mack for being a great mentor, allowing
me to join her research. In addition, thanks for always being supportive and helpful.
I would like to thank my committee members Dr. Howard Hodis and Dr. Roksana Karim for
their expertise and guidance
I would like to thank other professors who have helped me and my friends and
classmates who have always supported and encouraged me.
Lastly, I would like to thank my parents for all of their endless love and support.
Also, to my sister Sarah for always being there for me.

iv
List of Tables
Table 1. Baseline Demographic Characteristics ................................................................ 6
Table 2. Baseline Characteristics by Time since Menopause ............................................ 7
Table 3. Baseline association with IMT, GSM .................................................................. 8
Table 4. Baseline LP particle association with IMT, GSM ............................................... 9
Table 5. Baseline LP particle association with CIMT, by time since menopause ........... 10
Table 6. Baseline LP particle association with GSM, by time since menopause ............ 11
Table 7. HT effects on LP measures: on-trial total sample.............................................. 13
Table 8. HT effects on LP measures: on-trial early postmenopausal sample .................. 16
Table 9. HT effects on LP measures: on-trial late postmenopausal sample .................... 18

v
List of Figures
Figure a. LDL Peak Means over time by treatment group .................................................. 14
Figure b. Midzone Means over time by treatment group..................................................... 14
Figure c. HDL Large Means over time by treatment group ................................................ 14
Figure d. LDL Small Means over time by treatment group ................................................. 14
Figure e. LDL Medium and Small Means over time by treatment group ............................ 14
Figure f. LDL Medium Means over time by treatment group ............................................. 14
Figure g. IDL Small Means over time by treatment group .................................................. 15

vi
Abstract
Background
Results from ELITE and meta-analyses of randomized controlled trials suggest that
initiating oral estradiol therapy (HT) may reduce atherosclerosis progression and the risk of
cardiovascular disease in women who are younger than 60 years and/or within 10 years of
postmenopausal women (7-9). The HT timing hypothesis suggests that women respond to HT
differently depending on the timing of initiation of therapy relative to age and time since
menopause.
1
In this thesis, ELITE trial data and samples were used to:
1
evaluate the
association of LP particles with atherosclerosis in postmenopausal women at baseline (before
initiation of HT or placebo treatment) and;
2
to test the effects of estradiol therapy on
subclasses of LP particles and progression of subclinical atherosclerosis when estradiol was
initiated in relation to time since menopause.
Methods
ELITE was a single-center, randomized, double-blind, placebo-controlled clinical
trial of hormone therapy administered to women according to time since menopause. The
primary trial outcome was progression of subclinical atherosclerosis measured by carotid
artery intima-media thickness (CIMT). An additional measure of atherosclerosis, grey scale
median (GSM), was measured in the common carotid artery intima-media complex after the
trial was completed.
A total of 643 healthy post-menopausal women (271 in early postmenopausal, 372 in
late postmenopausal) were randomly assigned to oral 17β- estradiol (1 mg per day) or
placebo. The median (IQR) participant age for all participants was 60.0 (9.4) years, 55.4
(4.8) years for early postmenopausal women and 63.8 (7.5) years for late postmenopausal
women. Linear regression was used to analyze the association of log-transformed LP particle

vii
measures with atherosclerosis (CIMT and GSM) in ETLIE participants at baseline. Mixed
effects linear regression was used to evaluate the effects of estradiol therapy on subclasses of
LP particles by time since menopause strata.
Results
In the linear regression model, LDL particles (excluding LDL Large particles), were
associated with greater CIMT (thicker arterial wall) and lower GSM (greater arterial wall
lipid deposition) (p<0.05). Stratified (by time since menopause) linear regression model
states that CIMT is only significantly associated with early postmenopausal stratum, whereas
GSM shows significance association with both early and last postmenopausal strata (mostly
with LDL particles with p<0.05).
In the mixed effect linear regression model, among the 21 LP particles, 5 LDL
particles were statistically significantly had interaction between visit times and estradiol
treatment in total sample, There was a statistically significant interaction between treatment
group and visit number for LDL peak size (p=0.04), Midzone (p=0.01), LDL Medium and
Small (p=0.030, LDL Small (p=0.02), IDL Small (p=0.02), and HDL large (p=0.01) (Figures
a-g). In early menopause stratum, LDL Small (p=0.05) and LDL medium(p=0.01) have
significant difference between estradiol and placebo. The effect of HT on LP particle with
late menopause stratum had only Midzone particle significant interaction between visit time
and the estradiol treatment (p=0.04).
Conclusions
Although the LP particles are known correlates of atherosclerosis, not all LP particles
are atherogenic. The association with atherosclerosis components (wall thickness vs. lipid
deposition) with LP particles is differential. The hormone replacement therapy on LP particle
fraction, HT was associated with changes in some LP particles. In addition, the majority of
these associations (both HT on LP fractions and association with carotid artery CIMT and

viii
GSM) were evident in early, but not in late postmenopausal women. Further research will be
needed to understand and determine clinical implication of LP particle fractions effect on
CVD among postmenopausal women using HT.

1
Introduction
It is well known that males face a greater risk of heart disease than women.
4

However, cardiovascular disease (CVD) remains the leading cause of death in the United
States, responsible for 840,768 deaths (635,260 cardiac) in 2016 for both men and women.
3

The risk of heart attack increases for men after age 45 whereas for women after age 55,
around the time of menopause.
5
Women have an increasing risk of developing CVD after
their menopause.
5
Therefore, the decline in the natural hormone estrogen may contribute to
heart disease risk among post-menopausal women.
Motivated by these statistics, research has focused on menopausal hormone
replacement therapy in relation to risk of heart disease in postmenopausal women.
Specifically, the hormone-timing hypothesis suggests that estrogen-containing hormone
therapy (HT) is associated with beneficial effects on cardiovascular disease when the therapy
is initiated temporally close to menopause, but not in later menopause.
Atherosclerosis is the underlying cause of heart attack and stroke.
6
Early
observations suggest that triglyceride-rich lipoproteins contribute to the pathogenesis of
atherosclerosis.
1
Lipoprotein (LP) particles are the circulating protein-lipid complex that
transport hydrophobic lipid molecules, such as triglyceride and cholesterol, in the
extracellular water of the body to all cells and tissues. In the Monitored Atherosclerosis
Regression Study (MARS), analysis of lipoprotein (LP) subclasses suggested that
triglyceride-rich lipoproteins contribute to the progression of coronary artery disease.
Subclasses of LP particles may contribute differently to atherosclerosis based on their
respective physical properties. According to the low-density lipoprotein (LDL) receptor
hypothesis, elevation of LDL-cholesterol will contribute to development of atherosclerosis,
whereas the high-density (HDL) LP particles are a biomarker of atherosclerosis protection.

2
We analyzed data from the Early vs. Late Intervention Trial with Estradiol (ELITE),
a double-blinded, placebo-controlled, randomized trial performed at the USC Atherosclerosis
Research Unit. Our aims were: (1) to investigate the association of LP particles with
atherosclerosis in postmenopausal women at baseline (prior to estradiol treatment), (2) and to
study the effects of HT on subclasses of LP particles and progression of subclinical
atherosclerosis according to time since menopause when HT was initiated.
Methods
Trial Design
ELITE (clinicaltrial.gov registration: NCT00114517) was a single-center,
randomized, double-blinded, placebo-controlled clinical trial of HT administered to women
according to time since menopause (6 years ≤ [early postmenopausal] or ≥10 years [late
postmenopausal]).
10
The trial was conducted from July 2005 to February 2013. ELITE was
designed to test the HT timing hypothesis. Healthy women in post menopause were randomly
assigned to receive either HT or placebo according to time since menopause strata using a 1:1
ratio of stratified blocked randomization. Healthy women with an intact uterus were
randomly assigned to oral 17𝛽 -estradiol (1 mg per day, plus progesterone [45mg] vaginal gel
administered sequentially) or matching placebos. Women without an intact uterus were given
oral 17𝛽 -estradiol or matching placebo. The trial was approved by the institutional review
board of the University of Southern California.
Measurements
Atherosclerosis outcomes
Carotid artery ultrasound to assess atherosclerosis was completed at baseline and
every 6 months. In this thesis, two measures of subclinical atherosclerosis were analyzed.

3
Carotid artery intima-media thickness (CIMT) was the primary ELITE outcome; ELITE
showed that CIMT progression was significantly lower in women randomized to HT
compared to placebo in the early, but not in the late postmenopausal stratum (1). A second
atherosclerosis measure was the grey-scale median (GSM) measured in the common carotid
artery intima-media complex. As the primary atherosclerosis outcome, thicker CIMT
indicates greater subclinical atherosclerosis. The secondary atherosclerosis outcome of GSM
was arterial wall lipid deposition measured as GSM; lower values of GSM reflect greater
arterial wall lipid deposition and thus greater subclinical atherosclerosis.
LP subclasses
Plasma and serum blood samples were obtained at baseline and every 6 months
during ELITE. Using stored samples, LP fractions were measured according to LP particle
diameter [nmol] in baseline and 5-year on-trial (3-year recruitment period and 2 to 5 years of
randomized treatment) blood samples.
10

Study Population
Participants were recruited from the general population. Inclusion criteria were
healthy postmenopausal women without clinical evidence of CVD. Exclusion criteria were
inability to determine time-since-menopause; fasting plasma triglyceride levels >500 mg/dL;
diabetes mellitus or fasting serum glucose levels >140 mg/dL; serum creatinine level >2.0
mg/L; uncontrolled hypertension; untreated thyroid disease; life threatening disease with
prognosis of <5 years; a history of deep vein thrombosis, pulmonary embolism, or breast
cancer; and current use of menopausal HT within 1 month of screening.
Trial Follow-up
After randomization, participants were scheduled to complete a clinic trial visit every
month for the first 6 months and every other month until trial completion. During the fifth

4
year of follow up the trial was extended by 2.5 years with supplement funding for the NIH.
The median duration of follow-up was 4.8 years (range, 0.5 to 6.7 years).
Other data
Following clinical assessment at baseline prior to randomization, blood pressure and
weight were determined at each visit. Waist and hip circumference were obtained every
6months and height was obtained at baseline. Questionnaires covering medical history,
physical activity and smoking were administered every 6 months. Participants completed 3-
day dietary booklets (Nutrition Scientific) prior to the baseline visit and prior to each
subsequent clinic visit.
10

Statistical analysis
Baseline characteristics were reported as median (IQR) for continuous variables,
including age and LP particles. Categorical variables were reported as frequency (percent).
We used linear regression to analyze the baseline cross-sectional association of LP
particles (independent variables) with CIMT and GSM (dependent variables). Some variables
were log transformed to normalize the distributions. We next evaluated these baseline cross-
sectional associations of LP particles with atherosclerosis measures by time since menopause.
The analysis was performed separately for women in early vs late post-menopause.
Significance was set at two-sided p<0.05 for analysis.
On-trial changes in LP subclasses were compared between HT and placebo groups.
In order to compare mean changes and associations across measures, we generated
standardized Z scores for each of the 21 LP variables. The LP measures were standardized
using the baseline means and standard deviations from all participants contributing baseline
LP measures. The longitudinal LP data were analyzed with linear mixed effects models to
examine the HT treatment effect on LP subclasses. Dependent variables in these models

5
were the change from baseline of the LP particles. Independent variables were randomized
treatment (estradiol vs placebo) and visit number (trial month) at which the LP measures
were obtained. The mixed model used restricted maximum likelihood method for estimation
and specified a random intercept at the participant level. Least square means were computed
to summarize the mean changes by treatment group. Analyses were conducted in two
approaches: (1) adding an interaction of treatment-by-time, which provided treatment group
comparisons at each on-trial visit; and (2) main effects for treatment and visit, where the
treatment effect was estimated and tested as an average over on-trial visits. The significance
was set at two-sided p-value <0.05. All analyses used Statistical Analysis System software
(SAS institute, Inc., Cary, North Carolina).
Results
Baseline Characteristics of Participant Population

There was a total of 643 randomized participants (271 in early postmenopausal, 372
in late postmenopausal The median (IQR) participant age for all participants was 60.0 (9.4)
years (Table 1), 55.4 (4.8) years for late postmenopausal women and 63.8 (7.5) years for late
post- postmenopausal women (Table 2). The race/ethnicity distributions 68.4% of
participants were White, 9.3% were Black, 14.0% were Hispanic and 8.24% were Asian. The
median baseline level of
Systolic Blood Pressure and Diastolic Blood Pressure (117.3mmHg and 74.7mmHg),
indicating participants were on average normotensive.

6
Table 1. Baseline Demographic Characteristics (n=643 randomized)
Characteristics n Demographic
Age 643 60.0 (9.4)
Race or ethnicity 643
White,non-Hispanic 440 (68.4%)
Black, non-Hispanic 60 (9.3%)
Hispanic 90 (14%)
Asian 53 (8.2%)
Native American -
Other -
Smoking history 643
Current 22 (3.4%)
Former 236 (36.7%)
Never 385 (59.9%)
Family history of CVD 643
Yes 106 (16.49%)
No 537 (83.51%)
Diastolic Blood Pressure (mmHg) 643 74.7 (10.0)
Systolic Blood Pressure (mmHg) 643 117.3 (16.7)
BMI (Kg/𝑀 2
) 643 26.5 (7.2)
Weight (lbs.) 643 152.6 (41.3)
Total cholesterol (mg/dl) 643 222.5 (44.0)
HDL cholesterol (mg/dl) 643 63.5 (23.5)
LDL cholesterol (mg/dl) 643 134.0 (42.4)
Triglycerides (mg/dl) 643 91.5 (59.0)
Weekly hours in moderate activity 3-6 MET 643 4.0 (6.0)
Weekly total MET-hours 641 240.0 (20.0)
Carotid Intima-media thickness, mm 643 0.75 (0.13)
GSM 640 57.1 (15.8)
LDL Peak Size (1 angstrom = 0.1 nm) 640 221.1 (6.8)
HDL Particle Number 639 26147.0 (5017)
Non-HDL Particle Number 639 1525.0 (418.0)
Total LDL (nmol/L) 639 1133.0 (337.0)
HDL Small (nmol/L) 639 19924.0 (3774)
HDL Large (nmol/L) 639 5839.0 (2089)
MIDZONE (Range between HDL-LDL) 639 519.0 (197.0)
LDL Very Small a (nmol/L) 639 60.0 (29.0)
LDL Very Small b (nmol/L) 639 66.0 (26.0)
LDL Very Small c (nmol/L) 639 74.0 (27.0)
LDL Very Small d (nmol/L) 639 65.0 (23.0)
LDL Small (nmol/L) 639 153.0 (88.0)
LDL Medium (nmol/L) 639 228.0 (106.0)
LDL Medium and Small (nmol/L) 639 387.0 (187.0)
LDL Large a (nmol/L) 639 252.0 (121.0)
LDL Large b (nmol/L) 639 171.0 (74.0)
IDL Small (nmol/L) 639 157.0 (60.0)
IDL Large (nmol/L) 639 136.0 (50)
VLDL Small (nmol/L) 639 53.0 (23.0)
VLDL Medium (nmol/L) 639 36.0 (24.0)
VLDL Large (nmol/L) 639 9.0 (9)
1 Number in table are median (IQR) for continuous variable
2 Number in table are frequency (%) for categorical variable

7
Table 2. Baseline Characteristics by Time since Menopause
Characteristics n Early
Postmenopausal
n Late
Postmenopausal
Age 271 55.4 (4.8) 372 63.8 (7.5)
Diastolic Blood Pressure (mmHg) 271 75.6 (10.0) 372 74.0 (9.7)
Systolic Blood Pressure (mmHg) 271 116.7 (18.0) 372 118.3 (15.6)
BMI (Kg/𝑀 2
) 271 26.2 (7.1) 372 26.7 (7.3)
Weight (lbs.) 271 157.1 (41.2) 372 149.3 (41.5)
Total cholesterol (mg/dl) 271 223.5 (45.0) 372 221.0 (43.2)
HDL cholesterol (mg/dl) 270 26054.0 (4752) 369 26155.0 (5245)
LDL cholesterol (mg/dl) 270 388.0 (188.0) 369 387.0 (183.0)
Triglycerides (mg/dl) 271 91.5 (56.0) 372 92.3 (60.3)
Carotid Intima-media thickness(mm) 271 0.73 (0.12) 372 0.76 (0.01)
GSM AVG 271 58.8 (15.9) 369 55.8 (16.1)
LDL Peak Size (1 angstrom = 0.1 nm) 270 221.1 (6.8) 369 221.1 (6.8)
HDL Particle Number 270 26054.0 (4752) 369 26155.0 (5245)
Non-HDL Particle Number 270 1541 (391.0) 369 1514.0 (444.0)
Total LDL (nmol/L) 270 1148.0 (321.0) 369 1116.0 (359.0)
HDL Small (nmol/L) 270 20055.5 (3931) 369 19886.0 (3697)
HDL Large (nmol/L) 270 5774.5 (1645) 369 5999.0 (2251)
MIDZONE (Range between HDL-LDL) 270 579.5 (189.0) 369 601.0 (204.0)
LDL Very Small a (nmol/L) 270 59.0 (58.0) 369 61.0 (31.0)
LDL Very Small b (nmol/L) 270 65.0 (24.0) 369 69.0 (30.0)
LDL Very Small c (nmol/L) 270 72.0 (26.0) 369 74.0 (28.0)
LDL Very Small d (nmol/L) 270 66.0 (156.0) 369 65.0 (22.0)
LDL Small (nmol/L) 270 149.0 (96.0) 369 154.0 (81.0)
LDL Medium (nmol/L) 270 232.0 (107.0) 369 224.0 (106.0)
LDL Medium and Small (nmol/L) 270 388.0 (188.0) 369 387.0 (183.0)
LDL Large a (nmol/L) 270 256.0 (120.0) 369 247.0 (121.0)
LDL Large b (nmol/L) 270 173.5 (74.0) 369 168.0 (71.0)
IDL Small (nmol/L) 270 158.0 (62.0) 369 156.0 (58.0)
IDL Large (nmol/L) 270 138.0 (50) 369 129.0 (50.0)
VLDL Small (nmol/L) 270 55.0 (23.0) 369 52.0 (24.0)
VLDL Medium (nmol/L) 270 36.5 (25.0) 369 35.0 (23.0)
VLDL Large (nmol/L) 270 9.0 (9.0) 369 9.0 (8.0)
1 Number in table are median (IQR) for continuous variable
2 Number in table are frequency (%) for categorical variable

8
Baseline Atherosclerosis-LP associations
Table 3. Baseline association with IMT, GSM
Characteristics CIMT GSM
𝛽 (SE) P 𝛽 (SE) P
Race or ethnicity
White,non-Hispanic Ref 0.002 Ref 0.001
Black, non-Hispanic 43.3(14.4) -4226 (1718)
Hispanic -21.5 (12.1) -4946 (1444)
Asian -14.8(15.2) 391 (183)
Smoking history
Never Ref 0.25 Ref 0.58
Current -16.6 (23.1) 1787(2766)
Former 12.0 (8.70) -757 (1044.6)
Family history of CVD n (%)
Yes Ref 0.70 Ref 0.18
No 4.41 (11.2) -1783(1340)
Weight, lbs. 0.43(0.13) 0.001 -137(14.8) <0.001
Diastolic Blood Pressure (mmHg) 1.49 (0.59) 0.01 -297 (70) <0.001
Systolic Blood Pressure (mmHg) 2.61 (0.32) <0.001 -211 (39.7) <0.001
BMI (Kg/𝑀 2
) 2.72 (0.76) <0.001 -907 (85.0) <0.001
# weekly hours in moderate activity 3-6 MET -0.18 (0.58) 0.76 177 (70.1) 0.01
# weekly hours in vigorous activity >6MET) 6.22 (3.20) 0.05 938 (382) 0.01
weekly total MET-hours 0.03(0.20) 0.88 84.5(23.7) <0.001

We used CIMT and GSM as measures of subclinical atherosclerosis. The LP
measures were first log transformed and multiplied by 1000 for easier interpretation.
Table 4 shows the results from linear regression analyzing the cross-sectional
associations of demographic and LP measures with CIMT and GSM in the total sample at
baseline. Specifically, medium-sized LDL, small- and very small-sized (a and b) LDL were
statistically significantly associated with CIMT and GSM, with the directions indicating
positive associations with greater atherosclerosis. Large-sized LDL particles were not
associated with either CIMT or GSM Both small- and large-sized HDL were not significantly
associated with CIMT. However, there was a statistically significant positive association of
GSM with large-sized HDL (suggesting a beneficial association) and negative associations
with small-sized HDL (suggesting a detrimental association). Large- and medium-sized
VLDL were statistically significantly inversely associated with GSM (suggesting a

9
detrimental association) but were not significantly associated with CIMT. Small-sized VLDL
and IDL particles were not significantly associated with CIMT or GSM.
Table 4. Baseline LP particle association with IMT, GSM
Characteristics CIMT GSM
𝛽 (SE) P 𝛽 (SE) P
Total cholesterol (mg/dl) 0.17(0.12) 0.17 -29.8(14.8) 0.045
HDL cholesterol (mg/dl) -.50 (0.24) 0.03 135.5(27.9) <0.001
LDL cholesterol (mg/dl) 0.29(0.13) 0.03 -44.7(15.8) 0.005
Triglycerides (mg/dl) 0.10(0.08) 0.20 -51.8(8.9) <0.001
LDL Peak Size
∗
(1 angstrom = 0.1 nm ) -396.46 (166.34) 0.02 99304.3(19713.2) <0.001
HDL Particle Number 0.00014 (0.0011) 0.90 -0.10 (0.13) 0.46
Non-HDL Particle Number 0.017 (0.012) 0.15 -4.2(1.4) 0.003
Lipoprotein particle fractions
(µmol/L)

Total LDL 0.032 (0.016) 0.04 -6.4(1.9) <0.001
LDL Large a
∗
-5.6 (11.9) 0.63 2568.3 (1424.0) 0.07
LDL Large b 0.06 (0.08) 0.43 -5.9 (9.3) 0.52
LDL Medium
∗
28.3 (12.6) 0.02 -4403.0 (1510.1) 0.004
LDL Medium and Small
∗
32.7 (12.3) 0.008 -5822.7 (1473.5) <0.001
MIDZONE
∗
19.9 (17.3) 0.25 -6385.2 (2062.4) 0.002
LDL Small
∗
29.4 (10.5) 0.005 -5451.7 (1255.9) <0.001
LDL Very Small a
∗
27.8 (9.4) 0.003 -4943.2 (1123.6) <.0001
LDL Very Small b
∗
23.6 (10.6) 0.03 -4280.1 (1268.8) <0.001
LDL Very Small c
∗
20.4 (14.1) 0.15 -3125.2 (1694.6) 0.07
LDL Very Small d
∗
4.7 (15.6) 0.77 -3276.7 (1878.6) 0.08
IDL Large
∗
4.7 (14.3) 0.74 -2857.3 (1713.5) 0.10
IDL Small
∗
-6.9 (15.2) 065 2283.8 (1832.6) 0.21
VLDL Large
∗
-0.51 (5.9) 0.80 -1968.9 (699.0) 0.005
VLDL Medium
∗
0.004 (0.23) 0.99 -69.8 (27.0) 0.01
VLDL Small
∗
-0.19 (0.23) 0.42 -24.2 (27.9) 0.39
HDL Large
∗
-0.50 (16.6) 0.98 4683.5 (1988.5) 0.002
HDL Small
∗
6.28 (28.6) 0.82 -7544.4 (3427.1) 0.03
(*) variable was log transformed.

Baseline Atherosclerosis-LP associations, by time since postmenopausal.

Tables 5 and 6 show results from linear regression analyzing cross-sectional
associations of LP particles with CIMT and GSM based on each time since postmenopausal
stratum.
LP measure associations with CIMT
For linear regression analysis of LP associations with CIMT (Table 5), LDL particles
and non-HDL particle number, were associated with higher levels of CIMT (higher

10
atherosclerosis) in the early postmenopausal stratum. Specifically, total LDL, LDL very small
a, b, c, small-sized LDL, medium-sized LDL and medium- and small-sized LDL were
statistically significantly associated with CIMT, with the direction indicating a positive
association with greater atherosclerosis. Other LP particles were not significantly associated
with CIMT in the early postmenopausal stratum. There were no statistically significant
associations of LP measures with CIMT in the late postmenopausal stratum.
Table 5. Baseline LP particle association with CIMT, by time since menopause
Characteristics Early Late
𝛽 (SE) P 𝛽 (SE) P
Total cholesterol (mg/dl) -49.77(22.32) 0.03 -16.14(19.68) 0.41
HDL cholesterol (mg/dl) -0.90(0.36) 0.01 -0.42(0.31) 0.17
LDL cholesterol (mg/dl) 0.35(0.18) 0.06 0.34(0.18) 0.07
Triglycerides (mg/dl) 0.23(0.11) 0.03 0.048(0.048) 0.95
LDL Peak Size
∗
(1 angstrom = 0.1 nm ) -3.18(1.08) 0.004 -0.78(1.03) 0.45
HDL Particle Number -0.00056(0.0016) 0.73 0.00023(0.0014) 0.87
Non-HDL Particle Number 0.041 (0.017) 0.02 0.0036 (0.016) 0.82
Lipoprotein particle fractions (µmol/L)
Total LDL 0.067 (0.02) 0.003 0.0096 (0.021) 0.64
LDL Large a
∗
-10.8 (17.0) 0.53 1.1 (15.9) 0.94
LDL Large b 0.20 (0.11) 0.07 -0.011 (0.1) 0.91
LDL Medium
∗
56.5 (17.6) 0.002 10.5 (17.0) 0.54
LDL Medium and Small
∗
59.0 (17.0) <0.001 13.2 (16.9) 0.43
MIDZONE
∗
3.0 (25.3) 0.91 21.8 (22.9) 0.34
LDL Small
∗
46.9 (14.4) 0.001 14.0 (14.5) 0.34
LDL Very Small a
∗
36.5 (13.2) 0.006 17.3 (12.8) 0.18
LDL Very Small b
∗
32.7 (15.2) 0.03 11.7 (14.2) 0.41
LDL Very Small c
∗
40.3 (19.7) 0.04 2.7 (19.2) 0.89
LDL Very Small d
∗
20.6 (22.2) 0.35 -4.8 (21.1) 0.82
IDL Large
∗
35.1 (20.3) 0.09 -7.4 (19.3) 0.70
IDL Small
∗
-9.4 (21.9) 0.67 0.055 (20.4) 0.99
VLDL Large
∗
8.0 (8.5) 0.35 -6.2 (7.8) 0.43
VLDL Medium
∗
0.40 (0.32) 0.21 -0.19 (0.31) 0.55
VLDL Small
∗
0.0003 (0.32) 0.99 -0.18 (0.32) 0.57
HDL Large
∗
-42.9 (25.0) 0.09 8.5 (21.8) 0.70
HDL Small
∗
7.8 (40.9) 0.85 6.0 (38.3) 0.88
(*) variable was log transformed.

LP measure associations with GSM
Table 6 displays the results of the linear regression analyses for LP associations with
GSM in early and late postmenopausal women. In the early postmenopausal stratum, many of
the LP particles were statistically significantly associated with GSM, with an indication of
negative associations (higher atherosclerosis). However, large-sized HDL, Very Small b-, c-,

11
d- sized LDL, large a -sized LDL, Small-sized IDL and small-sized VLDL were not statistically
significantly associated with GSM. In the late postmenopausal stratum, large a-and very small
b- sized LDL had statistically significant negative associations with GSM (in the direction of
higher atherosclerosis). Most LP particles were negatively associated with GSM in both early
and late postmenopausal strata. Only large-sized HDL and large-sized LDL a particle had
positive associations with GSM in the early postmenopausal stratum.
Table 6. Baseline LP particle association with GSM, by time since menopause
Characteristics Early Late
𝛽 (SE) P 𝛽 (SE) P
Total cholesterol (mg/dl) -49.77(22.32) 0.03 -16.14(19.68) 0.41
HDL cholesterol (mg/dl) 2006.60(46.14) <0.001 1094.61(34.87) 0.002
LDL cholesterol (mg/dl) -70.19(23.46) 0.003 -30.47(21.25) 0.15
Triglycerides (mg/dl) -63.47 (13.69) <0.001 -42.91 (11.54) <0.001
LDL Peak Size
∗
(1 angstrom = 0.1 nm ) 485.70(142.40) <0.001 429.68(116.31) <0.001
HDL Particle Number -0.091(0.21) 0.67 -0.0.081(0.16) 0.62
Non-HDL Particle Number -8.0(2.2) <0.001 -1.9 (1.8) 0.31
Lipoprotein particle fractions (µmol/L)
Total LDL -11.1 (2.9) <0.001 -3.3 (2.4) 0.16
LDL Large a
∗
542.0 (2249.0) 0.81 3727.5 (1830.3) 0.04
LDL Large b -34.8 (14.8) 0.02 9.71 (11.68) 0.35
LDL Medium
∗
-8854.1 (2303.7) <0.001 -1437.8(1973.4) 0.47
LDL Medium and Small
∗
-983.6 (2218.5) <0.001 -3358.6 (1949.1) 0.09
MIDZONE
∗
-7162.8 (3308.5) 0.03 -5394.9 (2638.4) 0.04
LDL Small
∗
-7192.1 (1889.2) <0.001 -4014.1 (1669.9) 0.02
LDL Very Small a
∗
-4948. (1744.5) 0.005 -4690.9(1468.5) <0.001
LDL Very Small b
∗
-3189.8 (2018.6) 0.12 -4660.4 (1632.6) 0.005
LDL Very Small c
∗
-3424.5(2606.4) 0.19 -2712.7 (2221.6) 0.22
LDL Very Small d
∗
-5273.3(2911.4) 0.07 -2005.9 (2445.0) 0.41
IDL Large
∗
-8252.9(2648.1) <0.001 243.7 (2228.9) 0.91
IDL Small
∗
-192.0 (2885.1) 0.95 3637.8 (2362.6) 0.12
VLDL Large
∗
-3352.7 (1104.3) 0.003 -1178.9(896.8) 0.19
VLDL Medium
∗
-117.1 (41.2) <0.001 -42.0 (35.5) 0.24
VLDL Small
∗
-72.6 (41.8) 0.08 4.1 (37.4) 0.91
HDL Large
∗
8797.0(3271.7) 0.008 3403.5 (2517.7) 0.17
HDL Small
∗
-10309.9 (5361.0) 0.05 -5734.6 (4433.3) 0.20
(*) variable was log transformed.
HT effects on LP measures
Tables 7. 8 and 9 show the analysis of HT effects compared to placebo on the LP
particles. Mean treatment group differences are summarized as HT mean subtracted by placebo
mean); positive differences indicate the HT mean is higher than the placebo group mean.

12
HT effects on LP measures: Total sample
Table 7 shows the results for the treatment effect of HT compared to placebo on the
LP measures completed in the total ELITE sample. There was a statistically significant
interaction between treatment group and visit number for LDL peak size (p=0.04), midzone
(p=0.01), medium and small sized LDL (p=0.030), Small-sized LDL (p=0.02), small-sized IDL
(p=0.02), and Large-sized LDL (p=0.01). (Figures a-g). The figure depicts the LP particles
mean over time by each treatment groups (visit number). These indicated that beneficial HT
treatment effect occurred on LDL peak size and small-sized IDL particle (lower value on trial
level vs placebo, figure a,g). Moreover, HT effect had large-sized HDL level relative to placebo,
indicating beneficial HT effect (figure c). The LP particles of smaller diameter showed higher
mean levels in the estradiol compared to placebo group, whereas the LP particles of larger
diameter (large a-sized LDL) showed higher mean levels in placebo compared to estradiol
group. This result was reflected on the significant estradiol effect on LDL peak size because
LDL peak size are the particles where the most LDL particles are clustered.

13
Table 7. HT effects on LP measures: on-trial total sample

Hormone
Therapy

Placebo Group Comparison
(HT-Placebo)

N1, N2
1
LS Means
(SE)
LS Means
(SE)
Means on trial
Difference
(95% CI)
p
2

Total LDL 565,4989 0.16
(0.054)
0.063
(0.053)
0.098
(-0.050,0.25)
0.19
LDL Peak Size 565,4989 -0.13
(0.052)
0.016
(0.052)
-0.15
(-0.29, -0.006)
0.04
HDL Particle Number 565,4989 0.14
(0.05)
0.074
(0.051)
0.062
(-0.079,0.20)
0.39
LDL Large a 565,4989 0.0094
(0.054)
0.066
(0.054)
-0.057
(-0.20,0.091)
0.45
LDL Large b 565,4989 0.10
(0.054)
0.051
(0.054)
0.051
(-0.097,0.20)
0.50
LDL_Medium 565,4989 0.19
(0.055)
0.049
(0.055)
0.14
(-0.007,0.30)
0.06
LDL Medium and Small 565,4989 0.21
(0.056)
0.04
(0.055)
0.17
(0.018,3.32)
0.03
Midzone 565,4989 0.11
(0.050)
-0.081
(0.050)
0.19
(0.052,0.33)
0.01
LDL Small 565,4989 0.19
(0.054)
0.020
(0.053)
0.17
(0.024,0.32)
0.02
LDL Very Small a 565,4989 0.12
(0.052)
0.046
(0.052)
0.077
(0.067,0.22)
0.29
LDL Very Small b 565,4989 0.042
(0.047)
0.031
(0.047)
0.010
(-0.11,0.13)
0.87
LDL Very Small c 565,4989 0.00006
(0.069)
-0.026
(0.050)
0.026
(-0.11,0.16)
0.70
LDL Very Small d 565,4989 -0.048
(0.0049)
-0.063
(0.048)
0.015
(-0.12,0.15)
0.83
IDL Large 565,4989 -0.21
(0.053)
-0.18
(0.053)
-0.033
(-0.18,0.11)
0.65
IDL Small 565,4989 -0.008
(0.055)
0.17
(0.055)
-0.18
(-0.33,-0.032)
0.02
VLDL Large 565,4989 -0.037
(0.051)
-0.072
(0.05)
0.034
(-0.11,0.17)
0.63
VLDL Medium 565,4989 -0.15
(0.052)
-0.13
(0.052)
-0.025
(-0.17,0.12)
0.73
VLDL Small 565,4989 -0.37
(0.051)
-0.27
(0.051)
-0.10
(-0.24,0.04)
0.16
HDL Large 565,4989 0.25
(0.056)
0.053
(0.055)
0.20
(0.047,0.35)
0.01
HDL Small 565,4989 0.036
(0.051)
0.067
(0.051)
-0.032
(-0.17,0.11)
0.66

1 Sample size: N1= No. of participants, N2 = No. of visits
2 Linear mixed effect model, specifying random effect for participants, the LP dependent variables are rescaled using z-score
formula.
3 LS means values are post-randomization means over the trial
4 p-value from linear mixed effect model testing the effect of estradiol therapy on each lipoprotein subfractions.

14
Figure a. LDL Peak Means over time by treatment group

Figure b. Midzone Means over time by treatment group

Figure c. HDL Large Means over time by treatment group

Figure d. LDL Small Means over time by treatment group

Figure e. LDL Medium and Small Means over time by
treatment group

Figure f. LDL Medium Means over time by treatment
group

15
Figure g. IDL Small Means over time by treatment group

HT effects on LP measures: Effects by time since postmenopausal
The analysis of treatment effect on LP particles was analyzed separately in early and
late postmenopausal strata. The estradiol effects on LP particles in early postmenopausal
women are shown in Table 8. There were significant estradiol effects on Medium, medium
and small-sized LDL, and small-sized LDL particles in early postmenopausal (p<0.05). Since
the medium and small-sized LDL variable is the combined LP particle for small-sized LDL
medium-sized LDL, it can be concluded that only the medium- and small-sized LDL particles
were significantly affected by HT in the early postmenopausal stratum. However, the values
are not significant, like on-trial total sample, the group comparison value (HT vs. placebo)
decreased as the LPL particle size increased

16
Table 8. HT effects on LP measures: on-trial early postmenopausal sample

Hormone
Therapy

Placebo Group Comparison
(HT-Placebo)

N1, N2
1
LS Mean
(SE)
LS Mean
(SE)
Difference Mean
(95% CI)
p
2

Total LDL 242,2187 0.14
(0.14)
-0.037
(0.15)
0.18
(-0.049,0.40)
0.12
LDL Peak Size 242,2187 -0.15
(0.14)
-0.0021
(0.15)
-0.15
(-0.37,0.081)
0.21
HDL Particle Number 242,2187 0.046
(0.13)
-0.041
(0.14)
0.088
(-0.11,0.29)
0.39
LDL Large a 242,2187 -0.12
(0.15)
0.013
(0.18)
0.0047
(-0.22,0.23)
0.97
LDL Large b 242,2187 0.098
(0.14)
-0.093
(0.15)
0.19
(-0.028,0.41)
0.09
LDL_Medium 242,2187 0.28
(0.15)
-0.011
(0.16)
0.29
(0.069,0.52)
0.01
LDL Medium and Small 242,2187 0.29
(0.16)
-0.0093
(0.16)
0.30
(0.059,0.53)
0.01
Midzone 242,2187 0.14
(0.13)
-0.034
(0.14)
0.18
(-0.022,0.38)
0.08
LDL Small 242,2187 0.23
(0.16)
-0.0093
(0.17)
0.24
(-0.00058,0.49)
0.05
LDL Very Small a 242,2187 0.091
(0.14)
0.036
(0.17)
0.054
(-0.20,0.31)
0.68
LDL Very Small b 242,2187 0.030
(0.10)
0.15
(0.16)
-0.12
(-0.40,0.16)
0.39
LDL Very Small c 242,2187 -0.00028
(0.11)
0.14
(0.15)
-0.14
(-0.37,0.093)
0.24
LDL Very Small d 242,2187 -0.032
(0.012)
0.048
(0.14)
-0.080
(-0.28,0.12)
0.44
IDL Large 242,2187 -0.27
(0.15)
-0.25
(0.15)
-0.018
(-0.24,0.20)
0.87
IDL Small 242,2187 -0.22
(0.14)
-0.0092
(0.15)
-0.21
(-0.44,0.012)
0.06
VLDL Large 242,2187 -0.065
(0.12)
-0.071
(0.14)
0.0060
(-0.20,0.21)
0.95
VLDL Medium 242,2187 -0.20
(0.13)
-0.19
(0.14)
-0.016
(-0.22,0.19)
0.88
VLDL Small 242,2187 -0.44
(0.14)
-0.38
(0.14)
-0.062
(-0.27,0.14)
0.55
HDL Large 242,2187 0.19
(0.13)
-0.091
(0.14)
0.28
(0.077,0.49)
0.007
HDL Small 242,2187 -0.044
(0.14)
0.0067
(0.15)
-0.038
(-0.25,0.17)
0.72

1 Sample size: N1= No. of participants, N2 = No. of visits
2 Linear mixed effect model, specifying random effect for participants, the LP dependent variables are rescaled using z-score
formula.
3 LS means values are post-randomization means over the trial
4 p-value from linear mixed effect model testing the effect of estradiol therapy on each lipoprotein subfractions.

17
Table 9 shows that the HT effect in late postmenopausal was only apparent on the
midzone variable. However, the HT group has larger value than the placebo. Moreover,
midzone is the variable that covers region between HDL and LDL particle. It is hard to say
that greater HT vs placebo value will cause beneficial effect. Although the values are not
significant, like on-trial total sample and early postmenopausal, the trend of group
comparison value (HT vs. placebo) on LDL particle were evident in late postmenopausal.

18
Table 9. HT effects on LP measures: on-trial late postmenopausal sample

Hormone
Therapy

Placebo Group Comparison
(HT-Placebo)

N1, N2
1
LS Mean
(SE)
LS Mean
(SE)
Difference Mean
(95% CI)
p
2

Total LDL 323,2802 0.12
(0.073)
0.063
(0.079)
0.055
(-0.15,0.25)
0.59
LDL Peak Size 323,2802 -0.12
(0.071)
-0.012
(0.069)
-0.11
(-0.30,0.074)
0.24
HDL Particle Number 323,2802 0.20
(0.077)
0.15
(0.072)
0.046
(-0.15,0.24)
0.64
LDL Large a 323,2802 -0.024
(0.0075)
0.046
(0.073)
-0.070
(-0.27,0.12)
0.48
LDL Large b 323,2802 0.037
(0.071)
0.075
(0.083)
-0.038
(-0.24,0.17)
0.71
LDL_Medium 323,2802 0.12
(0.072)
0.097
(0.084)
0.026
(-0.18,0.23)
0.80
LDL Medium and Small 323,2802 0.15
(0.074)
0.070
(0.079)
0.078
(-0.12,0.28)
0.45
Midzone 323,2802 0.20
(0.076)
-0.0059
(0.069)
0.20
(0.012,0.40)
0.04
LDL Small 323,2802 0.15
(0.073)
0.03
(0.072)
0.12
(-0.074,0.31)
0.23
LDL Very Small a 323,2802 0.10
(0.065)
0.010
(0.067)
0.086
(-0.087,0.26)
0.33
LDL Very Small b 323,2802 0.084
(0.066)
0.020
(0.063)
0.064
(-0.11,0.23)
0.46
LDL Very Small c 323,2802 0.086
(0.090)
-0.013
(0.062)
0.099
(-0.11,0.30)
0.34
LDL Very Small d 323,2802 0.0062
(0.079)
-0.073
(0.068)
0.080
(-0.11,0.27)
0.42
IDL Large 323,2802 -0.29
(0.070)
-0.22
(0.076)
-0.072
(-0.26,0.12)
0.46
IDL Small 323,2802 -0.030
(0.077)
0.14
(0.077)
-0.17
(-0.38,0.029)
0.09
VLDL Large 323,2802 0.00015
(0.082)
-0.021
(0.068)
0.022
(-0.18,0.22)
0.83
VLDL Medium 323,2802 -0.16
(0.079)
-0.090
(0.073)
-0.068
(-0.27,0.13)
0.50
VLDL Small 323,2802 -0.44
(0.070)
-0.30
(0.073)
-0.14
(-0.33,0.046)
0.14
HDL Large 323,2802 0.35
(0.079)
0.20
(0.085)
0.15
(-0.064,0.37)
0.17
HDL Small 323,2802 0.060
(0.076)
0.084
(0.070)
-0.025
(-0.22,0.17)
0.80

1 Sample size: N1= No. of participants, N2 = No. of visits
2 Linear mixed effect model, specifying random effect for participants, the LP dependent variables are rescaled using z-score
formula.
3 LS means values are post-randomization means over the trial
4 p-value from linear mixed effect model testing the effect of estradiol therapy on each lipoprotein subfractions.

19
Discussion
In this sample of 643 ELITE participants, the population consisted of healthy post-
menopausal women with an average age of 60.0 years that were ethnically diverse. In the
baseline analysis, although the LDL- and HDL- cholesterol and triglycerides levels correlated
with atherosclerosis (triglycerides only correlated with GSM), LP particles had variable
associations with CIMT and GSM (atherosclerosis). CIMT is an anatomic measure of the
thickness of the arterial wall and GSM is a more direct measure of lipid deposition in the
wall. Higher CIMT indicates increased chance of atherosclerosis and lower GSM indicates
higher degrees of atherosclerosis.
LP particles had different associations with the two atherosclerosis measures (CIMT
and GSM). The baseline analysis illustrates that most subclasses of LP particles had a
positive association with CIMT and negative association with GSM. Specifically, Total LDL-
cholesterol, plasma concentration of medium-, small-, very small a-, and very small b sized
LDL particles were atherogenic (p<0.05). LP particles showed a similar significant trend
(higher CIMT and lower GSM) within in the subclass of LDL particles. This indicates that
LDL particle is an atherogenic .
11−14
Although, many studies found that HDL has an anti-
atherogenic functions,
15−17
the total HDL and large sized HDL particle were associated with
less lipid deposition (higher GSM) and thinner arterial wall (less CIMT), but, small sized
HDL had an adverse association with other HDL particles. This result indicates that not all
HDL particles are the biomarker of atherosclerosis protection.
The majority of CIMT association with atherosclerosis were evident in early, but not
in late menopausal women. The subclasses of LDL particles were significant positively
associated with CIMT only in early post-menopause. This indicates that LDL particles are
atherogenic to early menopausal women.

20
Meanwhile, the Analysis of Baseline association with GSM based on each time since
postmenopausal stratum, the LP particles were significantly associated with GSM for both
early and late postmenopausal. Most subclasses of LDL particles were significantly
associated with more lipid deposition (lower GSM) in early menopausal women. However,
IDL large- and VLDL medium sized LP particles were also negatively associated with GSM.
Except HDL large sized LP particle, other LP particles were atherogenic. Interestingly, in late
menopausal women, where LDL Very small a- and LDL small sized LP particles were
significantly associated as atherogenic, LDL large a sized LP particle was significantly
associated with less lipid deposition (higher GSM). LDL particles were known as the
indicator factor for atherogenesis, however, in this result, it shows that LDL large a sized LP
particle is a protective factor for atherosclerosis.
Based on the data, the significant association with LP particles and two
atherosclerosis measures are differential because CIMT and GSM measure different aspect of
atherosclerosis. The LP particles are more influential to arterial wall lipid deposition than
wall thickness.
It is well-known that estrogen-containing HT reduces progression of atherosclerosis
and certain LP particles are a biomarker for atherosclerosis risk (2). In the HT treatment
effect model for on-trial total sample, among the significant LDL peak size(p=0.04),
Midzone(p=0.01), LDL medium and small-( p=0.03) , LDL small-( p=0.02), IDL-small-
( p=0.02) and HDL- large(p=0.01) sized particles showed statistically significant difference
between HT treatment and placebo. Specifically, among those particle, LDL Peak size and
IDL small subfraction LP particle had beneficial treatment effect (lower on trial level vs.
placebo) and HDL large had a beneficial effect in treatment effect compare to placebo (higher
on trial level vs. placebo) (figure a, c, g). In early postmenopausal women stratum, the
smaller LDL Particles were lower in estradiol compared to placebo (but not significantly so).

21
While larger LDL particles were higher in estradiol compared to placebo. Also, HDL large
sized LP particle had a beneficial effect on HT compared to placebo. In contrast, although it
is not significant, in the late menopausal women stratum, the large LDL particles are lower in
estradiol compared to placebo. And the small LDL are higher in estradiol compared to
placebo. Results from this study suggest that in part, HT may reduce atherosclerosis
progression by base on LP particles chemical/ physical properties.
Our study and many previous studies indicate evidence of correlation between LP
particles and atherosclerosis.
1
However, not all LP particles were associated with
atherosclerosis. Even within the subclass of LDL and HDL particles the significance of
association with atherosclerosis (specifically CIMT and GSM) was differentiated. Moreover,
it showed a unique association relative to subclass LP particle size. The result showed that
as the LDL particle size increases, although they are not significant, the pattern showed that
decreasing trend for the beta estimate value for CIMT (thinner arterial wall) and increasing
trend for GSM (lower arterial wall lipid deposit). This indicates that larger size LDL particle
may act as an atherosclerosis protector. Moreover, IDL small sized particle, also not
significant, but had negative relationship with CIMT and positive association with GSM. IDL
small was also significantly beneficial on reducing atherosclerosis on HT treatment effect.
This indicate that IDL (not only HDL) may be a protective factor for atherosclerosis.
Thus, our results lead to investigating the molecular mechanisms of the physical
property of LP particles (LP subfractions) effect of HT and prepare for further studies
investigating the association between the effect of HT on LP particle and the timing of HT
initiation in relation to postmenopausal. Finally, this provides a potential exploration at a
clinical level that may determine the clinal importance and usage.

22
Conclusion
The data suggest that LP subfractions are associated with atherosclerosis in
postmenopausal women. However, not all LP particle fractions are associated with
subclinical atherosclerosis and have differential association with specific atherosclerosis
components (wall thickness vs. lipid deposition). Moreover, among the healthy
postmenopausal women, HT was associated with changes in some LP particle fractions. The
associations (both HT on LP fractions and association with carotid artery CIMT and GSM)
were more prominent in early than late postmenopausal women. In addition, these finding
also showed that LP particles contribute to atherosclerosis and HT effect changes based on
their chemical and physical properties. Further research will be needed to understand and
determine clinical implication of LP particle fractions effect on CVD among postmenopausal
women using HT.

23
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Abstract (if available)

Abstract BACKGROUND: Results from ELITE and meta-analyses of randomized controlled trials suggest that initiating oral estradiol therapy (HT) may reduce atherosclerosis progression and the risk of cardiovascular disease in women who are younger than 60 years and/or within 10 years of postmenopausal women (7-9). The HT timing hypothesis suggests that women respond to HT differently depending on the timing of initiation of therapy relative to age and time since menopause. In this thesis, ELITE trial data and samples were used to: 1 evaluate the association of LP particles with atherosclerosis in postmenopausal women at baseline (before initiation of HT or placebo treatment) and

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Asset Metadata

Creator Kim, Stephanie S. (author)

Core Title Effect of menopausal hormone replacement therapy on lipoprotein particle fractions and association with carotid artery intima-media thickness and grey-scale median, independent measurements of su...

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 05/15/2020

Defense Date 05/14/2020

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

Tag Biostatistics,Elite,grey-scale median,HT therapy,intima-media thickness,lipoprotein particle fractions,menopausal hormone replacement therapy,OAI-PMH Harvest,postmenopausal

Language English

Contributor Electronically uploaded by the author (provenance)

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

Creator Email kim197@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-309938

Unique identifier UC11663911

Identifier etd-KimStephan-8535.pdf (filename),usctheses-c89-309938 (legacy record id)

Legacy Identifier etd-KimStephan-8535.pdf

Dmrecord 309938

Document Type Thesis

Rights Kim, Stephanie S.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA