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Association of oophorectomy with progression of carotid atherosclerosis

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Association of oophorectomy with progression of carotid atherosclerosis

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Association of Oophorectomy with Progression of Carotid Atherosclerosis
By
Chan Chan Zhuo

Thesis Submitted in Partial Fulfillment
of the Requirements for the Degree of
Master of Science
In Applied Biostatistics and Epidemiology

University of Southern California
December 2014

ii

Abstract
Background and Purpose – Previous studies have shown association of increasing coronary heart
disease with surgical menopause (oophorectomy); however, it is not clear on how surgical menopause
affects atherosclerosis. This purpose of this study is determine whether the CIMT level and rate of
progression is higher in women who undergo oophorectomy compared to women who experienced
natural menopause or had a hysterectomy without oophorectomy.
Methods – We combined data from four clinical trials that contained post-menopausal women: the B-
Vitamin Atherosclerosis Intervention Trial (BVAIT) the Estrogen in the Prevention of Atherosclerosis
Trial (EPAT), the Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression
Trial (WELL-HART), and the Women’s Isoflavone Soy Health (WISH) trial. Our primary measurement
of atherosclerosis is intima–media thickness of the right distal common carotid artery far wall (CIMT).
Results – Our analysis included 873 participants from four trials BVAIT, EPAT, WELL-HART, and
WISH. BVAIT participants were excluded in our final analysis due to the low number of participants that
contained data regarding years since menopause. At baseline, women with <10 years since menopause
had the mean CIMT of the intact group lower than the mean CIMT of the hysterectomized/oophorectomy
group by about 8.6μm where as women who had ≥10 years since menopause had the mean CIMT of the
intact group higher than the mean CIMT of the hysterectomized/oophorectomy group for about 7μm. The
rate of the intact participants was lower than the rate of the hysterectomized/oophorectomy participants in
the WISH trial; however, the rate of the intact participants was higher than the hysterectomized/
oophorectomy group for individuals in both the EPAT and the WELL-HART trials. Our placebo only
analysis showed treatment effect might not affect the CIMT rate difference by menopause group in each
trial.
Conclusions –At baseline, the mean CIMT level was higher in hysterectomy/oophorectomy group over
the intact and hysterectomized/no oophorectomy groups primarily in women <10 years since menopause,
but the mean CIMT level was lower in hysterectomized/oophorectomy group compared to the intact and
hysterectomized/no oophorectomy groups in women ≥10 years since menopause. In addition, our
exploratory analyses suggest that the rate of CIMT progression is higher in healthy women who were in
the hysterectomy/oophorectomy group compared to women in the intact and hysterectomized/no
oophorectomy groups. However, this result was not consistent with participants of the EPAT and WELL-
HART trials. It is possible that the follow up time with an average of 2.7 years is not long enough to study
the rate of CIMT progression.

iii

Dedication
I would like to dedicate my thesis to my beloved parents, who supported me each step of the way.

iv

Acknowledgements
I would like to thanks all the people who helped and supported me in the completion of this research
project
First, I would like to express my deepest appreciation to my committee char Dr. Wendy J. Mack, who has
been guiding me through this project, I mean this educational journey. Without her guidance this research
project would not have been possible.
Second, I would like to thank Dr. Howard N. Hodis and Dr. Roksana Karim for help me proof reading
through this research project
Third, I also would like to thank the entire faculty from the preventive medicine the department and all
employees at the Soto Building for creating an amazing educational experience at the University of
Southern California

v

Table of Contents
Abstract…….……………………………………………………………………….………………………ii
List of Tables………………………………………………………………………………..…..……...…vii
Introduction…………………………………………………………………….…………………………...1
Methods
-Subjects…………………………………...………………………………….……………..……..2
-Data Collection……………………………………...……………….……………………………3
-Statistical Analysis……………………………………..…………..……………………………..4
Results
-Sample Characteristics ……………………………………………………………………...……6
-Correlates of CIMT at baseline……………………………………………………………...……8
-Correlates of CIMT Progression – Mixed Effect Models……………..…………………….……8
-Baseline CIMT by Menopause Group – Adjusted Associations………………………………...10
-Oophorectomy Associations with Baseline and Longitudinal CIMT – Adjusted Associations…13
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group -- Evaluations of
Interactions by Trial………………………………………………………………………………17
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group – Evaluation of
Interaction by Trial, Excluding Hysterectomized/No Oophorectomy Group………………….…19
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group - Evaluation of
Interaction by Trial, Excluding Hysterectomized/No Oophorectomy Group and Adjusted by
Years Since Menopause………………………………..…………………………………………22
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group Among Women
<10 Years since Menopause - Evaluation of Interaction by Trial, Excluding Hysterectomized/No
Oophorectomy Group…………………………………………………………………………….24
vi

-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group Among Women
≥10 Years since Menopause - Evaluation of Interaction by Trial, Excluding Hysterectomized/No
Oophorectomy Group ……………………………………………………………………………27
-Model Estimates of log CIMT Rates and difference by Menopause Group Among Women ≥10
Years since Menopause (Excluding BVAIT)……………………………………………….……29
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group Among Placebo
Women <10 Years since Menopause - Evaluation of Interaction by Trial, Excluding
Hysterectomized/No Oophorectomy Group ………………………..……………………………30
-Cross-sectional and Longitudinal Difference in CIMT by Menopause Group Among Placebo
Women ≥10 Years since Menopause - Evaluation of Interaction by Trial, Excluding
Hysterectomized/No Oophorectomy Group………………………………………………...……31
-Model Estimates of log CIMT Rates and difference by Menopause Group among Placebo
Women ≥10 Years since Menopause (Excluding BVAIT)…………………………………...….33
Discussion…………………………………………………………………………………………………33
Conclusions……...…………………………………………...……………………………………………36
References…...………………………………………………………………………………….…………37

vii

List of Tables
Table 1. Baseline Demographics by Menopause Group....…...……………………………………..…… 6
Table 2. Baseline Associations of Log CIMT with Demographic Variables by Menopause Group..……..7
Table 3. Cross-sectional and Longitudinal Associations of log CIMT with Demographic Variables by
Menopause Group..…………………………………………………………………………………….…...9
Table 4.1. Baseline Difference in Mean CIMT by Menopause Group with Demographic
Adjustment…………………………………………………………………………………………….…..10
Table 4.2. Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment
(BVAIT)…………………………………………………………………………………………………...10
Table 4.3. Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment
(EPAT)…………………………………………………………………………………………………….11
Table 4.4. Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment
(WELL-HART).………………………………………...……….………………………………….……..11
Table 4.5. Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment
(WISH)…………………………………………………………………………………………………….12
Table 5. Alternative Models - Baseline Mean CIMT by Menopause group……………...…….….……..12
Table 6. Alternative Models - Baseline mean CIMT by Menopause group (Excluding BVAIT).…...…..13
Table 7.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic
Adjustments……………………………………………………………………………………...………..14
Table 7.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic
Adjustments (BVAIT)……………………………………………. ……………….……………….……..14
Table 7.3. Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic
Adjustments (EPAT)….……………………………………………... …………………………….……..15
Table 7.4. Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic
Adjustments (WELL-HART)..……………………………………….…………………………….……..16
viii

Table 7.5. Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic
Adjustments (WISH).……………………………………………………………………………………...16
Table 8.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group – Evaluation of
Interactions by Trial.. ………………………………………………………………………………..……17
Table 8.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interactions by Trial (Excluding BVAIT).……………………………………….….……………….……18
Table 9.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group).……………………..……20
Table 9.1.1. Model-Estimated CIMT Rates by Menopause group and Trial (Excluding
Hysterectomized/No Oophorectomy Group)...…… ………………………………………………...……21
Table 9.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group and BVAIT).……….….…22
Table 10.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group) Adjusted by Years Since
Menopause.………………………………………………..…………………………………………..…..23
Table 10.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group and BVAIT) Adjusted by
Years Since Menopause…………………………………………………………………….………….….24
Table 11.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women
<10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group) …....………….…25
Table 11.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women
<10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and BVAIT)....…..26
Table 12.1. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women
≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group).……..……...……27
Table 12.2. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women
≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and BVAIT)..……28
ix

Table 13. Model-Estimated CIMT Rates in Women ≥ 10 Years since Menopause, By Menopause group
and Trial.……………………………………………….………………………..….………………..……29
Table 14. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Placebo
Women <10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT).……………………………………………….………………….………………...………..……31
Table 15. Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Placebo
Women ≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT)…………………………………………….…………………………………….…………...…...32
Table 16. Model-Estimated CIMT Rates in Placebo Women ≥ 10 Years since Menopause, By Menopause
group and Trial.……………………………………………………………………………………..….….33

1

INTRODUCTION
According to the Office on Women’s Health, menopause is operationally defined as cessation of
menstrual periods for at least one year (Office on Women’s Health, 2010b). Some women may show no
signs or symptoms of menopause while in others, it may impact their daily life with irregular periods, hot
flashes, trouble sleeping, vaginal and urinary problems, mood changes, sexless of libido, osteoporosis, or
other changes such as becoming forgetful or having trouble focusing, larger waist, loss and gain of fat
muscle, and stiff and achy joints and muscles (Office on Women’s Health, 2010b). It is however not clear
whether some of these changes result from the lower estrogen levels of menopause or are a result of aging
(Office on Women’s Health, 2010b).
Early menopause is defined as menopause occurring before the age of 40 which may occur as a
result of chemotherapy, oophorectomy (surgical removal of ovaries), or hysterectomy (surgical removal
of uterus) (Office on Women’s Health, 2010a). Although women who had a hysterectomy and retained
their ovaries do not experience their menopause right after surgery, they may still experience hot flashes
due to surgery when the blood supply to the ovaries are affected; moreover, their natural menopause may
occur a year or two earlier than normal (Office on Women’s Health, 2010a). Early menopause may also
occur on its own due to chromosome defects, family history of early menopause, or autoimmune diseases
that target a woman’s ovaries (Office on Women’s Health, 2010a). Women who experience early
menopause can also have symptoms (severe in some cases) similar to those with regular menopause.
Women who have early menopause are at higher risk of heart diseases and osteoporosis compared to
premenopausal women of the same age (Office on Women’s Health, 2010a).
Atherosclerosis is the process whereby cholesterol, cellular waste products, calcium and fibrin
build up (forming atherosclerotic plaque) in the inner lining of an artery. If the plaque blocks the blood
flow in the coronary arteries, the lack of oxygen to the heart will lead to a heart attack. The
atherosclerosis process starts as early as in childhood. While atherosclerosis may progress faster in young
adulthood, it is usually not a threat in relation to clinical cardiovascular events until after age 50 or 60
2

(American Heart Association, 2013). Previous studies have shown associated increased coronary heart
disease risk with surgical menopause (oophorectomy); however, whether surgical menopause affects
atherosclerosis is not clear (Dwyer KM et al., 2002).
We used data from four randomized clinical trials to study the association of surgical menopause
with carotid atherosclerosis in postmenopausal women. Our primary measurement of atherosclerosis is
intima–media thickness of the right distal common carotid artery far wall (CIMT). We hypothesized that
the CIMT level and rate of progression is higher in women who undergo oophorectomy compared to
women who experienced natural menopause or had a hysterectomy without oophorectomy.
METHODS
Subjects
We utilized data from four clinical trials since they all contained postmenopausal women: the B-
Vitamin Atherosclerosis Intervention Trial (BVAIT) (Hodis et al., 2009), the Estrogen in the Prevention
of Atherosclerosis Trial (EPAT) (Hodis et al., 2001), the Women’s Estrogen-progestin Lipid-Lowering
Hormone Atherosclerosis Regression Trial (WELL-HART) (Hodis et al., 2003), and the Women’s
Isoflavone Soy Health (WISH) trial (Hodis et al., 2011).
BVAIT was a randomized, double-blinded, placebo-controlled trial conducted to determine
whether decreasing total homocysteine levels with vitamin B supplementations reduces subclinical
atherosclerosis progression (measured by CIMT progression) (Hodis et al., 2009). The trial randomized
506 participants age 40 to 89 years old with initial total homocysteine level >8.5 μmol/L without diabetes
and cardiovascular disease. All women in the trial were required to be postmenopausal.
EPAT was a randomized, double-blinded, placebo-controlled trial conducted to determine
whether estrogen replacement therapy (17β-estradiol) reduces the progression of subclinical
atherosclerosis (measured by CIMT progression) in healthy postmenopausal women free of vascular
disease (Hodis et al., 2001). The trial randomized 222 postmenopausal women age 45 years or older free
of cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels ≥130 mg/dL.
3

WELL-HART was a randomized, double-blinded, placebo-controlled trial conducted to
determine whether the endogenous estrogen molecule, 17β-estradiol alone or administered sequentially
with medroxyprogesterone acetate can reduce the progression of atherosclerosis (measured by coronary
angiography and CIMT progression) in postmenopausal women with coronary artery disease (Hodis et
al., 2003). The trial randomized 226 post menopausal women with an average age of 63.5 years old who
had at least one coronary artery lesion.
WISH was a randomized, double-blinded, placebo-controlled trial conducted to determine
whether isoflavone soy protein supplementation reduces subclinical atherosclerosis (measured by CIMT
progression) (Hodis et al., 2011). The trial randomized 350 postmenopausal women aged 45 to 92 years
who were free of diabetes and cardiovascular disease.
A total of 995 postmenopausal women were obtained combining all four trials. We excluded 32
subjects (BVAIT=3, EPAT=7, WELL-HART=11, and WISH=11) who had their hysterectomy more than
a year of their last menstrual period. These women should be allocated in the natural menopause group;
however, for the purpose of this analysis, they were excluded to confine the natural menopausal group to
women who were intact (no hysterectomy/no oophorectomy). We excluded an additional 22 subjects
from the EPAT trial who did not have follow-up CIMT data, 24 subjects (BVAIT=6, EPAT=4, WELL-
HART=12, and WISH=2) for whom oophorectomy status could not be clearly defined (occurrence and/or
number of ovaries removed), 4 subjects from the WELL-HART trial who had a very large(outlier) value
of CIMT (>1500μm), and 40 subjects (BVAIT=8, EPAT=14, WELL-HART=9, and WISH=9) who did
not have both ovaries completely removed (partial oophorectomy). The final sample included a total of
873 subjects in the following groups: (1) 642 subjects who had natural menopause (intact uterus/ovaries),
(2) 93 subjects who had hysterectomy only (no oophorectomy), and (3) 138 subjects who had
hysterectomy and bilateral oophorectomy.
Data Collection
For all four trials, subject demographics including age, race, income, and years of education were
obtained from structured questionnaires. Reproductive history including date of last menstrual period,
4

hysterectomy status (yes/no), hysterectomy date, oophorectomy status (yes/no/don’t know), number of
ovaries removed (one/both), and age at menopause were also obtained from structured questionnaire.
Carotid ultrasonography was performed to measure CIMT at baseline (prior to randomization)
and at 6-month intervals during trial follow-up for each of the four trials. Participants were placed in a
supine position with the head rotated to the left using a 45-degree head block. The jugular vein and
carotid artery were located in the transverse view, with the jugular vein stacked above the carotid artery
The transducer was then rotated 90 degrees around the central line of the transverse image of the stacked
jugular vein and carotid artery to obtain a longitudinal image while the stacked position of the vessels was
maintained. All images contained anatomic landmarks for reproducing probe angulation, and each
participant’s baseline image was used as a guide for follow-up examinations. For each participant, the
depth of field, gain, monitor intensity setting, and other instrumentation settings used at baseline
examination were used at all follow-up examinations (Hodis et al., 2003, 2009, and 2011). These
techniques significantly reduce measurement variability (Selzer et al., 1994 and 2001).
The CIMT of the distal common carotid artery far wall was measured with automated
computerized edge detection. CIMT was the average of approximately 70 to 100 individual measurements
between the intima–lumen and media–adventitia interfaces along a 1cm length just distal to the carotid
artery bulb. This method standardized the location and the distance over which CIMT was measured and
ensured that the same portion of the arterial wall was measured in each image and compared within and
across all subjects (Selzer et al., 1994 and 2001). Technicians measuring CIMT were blinded to treatment
assignment.
Statistical Analysis
Variables at baseline including age, race, income, years of education, years since menopause, age
at menopause, and trial were compared by menopause group (intact, hysterectomized/no oophorectomy,
and hysterectomized/oophorectomy), using analysis of variance (ANOVA) for comparison of means for
continuous variables and chi-squared tests for the comparison of proportions for categorical variables. We
examined the distribution of CIMT and in linear regression models tested the residuals for possible
5

influential points using jackknife residuals; we found 4 influential points from the WELL-HART trial that
were very large values of CIMT (>1500 μm). Since the WELL-HART trial included participants with
established coronary artery disease who had at least one coronary artery lesion, the high CIMT
(>1500μm) might reflect a lesion rather than thickened CIMT; therefore, these 4 subjects were excluded
in these analyses. The dependent variable, CIMT, was log transformed to achieve a normal distribution
across all four trials.
To identify possible model covariates for adjustment, cross-sectional associations of the baseline
CIMT with covariates were analyzed by menopause group using linear regression, with log transformed
CIMT as the dependent variable. Differences in baseline log CIMT by menopause group (cross-sectional
associations of CIMT with type of menopause) were also analyzed using linear regression, unadjusted and
adjusted for covariates. In longitudinal modeling, the association with cross-sectional (intercept) and
longitudinal (slope) log CIMT among menopause groups was analyzed using mixed effects linear
regression models. In the mixed models, years since randomization at each CIMT assessment was
calculated and included as a continuous independent variable; the regression coefficient associated with
this variable estimated the annual rate of change in log CIMT. The main independent class variable of
menopause group tested for differences in the model intercept (log CIMT at years = 0, or baseline) among
menopause groups. An interaction term of menopause group by years tested for differences in log CIMT
rates by menopause group. Random effects were specified for the intercept and slope to allow for subject
random deviations around their group baseline and rate of change in log CIMT. All models included trials
as a single model covariate. Menopause group comparisons were analyzed unadjusted and adjusted for
covariates; comparisons were also conducted separately by trial. A triple interaction term of the follow up
time by menopause group by trial tested whether the effect of menopausal group on the CIMT rate
differed by trial. Estimates of the log CIMT rate were generated from the mixed models to show the
menstrual group effect on the log CIMT rate as well as the estimates for the log CIMT rate difference of
the hysterectomized/oophorectomy group over the intact group by trial. SAS 9.4 software was used for all
analyses.
6

RESULTS
Sample Characteristics
Data from a total of 873 participants (intact= 642, hysterectomized/no oophorectomy= 93, and
hysterectomized/oophorectomy= 138) were used in this study. The baseline demographics of study
participants by menopause group are presented in Table 1. Age and years of education at randomization
did not differ across the groups. In contrast, annual income, years since menopause, and trial significantly
differed across the groups. The distribution by race was of borderline statistical significance (p-
value=0.059). Participants were 45 to 92 years old with a mean (SD) of 62.1 (7.11) years at
randomization.
Table 1: Baseline Demographics by Menopause Group

Intact
Uterus/Ovaries
(n=642)
Hysterectomy/
No
Oophorectomy
(n=93)
Hysterectomy/
Oophorectomy
(n=138)
P-value²
Age At Randomization 62.0 (7.1)¹ 62.1 (7.4) 62.6 (6.8) 0.74

Race
White non-hispanic 365 (56.9%) 53 (57.0%) 68 (49.3%)
0.059
Black non-hispanic 68 (10.6%) 19 (20.4%) 18 (13.0%)
Hispanic 137 (21.3%) 14 (15.1%) 36 (26.1%)
Asian or Pacific Islander +
Native American + Other
72 (11.2%) 7 (7.5%) 16 (11.6%)

Incomeᶾ 5.3 (3.3) 4.8 (2.7) 4.5 (3.0) 0.044

Years of Education 14.7 (2.8) 14.6 (2.2) 14.2 (2.7) 0.14

Years Since Menopause ⁴* 11.7 (8.5)

17.9 (10.6) <0.0001
<10* 250 (46.3%) 27 (25.5%)
<0.0001
≥10* 290 (53.7%) 79 (74.5%)

Trial
BVAIT 124 (19.3%) 20 (21.5%) 36 (26.1%)
<0.0001
EPAT 122 (19.0%) 22 (23.7%) 31 (22.5%)
WELL-HART 121 (18.9%) 25 (26.9%) 44 (31.9%)
WISH 275 (42.8%) 26 (28.0%) 27 (19.6%)
¹ Values = Mean (SD) or n (%)
² P-value = ANOVA for continuous variables and Chi-Squared for categorical variables
³ Income values are per $10,000 per year
⁴* n=780

7

The proportion of non-Hispanic whites was lower in the hysterectomized/oophorectomy group
compared to the other groups; the proportion of non-Hispanic black women was almost double in the
hysterectomized/no oophorectomy compared to the intact group and also higher than the
hysterectomized/oophorectomy group. Annual income was slightly significantly higher in the intact group
over the other two groups. Years since menopause was not calculated for the hysterectomy/no
oophorectomy group as the date these women reached menopause is unknown.
Table 2: Baseline Associations of Log CIMT with Demographic Variables by Menopause Group

Intact
Uterus/
Ovaries
(n=642)
P-value
Hysterectomy/
No
Oophorectomy
(n=93)
P-value
Hysterectomy/
Oophorectomy
(n=138)
P-value
All
Subjects
(n=873)
P-value

Age At Randomization
0.0078
(0.0008)¹
<0.0001
0.0058
(0.0022)
0.0091
0.0059
(0.0018)
0.0017
0.0073
(0.0007)
<0.0001

Race
White non-
hispanic
0 (Ref)
0.88
0 (Ref)
0.23
0 (Ref)
0.63
0 (Ref)
0.55
Black non-
hispanic
0.0142
(0.0206)
0.0462
(0.0425)
0.0286
(0.0403)
0.0226
(0.0167)
Hispanic
0.0084
(0.0156)
0.0275
(0.0478)
-0.0244
(0.0314)
0.0048
(0.0134)
Asian or
Pacific
Islander +
Native
American +
Other
0.0068
(0.0201)
-0.0978
(0.0640)
-0.0227
(0.0423)
-0.0049
(0.0174)

Annual Income²
-0.0052
(0.0019)
0.0072
-0.0071
(0.0065)
0.27
-0.0101
(0.0045)
0.027
-0.0061
(0.0017)
0.0004

Years of Education
-0.0044
(0.0022)
0.047
-0.0064
(0.0077)
0.41
-0.0046
(0.0049)
0.35
-0.0047
(0.0020)
0.017

Years Since
Menopause ᶾ*
0.0063
(0.0007)
<0.0001

0.0019
(0.0014)
0.18
0.0050
(0.0006)
<0.0001
<10* 0 (Ref)
<0.0001
0 (Ref)
0.058
0 (Ref)
<0.0001
≥10*
0.0937
(0.0128)
0.0646
(0.0337)
0.0887
(0.0118)

Trial
BVAIT
-0.1065
(0.0160)
<0.0001
-0.1293
(0.0461)
0.028
-0.0556
(0.0384)
0.28
-0.0955
(0.0139)
<0.0001
EPAT
-0.0734
(0.0161)
-0.0947
(0.0449)
-0.0723
(0.0397)
-0.0727
(0.0140)
WELLHART
0.0202
(0.0162)
-0.0384
(0.0434)
-0.0311
(0.0369)
0.0051
(0.0136)
WISH 0 (Ref) 0 (Ref) 0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from linear regression of log CIMT with baseline variables
² Income beta estimate values are per $10,000
³* n=780
The average number of years since menopause was 6.2 years longer in the
hysterectomized/oophorectomy compared to the intact women. Consistent with this, the proportion of
8

women ≥10 years since menopause was much higher in hysterectomized/oophorectomy compared to
intact women. A higher proportion of WISH trial participants were represented in the intact group over
the other two groups while a higher proportion of WELL-HART trial participants were represented in the
hysterectomized/oophorectomy group.
Correlates of CIMT at baseline
Baseline associations of log CIMT with demographic variables by menopause group are
presented in Table 2; these associations were estimated in the total sample (“All Subjects” column) and
within each menopause group. Age, mean annual income, years of education, years since menopause, and
trial were statistically significantly associated with log CIMT at baseline. Race was not significantly
associated with log CIMT in the overall sample or within each menopause group (intact,
hysterectomized/no oophorectomy, and hysterectomized/oophorectomy). Age and years since menopause
were positively associated with log CIMT; income and years of education were negatively associated with
log CIMT. In the total sample, the mean log CIMT was lower in the BVAIT and EPAT compared to the
WISH trial participants; however, WELL-HART trial participants had higher mean CIMT compared to
WISH trial participants.
Correlates of CIMT Progression– Mixed Effect Models
Cross-sectional (association with intercept) and longitudinal (association with slope) associations
of log CIMT with demographic variables by menopause group using mixed effect linear models are
presented in Table 3; the associations were tested in the total sample (“All Subjects” column) and within
each menopause group. The cross-sectional analysis confirmed our linear regression results from Table 2.
Race, mean annual income, years of education, years since menopause, and trial were statistically
significantly associated with log CIMT rate in the total sample. Age was not significantly associated with
log CIMT rate in the overall sample or within each menopause group. Compared to non-Hispanic whites,
Hispanic participants had lower log CIMT progression rate. Annual income and years of education were
positively associated with log CIMT rate. As a continuous variable, years since menopause was
negatively associated with log CIMT rate in the total sample.
9

Table 3: Cross-sectional and Longitudinal Associations of log CIMT with Demographic Variables by Menopause Group.

Intact
Uterus/
Ovaries
(n=642)
P-value
Hysterectomy
/ No
Oophorectomy
(n=93)
P-value
Hysterectomy/
Oophorectomy
(n=138)
P-value
All
Subjects
(n=873)
P-value

Age At Randomization
0.0078
(0.0008)¹
<0.0001
0.0058
(0.0022)
0.0076
0.0058
(0.0018)
0.0015
0.0073
(0.0007)
<0.0001
Follow up time*Age At
Randomization
-1.0E-05
(8.4E-05)
0.89
-5.0E-05
(0.0002)
0.83
-7.0E-05
(0.0002)
0.71
-3.0E-05
(7.3E-05)
0.68

Race
White non-Hispanic 0 (Ref)
0.85
0 (Ref)
0.21
0 (Ref)
0.63
0 (Ref)
0.51
Black non-Hispanic
0.0153
(0.0206)
0.0467
(0.0426)
0.0294
(0.0402)
0.0237
(0.0167)
Hispanic
0.0092
(0.0156)
0.0272
(0.0478)
-0.0240
(0.0313)
0.0055
(0.0134)
Asian or Pacific
Islander + Native
American + Other
0.0072
(0.0201)
-0.0978
(0.0640)
-0.0214
(0.0422)
-0.0046
(0.0174)
Follow up time*White
non-Hispanic
0 (Ref)
0.017
0 (Ref)
0.23
0 (Ref)
0.83
0 (Ref)
0.017
Follow up time*Black
non-Hispanic
-0.0012
(0.0020)
-5.0E-05
(0.0043)
-1.0E-05
(0.0042)
-0.0010
(0.0016)
Follow up
time*Hispanic
-0.0043
(0.0015)
-0.0080
(0.0047)
-0.0004
(0.0031)
-0.0041
(0.0013)
Follow up time*Asian
or Pacific Islander +
Native American +
Other
-0.0040
(0.0019)
0.0054
(0.0063)
0.0036
(0.0042)
-0.0021
(0.0017)

Income²
-0.0052
(0.0019)
0.0066
-0.0073
(0.0065)
0.26
-0.0101
(0.0045)
0.026
-0.0061
(0.0017)
0.0003
Follow up time*Income
0.0003
(0.0002)
0.064
0.0005
(0.0007)
0.45
0.0002
(0.0005)
0.63
0.0004
(0.0002)
0.025

Years of Education
-0.0046
(0.0022)
0.039
-0.0064
(0.0077)
0.40
-0.0047
(0.0049)
0.34
-0.0048
(0.0020)
0.013
Follow up time*Year of
Education
0.0006
(0.0002)
0.0061
0.0004
(0.0008)
0.57
0.0007
(0.0005)
0.17
0.0006
(0.0002)
0.0010

Years Since Menopause³*
0.0063
(0.0007)
<0.0001

0.0019
(0.0014)
0.17
0.0050
(0.0006)
<0.0001
Follow up time*Years Since
Menopause
-0.0001
(8.0E-05)
0.098
-0.0001
(0.0002)
0.38
-0.0002
(6.9E-05)
0.0071
<10* 0 (Ref)
<0.0001
0 (Ref)
0.053
0 (Ref)
<0.0001
≥10*
0.0936
(0.0128)
0.0651
(0.0335)
0.0888
(0.0118)
Follow up time* <10 Years
Since Menopause
0 (Ref)
0.91
0 (Ref)
0.83
0 (Ref)
0.54
Follow up time* ≥10 Years
Since Menopause
-0.0002
(0.0014)
0.0008
(0.0037)
-0.0008
(0.0013)

Trial
BVAIT
-0.1058
(0.0160)
<0.0001
-0.1302
(0.0461)
0.024
-0.0562
(0.0383)
0.30
-0.0952
(0.0139)
<0.0001
EPAT
-0.0728
(0.0161)
-0.0939
(0.0449)
-0.0694
(0.0397)
-0.0716
(0.0140)
WELL-HART
0.0213
(0.0162)
-0.0381
(0.0434)
-0.0294
(0.0368)
0.0064
(0.0136)
WISH 0 (Ref) 0 (Ref) 0 (Ref) 0 (Ref)
Follow up time*BVAIT
-0.0031
(0.0016)
<0.0001
4.2E-05
(0.0047)
0.20
-0.0043
(0.0034)
<0.0001
-0.0028
(0.0013)
<0.0001
Follow up time*EPAT
-0.0023
(0.0016)
-0.0077
(0.0048)
-0.0147
(0.0036)
-0.0050
(0.0014)
Follow up time*
WELL-HART
-0.0101
(0.0016)
-0.0067
(0.0045)
-0.0156
(0.0033)
-0.0107
(0.0014)
Follow up time*WISH 0 (Ref) 0 (Ref) 0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from mixed effects linear models of log CIMT with variables over time
² Income beta estimate values are per $10,000
³* n=780
10

However, log CIMT rate did not differ between the dichotomized years since menopause variable (<10
vs. ≥10 years since menopause). Log CIMT rates significantly differed among trials; rates were lower in
all trials relative to WISH trial participants.
Baseline CIMT by Menopause Group – Adjusted Associations
Baseline differences in mean CIMT by menopause group are presented in Table 4.1. Although the
mean CIMT was not statistically significantly different by menopause group, the oophorectomy group
had a higher mean CIMT followed by the intact group, and finally the hysterectomized/no oophorectomy
group.
These baseline CIMT analyses are also presented separated by trial in Tables 4.2 to 4.5.
Table 4.1: Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment

Intact Uterus/
Ovaries (n=642)
Hysterectomy/ No
Oophorectomy (n=93)
Hysterectomy/
Oophorectomy
(n=138)
P-value
Unadjusted 776.6 (1.0)¹ 773.5 (1.0) 785.3 (1.0) 0.70
Adjusted for:
Age 777.1 (1.0) 773.6 (1.0) 782.8 (1.0) 0.81
Race 778.7 (1.0) 773.9 (1.0) 786.8 (1.0) 0.70
Annual Income 774.5 (1.0) 772.0 (1.0) 782.3 (1.0) 0.78
Education 777.2 (1.0) 773.6 (1.0) 784.3 (1.0) 0.77
Years since
Menopause
791.3 (1.0) 772.2 (1.0) 0.13
Trial 769.0 (1.0) 770.0 (1.0) 784.5 (1.0) 0.37
¹ Values = Mean CIMT (SE) of CIMT in μm
Table 4.2: Baseline Difference in Mean CIMT by Menopause Group with Demographic Adjustment
BVAIT

Intact
Uterus/Ovaries
(n=124)
Hysterectomy/ No
Oophorectomy (n=20)
Hysterectomy/
Oophorectomy
(n=36)
P-value
Unadjusted 720.0 (1.0)¹ 722.1 (1.0) 773.7 (1.0) 0.038
Adjusted for:
Age 720.5 (1.0) 732.7 (1.0) 765.5 (1.0) 0.071
Race 723.3 (1.0) 719.5 (1.0) 777.6 (1.0) 0.036
Annual Income 718.8 (1.0) 728.9 (1.0) 765.7 (1.0) 0.079
Education 721.8 (1.0) 725.1 (1.0) 768.9 (1.0) 0.076
Years since
Menopause
704.5 (1.0) 889.4 (1.1) 0.020
¹ Values = Mean CIMT (SE) of CIMT in μm
11

Baseline differences in mean CIMT by menopause group in the BVAIT trial are presented in
Table 4.2. Here the difference in the mean CIMT was significantly higher in the
hysterectomized/oophorectomy group than the other two groups (p=0.038). The mean CIMT of the intact
group was very similar to those in the hysterectomized/no oophorectomy group.
Baseline differences in mean CIMT did not significantly differ by menopause group in the EPAT,
WELL-HART, and WISH trials (Tables 4.3-4.5).

Table 4.3: Baseline Difference in Mean CIMT by Menopause group with Demographic
Adjustment
EPAT

Intact
Uterus/Ovaries
(n=122)
Hysterectomy/ No
Oophorectomy (n=22)
Hysterectomy/
Oophorectomy
(n=31)
P-value
Unadjusted 744.2 (1.0)¹ 747.4 (1.0) 760.8 (1.0) 0.77
Adjusted for:
Age 744.6 (1.0) 753.0 (1.0) 755.4 (1.0) 0.85
Race 745.9 (1.0) 748.5 (1.0) 763.4 (1.0) 0.75
Annual Income 741.3 (1.0) 747.7 (1.0) 739.8 (1.0) 0.97
Education 744.4 (1.0) 746.4 (1.0) 760.8 (1.0) 0.77
Years since
Menopause
750.0 (1.0) 737.8 (1.0) 0.59
¹ Values = Mean CIMT (SE) of CIMT in μm
Table 4.4: Baseline Difference in Mean CIMT by Menopause group with Demographic
Adjustment
WELL-HART

Intact
Uterus/Ovaries
(n=121)
Hysterectomy/ No
Oophorectomy (n=25)
Hysterectomy/
Oophorectomy
(n=44)
P-value
Unadjusted 817.2 (1.0)¹ 790.9 (1.0) 792.8 (1.0) 0.54
Adjusted for:
Age 814.3 (1.0) 795.4 (1.0) 798.0 (1.0) 0.74
Race 821.0 (1.0) 792.9 (1.0) 793.6 (1.0) 0.49
Annual Income 820.2 (1.0) 791.5 (1.0) 816.6 (1.0) 0.72
Education 817.4 (1.0) 790.0 (1.0) 794.5 (1.0) 0.57
Years since
Menopause
822.5 (1.0) 778.8 (1.0) 0.10
¹ Values = Mean CIMT (SE) of CIMT in μm

12

¹ Values = Mean CIMT (SE) of CIMT in μm

Table 5: Alternative Models - Baseline Mean CIMT by Menopause group

Base
Model*
Base Model
Excluding
Hysterectomy/
No
Oophorectomy
Adj. by
Years since
Menopause
Women
<10 Years
since
Menopause
Women ≥
10 Years
since
Menopause
Intact Uterus/Ovaries
(n=642)
772.1 (1.0)¹ 772.8 (1.0) 769.9 (1.0) 737.9 (1.0) 798.5 (1.0)
Hysterectomy/ No
Oophorectomy (n=93)
772.3 (1.0)

Hysterectomy/
Oophorectomy (n=138)
787.8 (1.0) 788.0 (1.0) 777.5 (1.0) 750.8 (1.0) 803.3 (1.0)
P-Value 0.35 0.16 0.57 0.56 0.79
*All models are adjusted for age, race, annual income, years of education, and trial
¹ Values = Mean CIMT (SE) of CIMT in μm

Baseline mean CIMT by menopause group adjusted by age, race, annual mean income, years of
education, and trial is presented in Table 5. Although the differences in mean CIMT at baseline were not
statistically significant in the base model, the mean CIMT was higher in the
hysterectomized/oophorectomy group compared to the intact and the hysterectomized/no oophorectomy
groups. When participants of the hysterectomized/no oophorectomy group were excluded from the
analysis, the mean CIMT was still higher in the hysterectomized/oophorectomy group than the intact
group, although these differences were not statistically significant.
Table 4.5: Baseline Difference in Mean CIMT by Menopause group with Demographic
Adjustment
WISH

Intact
Uterus/Ovaries
(n=275)
Hysterectomy/ No
Oophorectomy (n=26)
Hysterectomy/
Oophorectomy
(n=27)
P-value
Unadjusted 800.9 (1.0)¹ 821.8 (1.0) 817.9 (1.0) 0.44
Adjusted for:
Age 802.0 (1.0) 805.9 (1.0) 821.7 (1.0) 0.54
Race 797.2 (1.0) 812.9 (1.0) 821.3 (1.0) 0.38
Annual Income 796.4 (1.0) 819.5 (1.0) 813.9 (1.0) 0.39
Education 800.8 (1.0) 821.8 (1.0) 818.0 (1.0) 0.44
Years since
Menopause
802.8 (1.0) 798.0 (1.0) 0.80
13

Table 6: Alternative Models - Baseline mean CIMT by Menopause group (Excluding BVAIT)

Base
Model*
Base Model
Excluding
Hysterectomy/ No
Oophorectomy
Adj. by
Years since
Menopause
Women <10
Years since
Menopause
Women ≥ 10
Years since
Menopause
Intact
Uterus/Ovaries
(n=518)
788.7 (1.0)¹ 789.8 (1.0) 790.8 (1.0) 757.1 (1.0) 822.2 (1.0)
Hysterectomy/ No
Oophorectomy
(n=73)
787.2 (1.0)
Hysterectomy/
Oophorectomy
(n=102)
794.9 (1.0) 795.6 (1.0) 789.7 (1.0) 765.7 (1.0) 815.2 (1.0)
P-Value 0.88 0.66 0.94 0.71 0.70
*All models are adjusted for age, race, annual income, years of education, and trial
¹ Values = Mean CIMT (SE) of CIMT in μm
Out of 160 participants (intact and hysterectomized/oophorectomy groups) of the BVAIT trial,
only 26 participants had data regarding years since menopause. Therefore, using the same models
presented on Table 5 with the exclusion of the participants of the BVAIT trial, the baseline mean CIMT
by menopause group adjusted by age, race, annual mean income, years of education, and trial are
presented in Table 6. Although the differences in mean CIMT by menopause group at baseline were not
statistically significant in the base model, the mean CIMT was higher in the
hysterectomized/oophorectomy group than the intact and the hysterectomized/no oophorectomy group.
When participants of the hysterectomized/no oophorectomy group were excluded from the analysis, the
mean CIMT was still higher in the hysterectomized/oophorectomy group than the intact group, although
these differences were not statistically significant.

Oophorectomy Associations with Baseline and Longitudinal CIMT – Adjusted Associations
Cross-sectional and longitudinal differences in log CIMT by menopause group analyzed in mixed
effects linear models are presented in Table 7.1. The cross-sectional analysis confirmed our results from
Table 4.1. The CIMT progression rate was statistical significantly lowest in the
hysterectomized/oophorectomy group followed by the hysterectomized/ no oophorectomy group when
14

compared to the intact group in both unadjusted and demographic-adjusted analyses. The results of these
mixed effects models of CIMT rates are also presented by trial in Tables 7.2 to 7.5.
Table 7.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic Adjustments

Cross-sectional Longitudinal
Intact
Uterus/
Ovaries
(n=642)
Hysterectomy/
No
Oophorectom
y (n=93)
Hysterectomy/
Oophorectomy
(n=138)
P-value
Intact
Uterus/
Ovaries
(n=642)
*Follow up
Time
Hysterectomy/
No
Oophorectomy
(n=93)
*Follow up
Time
Hysterectomy/
Oophorectomy
(n=138)
*Follow up
Time
P-value
Unadjusted 0 (Ref)
-0.0033
(0.0172)
0.0120
(0.0146)
0.68 0 (Ref)
-0.0014
(0.0017)
-0.0046
(0.0014)
0.0052
Adjusted for:

Age 0 (Ref)
-0.0038
(0.0163)
0.0082
(0.0138)
0.79 0 (Ref)
-0.0014
(0.0017)
-0.0046
(0.0014)
0.0053
Race 0 (Ref)
-0.0058
(0.0173)
0.0115
(0.0146)
0.66 0 (Ref)
-0.0014
(0.0017)
-0.0046
(0.0014)
0.0052
Annual Income 0 (Ref)
-0.0023
(0.0176)
0.0112
(0.0156)
0.75 0 (Ref)
-0.0018
(0.0017)
-0.0036
(0.0015)
0.048
Education 0 (Ref)
-0.0039
(0.0172)
0.0103
(0.0146)
0.74 0 (Ref)
-0.0014
(0.0017)
-0.0046
(0.0014)
0.0053
Years since
Menopause
0 (Ref)

-0.0224
(0.0162)
0.17 0 (Ref)

-0.0062
(0.0017)
0.0003
Trial 0 (Ref)
0.0032
(0.0167)
0.0226
(0.0143)
0.28 0 (Ref)
-0.0014
(0.0017)
-0.0046
(0.0014)
0.0053
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time

Cross-sectional and longitudinal differences in log CIMT by menopause group in the BVAIT trial
are presented in Table 7.2. The cross-sectional analysis confirmed our results from Table 4.2. Although
the CIMT rate was not statistical significantly different by menopause group, the rate was highest in the
hysterectomized/ no oophorectomy group followed by the hysterectomized/oophorectomy group when
compared to the intact group for the unadjusted and adjusted analyses.
Table 7.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic Adjustments
BVAIT

Cross-sectional Longitudinal
Intact
Uterus/
Ovaries
(n=124)
Hysterectomy/
No
Oophorectomy
(n=20)
Hysterectomy/
Oophorectomy
(n=36)
P-value
Intact
Uterus/
Ovaries
(n=124)
*Follow up
Time
Hysterectomy/
No
Oophorectomy
(n=20) *Follow
up Time
Hysterectomy/
Oophorectomy
(n=36)
*Follow up
Time
P-value
Unadjusted 0 (Ref)
0.0025
(0.0360)
0.0711
(0.0283)
0.040 0 (Ref)
0.0023
(0.0024)
0.0005
(0.0019)
0.62
Adjusted for:

Age 0 (Ref)
0.0165
(0.0333)
0.0598
(0.0262)
0.074 0 (Ref)
0.0024
(0.0024)
0.0006
(0.0019)
0.60
Race 0 (Ref)
-0.0053
(0.0362)
0.0719
(0.0286)
0.036 0 (Ref)
0.0023
(0.0024)
0.0005
(0.0019)
0.62
Annual Income 0 (Ref)
0.0137
(0.0343)
0.0625
(0.0279)
0.081 0 (Ref)
0.0025
(0.0024)
0.0007
(0.0019)
0.57
Education 0 (Ref)
0.0043
(0.0353)
0.0619
(0.0279)
0.082 0 (Ref)
0.0023
(0.0024)
0.0005
(0.0019)
0.63
Years since
Menopause
0 (Ref)

0.2335
(0.0933)
0.013 0 (Ref)

0.0012
(0.0063)
0.85
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
15

Table 7.3: Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic Adjustments
EPAT

Cross-sectional Longitudinal
Intact
Uterus/
Ovaries
(n=122)
Hysterectomy/
No
Oophorectomy
(n=22)
Hysterectomy/
Oophorectomy
(n=31)
P-value
Intact
Uterus/
Ovaries
(n=122)
*Follow up
Time
Hysterectomy/
No
Oophorectomy
(n=22) *Follow
up Time
Hysterectomy/
Oophorectomy
(n=31)
*Follow up
Time
P-value
Unadjusted 0 (Ref)
0.0059
(0.0348)
0.0249
(0.0303)
0.71 0 (Ref)
-0.0060
(0.0055)
-0.0106
(0.0046)
0.060
Adjusted for:

Age 0 (Ref)
0.0130
(0.0321)
0.0171
(0.0279)
0.79 0 (Ref)
-0.0061
(0.0055)
-0.0106
(0.0046)
0.059
Race 0 (Ref)
0.0051
(0.0350)
0.0261
(0.0305)
0.69 0 (Ref)
-0.0060
(0.0055)
-0.0106
(0.0046)
0.060
Annual Income 0 (Ref)
0.0103
(0.0357)
0.0004
(0.0322)
0.96 0 (Ref)
-0.0058
(0.0057)
-0.0089
(0.0050)
0.17
Education 0 (Ref)
0.0043
(0.0349)
0.0246
(0.0303)
0.72 0 (Ref)
-0.0060
(0.0055)
-0.0106
(0.0046)
0.060
Years since
Menopause
0 (Ref)

-0.0136
(0.0301)
0.65 0 (Ref)

-0.0106
(0.0046)
0.022
¹ Values= Beta estimates (SE) from Mixed Model of log CIMT with variables over time
Cross-sectional and longitudinal differences in log CIMT by menopause group in the EPAT trial
are presented in Table 7.3. The cross-sectional analysis confirmed our results from Table 4.3. Although
the CIMT rate was not statistical significantly different by menopause group (the difference was of
borderline significance in unadjusted analyses, p = 0.06), the rate was lowest in the
hysterectomized/oophorectomy group followed by the hysterectomized/ no oophorectomy group when
compared to the intact group for the unadjusted and adjusted by age, race, annual mean income, and years
of education analyses. When adjusted by years since menopause, the CIMT rate was statistically
significantly lower in the hysterectomized/oophorectomy group than in the intact group (p=0.022).
Cross-sectional and longitudinal differences in log CIMT by menopause group in the WELL-
HART trial are presented in Table 7.4. The cross-sectional analysis confirmed our results from Table 4.4.
Although the CIMT rate was not statistical significantly different by menopause group, the rate was
highest in the hysterectomized/ no oophorectomy group, and lowest in the hysterectomized/oophorectomy
group when compared to the intact group for the unadjusted and adjusted analyses.

16

Table 7.4: Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic Adjustments
WELL-HART

Cross-sectional Longitudinal
Intact
Uterus/
Ovaries
(n=121)
Hysterectomy/
No
Oophorectomy
(n=25)
Hysterectomy/
Oophorectomy
(n=44)
P-value
Intact
Uterus/
Ovaries
(n=121)
*Follow
up Time
Hysterectomy/
No
Oophorectomy
(n=25) *Follow
up Time
Hysterectomy/
Oophorectomy
(n=44)
*Follow up
Time
P-value
Unadjusted 0 (Ref)
-0.0324
(0.0409)
-0.0293
(0.0328)
0.56 0 (Ref)
0.0025
(0.0028)
-0.0037
(0.0023)
0.12
Adjusted for:

Age 0 (Ref)
-0.0233
(0.0401)
-0.0194
(0.0322)
0.75 0 (Ref)
0.0025
(0.0028)
-0.0037
(0.0023)
0.12
Race 0 (Ref)
-0.0343
(0.0417)
-0.0334
(0.0333)
0.50 0 (Ref)
0.0026
(0.0028)
-0.0037
(0.0023)
0.12
Annual Income 0 (Ref)
-0.0348
(0.0439)
-0.0030
(0.0380)
0.73 0 (Ref)
0.0008
(0.0030)
-0.0037
(0.0026)
0.31
Education 0 (Ref)
-0.0330
(0.0416)
-0.0270
(0.0333)
0.59 0 (Ref)
0.0025
(0.0028)
-0.0038
(0.0023)
0.12
Years since
Menopause
0 (Ref)

-0.0538
(0.0331)
0.10 0 (Ref)

-0.0037
(0.0023)
0.11
¹ Values= Betas estimates (SE) from Mixed Model of Log CIMT with variables over time

Table 7.5: Cross-sectional and Longitudinal Difference in CIMT by Menopause group with Demographic Adjustments
WISH

Cross-sectional Longitudinal
Intact
Uterus/
Ovaries
(n=275)
Hysterectomy/
No
Oophorectomy
(n=26)
Hysterectomy/
Oophorectomy
(n=27)
P-value
Intact
Uterus/
Ovaries
(n=275)
*Follow
up Time
Hysterectomy/
No
Oophorectomy
(n=26) *Follow
up Time
Hysterectomy/
Oophorectomy
(n=27)
*Follow up
Time
P-value
Unadjusted 0 (Ref)
0.0269
(0.0251)
0.0215
(0.0246)
0.41 0 (Ref)
-0.0007
(0.0024)
0.0017
(0.0023)
0.73
Adjusted for:

Age 0 (Ref)
0.0065
(0.0227)
0.0247
(0.0222)
0.53 0 (Ref)
-0.0004
(0.0024)
0.0018
(0.0023)
0.72
Race 0 (Ref)
0.0196
(0.0250)
0.0317
(0.0246)
0.34 0 (Ref)
-0.0006
(0.0024)
0.0017
(0.0023)
0.72
Annual Income 0 (Ref)
0.0287
(0.0253)
0.0217
(0.0248)
0.39 0 (Ref)
-0.0012
(0.0025)
0.0017
(0.0023)
0.67
Education 0 (Ref)
0.0269
(0.0251)
0.0217
(0.0247)
0.41 0 (Ref)
-0.0007
(0.0024)
0.0017
(0.0023)
0.73
Years since
Menopause
0 (Ref)

-0.0048
(0.0233)
0.84 0 (Ref)

0.0017
(0.0023)
0.46
¹ Values= Betas estimates (SE) from Mixed Model of Log CIMT with variables over time
Cross-sectional and longitudinal differences in log CIMT by menopause group in the WISH trial
are presented in Table 7.5. The cross-sectional analysis confirmed our results from Table 4.5. Although
the CIMT rate was not statistical significantly different by menopause group, the rate was highest in the
hysterectomized/oophorectomy group, and lowest in the hysterectomized/ no oophorectomy group when
compared to the intact group for the unadjusted and adjusted analyses.
17

Cross-sectional and Longitudinal Difference in CIMT by Menopause group -- Evaluations of
Interactions by Trial
Cross-sectional and longitudinal difference in CIMT by menopause group adjusted by age, race,
annual mean income, years of education, and trial with tests for oophorectomy effect modification by trial
are presented in Table 8.1.
Table 8.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group – Evaluation of
Interactions by Trial

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0009) 0.053
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries (n=642) 0 (Ref)¹
0.36
0 (Ref)
0.24
Hysterectomy/ No Oophorectomy
(n=93)
0.0074 (0.0292) -0.0011 (0.0032)
Hysterectomy/
Oophorectomy (n=138)
0.0254 (0.0287) 0.0019 (0.0030)
Trial P-values Follow Up*Trial P-values
BVAIT -0.1279 (0.0160)
<0.0001
-0.0034 (0.0016)
<0.0001
EPAT -0.0815 (0.0164) -0.0030 (0.0017)
WELL-HART -0.0154 (0.0189) -0.0095 (0.0017)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-BVAIT 0 (Ref)
0.81
0 (Ref)
0.12
Hysterectomy/ No Oophorectomy-
BVAIT
0.0014 (0.0447) 0.0039 (0.0047)
Hysterectomy/
Oophorectomy-BVAIT
0.0267 (0.0396) -0.0011 (0.0041)
Intact-EPAT 0 (Ref) 0 (Ref)
Hysterectomy/ No Oophorectomy-
EPAT
0.0028 (0.0441) -0.0050 (0.0048)
Hysterectomy/
Oophorectomy-EPAT
-0.0271 (0.0413) -0.0108 (0.0044)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/ No Oophorectomy-
WELL-HART
-0.0329 (0.0433) 0.0020 (0.0046)
Hysterectomy/
Oophorectomy-WELL-HART
-0.0208 (0.0399) -0.0055 (0.0042)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/ No Oophorectomy-
WISH
0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
18

At baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly
differ over the intact group in reference of the WISH trial (p=0.36). There was a statistically significant
difference in CIMT by trial (p<0.0001). However, the difference in baseline values of CIMT by
menopause group did not differ over trials (p-value for ovarian group by trial interaction=0.81). The
CIMT rate significantly differed over trial (p<0.0001). The CIMT rate did not statistically differ by
ovarian group in the reference WISH trial (p=0.24) In addition, the mean differences in CIMT rates by
menopause group did not differ over the trials (p-value for follow up time by menopause group by trial
interaction=0.12).
Table 8.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of Interactions by
Trial (Excluding BVAIT)

Cross-Sectional Associations Longitudinal Associations

Follow Up P-value
0.0065 (0.0010) 0.62
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries (n=518) 0 (Ref)¹
0.86
0 (Ref)
0.13
Hysterectomy/ No
Oophorectomy (n=73)
0.0077 (0.0297) -0.0010 (0.0034)
Hysterectomy/
Oophorectomy (n=102)
0.0230 (0.0292) 0.0019 (0.0032)
Trial P-values Follow Up*Trial P-values
EPAT -0.0801 (0.0168)
<0.0001
-0.0029 (0.0018)
<0.0001 WELL-HART -0.0105 (0.0199) -0.0095 (0.0018)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values Follow Up*Ovarian Group*Trial P-values
Intact-EPAT 0 (Ref)
0.87
0 (Ref)
0.15
Hysterectomy/ No
Oophorectomy-EPAT
0.0040 (0.0448) -0.0050 (0.0051)
Hysterectomy/
Oophorectomy-EPAT
-0.0256 (0.0420) -0.0108 (0.0047)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/ No
Oophorectomy-WELL-HART
-0.0335 (0.0440) 0.0020 (0.0049)
Hysterectomy/
Oophorectomy-WELL-HART
-0.0177 (0.0406) -0.0056 (0.0045)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/ No
Oophorectomy-WISH
0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
19

An alternative model excluding the participants of the BVAIT trial is presented in Table 8.2. At
baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly differ over the
intact group in reference of the WISH trial (p=0.86). There was a statistically significant difference in
CIMT by trial (p<0.0001). However, the difference in baseline values of CIMT by menopause group did
not differ over trials (p-value for menopause group by trial interaction=0.87). The CIMT rate significantly
differed over trial (p<0.0001). The CIMT rate did not statistically differ by ovarian group in the reference
WISH trial (p=0.13). The mean differences in CIMT rates by menopause group did not differ over the
trials (p-value for follow up time by menopause group by trial interaction =0.15).

Cross-sectional and Longitudinal Difference in CIMT by Menopause group – Evaluation of
Interaction by Trial, Excluding Hysterectomized/No Oophorectomy Group
Cross-sectional and longitudinal differences in CIMT by menopause group adjusted by age, race,
annual mean income, years of education, and trial, with evaluation of effect modification by trial and
exclusion of participants in the hysterectomized/no oophorectomy group are presented in Table 9.1. Since
participants in the hysterectomized/no oophorectomy group do not have a certain day when they reached
menopause, we excluded them for this analysis because in further analysis we are going to adjust by the
variable years since menopause. At baseline, the log CIMT of the hysterectomized/oophorectomy group
did not significantly differ over the intact group in reference of the WISH trial (p=0.16). There was a
statistically significant difference in CIMT by trial (p<0.0001). However, the difference in baseline values
of CIMT by menopause group did not differ across trials (p-value for menopause group by trial
interaction=0.57). The CIMT rate significantly differed over trial (p<0.0001). A slightly higher CIMT rate
in the hysterectomized/oophorectomy compare to intact group in the reference WISH trial was of
borderline significance (p=0.089). In addition, the difference in the CIMT rate between
hysterectomized/oophorectomy and intact groups was statistically significantly different across trials (p-
value for follow up by menopause group by trial interaction=0.047). Specially, the group difference in
20

CIMT rate between hysterectomized/oophorectomy vs. intact women was smaller in the other trials
compared to WISH and even reversed direction
Table 9.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group -
Evaluation of Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0009) 0.085
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=642)
0 (Ref)¹
0.16
0 (Ref)
0.089
Hysterectomy/
Oophorectomy (n=138)
0.0233 (0.0283) 0.0019 (0.0030)
Trial P-values Follow Up*Trial P-values
BVAIT -0.1277 (0.0158)
<0.0001
-0.0034 (0.0016)
<0.0001
EPAT -0.0819 (0.0163) -0.0030 (0.0017)
WELL-HART -0.0162 (0.0189) -0.0095 (0.0017)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-BVAIT 0 (Ref)
0.57
0 (Ref)
0.047
Hysterectomy/
Oophorectomy-BVAIT
0.0267 (0.0390) -0.0011 (0.0040)
Intact-EPAT 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-EPAT
-0.0247 (0.0407) -0.0108 (0.0043)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0168 (0.0394) -0.0055 (0.0041)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time

As seen above, the difference in the CIMT rate between hysterectomized/oophorectomy and
intact groups was statistically significantly different across trials, with the direction of the effect changing
over trial. Therefore, the mean log CIMT rates by menopause group and the test of ovarian group
differences in CIMT rate by trial were estimated; estimates are shown in Table 9.1.1.
21

The log CIMT rate of the hysterectomized/oophorectomy women was significantly lower than the
intact group for individuals in the EPAT trial (p=0.0042). For BVAIT, WELL-HART and WISH trials,
although the difference in the rates between the hysterectomized/oophorectomy and the intact group were
not significant (p=0.79, p=0.21 and p=0.53 respectively), the hysterectomized/oophorectomy group had a
higher log CIMT rate than the intact group in the BVAIT and WISH trials, but the
hysterectomized/oophorectomy group had a lower log CIMT rate than the intact group in the WELL-
HART trial.
Table 9.1.1: Model-Estimated CIMT Rates by Menopause group and Trial (Excluding
Hysterectomized/No Oophorectomy Group)
Estimate
Standard
Error
P-value
BVAIT Rate in Intact (n=22) 0.0031¹ 0.0013 0.019
BVAIT Rate in Hysterectomy/Oophorectomized (n=4) 0.0038 0.0024 0.11
BVAIT Rate difference 0.0007 0.0027 0.79
EPAT Rate in Intact (n=122) 0.0035 0.0014 0.011
EPAT Rate in Hysterectomy/Oophorectomized (n=31) -0.0054 0.0028 0.053
EPAT Rate difference -0.0089 0.0031 0.0042
WELL-HART Rate in Intact (n=121) -0.0031 0.0014 0.029
WELL HART Rate in Hysterectomy/Oophorectomized (n=44) -0.0067 0.0025 0.0082
WELL-HART Rate difference -0.0037 0.0029 0.21
WISH Rate in Intact (n=275) 0.0065 0.0009 <.0001
WISH Rate in Hysterectomy/Oophorectomized (n=27) 0.0084 0.0028 0.0031
WISH Rate difference 0.0019 0.0030 0.53
¹ Values= Mean Beta estimates from Mixed Model of Log CIMT
An alternative model excluding the participants of the BVAIT trial is presented in Table 9.2. At
baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly differ over the
intact group in reference of the WISH trial (p=0.61). There was a statistically significant difference in
CIMT by trial (p<0.0001). However, the difference in baseline values of CIMT by menopause group did
not differ over trials (p-value for menopause group by trial interaction=0.85). The CIMT rate significantly
differed over trial (p<0.0001). The higher CIMT rate in the hysterectomized/oophorectomy compared to
intact group was borderline statistical significance in reference WISH trial (p=0.053). The mean
differences in CIMT rates by menopause group did not differ over the trials (p-value for follow up time
by menopause group by trial interaction=0.062).
22

Table 9.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group -
Evaluation of Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0010) 0.56
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=518)
0 (Ref)¹
0.61
0 (Ref)
0.053
Hysterectomy/
Oophorectomy (n=102)
0.0214 (0.0288) 0.0019 (0.0032)
Trial P-values Follow Up*Trial P-values
EPAT -0.0806 (0.0167)
<0.0001
-0.0029 (0.0018)
<0.0001 WELL-HART -0.0125 (0.0200) -0.0095 (0.0018)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.85
0 (Ref)
0.062
Hysterectomy/
Oophorectomy-EPAT
-0.0236 (0.0415) -0.0108 (0.0046)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0148 (0.0402) -0.0055 (0.0044)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
Cross-sectional and Longitudinal Difference in CIMT by Menopause group - Evaluation of
Interaction by Trial, Excluding Hysterectomized/No Oophorectomy Group and Adjusted by Years
Since Menopause
Cross-sectional and longitudinal difference in CIMT by menopause group adjusted by age, race,
annual mean income, years of education, and trial, with evaluation of effect modification by trial with
exclusion of participants in the hysterectomized/no oophorectomy group adjusted by years since
menopause are presented in Table 10.1. At baseline, the CIMT of the hysterectomized/oophorectomy
group was statistically significantly higher than the intact group in reference of the WISH trial
(p=0.0099). There was a statistically significant difference in CIMT by trial (p<0.0001), and the baseline
CIMT difference by ovarian group significantly differed by trial (p-value for menopause group by trial
23

interaction=0.018). The CIMT rate significantly differed over trial (p<0.0001). The CIMT rate did not
statistically differ by ovarian group in the reference WISH trial (p=0.34). In addition, the mean
differences in CIMT rates by menopause group did not differ over the trials (p-value for follow up time
by menopause group by trial interaction=0.11).
Table 10.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group -
Evaluation of Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group)
Adjusted by Years Since Menopause

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0010) 0.38
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=642)
0 (Ref)¹
0.0099
0 (Ref)
0.34
Hysterectomy/
Oophorectomy (n=138)
0.0158 (0.0292) 0.0019 (0.0031)
Trial P-values Follow Up*Trial P-values
BVAIT -0.1716 (0.0326)
<0.0001
-0.0045 (0.0036)
<0.0001
EPAT -0.0785 (0.0167) -0.0029 (0.0017)
WELL-HART -0.0102 (0.0198) -0.0095 (0.0018)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-BVAIT 0 (Ref)
0.018
0 (Ref)
0.11
Hysterectomy/
Oophorectomy-BVAIT
0.2261 (0.0816) -0.0005 (0.0086)
Intact-EPAT 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-EPAT
-0.0272 (0.0415) -0.0108 (0.0046)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0221 (0.0402) -0.0055 (0.0044)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
An alternative model excluding the participants of the BVAIT trial is presented in Table 10.2. At
baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly differ over the
intact group in reference of the WISH trial (p=1.00). There was a statistically significant difference in
CIMT by trial (p<0.0001). However, the difference in baseline values of CIMT by menopause group did
24

not differ over trials (p-value for menopause group by trial interaction=0.82). The CIMT rate significantly
differed over trial (p<0.0001). The CIMT rate did not statistically differ by ovarian group in the reference
WISH trial (p=0.053). In addition, the mean differences in CIMT rates by menopause group did not
differ over the trials (p-value for follow up time by menopause group by trial interaction=0.063).
Table 10.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group -
Evaluation of Interactions by Trial (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT) Adjusted by Years Since Menopause

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0010) 0.56
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=518)
0 (Ref)¹
1.00
0 (Ref)
0.053
Hysterectomy/
Oophorectomy (n=102)
0.0147 (0.0293) 0.0019 (0.0032)
Trial P-values Follow Up*Trial P-values
EPAT -0.0802 (0.0167)
<0.0001
-0.0029 (0.0018)
<0.0001 WELL-HART -0.0133 (0.0200) -0.0095 (0.0018)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.82
0 (Ref)
0.063
Hysterectomy/
Oophorectomy-EPAT
-0.0252 (0.0415) -0.0108 (0.0046)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0188 (0.0402) -0.0055 (0.0044)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women <10
Years since Menopause - Evaluation of Interaction by Trial, Excluding Hysterectomized/No
Oophorectomy Group
Cross-sectional and longitudinal difference in CIMT by menopause group adjusted by age, race,
annual mean income, years of education, and trial, with evaluation of effect modification by trial with
exclusion of participants in the hysterectomized/no oophorectomy group among women <10 years since
25

menopause are presented in Table 11.1. At baseline, the log CIMT of the hysterectomized/oophorectomy
group did not significantly differ over the intact group in reference of the WISH trial (p=0.41). There was
a statistically significant difference in CIMT by trial (p=0.034). However, the difference in baseline
values of CIMT by menopause group did not differ over trials (p-value for menopause group by trial
interaction=0.98). The CIMT rate significantly differed over trial (p=0.0097). The CIMT rate did not
statistically differ by ovarian group in reference of the WISH trial (p=0.59). In addition, the mean
differences in CIMT rates by menopause group did not differ over the trials (p-value for follow up time
by menopause group by trial interaction=0.98).
Table 11.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Women <10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0068 (0.0013) 0.64
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=250)
0 (Ref)¹
0.41
0 (Ref)
0.59
Hysterectomy/
Oophorectomy (n=27)
0.0247 (0.0474) -0.0045 (0.0052)
Trial P-values Follow Up*Trial P-values
BVAIT -0.1365 (0.0488)
0.034
0.0012 (0.0055)
0.0097
EPAT -0.0744 (0.0225) -0.0061 (0.0023)
WELL-HART 0.0084 (0.0304) -0.0133 (0.0028)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-BVAIT 0 (Ref)
0.98
0 (Ref)
0.98
Hysterectomy/
Oophorectomy-BVAIT
0.0509 (0.1522) 0.0063 (0.0159)
Intact-EPAT 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-EPAT
-0.0132 (0.0685) 0.0005 (0.0076)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
0.0016 (0.0728) 0.0015 (0.0080)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
26

An alternative model excluding the participants of the BVAIT trial is presented in Table 11.2. At
baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly differ over the
intact group in reference of the WISH trial (p=0.55). There was a statistically significant difference in
CIMT by trial (p=0.029). However, the difference in baseline values of CIMT by menopause group did
not differ over trials (p-value for menopause group by trial interaction=0.98). The CIMT rate significantly
differed over trial (p=0.0082). The CIMT rate did not statistically differ by ovarian group in reference of
the WISH trial (p=0.24). In addition, the mean differences in CIMT rates by menopause group did not
differ over the trials (p-value for follow up time by menopause group by trial interaction=0.98).
Table 11.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Women <10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0068 (0.0013) 0.33
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=242)
0 (Ref)¹
0.55
0 (Ref)
0.24
Hysterectomy/
Oophorectomy (n=26)
0.0215 (0.0478) -0.0045 (0.0052)
Trial P-values Follow Up*Trial P-values
EPAT -0.0735 (0.0227)
0.029
-0.0061 (0.0024)
0.0082 WELL-HART 0.0104 (0.0308) -0.0133 (0.0029)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.98
0 (Ref)
0.98
Hysterectomy/
Oophorectomy-EPAT
-0.0116 (0.0691) 0.0005 (0.0077)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
0.0023 (0.0734) 0.0015 (0.0081)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
27

Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Women ≥10
Years since Menopause - Evaluation of Interaction by Trial, Excluding Hysterectomized/No
Oophorectomy Group
Cross-sectional and longitudinal difference in CIMT by menopause group adjusted by age, race,
annual mean income, years of education, and trial, with evaluation of effect modification by trial with
exclusion of participants in the hysterectomized/no oophorectomy group among women ≥10 years since
menopause are presented in Table 12.1.
Table 12.1: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Women ≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0061 (0.0014) 0.41
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=290)
0 (Ref)¹
0.015
0 (Ref)
0.44
Hysterectomy/
Oophorectomy (n=79)
0.0069 (0.0384) 0.0053 (0.0040)
Trial P-values Follow Up*Trial P-values
BVAIT -0.2017 (0.0455)
0.0035
-0.0080 (0.0048)
<0.0001
EPAT -0.0827 (0.0252) 0.0006 (0.0026)
WELL-HART -0.0218 (0.0272) -0.0075 (0.0023)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-BVAIT 0 (Ref)
0.0092
0 (Ref)
0.015
Hysterectomy/
Oophorectomy-BVAIT
0.3096 (0.1021) -0.0021 (0.0105)
Intact-EPAT 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-EPAT
-0.0327 (0.0547) -0.0182 (0.0058)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0170 (0.0515) -0.0098 (0.0054)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
28

At baseline, the CIMT of the hysterectomized/oophorectomy group was statistically significantly
higher than the intact group in reference of the WISH trial (p=0.015). There was a statistical significant
difference in CIMT by trial (p=0.0035), and the hysterectomized/oophorectomy group was statistical
significantly different from the intact group in each trial when compared to the WISH trial (p-value for
menopause group by trial interaction=0.0092). The CIMT rate significantly differed over trial (p<0.0001).
The CIMT rate did not statistically differ by ovarian group in reference of the WISH trial (p=0.44). In
addition, the rate of the hysterectomized/oophorectomy group was statistical significant lower than the
intact group in each trial when compared to the WISH trial (p-value for follow up time by menopause
group by trial interaction=0.015).
Table 12.2: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Women ≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy Group and
BVAIT)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0061 (0.0014) 0.13
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=276)
0 (Ref)¹
0.74
0 (Ref)
0.076
Hysterectomy/
Oophorectomy (n=76)
0.0059 (0.0383) 0.0053 (0.0040)
Trial P-values Follow Up*Trial P-values
EPAT -0.0858 (0.0251)
0.0010
0.0006 (0.0026)
<0.0001 WELL-HART -0.0249 (0.0273) -0.0075 (0.0023)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.88
0 (Ref)
0.0074
Hysterectomy/
Oophorectomy-EPAT
-0.0280 (0.0544) -0.0182 (0.0058)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0122 (0.0512) -0.0098 (0.0054)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
29

An alternative model excluding the participants of the BVAIT trial is presented in Table 12.2. At
baseline, the log CIMT of the hysterectomized/oophorectomy group did not significantly differ over the
intact group in reference of the WISH trial (p=0.74). There was a statistical significant difference in
CIMT by trial (p=0.0010). However, the difference in baseline values of CIMT by menopause group did
not differ over trials (p-value for menopause group by trial interaction=0.88). The CIMT rate significantly
differed over trial (p<0.0001). The CIMT rate did not statistically differ by ovarian group in reference of
the WISH trial (p=0.076). In addition, the rate of the hysterectomized/oophorectomy group was statistical
significant lower than the intact group in each trial when compared to the WISH trial (p-value for follow
up time by menopause group by trial interaction=0.0074).
Model Estimates of log CIMT Rates and difference by Menopause group Among Women ≥10 Years
since Menopause (Excluding BVAIT)
As seen above, the rate difference in CIMT rates between hysterectomized/oophorectomy and the
intact women significantly differed over trial, with the direction of the effect changing over trial.
Therefore, the mean log CIMT rates by menopause group and the test of ovarian group differences in
CIMT rate by trial were estimated; estimates are shown in Table 13.
Table 13: Model-Estimated CIMT Rates in Women ≥ 10 Years since Menopause, By Menopause
group and Trial

Estimate
Standard
Error
P-value
EPAT Rate in Intact (n=59) 0.0066¹ 0.0022 0.0023
EPAT Rate in Hysterectomy/Oophorectomized (n=22) -0.0063 0.0036 0.083
EPAT Rate difference -0.0129 0.0042 0.0022
WELL-HART Rate in Intact (n=83) -0.0014 0.0018 0.44
WELL HART Rate in Hysterectomy/Oophorectomized (n=36) -0.0060 0.0031 0.056
WELL-HART Rate difference -0.0046 0.0036 0.21
WISH Rate in Intact (n=134) 0.0061 0.0014 <0.0001
WISH Rate in Hysterectomy/Oophorectomized (n=18) 0.0114 0.0037 0.0025
WISH Rate difference 0.0053 0.0040 0.19
¹ Values= Mean Beta estimates from Mixed Model of Log CIMT
For women ≥10 years since menopause, the log CIMT rate of the hysterectomized/oophorectomy
women was significantly lower than the intact group for individuals in the EPAT trial (p=0.0022). In the
30

WELL-HART and WISH trials, although the difference in both of the log CIMT rates between the
hysterectomized/oophorectomy and the intact group were not significant (p=0.21 and p=0.19
respectively), the hysterectomized/oophorectomy group had a lower log CIMT rate than the intact group
in the WELL-HART trial, but the hysterectomized/oophorectomy group had a higher log CIMT rate than
the intact group in the WISH trial.

Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Placebo
Women <10 Years since Menopause - Evaluation of Interaction by Trial, Excluding
Hysterectomized/No Oophorectomy Group

Because women form the BVAIT, EPAT, WELL-HART, and WISH trials were randomized to
different treatments, we limited our comparisons of CIMT by menopause group to women randomized to
placebo groups in these trials. We again excluded the BVAIT study in the analysis for years since
menopause because out of 81 placebo participants (intact + hysterectomized/oophorectomy groups) of the
BVAIT trial, only 10 participants had data regarding years since menopause.
A model excluding the participants of the BVAIT trial of the cross-sectional and longitudinal
difference in CIMT by menopause group adjusted by age, race, annual mean income, years of education,
and trial, with evaluation of effect modification by trial with exclusion of participants in the
hysterectomized/no oophorectomy group among placebo women <10 years since menopause are
presented in Table 14. At baseline, the log CIMT did not differ by menopause group in reference of the
WISH trial (p=0.75). The log CIMT did not differ by trial (p=0.50), and the difference in baseline values
of CIMT by menopause group did not differ over trials (p-value for menopause group by trial
interaction=0.86). The CIMT rate did not significantly differ over trial (p=0.11). The CIMT rate did not
statistically differ by ovarian group in reference of the WISH trial (p=0.87). In addition, the mean
differences in CIMT rates by menopause group did not differ over the trials (p-value for follow up time
by menopause group by trial interaction=0.28).
31

Table 14: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Placebo Women <10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy
Group and BVAIT)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0091 (0.0017) 0.29
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=113)
0 (Ref)¹
0.75
0 (Ref)
0.87
Hysterectomy/
Oophorectomy (n=10)
-0.0175 (0.0604) -0.0067 (0.0061)
Trial P-values Follow Up*Trial P-values
EPAT -0.0798 (0.0296)
0.50
-0.0067 (0.0030)
0.11 WELL-HART -0.0382 (0.0486) -0.0141 (0.0043)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.86
0 (Ref)
0.28
Hysterectomy/
Oophorectomy-EPAT
0.0415 (0.0983) 0.0164 (0.0103)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
0.0555 (0.1148) 0.0059 (0.0117)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time

Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among Placebo
Women ≥10 Years since Menopause - Evaluation of Interaction by Trial, Excluding
Hysterectomized/No Oophorectomy Group
A model excluding the participants of the BVAIT trial of the cross-sectional and longitudinal
difference in CIMT by menopause group adjusted by age, race, annual mean income, years of education,
and trial, with evaluation of effect modification by trial with exclusion of participants in the
hysterectomized/no oophorectomy group among placebo women ≥10 years since menopause are
presented in Table 15.

32

Table 15: Cross-sectional and Longitudinal Difference in CIMT by Menopause group Among
Placebo Women ≥10 Years since Menopause (Excluding Hysterectomized/No Oophorectomy
Group and BVAIT)

Cross-Sectional
Associations
Longitudinal Associations

Follow Up P-value
0.0065 (0.0023) 0.076
Ovarian Group P-values Follow Up*Ovarian Group P-values
Intact Uterus/Ovaries
(n=126)
0 (Ref)¹
0.68
0 (Ref)
0.33
Hysterectomy/
Oophorectomy (n=35)
0.0209 (0.0491) 0.0036 (0.0054)
Trial P-values Follow Up*Trial P-values
EPAT -0.0607 (0.0340)
0.039
0.0035 (0.0037)
0.0049 WELL-HART 0.0042 (0.0453) -0.0080 (0.0043)
WISH 0 (Ref) 0 (Ref)

Ovarian
Group*Trial
P-values
Follow Up*Ovarian
Group*Trial
P-values
Intact-EPAT 0 (Ref)
0.67
0 (Ref)
0.33
Hysterectomy/
Oophorectomy-EPAT
-0.0697 (0.0781) -0.0113 (0.0088)
Intact-WELL-HART 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WELL-
HART
-0.0359 (0.0749) -0.0100 (0.0082)
Intact-WISH 0 (Ref) 0 (Ref)
Hysterectomy/
Oophorectomy-WISH
0 (Ref) 0 (Ref)
¹ Values= Beta estimates (SE) from Mixed Model of Log CIMT with variables over time
At baseline, the log CIMT did not differ by menopause group in reference of the WISH trial
(p=0.68). The log CIMT significantly differed by trial (p=0.039). However, the difference in baseline
values of CIMT by menopause group did not differ over trials (p-value for menopause group by trial
interaction=0.67). The CIMT rate significantly differed over trial (p=0.0049). The CIMT rate did not
statistically differ by ovarian group in reference of the WISH trial (p=0.33). In addition, the mean
differences in CIMT rates by menopause group did not differ over the trials (p-value for follow up time
by menopause group by trial interaction=0.33).

33

Model Estimates of log CIMT Rates and difference by Menopause group Among Placebo Women
≥10 Years since Menopause (Excluding BVAIT)
Although the mean differences in log CIMT rates by menopause group did not differ over the
trials, the mean log CIMT rates by menopause group and the test of ovarian group differences in CIMT
rate by trial were estimated on placebo only participants; estimates are shown in Table 16.
Table 16: Model-Estimated CIMT Rates in Placebo Women ≥ 10 Years since Menopause, By
Menopause group and Trial

Estimate
Standard
Error
P-value
EPAT Rate in Intact (n=35) 0.0100¹ 0.0029 0.0008
EPAT Rate in Hysterectomy/Oophorectomized (n=9) 0.0023 0.0063 0.71
EPAT Rate difference -0.0077 0.0069 0.27
WELL-HART Rate in Intact (n=28) -0.0016 0.0037 0.67
WELL HART Rate in Hysterectomy/Oophorectomized (n=15) -0.0079 0.0050 0.12
WELL-HART Rate difference -0.0064 0.0062 0.31
WISH Rate in Intact (n=63) 0.0065 0.0023 0.0046
WISH Rate in Hysterectomy/Oophorectomized (n=11) 0.0101 0.0049 0.039
WISH Rate difference 0.0036 0.0054 0.50
¹ Values= Mean Beta estimates from Mixed Model of Log CIMT

For women ≥10 years since menopause in the EPAT, WELL-HART and WISH trials, although
the difference in the log CIMT rates between the hysterectomized/oophorectomy and the intact group
were not significant (p=0.27, p=0.31 and p=0.50 respectively), the hysterectomized/oophorectomy group
had a lower log CIMT rate than the intact group in the EPAT and WELL-HART trials, but the
hysterectomized/oophorectomy group had a higher log CIMT rate than the intact group in the WISH trial.
DISCUSSION
Our analysis included 873 participants from four trials BVAIT, EPAT, WELL-HART, and
WISH. At baseline, in the base model (Table 5) the mean CIMT of the intact group did not differ from
those in the hysterectomy/no oophorectomy group, but they both where lower than the mean CIMT of the
hysterectomized/oophorectomy group by about 15.6μm. The difference didn’t change (~15.2μm) when
the hysterectomized/no oophorectomy group was removed from the analysis. When we adjust the base
34

model by years since menopause, this difference was cut in half (~7.6μm). We further analyze this
difference by looking at women <10 vs. ≥10 years since menopause. Women with <10 years since
menopause had a mean CIMT of the intact group lower than the mean CIMT of the oophorectomy group
by about 12.9μm where as women who had ≥10 years since menopause had a mean CIMT of the intact
group lower than the mean CIMT of the oophorectomy group by about 4.8μm. When analyzing the cross-
sectional and longitudinal differences in log CIMT by menopause group in the BVAIT trial (Table 7.2),
we notice that the estimate for the hysterectomized/oophorectomy group was far higher than the rest of
the estimates when adjusting for years since menopause, and this difference was due to the number of
participants in the BVAIT study that had data regarding years since menopause (26 out of 160).
Therefore, we did further analysis with and without the BVAIT participants. When we excluded BVAIT
participants at baseline, in the base model (Table 6) the mean CIMT of the intact group again did not
differ from those in the hysterectomy/no oophorectomy group, but they both were lower than the mean
CIMT of the oophorectomy group by about 6.2μm. The difference didn’t change (~5.8μm) when the
hysterectomized/no oophorectomy group was removed from the analysis. When we adjust the base model
by years since menopause, this difference was almost none since they were really close (~ 1.1μm). We
further analyze this difference by looking at women <10 vs. ≥10 years since menopause. Women with
<10 years since menopause had the mean CIMT of the intact group lower than the mean CIMT of the
hysterectomized/oophorectomy group for about 8.6μm where as women who had ≥10 years since
menopause had the mean CIMT of the intact group higher than the mean CIMT of the
hysterectomized/oophorectomy group for about 7μm.
At baseline in women ≥10 years since menopause, the CIMT of the
hysterectomized/oophorectomy group was statistically significantly higher than the intact group in
reference of the WISH trial (p=0.015), and the hysterectomized/oophorectomy group was statistical
significantly different from the intact group in each trial when compared to the WISH trial (p=0.0092)
(Table 12.1). However, these two effects were not significant when we exclude BVAIT participants
(Table 12.2). Out of 160 participants of BVAIT trial 26 had years since menopause data, and from those
35

26, 17 participants were women with ≥10 years since menopause, and therefore the low number of
participants from the BVAIT trial possibly changed the effect.
According to the estimates for women ≥10 years since menopause (Table 13), the rate of the
intact participants was lower than the rate of the hysterectomized/oophorectomy participants in the WISH
trial; however, the rate of the intact participants was higher than the hysterectomized/oophorectomy group
for individuals in both the EPAT and the WELL-HART trials. Since women in these trials had different
treatment, it is possible that different treatment is causing our results to vary. In addition, the higher rate
that the intact participants from the EPAT and the WELL-HART trials have over the
hysterectomized/oophorectomy participants is different on what has been previously found (Dwyer KM et
al., 2002). The reason for this could be that our analysis does not only look at cross-sectional data but
longitudinal data as well. Furthermore, the follow up time of EPAT, WELL-HART, and WISH were 2, 3
and 3 years respectively. It is possible that the follow up time (average = 2.7 years) is not long enough to
study the rate of CIMT progression.
We then, analyze placebo only participants form EPAT, WELL-HART and WISH trials. BVAIT
participants were excluded from the analysis since there were only 10 out of 81 placebo only participants
in the BVAIT study who had data on years since menopause. The three way interaction term that showed
that the rate of the hysterectomized/oophorectomy group was statistical significant lower than the intact
group in each trial when compared to the WISH trial (p=0.0074) (Table 12.2) was no longer significant
(Table 15); however, looking at the estimates on Table 16, we see the similar results as in Table 13 where
we can conclude that we may not have a sufficiently large sample size to see significance in placebo only
women, and that the different treatments might not affect the CIMT rate difference by menopause group
in each trial. Therefore, our results are less generalizable than our expectation at the beginning of our
analysis. The EPAT and WELL-HART trials contained participants may or may not have diabetes
mellitus (excluded fast blood glucose >200mg/dL), serum creatinine <2.5mg/dL, triglycerides
<400mg/dL; on the other hand, in the WISH trial, participants with diabetes mellitus (fast blood glucose >
126mg/dL), serum creatinine >2.0mg/dL, triglycerides >500mg/dL were excluded.
36

CONCLUSION
We conclude that although we could not find significant differences at baseline CIMT level in
women who had hysterectomy with bilateral oophorectomy compared to women who experienced natural
menopause or had a hysterectomy without oophorectomy in the EPAT, WELL-HART and WISH trial,
the mean CIMT level was higher in hysterectomized/oophorectomy group over the intact and
hysterectomized/no oophorectomy groups primarily in women <10 years since menopause, but the mean
CIMT level was lower in hysterectomized/oophorectomy group compared to the intact and
hysterectomized/no oophorectomy groups in women ≥10 years since menopause. In addition, our
exploratory analyses suggest that the rate of CIMT progression is higher in healthy women who undergo
hysterectomy with bilateral oophorectomy compared to women who experienced natural menopause or
had a hysterectomy without oophorectomy. However, this result is not consistent with participants of the
EPAT and WELL-HART trials. It is possible that the follow up time with an average of 2.7 years is not
long enough to study the rate of CIMT progression.

37

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Abstract (if available)

Abstract Background and Purpose: Previous studies have shown association of increasing coronary heart disease with surgical menopause (oophorectomy)

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Asset Metadata

Creator Chan Zhuo, Chan (author)

Core Title Association of oophorectomy with progression of carotid atherosclerosis

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 09/22/2014

Defense Date 09/20/2014

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

Tag carotid atherosclerosis,CIMT,OAI-PMH Harvest,oophorectomy

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

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

Creator Email cchanzhu@usc.edu,chan4work@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-481588

Unique identifier UC11286674

Identifier etd-ChanZhuoCh-2971.pdf (filename),usctheses-c3-481588 (legacy record id)

Legacy Identifier etd-ChanZhuoCh-2971.pdf

Dmrecord 481588

Document Type Thesis

Format application/pdf (imt)

Rights Chan Zhuo, Chan

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