University of Southern California Dissertations and Theses

A randomized controlled trial of hormone therapy on postmenopausal women’s quality of life

(USC Thesis Other)

A randomized controlled trial of hormone therapy on postmenopausal women’s quality of life

PDF

Download

Open document

Flip pages

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content
A Randomized Controlled Trial of Hormone Therapy on Postmenopausal Women’s
Quality of Life

By
Anni Zheng

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

December 2015

1
ABSTRACT
Objective: This study used Women's Health Questionnaire (WHQ) data from the Early
versus Late Intervention Trial with Estradiol (ELITE) to test whether: (1) postmenopausal
hormone therapy (HT) benefits emotional and physical health in healthy postmenopausal
women; and (2) HT has different benefits on emotional and physical health among women
who have more recently experienced menopause (within 6 years) vs. later menopause (10
or more years).
Methods: ELITE was a randomized, double-blinded, placebo-controlled trial with a sample
size of six hundred forty-three healthy postmenopausal women without cardiovascular
disease. The data of interest for this analysis used the Women’s Health Questionnaire
(WHQ), which has been widely used as a quality of life measure in studies of hormonal
preparations for peri- and postmenopausal women [10]. The WHQ includes 9 subscales:
Depression, Somatic Symptoms, Memory/Concentration, Vasomotor
Symptoms, Anxiety/Fears, Sexual Behavior, Sleep Problems, Menstrual Symptoms, and
Attractiveness; higher scores indicate worse quality of life. In ELITE, WHQ was completed
at baseline (before randomization to active hormones or placebo) and subsequently at
every 6 months during the trial follow-up, which lasted for up to 6 years. Linear mixed
effect models were used to test whether randomization to HT benefits changes from
baseline in WHQ subscales.
Results: Compared with the placebo group, women randomized to the treatment group
had significantly larger reductions (indicating greater improvements) in: overall WHQ
score by 0.163 units (p=0.040, 95% CI=-0.316, -0.012), Vasomotor Symptoms score by

2
0.113 units (P <0.0001, 95% CI = -0.129, -0.068), and Sexual Behavior score by 0.069 units
(P ＝0.002, 95% CI =-0.113, -0.025). HT women had significantly greater increases from
baseline (indicating greater decrements) in the Menstrual Symptoms score by 0.046 units
(P <0.0001, 95% CI=0.022, 0.054). The HT effect on the WHQ subscale of Attractiveness
differed in early vs. late menopause. In the late menopause group, the treatment effect was
-0.021 units (p=0.040, 95% CI=-0.316, -0.012), while the treatment effect was 0.051 units
(p=0.050, 95% CI= 0.0004, 0.1014) in the early menopause group. The treatment group
differences on rates of change of the WHQ subscale score were statistically significant on
scores of total WHQ (β= 0.048 units/year, p = 0.0006, 95%vCI=0.020, 0.075), Somatic
Symptoms (β= 0.010 units/year, p = 0.0002, 95% CI=0.005, 0.015), Memory/Concentration
(β= 0.008 units/year, p= 0.047, 95% CI=0.0001, 0.015), Vasomotor Symptoms (β= 0.024
units/year, p < 0.0001, 95% CI=0.016, 0.032), Sleep Problems (β= 0.012 units/year, p=
0.002, 95% CI=0.004, 0.020), and Menstrual Symptoms (β= -0.005 units/year, p= 0.048,
95% CI=-0.010, -3.850).
Conclusions: Randomization to HT had both positive and negative effects on quality of life
measured by the WHQ. HT benefits were noted for overall quality of life, Vasomotor
Symptoms and Sexual Behavior. In contrast, HT negatively influenced Menstrual
Symptoms. Importantly, HT effects on quality of life did not differ among women in early
vs. late menopause (except for the Attractiveness subscale). The timing of HT initiation in
early vs. later menopause also did not moderate the HT effect on WHQ subscales rates of
change.
Key Words: Menopause Status, Women’s Health Questionnaire, Hormone Therapy,
Randomized Trials, Timing Hypothesis, Quality of Life

3
ACKNOWLEDGEMENT
I would like to thank all my committee members. First and foremost I offer my
sincerest gratitude to my committee chair, Professor Wendy Mack, for her patience and
guidance. It was her vision and advice that help me improve my thesis.
Besides my committee chair, I would like to thank the rest of my thesis committee:
Dr. Howard N Hodis and Dr. Roksana Karim for their insightful comments and constructive
feedback.

4
TABLE OF CONTENTS

ABSTRACT ............................................................................................................................................................... 1
ACKNOWLEDGEMENT ........................................................................................................................................ 3
TABLE OF CONTENTS ......................................................................................................................................... 4
LIST OF TABLES ..................................................................................................................................................... 6
INTRODUCTION ...................................................................................................................................................... 7
METHODS ................................................................................................................................................................. 9
ELITE DESIGN AND DATA COLLECTION ............................................................................................................. 9
WOMEN’S HEALTH QUESTIONNAIRE (WHQ) ................................................................................................... 9
STATISTICAL ANALYSIS .................................................................................................................................. 11
HYPOTHESIS 1 ..................................................................................................................................................... 11
HYPOTHESIS 2 ..................................................................................................................................................... 11
HYPOTHESIS 3 ..................................................................................................................................................... 11
HYPOTHESIS 4 ..................................................................................................................................................... 12
RESULTS ................................................................................................................................................................ 15
SAMPLE CHARACTERISTICS................................................................................................................................ 15
HORMONE THERAPY EFFECTS ON QOL ACROSS TRIAL FOLLOW-UP IN THE TOTAL SAMPLE
(HYPOTHESIS 1) ................................................................................................................................................. 16
HORMONE THERAPY EFFECTS ON QOL ACROSS TRIAL FOLLOW-UP: TIME SINCE MENOPAUSE
SUBGROUPS (HYPOTHESIS 2) ............................................................................................................................ 17
EVALUATION OF DIFFERENTIAL HORMONE THERAPY EFFECTS BY FOLLOW-UP TIME (HYPOTHESIS 3). 18

5
EVALUATION OF TIME-RELATED HORMONE THERAPY EFFECTS BY TIME SINCE MENOPAUSE
SUBGROUPS (HYPOTHESIS 4) ............................................................................................................................ 19
DISCUSSION.......................................................................................................................................................... 20
REFERENCES ....................................................................................................................................................... 28
APPENDIX ............................................................................................................................................................. 30

6
LIST OF TABLES

Table 1. ELITE Sample Characteristics by Menopause Stratum ........................................... …….24

Table 2. HT Treatment Effects on WHQ Subscales

(Linear Mixed Models) ........................................................................................................ …….25

Table 3. HT Treatment Effects on WHQ Subscales (Linear Mixed Models

with interaction terms of treatment*menopause stratum) ................................. …….26

Table 4. HT Treatment Effects on WHQ Subscales (Linear Mixed Models
with interaction terms of treatment *measurement year) ................................... …….27

Table 5. HT Treatment Effects on WHQ Subscales (Linear Mixed Models with Interaction
terms of treatment*measurement year *time since menopause)…………......................28

7
INTRODUCTION

Menopause, defined as the end of menstruation, occurs in a woman’s midlife, at an
average age of 50 years in developed countries [1]. Menopause is associated with
biological changes as well as social and cultural changes [2]. The menopausal transition
can be associated with differential understanding and needs according to cultural group
[3].
Biological aspects of menopause include vasomotor symptoms such as hot flushes
and diaphoresis [4], which may lead to distress and fatigue [5]. Other menopause-related
symptoms include vaginal dryness and dyspareunia, insomnia or sleep disturbances,
frequent urination or urinary incontinence, urinary tract infections, decreased libido,
vaginal atrophy, depression and mood swings, and increased anxiety or irritability.
Previous studies also indicate that menopause is a risk factor for medium- and long-term
illnesses, including atrophic urogenital disorders, osteoporotic fractures and coronary
heart disease [1]. The prevalence of cardiovascular disease increases dramatically in older
post-menopausal women [6].
Menopausal hormone therapy (HT) encompasses exogenous steroid hormones used
in the peri- and post-menopause for treatment of menopausal symptoms. For
postmenopausal women, HT can reduce menopausal symptoms and improve quality of life
(QOL) [7]. Postmenopausal hormone therapy reduces hot flashes, sleep disturbances,
vaginal dryness and vaginal atrophy [8].
ELITE was a randomized, double-blinded, placebo-controlled, 2 x 2 factorial design
trial that was originally designed to test whether HT effects on subclinical atherosclerosis
differ in women who have more recently experienced menopause compared with women
who have been many years post-menopausal [9]. While not a planned trial outcome, we

8
investigate the randomized HT effect on menopause-related quality of life in the Early
versus Late Intervention Trial with Estradiol (ELITE). In this post hoc analysis, we
specifically tested: (1) Whether randomization to HT benefits quality-of-life compared with
placebo group; and (2) Whether any HT benefit on quality of life differs among women in
early vs. late menopause.

9
METHODS

ELITE Design and Data Collection

The ELITE was designed to specifically test the timing hypothesis of
postmenopausal hormone therapy (HT) [9]. ELITE was a randomized, double-blinded,
placebo-controlled trial conducted among healthy postmenopausal women without
cardiovascular disease. A total number of 643 participants were randomized to oral
micronized 17β-estradiol 1 mg/day or matching placebo. Women with an intact uterus
were also given 4% vaginal micronized progesterone gel 45 mg/day or matching placebo
for 10 days each month. Randomization was stratified on baseline carotid artery intima-
media thickness CIMT (dichotomous: <0.75 mm or ≥0.75 mm) and hysterectomy
(dichotomous: yes or no). After randomization, participant evaluations were conducted
every month for the first 6 months of the trial and then every other month until trial
completion.
Women’s Health Questionnaire (WHQ)

The data of interest for this analysis used the Women’s Health Questionnaire (WHQ)
(see Appendix). The WHQ has been widely used as a quality of life measure in studies of
hormonal preparations for peri- and postmenopausal women; its reliability and validity
have been well-tested and well-established [10]. The WHQ Subscales include assessments
of dimensions of emotional and physical health, including Depression, Sleep Problems,
Somatic Symptoms, Vasomotor Symptoms, Anxiety/Fears, Attractiveness,
Memory/Concentration, Menstrual Problems and Sexual Difficulties. WHQ items are each
answered on a four-point scale (yes definitely, yes sometimes, no not much, no not at all).

According to the scoring instructions, the 4-point scores are then reduced to binary options

10
(0: negative response (no not much, no not at all)/1: positive response (yes sometimes, yes
definitely)). These dichotomized subscale items are summed and divided by the number of
items in each subscale. Higher scores correspond to worse quality of life. In the ELITE
trial, the WHQ was completed at baseline (before randomization to active hormones or
placebo) and subsequently at every 6 months during the trial follow-up, which lasted up to
6 years.

11
STATISTICAL ANALYSIS

This analysis aims to test four hypotheses:
Hypothesis 1

Null: Hormone therapy (HT) does not benefit postmenopausal women’s emotional
and physical health as measured by changes in WHQ total and subscale scores.
Alternative: Hormone therapy (HT) benefits postmenopausal women’s emotional
and physical health as measured by changes in WHQ total and subscale scores.
Equation form : Change scores (on-trial minus baseline) of WHQ Subscales = HT
Treatment + Measurement Year (as a continuous variable, centered at the mean of 2.7) +
Hysterectomy + CIMT stratum + Postmenopause stratum + Baseline WHQ Subscale
(continuous)
Hypothesis 2

Null: HT effects on the changes in WHQ total and subscales are the same in each
menopause group (time since menopause < 6 years and time since menopause ≥ 10 years).
Alternative: HT effects on changes in WHQ total and subscales differ by menopause
group (time since menopause < 6 years and time since menopause ≥ 10 years).
Equation form : Change scores in WHQ Subscales = HT Treatment + Measurement
Year (as a continuous variable, centered at the mean of 2.7) + Hysterectomy + CIMT
stratum + Postmenopause stratum + Baseline WHQ Subscale (continuous) + HT
Treatment* Menopause stratum
Hypothesis 3

Null: The magnitude of the HT effect on WHQ Subscales does not change over the
trial follow-up.

12
Alternative: The magnitude of the HT effect of WHQ Subscales changes over the trial
follow-up.
Equation form: Change scores of WHQ subscales = HT Treatment + Measurement
Year (as a continuous variable, centered at 2.7) + Hysterectomy + CIMT stratum +
Postmenopause Stratum + Baseline WHQ Subscale (continuous) + HT Treatment*
Measurement Year
Hypothesis 4

Null: A time-related HT effect on change in WHQ subscales does not differ in early
vs. late menopause subgroups.
Alternative: The time-related HT treatment effect on rate of change in WHQ
subscales measured over the trial differs in early vs. late menopause subgroups.
Equation form: Change scores of WHQ Subscales = HT Treatment + Measurement
Year (as a continuous variable, centered at 2.7) + Hysterectomy + CIMT stratum +
Postmenopause Stratum + Baseline WHQ Subscale (continuous) + HT Treatment*
Measurement Year + HT Treatment* Menopause stratum + HT Treatment* Menopause
stratum* Measurement Year
Since the dataset is longitudinal, and we are interested in the effect of HT for any
individual woman rather than for the population, linear mixed effects models were used to
address the above hypotheses. The rationale of using linear mixed effect model is that: (1)
This is a longitudinal study with multiple measurements for each subject, and the linear
mixed effect model is well suited to analyze longitudinal data; (2) Linear mixed effect
models can better handle missing data because it does not require complete data on all
subjects at each follow-up; (3) Linear mixed effect models are flexible in that they do not
require all observations to be completed at the same time points; (4) Linear mixed effects

13
models allow us to estimate the effect of HT at the individual level, which is the major
objective of this study. In contrast, marginal effect models only give us the population
averaged effect of the intervention. One key assumption of the linear mixed effects model
is that random effects are not correlated with the independent variables.
The randomization and stratification process helped to make sure that subjects in
each group were comparable and also ensured that individual effects were not correlated
with covariates such as carotid artery intima-media thickness and hysterectomy.
Dependent variables in the linear mixed effects models were the change scores of
on-trial scores of the nine WHQ subscales and one overall score of quality of life. A total
WHQ score was computed as the sum of the nine WHQ subscales. At each visit at which
WHQ was completed, a change score for the total and each subscale was computed as the
visit measure minus the baseline measure. Since this is a longitudinal dataset, the
dependent variables measured repeatedly over trial follow-up are very likely to be
correlated with one another.
The primary independent variable was randomized treatment assignment. Stratum
variables of time since menopause (early post-menopause or late post-menopause),
baseline carotid artery intima-media thickness CIMT (dichotomous: <0.75mm or
≥0.75mm), and hysterectomy (dichotomous: yes or no) were included as covariates.
Baseline levels of each dependent variable were also included as a covariate. The
regression coefficient for treatment assignment tested whether HT influenced changes
from baseline in emotional and physical health measured by WHQ total and subscales.
Follow-up observations were not conducted in the same months for all subjects, so
measurement year (defined as year since randomization) was categorized in the following
way: 1-6 months was categorized as 0.5 years, 7-12 months was categorized as 1 year, 13-

14
18 months was categorized as 1.5 year, 19-24 months was categorized as 2.0 years, 25-30
months was categorized as 2.5 years, 31-36 months was categorized as 3.0 years, 37-42
months was categorized as 3.5 years, 43-48 months was categorized as 4.0 years, 49-54
months was categorized as 4.5 years, 55-60 months was categorized as 5.0 years, 61-66
months was categorized as 5.5 years, 67-72 months was categorized as 6.0 years, and 73-
78 months was categorized as 6.5 years. In the mixed effects models, we then redefined the
measurement year, so the regression coefficient of measurement year estimated the
annualized rate of change over the measurement period (0.5 to 6.5 years).
The Hypothesis 1 model assumed that the magnitude of the HT effect on changes in
WHQ was equivalent over all on-trial measurement periods. To test whether the treatment
effect differed among women in early versus late postmenopause (Hypothesis 2), an
interaction term between treatment and menopause stratum was included in the model.
To test whether HT modified the rate of change in any WHQ subscale (Hypothesis 3), an
interaction term between treatment and measurement year was included in the analysis.
Finally, to test the hypothesis that any HT effect on rate of change in quality of life differs
among women in early vs. late postmenopause (Hypothesis 4), a 3-term interaction
including menopause stratum, measurement year and treatment assignment was included
as an independent variable (as well as all two-order interactions).

15
RESULTS

Sample Characteristics

Table 1 shows baseline characteristics of the ELITE sample by menopause stratum
and treatment group. The 643 randomized participants were composed of White (56.2%),
Black (20.4%), Hispanic (13.1%) and Asian (10.2%) women. More than 99% of the
participants had a high school or greater education. The mean age for women in the
stratum of early post-menopause was 55 years, and the mean age for women in the stratum
of late post-menopause was 63 years. Table 1 also shows the median score for each WHQ
subscale measured at baseline among the four groups.
The Attractiveness Symptoms scale had the highest score (median = 0.5) at baseline,
indicating the lowest quality of life among the WHQ subscales. Among the early post-
menopause group, the ranking (high to low) of medians on the WHQ subscales for HT-
treated women was Attractiveness Symptoms (0.5), Sleep Problems (0.3), Sexual Behavior
(0.3), Somatic Symptoms (0.1), Memory/Concentration (0.0), Anxiety/Fears (0.0),
Vasomotor Symptoms (0.0), Depressed Mood (0.0) and Menstrual Symptoms (0.0). The
ranking (high to low) of medians on the WHQ subscales for placebo-treated women was
Attractiveness Symptoms (0.5), Sexual Behavior (0.3), Sleep Problems (0.3), Somatic
Symptoms (0.1), Vasomotor Symptoms (0.0), Memory/Concentration (0.0), Anxiety/Fears
(0.0), Depressed Mood (0.0), and Menstrual Symptoms (0.0). Among the late
postmenopause group, the ranking (high to low) of averages on the WHQ subscales for HT-
treated women was Attractiveness (0.5), Sexual Behavior (0.3), Memory/Concentration
(0.3), Attractiveness (0.3), Sleep Problems (0.0), Anxiety/Fears (0.0), Depressed Mood
(0.0), Menstrual Symptoms (0.0), Vasomotor Symptoms (0.0) and. The ranking (high to
low) of averages on the WHQ subscales for placebo-treated women was Vasomotor

16
Symptoms (0.5), Sexual Behavior (0.3), Memory/Concentration (0.3), Sleep Problems (0.3),
Somatic Symptoms (0.1), Attractiveness (0.0), Anxiety/Fears (0.0), Depressed Mood (0.0),
and Menstrual Symptoms (0.0).
Hormone Therapy effects on QOL across trial follow-up in the total sample
(Hypothesis 1)
Table 2 presents results of the first mixed model. Measurement year had a negative
and statistically significant association with change scores of the total WHQ, as well as the
WHQ subscales of Depression, Vasomotor Symptoms, Anxiety, Sleep Problem and
Menstrual Symptoms, suggesting that these symptoms tended to improve over the trial,
controlling for other covariates. However, measurement year had a positive and
statistically significant association with changes in Sexual Behavior, showing that sexual
problems tended to worsen over the trial. The baseline WHQ scores had a negative and
statistically significant association with all change scores. Hysterectomy had a negative
(indicating larger reductions in symptoms) and statistically significant association with
changes in Vasomotor Symptoms and Menstrual Symptoms. The CIMT stratification factor
was not significantly associated with any of the WHQ change scores. Compared with the
early postmenopause group, the late postmenopause group had a larger increase in the
Sexual Behavior score by 0.062 units (SE, 0.024, p=0.009, 95%CI=0.015, 0.108), indicating
worsening of symptoms.
In terms of treatment effects, HT and placebo treated women significantly differed
on changes in some subscales of the WHQ. Compared with the placebo group, the average
(SE) change score of Vasomotor Symptoms (averaged over the trial follow-up) of the HT
group was 0.113 units (SE, 0.018) lower than the placebo group (p=<0.0001, 95% CI=-
0.149, -0.077), indicating significantly improved QOL in this area. The average (SE) change

17
score of Sexual Behavior of the HT group was 0.069 (SE, 0.022) units (p=0.002, 95% CI=-
0.113, -0.025) lower than the placebo group, again indicating significantly better QOL in
this area. Conversely, compared with the placebo group, the average change score of
Menstrual Symptoms was 0.046 (SE, 0.010) units (p<0.0001, 95% CI= 0.027, 0.065) higher
in the treatment group, suggesting significantly poorer QOL in this area in the HT group.
The average change scores of Anxiety/Fears, Depression, Sleep Problems,
Memory/Concentration, Somatic Symptoms, and Attractiveness did not significantly differ
between HT and placebo groups.
A composite scale of the sum of the nine subscales was constructed to capture the
overall quality of life. Compared with the placebo group, the average change from baseline
in the total WHQ score of the HT group was 0.164 (SE, 0.078) units (p=0.036, 95% CI= -
0.316, -0.012) lower, indicating overall better QOL measured by the WHQ. In summary,
testing of hypothesis 1 demonstrated that randomization to HT benefited quality of life,
averaged over the trial follow-up, compared to the placebo group on changes from baseline
in the WHQ subscales of Vasomotor Symptoms and Sexual Behavior as well as the WHQ
total. However, HT worsened Menstrual Symptoms (breasts feel tender or uncomfortable;
abdominal cramps or discomfort; stomach feels bloated) compared to placebo.
Hormone Therapy effects on QOL across trial follow-up: Time Since Menopause
Subgroups (Hypothesis 2)
To further test whether the treatment effects on average change in WHQ scores
differed by postmenopause group (time since menopause < 6 years and time since
menopause ≥ 10 years), an interaction term between treatment and postmenopause
stratum (early vs. late) was added to the above model. Results of these analyses are
presented in Table 3.

18
The HT effect on change in the WHQ Attractiveness subscale differed in the early vs.
late postmenopause strata. In the late postmenopause group, the treatment effect was -
0.021 units (p=0.040, 95%CI=-0.316, -0.012), while the treatment effect was 0.051 units
(p=0.050, 95%CI=0.0004, 0.1014) in the early postmenopause group. These results
suggest that HT improved the Attractiveness subscale in the late postmenopause group, but
worsened in the early postmenopause group. The interaction terms were not statistically
significant in any of the other WHQ subscale regressions, suggesting that treatment effects
did not differ by postmenopause group.
Evaluation of Differential Hormone Therapy Effects by Follow-up Time (Hypothesis
3)
To test if the effect of HT on WHQ changed over the trial follow-up, an interaction
term between treatment and measurement year was added to the model. As Table 4
shows, the interaction term testing treatment group differences on rates of change of WHQ
subscale score showed statistical significance on scores of total WHQ (β= 0.048 units,
SE=0.014, p=0.0006), Somatic Symptoms (β= 0.010 units, SE=0.003, p= 0.0001),
Memory/Concentration (β= 0.008 units, SE=0.004, p= 0.047), Vasomotor Symptoms (β=
0.024 units, SE=0.004, p<0.0001), Sleep Problems (β= 0.012 units, SE=0.004, p =0.002), and
Menstrual Symptoms (β= -0.005 units, SE=0.002, p=0.048). The positive interaction terms
for total WHQ, Vasomotor Symptoms, Somatic Symptoms, Memory/Concentration and
Sleep Problems indicate that any HT benefit on these subscales is attenuated over the trial
follow-up, such that differences between HT and placebo become smaller. The negative
interaction term for Menstrual Symptoms indicate that the HT effect on increasing
Menstrual Symptoms gets bigger over time. For example, the model-predicted variation in
HT effects on total WHQ over the trial follow-up (p-value for HT*measurement year

19
interaction<0.01) provides the following estimates for HT effects: -0.410 units at 0.5 years,
-0.283 units at 2.7 years, and -0.173 units at 5 years post-randomization.
Evaluation of Time-Related Hormone Therapy Effects by Time Since Menopause
Subgroups (Hypothesis 4)
To further test whether the differential HT effect on changes in WHQ according to
follow-up time differed in early vs. late postmenopause subgroups, a three-level interaction
term (menopause stratum-HT-measurement year) was added to the above model. As Table
5 shows, none of these 3-level interaction terms were significant on any WHQ subscale,
suggesting that the timing of HT initiation in early vs. late postmenopause did not moderate
the time-related HT effect on WHQ subscales.

20
DISCUSSION

These data from the ELITE trial provide additional evidence regarding HT effects on
menopause-related aspects of QOL. Hormone therapy (HT) significantly improved the
overall quality of life and quality of life on certain subscales including Vasomotor
Symptoms and Sexual Behavior. However, HT was associated with worsening QOL on
Menstrual Symptoms, which included known and established side effects of estrogen-based
therapy including uterine bleeding and breast tenderness.
Our analysis suggested that the hormone treatment effect in Attractiveness differed
in early vs. late menopause groups. HT improve the Attractiveness subscale in the late
menopause group, but worsened the problem in the early menopause group. However, HT
effects were comparably observed on the total WHQ and all other subscales among women
who had more recently experienced menopause (within 6 years) and those who had
experienced menopause 10 or more years previously. Therefore, we conclude that
initiating HT in late or early postmenopause does not make a difference in QOL-related
treatment effects except on the factors that define the Attractiveness subscale (feel rather
lively and Excitable/ feel physically attractive).
Our results also suggest that the HT effects noted above were attenuated over the
trial follow-up. Specifically HT-by-measurement year interaction terms were statistically
significant for all of the main effects noted above (total WHQ, Vasomotor Symptoms, Sexual
Behavior and Menstrual Symptoms). The timing of HT initiation in the early and late
postmenopause groups did not moderate the treatment effects on these time-related HT
effects. The attenuation of the HT effect over trial follow-up might be due to biological
mechanisms, but may also be due to reduced adherence to the HT treatment over trial
follow-up (for example, if women stopped HT).

21
In a randomized clinical trial of 3721 postmenopausal women aged 50-69 years at
randomization conducted in the UK, Australia and New Zealand [12], the investigators
reported results similar to ours. In this trial, subjects were randomized to combined
estrogen and progestogen (n=1862) or placebo (n=1859). Investigators used the Women’s
Health Questionnaire to assess quality of life at baseline and at 1-year post-
randomization. Improvements were observed in the Women’s Health Questionnaire for
those taking combined HT compared with those taking placebo in vasomotor symptoms
(P<0.001), sexual functioning (P<0.001), and sleep problems (P<0.001). The
improvements in vasomotor symptoms and sexual functioning were consistent with our
findings. Although we did find a benefit of HT on Sleep Problems (beta (SE) = -0.021 units
(0.016), p=0.19; Table 2), our findings did not reach statistical significance.
One strength of our study is the testing of the timing hypothesis based on the ELITE
trial design. Although ELITE was designed to test the timing hypothesis in relation to
atherosclerosis, the trial also provided consistent data with regards to quality-of-life
outcomes for testing the benefits of HT on emotional and physical health. The ELITE trial
design is appropriate for testing the timing hypothesis as there was by design excellent
separation without overlap between the two menopause groups (time since menopause < 6
years and time since menopause ≥ 10 years) [9]. In terms of the statistical analysis, linear
mixed effects models were used to estimate the effect of HT at the individual level, which is
the major objective of this study.
In our studies, women who were randomized to HT within 6 years after the final
menstrual period demonstrated effects on WHQ QOL that were comparable to women who
were randomized to HT more than 10 years after the final menstrual period. Further
exploration should be conducted in a larger study to test when the optimum time to initiate

22
HT is, although our results suggest that improvements in certain aspects of menopause-
related QOL are evident regardless as to when HT is initiated [9].
The statistical analysis used linear mixed effects models for testing the study
hypotheses of these longitudinal data, testing these hypotheses at the individual level.
Further analyses may use models such as the GEE model to test the effect of HT at the
population level.
The WHQ questionnaire has some limitations. For example, as the WHQ
Questionnaire User Manual points out, the longitudinal psychometric properties of the
WHQ still need validation. Another limitation is the way that data were treated. Per the
WHQ scoring protocol, each item was dichotomized, which may lead to loss of useful
information and cause the distribution of the dependent variables to be less normal.
In conclusion, HT benefits quality-of-life in vasomotor and sexual function areas, as
measured by the WHQ. These effects are comparable in early and late postmenopause
women when HT is initiated. Oral estradiol therapy could be recommended to women who
suffer from vasomotor and sexual-related menopausal problems.

23
Table 1 ELITE Sample Characteristics by Menopause Stratum

Menopause <6years Menopause≥10years

HT(N=137) Placebo(N=134) HT(N=186) Placebo(N=186)
Demographic Factors

Age
55.0(4.0) 55.0(5.0) 64.0(8.0) 62.0(7.0)
Race

White
77(56.2%) 77(57.4%) 134(72.0%) 132(71.0%)
Black
28(20.4%) 16(11.9%) 20(10.8%) 16(8.6%)
Hispanic
18(13.1%) 23(17.2%) 23(12.4%) 26(14.0%)
Asian
14(10.2%) 18(13.4%) 9(5%) 12(6.5%)
Education

Less than high school
1(0.7%) 0 0 2
High school and some
college
33(24.1%) 42(31.3%) 62(33.3%) 75(40.3%)
College graduate
103(75.2%) 92(68.7%) 124(66.7%) 109(58.7%)
WHQ Subscales

Depressed Mood
0.0(0.1) 0.0(0.1) 0.0(0.1) 0.0(0.1)
Somatic Symptoms
0.1(0.3) 0.1(0.3) 0.1(0.3) 0.1(0.3)
Memory/Concentration
0.0(0.7) 0.3(0.7) 0.3(0.7) 0.3(0.7)
Vasomotor Symptoms
0.0(0.5) 0.0(0.5) 0.0(0.0) 0.0(0.5)
Anxiety/Fears
0.0(0.3) 0.0(0.3) 0.0(0.3) 0.0(0.3)
Sexual Behavior
0.0(0.7) 0.3(1.0) 0.3(0.7) 0.3(0.0)
Menstrual Symptoms
0.0(0.3) 0.0(0.3) 0.0(0.3) 0.0(0.3)
Attractiveness
0.5(0.5) 0.5(0.5) 0.5(0.5) 0.5(0.5)
Sleep Problems
0.3(0.7) 0.3(0.7) 0.0(0.3) 0.3(0.7)
All WHQ Subscales values and also age values are presented as median (IQR),
categorical variables are summarized as number (percentages)

24
Table 2 HT Treatment Effects on WHQ Subscales (Linear Mixed Models)
Total WHQ Depression Attractiveness Somatic Symptoms Memory/Concentration Vasomotor Symptoms Anxiety/Fears Sexual Behavior Sleep Problems Menstrual symptoms
Number of observations 4693 4986 4986 4986 4986 4986 4986 4693 4986 4986
Intercept 0.892(0.193) 0.047(0.020) 0.206(0.039) 0.111(0.025) 0.058(0.004) 0.182(0.042) 0.087(0.023) 0.184(0.052) 0.197(0.038) 0.113(0.022)
HT Treatment -0.163(0.077)* -0.009(0.009) 0.010(0.017) -0.013(0.011) 0.006(0.019) -0.113(0.018)*** -0.003(0.010) -0.069(0.022)** -0.021(0.016) 0.046(0.010)***
Measurement year -0.02(0.007)** -0.002(0.001)* -0.001(0.002) 0.001(0.001) 0.001(0.002) -0.012(0.002)*** -0.003(0.001)* 0.008(0.003)** -0.004(0.002)* -0.008(0.001)***
Hysterectomy -0.158(0.107) 0.002(0.012) -0.022(0.023) -0.007(0.015) 0.007(0.025) -0.079(0.025)** -0.008(0.014) 0.042(0.030) -0.039(0.022) -0.027(0.013)*
CIMT -0.023(0.080) -0.001(0.009) -0.018(0.017) -0.011(0.011) 0.032(0.019) 0.011(0.019) -0.012(0.010) -0.037(0.023) -0.017(0.017) -0.015(0.010)
Menopause
>=10yrs
0.115(0.084) -0.007(0.009) 0.033(0.018) 0.021(0.012) -0.000(0.020) -0.017(0.020) -0.014(0.011) 0.062(0.024)** 0.001(0.018) -0.012(0.010)
Baseline value -0.433(0.028)*** -0.473(0.027)*** -0.509(0.023)*** -0.528(0.026)*** -0.448(0.027)*** -0.634(0.022)*** -0.578(0.023)*** -0.514(0.027)*** -0.500(0.026)*** -0.624(0.031)***
All WHQ Subscales values are presented as β (SE)
* P<0.05 ** P<0.01 *** P<0.001

25
Table 3. HT Treatment Effects on WHQ Subscales (Linear Mixed Models with interaction terms of
treatment*menopause stratum)

All WHQ Subscales values are presented as β (SE)
* P<0.05 ** P<0.01 *** P<0.001

Total WHQ Depression Attractiveness Somatic Symptoms Memory/
Concentration
Vasomotor Symptoms Anxiety/Fears Sexual Behavior Sleep Problems Menstrual Symptoms
Number of observation 4693 4986 4986 4986 4986 4986 4986 4693 4986 4986
Intercept 0.864(0.198) 0.047(0.021) 0.186(0.040) 0.109(0.026) 0.062(0.046) 0.187(0.044) 0.094(0.024) 0.181(0.054) 0.185(0.039) 0.113(0.023)
HT Treatment -0.105(0.118) -0.010(0.013) 0.051(0.026)* -0.009(0.017) -0.002(0.028) -0.123(0.028)*** -0.016(0.016) -0.062(0.034) 0.004(0.025) 0.046(0.015)**
Measurement year -0.020(0.007)** -0.002(0.001)* -0.001(0.002) 0.001(0.001) 0.001(0.002) -0.012(0.002)*** -0.003(0.001)* 0.008(0.003)** -0.005(0.002)* -0.008(0.001)***
Hysterectomy -0.161(0.107) 0.002(0.012) -0.023(0.023) -0.007(0.015) 0.007(0.025) -0.078(0.025)** -0.008(0.014) 0.042(0.031) -0.040(0.023) -0.027(0.013)*
CIMT -0.023(0.080) -0.001(0.009) -0.018(0.017) -0.011(0.011) 0.032(0.20) 0.011(0.019) -0.012(0.010) -0.037(0.023) -0.018(0.017) -0.015(0.010)
Menopause>=10yrs 0.168(0.116) -0.008(0.013) 0.070(0.025)** 0.024(0.016) -0.007(0.028) -0.026(0.028) -0.025(0.015) 0.068(0.033)* 0.024(0.025) -0.011(0.014)
Baseline value -0.433(0.028)*** -0.472(0.027)*** -0.510(0.024)*** -0.528(0.027)*** -0.448(0.027)*** -0.635(0.022)*** -0.580(0.023)*** -0.514(0.027)*** -0.500(0.026)*** -0.624(0.031)***
HT Treatment*
menopause
Stratum
-0.103(0.157) 0.002(0.018) -0.072(0.034)* -0.006(0.022) 0.014(0.038) 0.018(0.037) 0.022(0.020) -0.012(0.045) -0.044(0.033) -0.001(0.020)

26
Table 4. HT Treatment Effects on WHQ Subscales (Linear Mixed Models with interaction terms of treatment
*measurement year)

All WHQ Subscales values are presented as β (SE)

* P<0.05 ** P<0.01 *** P<0.001

Total WHQ Depression Depression Attractiveness Somatic
Symptoms
Memory/
Concentration
Vasomotor
Symptoms
Anxiety/Fears Sexual
Behavior
Sleep
Problems
Menstrual
Symptoms
Number
of observation
4693 4986 4986 4986 4986 4986 4986 4986 4693 4986 4986
Intercept 1.016(0.197) 0.047(0.020) 0.047(0.019) 0.205(0.039) 0.109(0.025) 0.057(0.044) 0.180(0.043) 0.087(0.023) 0.185(0.052) 0.196(0.038) 0.114(0.022)
HT Treatment -
0.283(0.085)**
-0.009(0.009) -0.009(0.008) 0.011(0.017) -0.012(0.011) 0.007(0.019) -
0.109(0.018)**
*
-0.003(0.010) -
0.071(0.022)**
-0.020(0.017) 0.045(0.010)**
*
Measurement year 0.004(0.010) -0.003(0.002)* -0.003(0.001)* -0.004(0.003) -0.003(0.002) -0.003(0.003) -
0.023(0.003)**
*
-0.002(0.002) 0.013(0.003)**
*
-
0.010(0.003)**
*
-
0.005(0.002)**
Hysterectomy -0.159(0.107) 0.002(0.012) 0.002(0.012) -0.022(0.023) -0.007(0.015) 0.007(0.025) -
0.079(0.025)**
-0.008(0.014) 0.042(0.030) -0.039(0.023) -0.027(0.013)*
CIMT -0.023(0.080) -0.001(0.009) -0.001(0.008) -0.018(0.017) -0.011(0.011) 0.032(0.019) 0.011(0.019) -0.012(0.010) -0.037(0.023) -0.017(0.017) -0.015(0.010)
Menopause>=10yr
s

0.119(0.084) -0.007(0.009) -0.007(0.009) 0.034(0.018) 0.022(0.012) 0.000(0.020) -0.016(0.020) -0.014(0.011) 0.062(0.024)* 0.002(0.018) -0.012(0.010)
Baseline value -
0.433(0.028)**
*
-
0.472(0.027)**
*
0.527(0.027)**
*
-
0.509(0.024)**
*
-
0.528(0.026)**
*
-
0.448(0.027)**
*
-
0.635(0.022)**
*
-
0.578(0.023)**
*
-
0.514(0.027)**
*
-
0.500(0.028)**
*
-
0.624(0.031)**
*
HT Treatment*
measurement year
0.048(0.014)** 0.002(0.002) 0.002(0.002) 0.005(0.005) 0.010(0.003)**
*
0.008(0.004)* 0.024(0.004)**
*
-0.000(0.002) -0.010(0.005) 0.012(0.004)** -0.005(0.003)*

27
Table 5. HT Treatment Effects on WHQ Subscales (Linear Mixed Models with interaction terms of treatment*measurement year
*time since menopause)
All WHQ Subscales values (except for # of observation) are presented as β (SE)
* P<0.05 ** P<0.01 *** P<0.001
Total WHQ Depression Attractiveness Somatic Symptoms Memory/Concentrati
on
Vasomotor
Symptoms
Anxiety/Fears Sexual Behavior Sleep Problems Menstrual
Symptoms
Number of observation 4693 4986 4986 4986 4986 4986 4986 4693 4986 4986
Intercept 0.856(0.199) 0.047(0.021) 0.186(0.040) 0.107(0.026) 0.060(0.046) 0.183(0.043) 0.093(0.023) 0.182(0.053) 0.184(0.040) 0.113(0.022)
HT Treatment -0.096(0.118) -0.010(0.013) 0.051(0.026)* -0.018(0.017) -0.000(0.029) -0.119(0.028)*** -0.015(0.015) -0.063(0.033) 0.005(0.025) 0.046(0.015)**
Measurement year -0.067(0.015)*** -0.003(0.002) -0.002(0.005) -0.006(0.003)* -0.009(0.004)* -0.033(0.004)*** -0.005(0.03)* 0.014(0.006)* -0.015(0.004)*** -0.008(0.003)**
Hysterectomy -0.161(0.108) 0.002(0.011) -0.023(0.023) -0.007(0.015) 0.007(0.025) -0.079(0.025)** -0.008(0.014) 0.042(0.031) -0.040(0.023) -0.027(0.013)*
CIMT -0.023(0.080) -0.001(0.009) -0.018(0.017) -0.011(0.011) 0.032(0.019) 0.011(0.018) -0.012(0.010) -0.037(0.023) -0.017(0.017) -0.015(0.010)
Menopause>=10ys 0.176(0.116) -0.008(0.013) 0.069(0.025)** 0.025(0.016) -0.006(0.028) -0.024(0.028) -0.024(0.014) 0.068(0.033)* 0.025(0.025) -0.011(0.014)
Baseline value -0.433(0.028)*** 0.472(0.027)*** -0.510(0.023)*** -0.527(0.027)*** -0.448(0.027)*** -0.635(0.022)*** -0.580(0.023)*** -0.514(0.027)*** -0.500(0.026)*** -0.624(0.031)***
HT Treatment*
measurement year
0.055(0.020)** 0.002(0.003) -0.001(0.007) 0.009(0.004)* 0.013(0.006)* 0.030(0.006)*** 0.000(0.003) -0.006(0.007) 0.014(0.006)* -0.008(0.004)*
Measurement year
*menopause stratum
0.043(0.020)* -0.000(0.003) -0.004(0.006) 0.004(0.004) 0.010(0.006) 0.017(0.005)** 0.005(0.003) -0.014(0.007) 0.008(0.006) 0.004(0.004)
HT Treatment
*menopause stratum
-0.101(0.157) 0.002(0.018) -0.070(0.034)* -0.005(0.022) 0.013(0.038) 0.018(0.037) 0.022(0.020) -0.000(0.045) -0.043(0.033) -0.000(0.020)
Measurement year
*menopause stratum
*HT Treatment
-0.010(0.028) -0.000(0.004) 0.011(0.009) 0.001(0.005) -0.009(0.008) -0.011(0.008) -0.000(0.005) -0.009(0.011) -0.004(0.008) 0.007(0.005)

28
REFERENCES

1. World Health Organization. (1996). Research on the menopause in the 1990s: Report of a
WHO Scientific Group.
2. Zöllner, Y. F., Acquadro, C., & Schaefer, M. (2005). Literature review of instruments to
assess health-related quality of life during and after menopause.Quality of life
research, 14(2), 309-327.
3. Jones, E. K., Jurgenson, J. R., Katzenellenbogen, J. M., & Thompson, S. C. (2012). Menopause
and the influence of culture: another gap for Indigenous Australian women? BMC women's
health, 12(1), 43.
4. Dennerstein, L., Smith, A. M., Morse, C., Burger, H., Green, A., Hopper, J., & Ryan, M. (1993).
Menopausal symptoms in Australian women. The Medical Journal of Australia, 159(4), 232-
236.
5. Hilditch, J. R., Lewis, J., Peter, A., van Maris, B., Ross, A., Franssen, E., Guyatt, G. H., Nortona,
P. G., & Dunn, E. (2008). A menopause-specific quality of life questionnaire: development and
psychometric properties. Maturitas, 61(1), 107-121.
6. Teede, H. J. (2007). Sex hormones and the cardiovascular system: effects on arterial
function in women. Clinical and Experimental Pharmacology and Physiology, 34(7), 672-676.
7. Veerus, P., Hovi, S. L., Sevón, T., Hunter, M., & Hemminki, E. (2012). The effect of hormone
therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone
Therapy trial. BMC research notes, 5(1), 176.

29
8 Barnabei, V. M., Grady, D., Stovall, D. W., Cauley, J. A., Lin, F., Stuenkel, C., Stefanick, M. L., &
Pickar, J. H. (2002). Menopausal symptoms in older women and the effects of treatment with
hormone therapy. Obstetrics & Gynecology, 100(6), 1209-1218.
9 Hodis, H. N., Mack, W. J., Shoupe, D., Azen, S. P., Stanczyk, F. Z., Hwang-Levine, J., Budoff, M.
J., & Henderson, V. W. (2015). Methods and baseline cardiovascular data from the Early
versus Late Intervention Trial with Estradiol testing the menopausal hormone timing
hypothesis. Menopause, 22(4), 391-401.
10. Hunter, M. S. (2003). The Women's Health Questionnaire (WHQ): frequently asked
questions (FAQ). Health Qual Life Outcomes, 1(1), 41.
11. Hovelius, H. E. B. (2000). Quality of life and hormone therapy in women before and after
menopause. Scandinavian journal of primary health care, 18(2), 115-121.
12. Welton, A. J., Vickers, M. R., Kim, J., Ford, D., Lawton, B. A., MacLennan, A. H., Meredith, S.
K., Martin, J., & Meade, T. W. (2008). Health related quality of life after combined hormone
replacement therapy: randomized controlled trial. Bmj, 337:a1190

30
APPENDIX

THE WOMEN’S HEALTH QUESTIONNAIRE, ORGANIZED BY SUBSCALE
Yes
definitely
Yes
sometimes
No not
much
No not at all
Sleep Problems
1. I wake early and then sleep
badly for the rest of the night

2. I am restless and can’t keep
Still

3. I have difficulty in getting
off to sleep

Anxiety/fears
1. I get very frightened or panic
feelings for apparently no
reason at all

2. I get palpitations or a
sensation of ‘butterflies’ in my
stomach or chest

3. I feel anxious when I go out of
the house on my own

4. I feel tense or ‘wound up’
Depression
1. I feel miserable and sad
2. I have feelings of well-being
3. I have lost interest in things
4. I still enjoy the things I used
To

31
5. I feel life is not worth living
6. I have good appetite
7. I am more irritable than usual
Somatic Symptoms
1. I have a headache
2. I feel more tired than usual
3. I have dizzy spells
4. I suffer from back-ache/or pain
in my limbs

5. I feel sick or nauseous
6. I often notice pins and needles
in my hands and feet

7. I need to pass urine/water more
frequently than usual

Menstrual symptoms
1. My breasts feel tender or
Uncomfortable

2. I have abdominal cramps or
Discomfort

3. My stomach feels bloated

Vasomotor symptoms
1. I have hot flashes

32
2. I suffer from night sweats
Memory/Concentration
1. I am more clumsy than usual
2. My memory is poor
3. I have difficulty in
Concentrating

Attractiveness
1. I feel rather lively and
Excitable

2. I feel physically attractive
Sexual Behavior
1. I have lost interest in sexual
Activity

2. I have heavy periods
3. I am satisfied with my current
sexual relationship (please
omit if not sexually active)

4. As a result of vaginal dryness
sexual intercourse has become
uncomfortable (please omit if
not sexually active)

1. I worry about growing old

Abstract (if available)

Abstract This study used Women's Health Questionnaire (WHQ) data from the Early versus Late Intervention Trial with Estradiol (ELITE) to test whether: (1) postmenopausal hormone therapy (HT) benefits emotional and physical health in healthy postmenopausal women

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

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

PDF

The impact of hormone therapy on Alzheimer’s disease biomarkers in early and late postmenopausal women

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

PDF

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...

PDF

Associations between physical activities with bone mineral density in postmenopausal women

PDF

Effect of estradiol on circulating levels of inflammatory cytokines in postmenopausal women

PDF

Sex hormones and atherosclerosis in postmenopausal women

PDF

Relationship of blood pressure and antihypertensive medications to cognitive change in the BVAIT, WISH, and ELITE clinical trials

PDF

Hormone therapy timing hypothesis and atherosclerosis

PDF

The effects of hormone therapy on carotid artery intima-media thickness and serum lipids by ApoE4 genotype

PDF

Association between endogenous sex hormone levels and cognition: the Women’s Isoflavone Soy Health (WISH) trial

PDF

Association of oophorectomy with progression of carotid atherosclerosis

PDF

The associations of inflammatory markers with progression of subclinical atherosclerosis in early and late postmenopausal women

PDF

Bone mineral density is associated with carotid atherosclerosis in healthy postmenopausal women: a longitudinal analysis of randomized clinical trial data

PDF

Physical activity and sex hormone levels in postmenopausal women

PDF

Associations between isoflavone soy protein (ISP) supplementation and breast cancer in postmenopausal women in the Women’s Isoflavone Soy Health (WISH) clinical trial

PDF

Association of carotid artery stiffness with measures of cognition in older adults

PDF

Exploring the relationship between menopausal hot flushes and Alzheimer's disease biomarkers: a cross-sectional analysis in postmenopausal women

PDF

Soy isoflavone supplements for the treatment of menopausal hot flashes: the Women’s Isoflavone Soy Health (WISH) trial

PDF

Association of arterial stiffness progression with subclinical atherosclerosis measurements in postmenopausal women

PDF

Association of subclinical atherosclerosis with plasma B-vitamin, cysteine, homocysteine, and cysteinyl glycine in a cardiovascular disease-free population

Asset Metadata

Creator Zheng, Anni (author)

Core Title A randomized controlled trial of hormone therapy on postmenopausal women’s quality of life

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 11/19/2015

Defense Date 10/22/2015

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

Tag hormone therapy,menopause status,OAI-PMH Harvest,Quality of life,randomized trials,timing hypothesis,women’s health questionnaire

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

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

Creator Email annizhen@usc.edu,annizheng2015@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-200977

Unique identifier UC11277044

Identifier etd-ZhengAnni-4049.pdf (filename),usctheses-c40-200977 (legacy record id)

Legacy Identifier etd-ZhengAnni-4049.pdf

Dmrecord 200977

Document Type Thesis

Format application/pdf (imt)

Rights Zheng, Anni

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