UNIVERSITY OF CALGARY

UNIVERSITY OF CALGARY
Evaluating the Association between Estradiol and Quality of Life and Cardiovascular Risk and
Mortality in Healthy Women and Women with Chronic Kidney Disease
by
Sharanya Ramesh
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY
GRADUATE PROGRAM IN MEDICAL SCIENCE
CALGARY, ALBERTA
AUGUST, 2016
© Sharanya Ramesh 2016

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Abstract
Chronic kidney disease (CKD) is associated with a poor quality of life and high risk of
cardiovascular (CV) mortality, specifically sudden cardiac death (SCD), and an upregulated
renin angiotensin system. Women with end stage kidney disease (ESKD) experience premature
menopause, and in healthy women menopause is correlated with a poor quality of life and higher
CV mortality. A series of studies was conducted in healthy women and women with CKD to
determine the associations between menopause status, serum estradiol and 1) cardiac autonomic
tone (CAT), a surrogate marker for SCD, in a high Angiotensin II (AngII) state 2) mortality in
women with ESKD and 3) quality of life(QoL) in women with CKD. We also summarized the
impressions of healthcare workers and patients on the discussion of symptoms of low sex
hormones in a clinical setting. In healthy men and women, sex hormones did not correlate with
baseline CAT; however, men with lower testosterone levels were unable to maintain CAT in
response to AngII. At baseline, postmenopausal women had a lower CAT in comparison to
premenopausal women. In response to AngII postmenopausal women and premenopausal
women in the luteal phase were unable to maintain their CAT. Through a survey of nephrologists
we found that nephrologists recognize the impact of CKD on sex hormones in women but report
infrequently discussing sex hormone related issues with patients. In a systematic review of
studies examining the effect of postmenopausal hormone therapy on CV outcomes in women
with ESKD, hormone therapy was associated with a favourable lipid profile. However, we found
that peri- and premenopausal women with ESKD on hemodialysis had a higher risk of all-cause,
cardiovascular and non-cardiovascular mortality compared to postmenopausal women.
Furthermore menopause specific QoL scores did not correlate with kidney function in CKD

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women. We found that associations between menopause status and CV risk and QoL in the CKD
population are complex. This body of work can be used for hypothesis generation for future
studies and trials aimed to determine the mediators of cardiovascular risk and poor quality of life
in this population.

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Acknowledgements
I am very thankful for the opportunity to have spent the past four years of my life
studying this important area of research, which I am very passionate about. This would not have
been possible without the support and guidance of incredible people. First, I would like to thank
my supervisor and my valued mentor, Dr. Sofia Ahmed, from the bottom of my heart. Her
unwavering support, mentorship, kindness, guidance, and trust have carried me through these
four years, and this thesis would not have been possible without her. I would also like to extend a
heartfelt thank you to my thesis committee members, Dr. Jayna Holroyd-Leduc, Dr. Stephen
Wilton, and Dr. Matthew James, for their commitment to my academic and personal
development, valuable input and time, and mentorship throughout the years.
To my parents, Mallika and Ramesh, thank you so much for instilling in me the values of
hard-work, resilience and a passion for learning, without your love and support I would not be
who I am today. A very special thank you to my sister, Sanjana, who has been my rock for the
past few years and who held my hand through many doubtful moments, you continue to amaze
me with your understanding and kindness. To my friends near and far, who have always been
there to keep me grounded and supported, I am so thankful for your uplifting messages, votes of
confidence and wonderful company.
Last but not least, I would like to express my deep gratitude to the patients who
volunteered to participate in my studies, and the nurses, nephrologists and administrators of the
Southern Alberta Renal Program who took the time out of their busy schedules to help with my
project. Your kindness will not be forgotten.

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Table of Contents
Abstract ............................................................................................................................... ii
Acknowledgements ............................................................................................................ iv
Table of Contents .................................................................................................................v
List of Tables .................................................................................................................... vii
List of Figures and Illustrations ....................................................................................... viii
List of Symbols, Abbreviations and Nomenclature .............................................................x
CHAPTER ONE: INTRODUCTION ..................................................................................1
1.1 Chronic Kidney Disease ............................................................................................1
1.1.1 Chronic kidney disease prevalence and burden of disease ................................1
1.1.2 Physical and psychological symptoms of uremia ..............................................1
1.1.3 Reproductive dysfunction, sexual dysfunction and premature menopause in
women with CKD ..............................................................................................2
1.1.4 Cardiovascular (CV) mortality in chronic kidney disease ................................2
1.2 Menopause and the role of estradiol ..........................................................................4
1.2.1 Menopause associated poor quality of life and high cardiovascular risk ..........4
1.2.1.1 Menopause and quality of life .................................................................5
1.2.1.2 Menopause and cardiovascular risk .........................................................5
1.2.2 Estradiol .............................................................................................................6
1.2.3 Normal hypothalamus pituitary gonadal axis ....................................................6
1.2.4 Endogenous estradiol on quality of life .............................................................8
1.2.5 Cardioprotective role of endogenous estradiol ..................................................9
1.2.6 Cardiovascular risk and exogenous estradiol ..................................................10
1.2.7 WISE classification for menopausal status .....................................................12
1.3 Abnormalities in the hypothalamic pituitary gonadal axis in CKD .........................13
1.4 Assessment of Cardiovascular Risk, Quality of Life and Menopausal Symptoms .15
1.4.1 Heart rate variability (HRV) as a predictor of CVD risk ................................15
1.4.2 Using the Menopausal Specific Quality of Life (MENQOL) survey to determine
menopausal symptoms .....................................................................................17
1.5 Current state of the science ......................................................................................17
1.6 Objective ..................................................................................................................18
1.7 Thesis Outline ..........................................................................................................19
CHAPTER TWO: TESTOSTERONE IS ASSOCIATED WITH THE CARDIOVASCULAR
AUTONOMIC RESPONSE TO A STRESSOR IN HEALTHY MEN ...................20
CHAPTER THREE: CARDIAC AUTONOMIC RESPONSE TO ANGIOTENSIN II IN
HEALTHY PREMENOPAUSAL AND POSTMENOPAUSAL WOMEN ............39
CHAPTER FOUR: SEX HORMONE STATUS IN WOMEN WITH CHRONIC KIDNEY
DISEASE: SURVEY OF NEPHROLOGISTS’ AND RENAL ALLIED HEALTH
CARE PROVIDERS’ PERCEPTIONS. ...................................................................59