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Comprehensive evaluation of response and failure of medical treatment in patients with endometriosis-associated… Alsowayan, Najla 2019

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  Comprehensive Evaluation of Response and Failure of Medical Treatment in Patients With Endometriosis-associated Chronic Pelvic Pain.  by  Najla Alsowayan  MBBS, Qassim University, 2012  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (REPRODUCTIVE AND DEVELOPMENTAL SCIENCES)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  March 2019  © Najla Alsowayan, 2019 ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis/dissertation entitled:  Comprehensive evaluation of response and failure of medical treatment in patients with endometriosis- associated chronic pelvic pain  submitted by Najla Alsowayan in partial fulfillment of the requirements for the degree of Master of Science in Reproductive and Developmental Sciences  Examining Committee: Paul J. Yong Supervisor  Sarka Lisonkova Supervisory Committee Member  Mohamed Bedaiwy Supervisory Committee Member Christina Williams Additional Examiner   Additional Supervisory Committee Members: Christian Clausen Supervisory Committee Member   iii  Abstract      Endometriosis is a common gynecological condition affecting 6-10% of women of reproductive age that produces significant morbidity and constitutes a substantial burden on health care systems. Endometriosis is one of the main causes of pelvic pain as it has been estimated that 33% of patients with chronic pelvic pain have endometriosis. Several medical and surgical approaches are available for the management of endometriosis.  Suppressive hormonal treatments are generally considered safe and commonly prescribed, however the desired effect of pain relief is not achieved in all patients. Less attention is paid to the reasons for discontinuation and risk factors associated with it. Identifying the proportion of patients who do not benefit from these medications and the risk factors will aid in patient counseling for pain management. In this thesis, I am evaluating patients that did not respond to the first and second line medical treatment of endometriosis.     This cohort included 1440 patients of reproductive age that had confirmed or clinical suspicion of endometriosis. Through an online questionnaire, we asked these patients if they have ever used each hormonal medication to treat their pelvic pain and, if the answer was yes, if the treatment did not help or whether they discontinued due to side effects.      In this cohort, 58.3% (839/1440) reported prior use of cyclic hormonal contraceptives, while 42.4% (611/1440) reported prior use of continuous hormonal contraceptives.  For progestins, there were 24% (344/1440) patients who used levonorgestrel intrauterine device and 20.2% (287/1440) who used dienogest. Patients who reported ineffectiveness of any hormonal treatment or discontinuation due to side-effects were younger, had higher pain severity, worse quality of life, more non-gynecological contributors to pain, and greater psychological comorbidities.   iv      My results highlight the importance of further studying non-responders to hormonal therapy.  Prospective longitudinal studies are needed to confirm these findings and further classify the side-effects experienced by patients. Moreover, additional details on treatment inefficacy are required to identify patients that are truly non-responsive versus patients who are not adherent to mediation regimens or have financial difficulties with medication costs. v  Lay Summary        Endometriosis is a disease that is caused by the presence of the cells lining the uterus abnormally growing outside the uterus. It affects 1 in 10 women and pain in the pelvic area is one of its main symptoms. In my thesis I am examining if patients who do not improve after hormonal drugs have special characteristics that can help us to estimate in advance whether hormonal treatment is likely to help in certain groups of women..  I have investigated 1440 women with pain in the pelvic area because of endometriosis.  Those women who reported that hormonal drugs were not effective, or that they had to stop hormonal medications due to side-effects, tended to be younger, have higher pelvic pain levels and worse quality of life, and were more likely to be diagnosed with psychological conditions.  More research is needed to improve care for these non-responders to hormonal treatment of endometriosis.   vi  Preface  The research project presented in this thesis was originally developed in Dr. Paul Yong’s laboratory. Preliminary draft of this thesis was fully developed by me then revised based on suggestions from my supervisory committee. The research was approved by the University of British Columbia Ethics Board (REB) (H11-02882). For the entire thesis, data was extracted from a prospective data registry (Endometriosis Pelvic Pain Interdisciplinary cohort). I performed statistical analysis under the guidance of Drs. Paul Yong, Mohamed Bedaiwy, Arianne Albert, and Sarka Lisonkova. Appendix 1 has been submitted for publication.  Chapter 2 will be submitted for publication. Two abstracts were presented from this thesis: 1. Oral Contraceptives Use in Women with Pelvic Pain and Endometriosis: History of Ineffectiveness or Discontinuation Due to Side Effects. This poster abstract was presented at the 34th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE) on July 1-4, 2018, Barcelona, Spain. 2. Progestin Only Medications for Chronic Pelvic Pain: Use Patterns and Causes of Discontinuation. This oral abstract was presented at the annual meeting of the American Society Reproductive Medicine (ASRM) on October 6-10, 2018, Denver, CO, United States of America.  vii  Table of Contents  Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ........................................................................................................................ vii List of Tables ................................................................................................................................ xi List of Figures ............................................................................................................................. xiii List of Abbreviations ................................................................................................................. xiv Acknowledgements .................................................................................................................... xvi Dedication ................................................................................................................................. xviii Chapter 1: Introduction ................................................................................................................1 1.1 Endometriosis ................................................................................................................. 2 1.1.1 Etiology and pathophysiology .................................................................................... 3 1.1.2 Phenotypes .................................................................................................................. 5 1.1.3 Stages .......................................................................................................................... 7 1.1.4 Diagnosis..................................................................................................................... 9 1.1.5 Management ................................................................................................................ 9 1.2 Endometriosis associated pain ...................................................................................... 12 1.2.1 Mechanisms of pain in endometriosis....................................................................... 12 1.2.2 Chronic pelvic pain ................................................................................................... 15 1.3 Hormonal treatments ..................................................................................................... 16 1.3.1 Combined hormonal contraceptives ......................................................................... 17 viii  1.3.2 Progestin ................................................................................................................... 21 1.3.3 Gonadotropin releasing hormone analogue .............................................................. 26 1.4 Objective and hypothesis .............................................................................................. 29 1.4.1 Aim 1: To evaluate the patterns of hormonal treatment use in endometriosis- associated pelvic pain ........................................................................................................... 29 Chapter 2: Patterns of Hormonal Medications Use for Endometriosis- Associated Pelvic Pain ................................................................................................................................................30 2.1 Introduction ................................................................................................................... 30 2.2 Materials and methods .................................................................................................. 33 2.2.1 Settings ...................................................................................................................... 33 2.2.2 Study population ....................................................................................................... 33 2.2.3 Drug usage ................................................................................................................ 33 2.2.4 Variables of interest .................................................................................................. 34 2.2.5 Statistical analysis ..................................................................................................... 35 2.3 Results: .......................................................................................................................... 35 2.3.1 Study sample: ............................................................................................................ 35 2.3.2 Combined hormonal contraceptives: ........................................................................ 38 2.3.3 Progestins: ................................................................................................................. 46 2.4 Discussion: .................................................................................................................... 54 Chapter 3: Conclusion .................................................................................................................57 3.1 Implications................................................................................................................... 57 3.2 Limitations .................................................................................................................... 58 3.3 Future direction ............................................................................................................. 58 ix  References .....................................................................................................................................60 Appendices ....................................................................................................................................82 Appendix A Combined hormonal contraceptives for chronic pelvic pain: ineffectiveness of discontinuation due to side effects ............................................................................................ 82 A.1 Introduction ............................................................................................................... 82 A.2 Materials and methods .............................................................................................. 83 A.3 Results ....................................................................................................................... 86 A.4 Discussion ................................................................................................................. 98 Appendix B Progestins use for endometriosis- associated chronic pelvic pain...................... 100 B.1 Rationale ................................................................................................................. 100 B.2 Study sample ........................................................................................................... 100 B.3 Results ..................................................................................................................... 100 B.4 Discussion ............................................................................................................... 100 Appendix C Gonadotropin releasing hormone analogue for endometriosis-associated chronic pelvic pain, patterns of use ...................................................................................................... 101 C.1 Rationale ................................................................................................................. 101 C.2 Study sample ........................................................................................................... 101 C.3 Results ..................................................................................................................... 101 C.4 Discussion ............................................................................................................... 101 Appendix D Corollary diagnoses Fisher’s exact test tables.................................................... 102 D.1 Cyclic ineffective .................................................................................................... 102 D.2 Cyclic side effects ................................................................................................... 103 D.3 Continuous ineffective ............................................................................................ 104 x  D.4 Continuous side effects ........................................................................................... 105 D.5 LNG-IUD ineffective .............................................................................................. 106 D.6 LNG-IUD side effects ............................................................................................. 106 D.7 DNG ineffective ...................................................................................................... 107 D.8 DNG side effects ..................................................................................................... 107 Appendix E Fisher’s exact test tables ..................................................................................... 109  xi  List of Tables  Table 1.1 Summary of the medications used to treat endometriosis pain with its main mechanism of action ........................................................................................................................................ 11 Table 1.2 Causes and differential diagnosis of chronic pelvic pain ............................................. 16 Table 1.3 Summary of study arms on the efficacy and failure of combined hormonal contraceptives in treating endometriosis-associated pain ............................................................. 19 Table 1.4 Summary of study arms on the efficacy and failure of progestins in treating endometriosis-associated pain…………………………………………………………………...22 Table 1.5 Summary of study arms on the efficacy and failure of gonadotropin releasing hormone analogue in treating endometriosis-associated pain……………………………………………...27 Table 2.1 Progestins properties and characteristics……………………………………………...31 Table 2.2 Proportion of confirmed and suspected endometriosis cases among the study cohort . 38 Table 2.3 Demographic characteristics of included participants .................................................. 39 Table 2.4 Pain levels and quality of life levels in patients who discontinued cyclic and continuous CHCs .......................................................................................................................... 42  Table 2.5 Association between cyclic and continuous CHC ineffectiveness or side effects and the underlying diagnoses............................................................................................................... 44 Table 2.6 Demographics in patients who reported using DNG and LNG-IUD ineffectiveness and side effects .................................................................................................................................... 47 Table 2.7 Pain levels and quality of life levels in patients who reported levonorgestrel and dienogest ineffectiveness and side effects .................................................................................... 50 xii  Table 2.8 Association between levonorgestrel IUD and dienogest ineffectiveness or side effects and the underlying diagnoses…………………………………………………………………….52 Table A.1 Demographic characteristics of included participants in the four groups of interest…86 Table Table A.2 Various pain symptoms and quality of life levels in patients who reported prior cyclic CHC use………………………………………………………………………………………….90 Table A.3 Various pain symptoms and quality of life levels in patients who reported prior continuous CHC use……………………………………………………………………………..91 Table A.4 Binary logistic regression for CHCs ineffectiveness…………………………………92 Table A.5 Association between CHC ineffectiveness or side effects and the underlying diagnoses………………………………………………………………………………..………. 93 xiii  List of Figures  Figure 1.1 Steps of estradiol formation and positive feedback loop of inflammation and endometriosis survival .................................................................................................................... 4 Figure 1.2 Illustration of the different pheotypes of endometriosis ................................................ 5 Figure 1.3 Steps of the updated endometriotic disease theory........................................................ 6 Figure 1.4 Illustrative representation endometriosis stages ............................................................ 8 Figure 1.5 Suggested algorithm for endometriosis pain management .......................................... 10 Figure 1.6 Main pathways involved in endometriosis inflammatory pain ................................... 14 Figure 1.7 Main pathways involved in endometriosis inflammatory pain ................................... 14 Figure 2.1 Hormonal drugs used for chronic pelvic pain treatment in our cohort and reported ineffectiveness and side effects ..................................................................................................... 36 Figure 2.2 Overall frequency of prior hormonal treatment use in cohort population ................... 37 Figure A.1 Flow chart that shows study participants according to the type of CHC used and the reported variables of interest (ineffectiveness, side effects)……………………………………..85     xiv  List of Abbreviations  17βHSD17        17 beta hydroxysteroid dehydrogenase  ASRM               American Society for Reproductive Medicine  BMI                   Body mass index CHC                  Combined hormonal contraceptives CPP                   Chronic pelvic pain COX2                Cyclooygenase 2 enzyme CGRP               Calcitonin gene-related peptide DAMPS            Damage-associated molecular patterns DNG                 Dienogest DMPA              Depo medroxyprogesterone acetate DIE                   Deep infiltrating endometriosis EPPIC               Endometriosis and pelvic pain interdisciplinary cohort EHP-30             Endometriosis health profile questionnaire 30 GAD-7              Generalized anxiety disorder  GnRH               Gonadotropic releasing hormone  H+                     Hydrogen ion IBS                    Irritable bowel syndrome  IL-1β                 Interleukin 1 beta IUD                   Intrauterine device  IBS                    Irritable bowel syndrome KT                     Knowledge translation xv  LNG                  Levonorgestrel MRI                   Magnetic resonance imaging\ NSAID              Non-steroidal anti-inflammatory drug NF-κβ                Nuclear factor kappa-light-chain-enhancer of activated B cells NGF                  Nerve growth factor NETA                Norethindrone acetate OMA                 Ovarian endometrioma OS                     Oxidative stress P                        Substance P PBS                   Painful bladder syndrome  PCS                   Pain catastrophizing scale  PHQ-9               Patient health questionnaire 9 PGE2                 Prostaglandin E2 QOL                  Quality of life RCT                  Randomized controlled trail SF1                   Steroidogenic factor  STAR               Steroidogenic acute regulatory protein SUP                   Superficial endometriosis TNF-α               Tumor necrosis factor alpha VAS                 Visual analogue scale xvi  Acknowledgements  I would like to express my sincere gratitude for Dr. Paul Yong, my thesis supervisor for his tremendous support and guidance. I am thankful for his patience and consistency in refining my work and widen my horizons.  I would like to thank Drs. Christian Klausen, Sarka Lisnokova, and Mohamed Bedaiwy, my thesis committee members. I would like to extend my gratitude to Dr. Mohamed Bedaiwy for introducing me into the exciting endometriosis research field and all the wonderful opportunities. This research could not have been done without the physicians and staff at the BC Women’s Centre for Pelvic Pain and Endometriosis, Drs. Paul Yong, Christina Williams, Catherine Allaire, and Mohamed Bedaiwy. I would like to also thank the Canadian Institutes of Health Research (CIHR) for funding this project. Special thanks to Heather Noga for always taking time out of her busy schedule to help and support me in every possible way she could. Sincere thanks to all the patients who contributed to my research by participating in the EPPIC data registry. I would not be able to make it without the support from my friends and colleagues at Drs. Yong’s and Bedaiwy’s laboratory for their support. A genuine gratitude to Kate Wahl, Natasha Orr and Sukainah Alfaraj for their whole-hearted encouragement and support.  My sincere gratitude to Drs. Saleh Aldamegh and Ashwag Aleed from Unayzah College of Medicine, Qassim University, for believing in me and for their support through my career. I owe particular thanks to my mentor Dr. Abdulaziz Alobaid for always guiding me in my career.   xvii  Lastly, I thank my two corner stones, my fiancé Dr. Abdullah Alhassan for always believing and supporting me through stressful times and constantly reminding me of my strength, and my dear sister Dr. Hend Alsowayan for her love, faith, and for leading me through life.  xviii  Dedication        To All women with endometriosis.   1  Chapter 1: Introduction The heterogeneity of pain symptoms in endometriosis is one of the major challenges in treating endometriosis-associated pain. It is generally known that endometriosis stage does not reflect the degree of pain perceived by patients[1], rendering treatment approaches more challenging. Both surgical and medical treatments are valid options to treat endometriosis; however, getting the desired outcome of pain relief is not always achieved. For example, some patients may experience the same pain even after complete surgical eradication of the disease or hysterectomy, or complete medical hormonal suppression of menses. This observation mandates further identification of medication inefficacy risk factors in order to achieve better treatment response and more personalized medicine approach rather than “one size fits all” approach. There is no curative treatment for endometriosis associated pain. Although endometriotic implants can be surgically removed, not all patients are responders in terms of pelvic pain. In fact, in a mouse model, it was shown that incomplete surgical excision can further accelerate the growth rate of endometriotic implants, thus increasing the risk of recurrence and the need to re-operate which can lead to adhesions that may worsen pain and increase the risk of surgical complications [2–4]. Medical treatment is non-curative, but is commonly used pre-operatively to lower pain levels in patients waiting for their operation, or postoperatively to delay recurrence of pain symptoms [5]. In addition to low tolerability due to associated side effects in some patients taking hormonal medication, long-term use is impractical due to the contraceptive nature of the medications in patients who desire pregnancy.  There is no standardized definition of treatment failure. F.Tennat defines pain treatment failure as “when a treatment regimen does not keep the pain patient physically and mentally functional, such that they are able to carry on activities of daily living, achieve some quality of 2  life”[6]. Some studies have investigated the possible reasons for medical treatment failure, after excluding dose adjustment, correct use, and malabsorption. Reasons included lack of adherence, psychological distress, and inadequate interaction among health care professionals and with patients [7,8]. No studies to date have addressed the causes or risk factors of endometriosis-associated pain medical treatment failure. In light of the above facts, I evaluated medical treatment of endometriosis-associated pain by examining the patterns of use of hormonal treatment. I also investigated factors that are associated with treatment inefficacy and discontinuation due side effects, in order to provide more insight into the process of choosing the most appropriate medication for each patient.  1.1 Endometriosis Endometriosis is a chronic inflammatory disease caused by the presence of endometrial stroma and glands outside the uterine cavity, predisposing to pelvic pain, infertility, and other symptoms like fatigue. It is estimated that endometriosis affects 6-10% of women of reproductive age, more than 33% of women with pelvic pain, and up to 50% of women with infertility[5,9,10]. Endometriosis constitutes a notable burden on health systems. In Canada, the annual societal cost of endometriosis is estimated to be $5200 per patient with a total annual cost of $1.8 billion attributable to surgically confirmed endometriosis. In the United States, the annual healthcare cost is estimated to be $22 billion and $2801 per patient [11,12]; while in Europe, the annual cost is  €10,000 per patient [13].  3  1.1.1 Etiology and pathophysiology The exact cause of endometriosis is not completely known, however, the pathogenesis can be summarized by three major steps: cell migration, implantation, and disease development. Several theories have been proposed to explain cell migration. Sampson’s theory of retrograde menstruation is the most accepted theory, where endometrial cells are refluxed into the peritoneal cavity through the fallopian tubes via negative peritoneal pressure and fallopian tube peristaltic contractions, and subsequently these cells implant into the peritoneum, ovary or any surrounding structure [14]. Sampson added on this theory by proposing that endometrial cells may migrate through venous and lymphatic circulations, explaining extra-pelvic endometriosis [15]. Coelomic metaplasia is the opposing theory to Sampson’s, proposing that the endometrial tissues in the pelvic cavity result from metaplasia of mesothelial cells [16] . The second step is cell implantation. Typically, the presence of endometrial tissues outside the pelvic cavity alone does not cause endometriosis by itself; however, molecular and immunologic defects allow these cells to escape removal and allows growth. It is proposed that the immune system fails to clear implants from peritoneal surface [17–19]. In addition, endometrial cells are molecularly abnormal, and once they attach to the peritoneal mesothelium, these abnormalities are amplified greatly to allow survival and invasion of the implant [20].  The third step is implant growth and inflammation. Two enzymes play a role in endometriosis growth, aromatase and 17-β hydroxysteroid dehydrogenase (17 βHSD). Aromatase is a key enzyme for estradiol synthesis; normally it is not expressed in healthy endometrium, but it is highly expressed in endometriotic implants which gives them the ability to synthesize their own estradiol [21,22]. Two major subtypes of 17 βHSD are involved; 17 βHSD-1 is responsible for the conversion of estrone to estradiol, whereas 17 βHSD-2 converts estradiol back to estrone. In 4  endometriotic implants, 17 βHSD-2  is deficient, which leads to accumulation of highly potent estradiol [23]. Expression of 17 βHSD-2 is induced by progesterone, however, endometriotic implants lack the expression of progesterone receptors [24].  High levels of estradiol are maintained via positive feedback mechanism. Steroidogenic acute regulatory protein facilitates the initial step of estrogen formation by initiating the conversion of cholesterol to androstenedione, which is converted to estrone by aromatase [25]. Estrone is further converted into the potent estradiol via HSD17B1, which binds into its nuclear receptor estrogen receptor β , which induced cyclooxygenase 2 enzyme that coverts arachidonic acid to prostaglandin E2 (PGE2), a potent pro-inflammatory hormone that further stimulate cyclooygenase 2 enzyme (COX2) via positive feedback mechanism to further increase its production. PGE2 increases endometriosis growth by stimulating steroidogenic factor 1  and aromatase, thus further enhancing estradiol production (Figure 1.1) [26–29].   Figure1.1: Steps of estradiol formation and positive feedback loop of inflammation and endometriosis survival [30]. 5  1.1.2 Phenotypes  Based on the location and depth of endometriosis implantation, it is classified into three phenotypes: superficial endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE, invasion >5mm; Figure 1.2). Why these differences exist is controversial, however the genetic/epigenetic theory is one explanation. This theory proposes that the original cell of endometriosis undergoes genetic and epigenetic changes that interact with the surrounding environment to facilitate development of each lesion/phenotype [31–33] (Figure 1.3).    Figure 1.3: Steps of the updated endometriotic disease theory [32]. 6         Figure 1.2: Illustration of the different phenotypes of endometriosis.  Panel A shows superficial endometriosis implants over the peritoneum.  Panel B shows an ovarian cyst that has opened and thickened old blood “chocolate fluid” leaking at the cul-de-sac. Panel C shows vaginal nodule that occupies the posterior vaginal fornix [34].    7  1.1.3 Stages Endometriosis is classified into four stages according to the revised American Society of Reproductive Medicine (r-ASRM) criteria. This staging is done surgically through a complex points system based on the location, extent, depth of disease in relation to pelvic structures in addition to the severity of the disease and associated adhesions and fibrosis [35,36] (Figure 1.4).  Stage I is between 1-5, Stage II is between 6-15, Stage III is between 16-40, and Stage IV is 40 or more. Complete obliteration of posterior cul-de-sac automatically results in Stage IV endometriosis.                 8                       Figure 1.4: Illustrative representation of endometriosis stages [36].  9  1.1.4 Diagnosis  To date, there is no clinical biomarker to screen or monitor endometriosis progress. Ultrasonographic and radiological technology can detect ovarian endometriomas, however other phenotypes may be more challenging to detect [5]. Negative sliding sign on transvaginal ultrasonography can be used to detect posterior cul-de-sac deep infiltrating nodules [37]. In addition, magnetic resonance imagining (MRI) is useful in detecting endometriosis; however, it has limited use in detecting superficial lesions and nodules. A prospective study concluded that the use of MRI for the detection of biopsy-proven endometriosis had a sensitivity of 69% and specificity of 75% [38]. Although these modalities can aid in diagnosing endometriosis, surgical visualization and histopathological confirmation remain the gold standard for endometriosis diagnosis [5].  1.1.5 Management Goal-oriented targeted management of patient’s symptoms is the advised approach to treatment. General goals are pain control, improvement of quality of life, prevention of recurrence, reduction of the number of surgeries, and preservation of fertility - if desired [39]. Both medical and surgical treatments can treat endometriosis. Analgesics, including non-steroidal anti-inflammatory drugs (NSAID), and combined hormonal contraceptives can be used empirically to treat pelvic pain [5]. Patient’s future reproductive desire is important to consider before choosing a treatment. Patients who desire pregnancy immediately would try for conception on natural cycles; if there are difficulties in conceiving, they can undergo surgical removal of lesions or are referred to 10  assisted reproductive technology. Patients who desire pregnancy in the future can be started with combined hormonal contraceptives, or any other temporary hormonal contraception method until the right time of conception. Patients who have no desire of pregnancy in the future can remain on hormonal suppression, unless definitive treatment is desired then hysterectomy can be undertaken [36]. Figure 1.5 summarizes an algorithm of endometriosis pain treatment.        Figure 1.5: Suggested algorithm for endometriosis pain management [36].   11   Combined hormonal contraceptives are considered to be the first line of endometriosis treatment, followed by progestins and gonadotropin releasing hormone analogue (GnRHa) as second line treatments [5]. Other new therapies can help in treating endometriosis pain but are not yet commonly used, including GnRH antagonists, aromatase inhibitors, selective progesterone receptor modulators, and selective estrogen receptor modulators [40].  Combined hormonal contraceptives aim to mimic a “pseudo-pregnancy”, and hormonal therapies in general work by suppressing the ovaries or inhibit endometrial implant growth directly. Table 1.1 describes the mechanisms associated with each type of medication.    Table 1.1: Summary of the medications used to treat endometriosis pain with their main mechanisms of action [39].     12  Neuromodulators and opioids can be used in patients with severe pain that is not responding to hormonal treatment or in cases of central sensitization. Other non-pharmacological therapies can be used in combinationwith hormonal suppression such as psychotherapy, meditation and mindfulness, physiotherapy, and other complimentary therapies such as Chinese medicine [41,5]. Surgery is reserved for cases where medical treatment is not effective, when deemed medically indicated due to ureteric stenosis, or with infertility. Several surgical techniques are available according to the patient’s condition and pathology, including but not limited to excision/ablation of endometriotic implants, oophorectomy, or even hysterectomy [5].   1.2 Endometriosis associated pain  Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [42]. Endometriosis patients commonly report pain in the pelvic area, and several pain symptoms can present such as pain during menstruation,(dysmenorrhea), or during intercourse,(dyspareunia), and chronic pelvic pain.  The mechanism of pain in endometriosis can be classified into two categories, nociceptive and neuropathic. Nociceptive pain arises from non-neural tissue damage that lead to activation of nociceptive neurons, and when associated with inflammation, it is called inflammatory pain. Neuropathic pain is pain related to altered neural processing.   1.2.1 Mechanisms of pain in endometriosis Endometriotic lesions, just like uterine (eutopic) endometrium, undergo necrosis and menstrual shedding. As part of this process, inflammatory mediators are released from the necrotic cells, 13  including PGE2, hydrogen atoms, and oxidative stress iron that directly stimulate sensory nerve endings. Other tissue degeneration byproducts, oxidative stress and damage-associated molecular patterns stimulate innate immune response via nuclear factor pathway to release pro-inflammatory mediators such as PGE2, nerve growth factor, interleukin 1, and tumor necrosis factor α  that will also stimulate sensory nerve ending. As a response, sensory nerves send nociceptive signals to the spinal cord and maintain inflammation by secreting substance P and calcitonin gene-related peptide [43–50]. In addition, estrogen neuromodulatory effects help in increasing sensory innervation and reducing sympathetic innervation around the endometriotic implants [51]. Figures 1.6 and 1.7 summarize the complex steps of endometriosis pain.          14   Figure 1.6:  Main pathways involved in endometriosis inflammatory pain [43].    Figure 1.7: Main pathways involved in endometriosis inflammatory pain [43]. 15  1.2.2 Chronic pelvic pain Chronic pelvic pain (CPP) is an intermittent or continuous lower abdominal or pelvic pain that is not related to menstruation or intercourse and lasts for 3-6 months [52,53]. Several body systems can be involved in causing chronic pelvic pain; some of the main gynecological causes are endometriosis, adenomyosis, fibroids, pelvic adhesions and infections [52]. In addition to these conditions, several other factors were identified that are associated with chronic pelvic pain, including psychological morbidity, childhood or adulthood abuse in any form [54] (Table 1.2). Endometriosis has been shown to be associated with chronic pelvic pain, however other studies have concluded that the severity chronic pelvic pain did not differ between patients with and without endometriosis [55]. Worsening chronic pelvic pain severity was identified to be associated with abdominal wall and pelvic floor tenderness, painful bladder syndrome, higher body mass index (BMI), smoking and family history of chronic pain. These patients were also found to have higher pain catastrophizing scores [55].  Several approaches have been proposed to treat chronic pelvic pain, involving treating the underlying cause as the first step, along with management of the pain. Medical treatment solely may not be adequate for pain treatment; multidisciplinary management may be required including surgery, physiotherapy, acupuncture, psychological counseling and cognitive behavioral therapy [52]. A study concluded chronic pelvic pain reduction and improvement in quality of life were achieved by this interdisciplinary approach [56]. In cases of CPP of gynecologic origin, hormonal treatment is recommended as a first line of treatment, along with adjuvant treatments such as antidepressants which can help in certain situations [52]. 16  Table 1.2: Causes and differential diagnosis of chronic pelvic pain [52].   1.3 Hormonal treatments Use of hormonal drugs in the treatment of endometriosis has been extensively studied. A systematic review on evaluating responsiveness and failure of endometriosis medical treatment concluded that 11-19% of women reported no reduction in their pain symptoms, 5-59% had persistent pain after treatment cessation and 5-16% reported discontinuation of treatment due to inefficacy or adverse events [11]. In patients who used GnRH-a, 19% reported lack of response to treatment, while 31% reported persistence of pain at the end of treatment. Moreover, 12% discontinued the treatment after 5 months on average duration due to inefficacy or intolerability of side effects. In patients who used progestin only medications, 14% reported lack of response to treatment and 34% reported persistence of symptoms at the end of treatment. This review did not 17  examine progestin discontinuation, however treatment satisfaction was reported by 62% of patients and 27% were dissatisfied with the treatment. In the combined hormonal contraceptive (CHC) group, 59% reported persistence of pain at the end of treatment and 8% reported discontinuation due to side effects or inefficacy. Additionally, 43% reported satisfaction with their treatment while 31% reported dissatisfaction. From this review, we can observe that non-responders to hormonal therapy constitute a significant minority of patients. Another systematic review on the efficacy of combined hormonal contraceptives on treating endometriosis pain concluded significant reduction on menstrual and non-menstrual pain symptoms with the superiority of cyclic over continuous use in pain reduction [57]. A systematic review on progestins concluded equal efficacy of progestins to GnRHa and danazol. Although this study included studies on several forms of progestins, the studies had small sample size [58].   1.3.1 Combined hormonal contraceptives Combined hormonal contraceptives work by suppressing endometriosis lesions and by suppressing the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism and preventing ovulation and menstruation, hence relieving dysmenorrhea pain [59]. Several studies evaluated its effectiveness in treating endometriosis associated pain; most agree on the efficacy of continuous use in relieving dysmenorrhea, with less efficacy on non-cyclical chronic pelvic pain and other pain symptoms [60–63] (Table 1.3). In deep infiltrating endometriosis (DIE), use of combined oral contraceptives was associated with significant partial reduction of nerve growth density [64]. In a study that investigated the role of combined oral contraceptives in treating DIE compared with no treatment, the mean nodule diameter progressed less than the group with no treatment, 18  while both visual analogue scale (VAS) score, that was used to evaluate pain severity,  and short form-36 total score, that was used to evaluate quality of life did not vary significantly in the treatment group [60]. Another prospective study evaluated the efficacy of combined oral contraceptives in treating ovarian endometriomas and concluded significant reduction in VAS scores, endometrioma diameter and volume [65]. The same group assessed the efficacy of CHC in treating endometriosis associated pain symptoms and reported significant reduction in dysmenorrhea, dyspareunia and chronic pelvic pain levels after 3 and 6 cycles in comparison to baseline pain levels [66]. Another pilot study concluded a significant reduction of pain symptoms in CHC group compared with non-steroidal anti-inflammatory drugs group [67], while another reported superiority of continuous CHC over cyclic pattern in improving patients quality of life [68] and with patients non responsive to cyclic regimens [69]. However, a recent review has argued that combined hormonal contraceptives might not be the best choice for a first line of endometriosis pain treatment; as the estrogen dose provided in this medication is more than the physiologic dose of estrogen, thus augmenting the already estrogen dominant environment and leading to further tissue growth [70]. Despite the abundancy of the studies on CHC efficacy, there are limitations in these studies; such as different designs, use of different comparators, and sample size. [71].       19  Table 1.3. Summary of study arms on the efficacy and failure of combined hormonal contraceptives in treating endometriosis-associated pain. Combined oral contraceptives Efficacy Discontinuation Study Drug used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Unknown/other Harada. OCP for dysmenorrhea with endometriosis. Fertil Steril 2008.[63]  Cyclic COC RCT NA Significant reduction  Non-significant reduction 0 4/51 3/51 Y. Tanaka et al. effect of low dose combined DE. Int J of Gyn and Obs 2016. [66] prospective NA Significant reduction  0 2/46 3/46 M. Morotti et al. progestin only pill vs. combined oral contraceptives Euro J of Obst & Gyn and Repro Bio. 2014.[72] prospective DIE Significant reduction  0 20/82 0 Muzii. Postoperative monophasic combined oral contraceptives. Am J of Obst & Gyn 2000. [73] prospective OMA NA 0 0 2/35 Mabrouk, impact of laproscopic treatment of sexual function. Int. society of sexual medicine 2012. [74] prospective DIE Significant reduction  0 6/125 13/125 Grandi. Pelvic pain and QOL. Repro sciences 2014. [67] prospective OMA Significant reduction  0 0 3/19  S. Caruso et al. QOL and sexual function in endometriosis. J Endocrinol Invest 2016.[68] Continuous vs. cyclic COC  prospective NA Significant reduction  0 10/96 0 Vlahos. Oral contraceptives for endometriosis. Fertil Steril 2013.[75]  Prospective  all Significant reduction Significant reduction except dyspareunia. 0 0 Cyclic= 30/167 Continuous= 11/85 Seracchioli. OC in painful endometriosis recurrence. Fertil Steril 2010. [76] RCT OMA Significant reduction Non-significant reduction 0 Cyclic=8/103 Continuous=6/104 Cyclic=3/103 Continuous=3/104 Vercellini. Continuous OC use for recurrent endometriosis. Fertil Steril 2003.[69]  Prospective  NA Reduced † 5/50 2/50 2/50 Muzii et al. Postoperative Estroprogestins for RCT OMA Reduced  0 Cyclic=4/28 0 20  Combined oral contraceptives Efficacy Discontinuation Study Drug used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Unknown/other Endometriomas. JMIG 2011 [77] Continuous=12/29  S. Cheewadhanaraks et al. Postoperative Depot Medroxy Acetate. Gynecol Obstet Invest 2012 [78] Continuous COC RCT All Reduced  3/42 1/42 0 Vercellini. Cyproterone vs. OC for endometriosis. Fertil Steril 2002. [79] RCT NA Reduced †  4/90 9/90 2/90 Sesti. Postoperative therapy of endometriosis. Fertil Steril 2007.[80] RCT All Significant reduction  0 4/40 3/40 Zhu et al. BMC Complementary and Alternative Medicine 2014.[81] RCT NA Significant reduction  0 0 2/52 Guzick. Treatment of endometriosis pain. Fertil Steril 2011. [82] RCT NA Significant reduction  0 0 3/26  Vercellini. Contraceptive ring and patch for endometriosis. Fertil Steril 2010 [83] Continuous ring vs. patch prospective All Significant reduction † 10/207 26/207 59/207 Harada. FlexibleMIB for endometriosis pain. Fertil Steril 2017.[84] Cyclic COC vs.  FlexibleMIB RCT All Significant reduction  0 0 18/130 Vercellini et al. GnRH-a vs. OC for endo pain. Fertil Steril 1993. [85] Cyclic COC vs. Goserlin RCT NA Significant reduction  0 Cyc ocp = 1/28 Goserelin= 0 Cyc ocp = 2/28 Goserelin=1/29    * Reported as lost to follow up               † P value was not provided.       21  1.3.2 Progestin Progesterone only medications are an effective second line treatment for endometriosis pain [5,86,87]. Progestins work by inducing atrophy and inhibiting angiogenesis and extracellular matrix in endometriotic implants, as well as suppression of the hypothalamic-pituitary-ovarian axis [88]. The most clinically used progestins are dienogest and norethindrone acetate (NETA) orally, medroxyprogesterone acetate intramuscular injection (DMPA), and the levonogestrel intrauterine device (LNG-IUD).  Several studies have demonstrated favorable responses of DIE lesions to progesterone treatment  (Table 1.4) [70,89,90]. NETA was shown to be effective in rectovaginal DIE lesions and dyspareunia treatment [91,92]. Another prospective study concluded similar effectiveness and better tolerability of dienogest in comparison with NETA [93]. Dienogest was investigated in three RCTs where it proved of equal efficacy to various GnRH-a medications [94–96]. A randomized controlled trail demonstrated levonogestrel IUD group to have significantly lower dysmenorrhea recurrence and higher quality of life compared with expectant management [97], while it had similar effect on pain symptoms and quality of life compared with GnRH agonist [98]. Interestingly, a randomized trail concluded no difference in pain recurrence rate between postoperative IUD use and GnRH-a group [99].  Evidence suggests progestin only medications might be superior to combined hormonal contraceptives because of its hypoestrogenic effect [70]. A recent study investigated its efficacy in patients who reported dissatisfactory combined hormonal contraceptive use in a self-control design where 70% of participants were very satisfied or satisfied with progestin treatment. Moreover, 58 out of 125 reported suboptimal drug tolerability, although complaints were not severe enough to discontinue the treatment [100].  22  Table 1.4. Summary of study arms on the efficacy and failure of progestins in treating endometriosis-associated pain. Progestins Effectiveness Discontinuation Study Medication used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Others/ unknown Chen et al. Postoperative maintenance therapy for endometriomas. Am J Obstet Gynecol 2017.[99] LNG-IUS RCT OMA Significant reduction  0 0 1/40 Fedele. LNG-IUD in rectovaginal endometriosis. Fertil Steril 2001. [101] Prospective DIE reduced  0/11 0/11 0/11 Vercellini. Levonorgestrel-releasing system. Fertil Steril 1999.[102] prospective NA reduced NA 0 1/20 2/20 Tanmahasamut et al LNG-IUD for Endo. ACOG 2012.[97] RCT NA Significant reduction 0 0 1/28 Kim et al. Post op LNG for recurrence. Repro sciences 2018.[103] Prospective OMA Significant reduction 0 0 4/28 C.A.Petta et al. LNG-IUS or GnRH analogue for pain in endometriosis. Human Reproduction 2005.[98] RCT NA Non-significant reduction Significant reduction 0 0 5/40 Yucel et al. LNG-IUS in patients with suspected endometriosis. Aust N Z J Obstet Gynaecol 2018.[104] prospective NA Significant reduction 0 3/45 0 Lockhat. 3 year follow up of LNG-IUD endo prospective SUP Significant reduction 4/45 10/45 1/45 23  Progestins Effectiveness Discontinuation Study Medication used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Others/ unknown treatment. Human Repro 2005. [105] S. Ferrero et al. LNG-IUD vs. danazol for endometriosis pain. International Journal of Gynecology and Obstetrics 2011.[106] LNG-IUD and danazol Prospective DIE Significant reduction  0 1/15 0 K.Lee et al. Diegnogest or LNG-IUS for endometriosis. J. Obstet. Gynaecol. 2018.[107] LNG vs DNG retrospective OMA Significant reduction LNG= 12/72 DNG= 43/160 ◊  Vercellini. Medical therapy for deep endometriosis. Fertil Steril 2005. [108] NETA vs. OCP  RCT DIE Significant reduction OCP= 3/45 NETA= 3/45 OCP= 3/45 NETA= 2/45 OCP= 1/45 NETA= 0/45 C. Scala et al. NETA vs. Seasonique1 for endo. Euro J of Obst & Gyn and Repro Bio 2018.[109] Prospective All Significant reduction OCP= 12/50 NETA= 5/50  ◊ M. Morotti et al. NETA for rectovaginal endometriosis. Euro J of Obst & Gyn and Repro Bio 2017.[110] NETA  retrospective DIE Significant reduction 0 16/103 19/103 Vercellini. Intolerance to Estrogen-Progestins and Progestins for Endo. Gynecol Obstet Invest 2018.[111] prospective DIE and OMA Significant reduction Non-significant reduction 0 9/67  0 P. Vercellini et al. Endo-associated dyspareunia. Human Prospective All NA Dyspareunia- significant reduction 0 8/103 13/103 24  Progestins Effectiveness Discontinuation Study Medication used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Others/ unknown reproduction 2012.[91]  Vercellini. Progestins for endo. Fertil Steril 2016.[93] NETA vs. DNG Prospective NA Significant reduction NETA= 7/90 DNG= 9/90 NETA= 17/90 DNG= 15/90 NETA= 4/90 DNG= 15/90 Lee. Efficacy of long term DNG. Repro sciences 2018.[107] DNG retrospective OMA Significant reduction 209/514 *◊ Lang et al. DNG for Endo. J of women health2018[112] RCT NA Significant reduction ‡ 0 2/130 16/130 Y. Takaesu et al. DNG and GnRHa. J. Obstet. Gynaecol 2016 [113] Prospective all Significant reduction 0 1/56 3/56 T. Strowitzki et al. DNG for Endo. Euro J of Obst & Gyn and Repro Bio 2010.[95] RCT NA Significant reduction  0 2/102 2/102 M. Morotti et al.  Euro J of Obs & Gyn and Repro Bio 2014.[114] Prospective DIE Significant reduction 0 0 11/36 Harada. Dienogest vs. buserelin in endometriosis. Fertil Steril 2009. [94] RCT NA Significant reduction reduced 0 6/129 2/129 Cosson. Postoperative treatment of endometriosis. Fertil Steril 2002. [96] prospective NA Reduced † 0 4/74 1/74  Carr et al. Egolix versus medroxyprogesterone acetate for endometriosis.Repro sciences [115] DMPA RCT NA Significant reduction † 0 15/83 0 P.G.Crosignani et al. DMPA-SC 104 vs. leuprolide for RCT Significant reduction Significant reduction 0 12/153 42/153 25  Progestins Effectiveness Discontinuation Study Medication used Study design Endometriosis phenotype Menstrual pain Non menstrual pain Ineffective Side effects Others/ unknown endo. Human reproduction 2006. [116] Vercellini et al.  DMPA vs. OCP plus danazol for endo pain. Am J Obstet Gynecol 1996. [117] prospective Significant reduction Significant reduction 1/40 3/40 0 P. Tanmahasamut et al. Desogestrel for endo-related pain. Gynecol Endocrinol, 2017.[118] desogestrel RCT NA Significant reduction 0 0 1/20 MAGGIORE, Desogestrel vs. vaginal ring. ACTA 2014 [119] Cyclic vaginal ring vs. desogestrel Prospective DIE Significant reduction Cyc ocp= 7/83 Desogestrel= 2/60 Cyc ocp= 5/83 Desogestrel= 4/60 0 * The most common reason for discontinuation was the data printed on the drug information sheet discouraging the use of DNG for more than approximately 18 months. ‡ The authors did not differentiate between menstrual and non-menstrual pain symptoms. † P value was not provided. ◊ Author did not explain the reason for discontinuation.                 26  1.3.3 Gonadotropin releasing hormone analogue Gonadotropin releasing hormone analogues are another second line treatment for endometriosis pain.  It has been used to treat moderate and severe endometriosis pain by direct suppression of lesions and by downregulating ovarian steroidogenesis through inhibiting gonadotropin secretion via negative feedback mechanism [88]. Different forms of the drug are available, including intramuscular injection, subdermal implant, and nasal spray, which proved to be as effective as danazol [55]. There are many randomized controlled trails investigating the efficacy of GnRH-a in treating endometriosis associated pain (table 1.5) [82,120,94,116]. A study comparing the efficacy of GnRH-ato continuous CHC concluded no significant difference between the efficacy of these two medications (82), while another study concluded that goserelin is slightly better in relieving pain (85). Another prospective study comparing the efficacy of COC to GnRH-a for 4 months followed by COC concluded similar pain relief results in both groups [121]. Cochrane meta-analysis evaluating the effectiveness and safety of GnRH-a on treating endometriosis pain concluded no statistically significant difference between GnRH-a and danazol for dysmenorrhea. Moreover, no statistical significance difference in overall pain relief between GnRH-a and levonorgestrel [122]. Another systematic review proved the efficacy of GnRH-a treatment in relieving pain 80-90% in cases with documented endometriosis [123].  Despite its profound hypoestrogenic effects, it has limited tolerability and hypoestrogenic side effects; thus GnRH-a must be accompanied by progestin only addback therapy. Addback therapy has been proven not to interfere with the ability of GnRH-a to relieve pain [124]. Due to its low tolerability and side effects profile, GnRH-a are often used for 6 months to 1 year, however, extended periods are safe provided the appropriate add back therapy is used [125]. 27  Table 1.5: Summary of studies on the efficacy and failure of gonadotropin releasing hormone analogue in treating endometriosis-associated pain. GnRH agonists Effectiveness Discontinuation Study Drug Study design Phenotype Menstrual pain Non menstrual pain Ineffectiveness Side effects Other/ unknown P.G.Crosignani et al. DMPA-SC 104 vs. leuprolide for endo- associated pain. Human reproduction 2006. [116] leuprolide  RCT NA Significant reduction 0 9/146 37/146 C.A.Petta et al. LNG-IUS or GnRH a for pain in endo. Human Reproduction 2005.[98] RCT NA Reduced Significant reduction 0 0 6/43 Fedele et al. GnRHa for rectovaginal endometriosis. Am J Obstet Gynecol 2000. [126] prospective DIE Significant reduction  2/15 0 0 Strowitzki et al. DNG vs. leuprolide in endo. Human reproduction 2010 [95] RCT NA Significant reduction 0 5/128 3/128 Guzick. Treatment of endo pain. Fertil Steril 2011. [82] RCT NA Significant reduction ‡ 0 0 4/21 Kim et al. Post op LNG for recurrence. Repro sciences 2018.[103] leuprorelin or triptorelin SC injection Prospective  OMA Significant reduction‡ 0 3/25  0  S. Angioni. Pain after laparoscopic DIE. Arch triptorelin   RCT DIE significant reduction ‡ 0 0 5/159 28  GnRH agonists Effectiveness Discontinuation Study Drug Study design Phenotype Menstrual pain Non menstrual pain Ineffectiveness Side effects Other/ unknown Gynecol Obstet 2015.[120] Cosson. Postop treatment of endo Fertil Steril 2002. [96] prospective NA Reduced † 0 1/68 3/68   Harada. DNG vs. buserelin in endo. Fertil Steril 2009.[94]  intranasal buserelin acetate RCT NA Significant reduction reduced 0 7/126 5/126 Y. Takaesu et al. DNG and GnRHa. J. Obstet. Gyn2016 [113] Gosereline  Prospective  all Significant reduction 0 3/55 5/55 ‡ The authors did not differentiate between menstrual and non-menstrual pain symptoms. † P value was not provided.              29  1.4 Objective and hypothesis  1.4.1 Aim 1: To evaluate the patterns of hormonal treatment use in endometriosis- associated pelvic pain  My objective is to investigate patient’s previous use of hormonal drugs to treat pelvic pain that is due to endometriosis. The rationale behind this objective is that some patient’s pain does not improve on these medications despite the widely reported efficacy, and also some patients discontinue hormonal medications due to side-effects. For this reason, I will analyze the first and second line of endometriosis-pain medical treatment: combined hormonal contraceptives, progestin only medications, and gonadotropin releasing hormone analogues.  I will also analyze which factors are associated with hormonal treatment ineffectiveness and discontinuation due to side-effects.  I hypothesize that more patients will report ineffectiveness rather than discontinuation due side effects when using hormonal drugs to treat pain, and patients who report ineffectiveness or discontinuation are more likely to have worse pain and worse quality-of-life.   NOTE: Prior to my main study in Chapter 2, I performed a pilot study on patients with or without endometriosis on a smaller sample from our cohort, focusing on CHC ineffectiveness or discontinuation due to side-effects.  This study has been submitted for publication, and is attached as Appendix A.  30  Chapter 2: Patterns of Hormonal Medications Use for Endometriosis- Associated Pelvic Pain 2.1 Introduction Endometriosis is a chronic inflammatory disease caused by the presence of endometrial tissues outside the uterine cavity, predisposing to pelvic pain, infertility, and other symptoms such as fatigue. It is estimated that endometriosis affects 6-10% of women of reproductive age, more than 33% of women with pelvic pain, and up to 50% of women with infertility [5,9,10]. In Canada, the annual societal cost of endometriosis is $5200 per patient and total annual cost to of $1.8 billion attributable to surgically confirmed endometriosis. While in the United States, the annual healthcare cost is estimated to be $22 billion and $2801 per patient [11,12]. Combined hormonal contraceptives are regarded as the first line of endometriosis-associated pain treatment followed by progestin only medications and gonadotropin releasing hormone analogues [5]. CHCs suppress endometriosis lesions and inhibit estrogen production from the ovaries via a classical feedback mechanism, thereby reducing the production of estrogen-induced prostaglandin and resultant inflammation [127]. Although several studies reported effective pain relief with CHCs, its role as a first line of treatment has been questioned recently due to the limitations in the studies on its efficacy and the risk of bias in the existing literature, in addition to the insufficient data to evaluate its benefit compared to other medications [57,128,129]. Synthetic progestin hormonal therapies are derived from either testosterone or progesterone and are used in patients where oral contraceptives are contraindicated or ineffective [5]. Progestins induce endometrial atrophy and inhibit angiogenesis in endometriosis lesions, and also suppress the hypothalamic pituitary ovarian axis [88]. Several forms are available based on 31  the chemical structure of the drug and the hormone it is derived from (Table 2.1). The first generation includes norethindrone that is derived from testosterone, and medroxyprogesterone acetate derived from hydroxyprogesterone. The second generation includes levonogestrel (LNG) that is derived from testosterone, while the fourth generation includes dienogest (DNG), a testosterone derivative. These progestins are available in oral forms, except medroxyprogesterone acetate is available as depot intramuscular or subcutaneous injection (DMPA), and LNG as an intrauterine device [130].  Table 2.1: Progestins properties and characteristics. Drug  Chemical structure Class Administration route  generation Norethindrone  19-Nortesterone derivative Estranes derived from testosterone oral 1st generation (Depot-) Medroxyprogesterone acetate (DMPA) 17-OH progesterone derivative Pregnanes derived from 17-OH progesterone IM/SC injection 1st generation Levonogestrel (LNG) 19-Nortesterone derivative Gonanes derived from testosterone  IUD 2nd  generation Dienogest (DNG) 19-Nortesterone derivative Non ethylated estranes Oral 4th  generation    32  In a systematic review on the efficacy of hormonal drugs in treating endometriosis-associated pain, 8% of patients who used CHC reported discontinuation due to side effects or inefficacy. This study pooled progestins with other hormonal medications in terms of inefficacy and side effects, which was 5-9%. In terms of satisfaction of treatment, 43% reported satisfaction with their CHC treatment and 31% reported dissatisfaction, while in the progestin group 62% of women were satisfied and 27% were dissatisfied with treatment [129].  A prospective study investigated the efficacy of norethindrone acetate (NETA) in treating endometriosis pain in patients who did not respond to CHC and concluded a significant improvement in sexual function, psychological wellbeing and quality of life. While 46.4% of participants reported suboptimal NETA tolerability, it was not significant enough to discontinue the treatment, with overall 70% of participants were satisfied after a year of treatment [100]. The same group investigated patients who did not respond to both CHC or NETA then switched between the patients in each group which concluded 52% of CHC group tolerated their treatment with overall 65% satisfaction rate, while in the NETA group the tolerability rate was 37% with 51% satisfaction rate at the end of 12 months treatment [111].  In this study, I describe the use in CHC and progestins that were utilized for treating endometriosis-associated pain upon presenting to our center.  I also evaluated the clinical factors or risk factors associated with CHC or progestin ineffectiveness, or CHC or progestin discontinuation due to side-effects.    33  2.2 Materials and methods 2.2.1 Settings Ethics approval was granted by the University of British Columbia (H11-02882). We performed an analysis of a prospective data registry (Endometriosis Pelvic Pain Interdisciplinary Cohort-EPPIC-ClinicalTrials.gov#NCT02911090) that has been previously described in detail [55,56]. Patients were recruited from BC Women’s Center of Pelvic Pain and Endometriosis, an interdisciplinary tertiary referral center in Vancouver, British Columbia.   2.2.2 Study population Patients were recruited between December 2013 and February 2017. We included patients aged between 18-49, referred or re-referred to our clinic within this time, pre-menopausal, and had confirmed or suspected endometriosis. We excluded patients aged outside our range or at menopausal status, or if the patient failed to complete the online questionnaire prior to the initial gynecologist visit. Confirmed endometriosis cases were based on previous surgical diagnosis, direct ultrasonographic visualization of endometrioma, or palpation or ultrasound detection of deep endometriotic nodules. Suspected cases were based on physician impression after detailed history and physical examination.   2.2.3 Drug usage In our cohort, patients were asked to retrospectively recall prior use of cyclic and continuous CHC, as well as progestins and other hormonal treatments. If they responded yes to any, they were also asked if it did not help (i.e. ineffective) or whether they had to discontinue due to side-34  effects. Patients could choose more than one response (i.e. could have tried multiple medications or have stated a particular drug did not help and they had to discontinue due to side-effects).  2.2.4 Variables of interest (at baseline)  Our primary variable of interest was chronic pelvic pain severity in the last 3 months on a numeric rating scale (0-10).  In addition, we assessed other secondary variables of interest: dysmenorrhea in the last 3 months on numeric rating scale (0-10); quality of life using Endometriosis Health Profile questionnaire (EHP 30) [131]; moderate depression in patients scoring ≥ 10 on Patient Health Questionnaire (PHQ 9) [132], moderate anxiety in patients scoring  ≥ 10 on Generalized Anxiety Disorder questionnaire (GAD 7) [133], pain catastrophizing in patients scoring ≥ 30 (75th centile) on Pain Catastrophizing Scale (PSC) [134]. Painful bladder syndrome was diagnosed via the American Urological Association or International Continence Society criteria [135], irritable bowel syndrome using Rome III criteria [136], pelvic floor myalgia assessed by levator ani tenderness on pelvic examination, bladder tenderness also assessed on pelvic examination, and abdominal wall pain assessed by a positive Carnett test where tenderness worsens with abdominal wall contraction. Carnett test involves the examiner palpating an abdominal wall source of pain (e.g. myofascial trigger point) rather than intra-abdominal structure, thus differentiating between myofascial tenderness and intra-abdominal tenderness[137]. Standardized examination was performed by expert gynecologists at our clinic. These variables were collected from an online questionnaire that was filled by patients before the initial clinic appointment at baseline.   35   2.2.5 Statistical analysis For each medication, women with history of ineffectiveness (yes/no) was compared to those who did not find the treatment ineffective. Patterns of use were analyzed using frequency tables and results displayed as numbers and percentages. The characteristics of interest compared using independent sample t-test for continuous variables, and Fisher exact test or Chi-square test for categorical variables. Similar analyses were performed for discontinuation due to side-effects (yes/no). Statistical analyses were performed using IBM SPSS Statistics 24 (SPSS Inc, Chicago, IL, USA). P value ≤ 0.05 was considered statistically significant. Correction for multiple comparisons was not done for the secondary variables of interest. Variables being investigated did not have any missing values.  2.3 Results:  2.3.1 Study sample: Our cohort included 1440 patients (Figure 2.1). Cyclic CHC was the most commonly used drug regimen reported by 839 (58.3%) patients; of these 369 (25.6%) reported ineffectiveness while 325 (22.6%) discontinued because of side effects. Other categories were also collected, such as if patients reported helpful treatment or were currently using, but these were not included in the current analysis. Continuous CHC was the second most commonly used drug regimen, reported by 611 (42.4%) of our cohort; of these 241 (16.7%) reported ineffectiveness and 208 (14.4%) reported side effects intolerability. Third was the LNG-IUD with total of 334 (23.9%) patients reporting use; of these 147 (10.2%) stated ineffectiveness, and 113 (7.8%) discontinued because of side effects. Dienogest was the next commonly used progestin with 287 (20.2%) patients 36  reporting usage; 96 (6.7%) reported ineffectiveness and 82 (5.7%) discontinued due to side effects. Note that sample sizes for DMPA and NETA were too small for analysis, but I have provided the data in Appendix B.  In addition, for comparison, there was a small sample for GnRH agonist (Lupron) usage, and this data are in Appendix C. Figure 2.2 displays the number of previous hormonal treatments used by our cohort. 341 (23.7%) never used any hormonal treatment prior to presenting to our clinic, while 322 (22.4%) used one form of hormonal treatment, 383 (26.6%) used two forms, and 394 (27.4%) used three or more forms of hormonal treatments to treat pelvic pain.  Figure 2.1.  Hormonal drugs used for treatment of chronic pelvic pain in our cohort and reported ineffectiveness and side effects.    37  Figure 2.2: Overall frequency of prior hormonal treatment use in cohort population.       We divided the proportion of patients according to their endometriosis status, confirmed or suspected (Table 2.2). As can be seen, 302 (21% of the total dataset) of patients who ever used cyclic CHC had suspected endometriosis, while 537 (37.3%) had confirmed endometriosis. For continuous CHC, 205 (14.2%) of patients had suspected endometriosis, and 406 (28.2%) were confirmed. In LNG-IUD group, 126 (8.8%) had suspected endometriosis, while 218 (15.1%) were confirmed cases. Lastly, in the dienogest group, 78 (5.5%) had suspected endometriosis, and 209 (14.7%) were confirmed.  341 (23.7%)322 (22.4%)383 (26.6%)394 (27.4%)Never One form of hormonal treatment Two forms of hormonal treatment Three or more38  Table 2.2: Proportion of confirmed and suspected endometriosis cases among the study cohort.  Suspected endometriosis* Confirmed endometriosis* Cyclic CHC (total)  302 (21%) 537 (37.3%) Did not help 141 (10%) 228 (16%) Side effects 115 (8%) 210 (15%) Continuous CHC (total) 205 (14.2%) 406 (28.2%) Did not help 87 (6%) 154 (11%) Side effects 70 (5%) 138 (10%) Levonorgestrel IUD (total) 126 (9%) 218 (15.1%) Did not help  57 (4%) 90 (6.3%) Side effects 38 (2%) 75 (9%) Dienogest (total) 78 (5.5%) 209 (15%) Did not help 27 (2%) 69 (8.1%) Side effects 20 (1.4%) 62 4.3%) *Reported in numbers of patients and percentages between parentheses.    2.3.2 Combined hormonal contraceptives: Table 2.3 summarizes demographic characteristics of patients used CHCs. Patients who reported cyclic and continuous CHCs ineffectiveness were significantly younger, less likely to be married, less educated and had lower income (P< .01). 39  Table 2.3: Demographic characteristics of included participants. Data shown in mean and standard deviations or numbers and percentage in parentheses.  Cyclic CHC ineffective          Cyclic CHC side effects Continuous CHC ineffective Continuous CHC side effects Yes (n=369) No (1071) P Yes (n=325) No (n=1115) P Yes (n=241) No (n=1199) P Yes (n=208) No (n=1232) P  Age* 31.5 ± 7 34.7 ± 7.5 <0.001† 33.5± 7 34± 7.6 .28 30.7± 6.8 34.5±7.5 <0.001† 33.4± 7 34± 7.6 .33 BMI‡ 18.5 or below 17 (4.7%) 46 (4.4%)  13 (4.1%) 50 (4.6%)  12 (5.1%) 51 (4.4%)  6 (3%) 57 (5%)  18.5- 24.9 198 (54.5%) 584 (56%) .49 189 (60%) 593 (54.4%) .36 123 (53%) 659 (56.2%) .9 121 (60%) 661 (55%) .22 25- 29.9 57 (21%) 238 (23%)  61 (19.3%) 252 (23%)  45 (19.2%) 268 (23%)  36 (18%) 277 (23%)  40  30 or above 73 (20%) 175 (17%)  53 (17%) 195 (18%)  54 (23.1%) 194 (16.6%)  39 (19.3%) 209 (17.4%)  Married‡ 126 (34.1%) 243 (66%) <0.001† 135 (41.5%) 190 (58.5%) .18 81 (33.6%) 160 (66.4%) <0.001† 87 (41.8%) 121 (58.2%) .36 Smoker‡ 60 (16.3%) 309 (84%) .08 45 (14%) 279 (86.1%) .78 37 (15.4%) 204 (85%) .35 27 (13.1%) 179 (87%) 1.00 Parous‡ 319 (86.4%) 50 (13.6%) .22 282 (87%) 43 (13.2%) .38 203 (84.2%) 38 (16%) .05 181 (87%) 27 (13%) .56 Education‡ high school 61 (16.5%) 143 (13.5%)  43 (13.3%) 161 (14.5%)  40 (16.6%) 164 (13.8%)  29 (14.1%) 175 (14.3%)  College 236 (64%) 674 (63%) .31 212 (65.4%) 698 (63.1%) .79 156 (64.7%) 754 (63.4%) .23 128 (62.1%) 782 (63.8%) .94 Graduate education 62 (16.8%) 206 (19.4%)  60 (18.5%) 208 (18.8%)  35 (14.5%) 233 (19.6%)  41 (20%) 227 (18.5%)  other 10 (2.7%) 39 (3.7%)  9 (3.6%) 40 (2.8%)  10 (3.3%) 39 (4.1%)  8 (3.3%) 41 (3.9%)  41  Income‡ 59.999 or less 194 (53%) 462 (43.5%) <0.001† 152 (50%) 504 (45.5%) .70 132 (55%) 524 (44%) <0.001† 93 (54%) 563 (39%) .88 60.000 or more 175 (47.4%) 600 (56.5%)  172 (53%) 603 (54.5%)  109 (45%) 666 (56%)  113 (55%) 662 (54%)   † Significant P value. *Reported in means and standard deviation. ‡Reported in number of patients and percentage in parentheses.42  Table 2.4 summarizes pain levels and quality of life in patients who used CHCs. Patients who reported CHC ineffectiveness had significantly higher chronic pelvic pain (CPP) and dysmenorrhea, in addition to worse quality of life (P< .05).  Patients who discontinued CHCs due side-effects had significantly higher dysmenorrhea and worse quality of life (P< .05).  Table 2.4: Pain levels and quality of life levels in patients who discontinued cyclic and continuous CHCs shown in mean and standard deviation.   Ineffective Side effects Cyclic COC Yes No P value Yes  No  P value Chronic pelvic pain* 7.1 ± 2.2 6.5± 2.2 <0.001† 6.6± 2.2 6.7± 2.3 .65 Dysmenorrhea* 7.5 ± 3 7 ± 3 .02† 7.7± 2.5 7± 3.1 <0.001† Quality of life* 24± 10 21± 10.4 <0.001† 23.3± 9.1 21.1± 11 <0.001† Continuous CHC  Chronic pelvic pain* 7.3± 2.1 6.6± 2.3 <0.001† 6.8± 2 6.7± 2.3 .37 Dysmenorrhea* 7.7± 3 7± 3 .002† 7.6± 2.6 7.1± 3 .02† Quality of life* 24.4± 10 21± 10.4 <0.001† 23.7±9 21.2±10.5 <0.001†  † Significant P value. *Reported in means and standard deviation    43  Table 2.5 displays the associated diagnoses of patients that used CHCs. Painful bladder syndrome (IBS), abdominal wall and bladder tenderness, depression and pain catastrophizing were more likely to be associated with cyclic and continuous CHC ineffectiveness (P< .05). Patients who discontinued cyclic CHC due to side effects had more IBS (P=.001), while patients who discontinued continuous CHC were more likely to have depression and anxiety (P< .05).                 44  Table 2.5: Association between cyclic and continuous CHC ineffectiveness or side effects and the underlying diagnoses. Diagnosis Cyclic CHC ineffective Cyclic CHC side effects Continuous CHC ineffective Continuous CHC side effects Yes (n=369) No (1071) P Yes (n=325) No (n=1115) P Yes (n=241) No (n=1199) P Yes (n=208) No (n=1232) P  Irritable bowel syndrome * 118 (22%) 418 (78%) .02† 96 (18%) 440 (82.1%) .001† 79 (15%) 457 (85.3%) .12 66 (12.3%) 470 (88%) .09 Painful bladder syndrome * 159 (23.5%) 519 (76.5%) .02† 146 (21.5%) 532 (78.5%) .17 94 (14%) 584 (86.1%) .003† 94 (14%) 584 (86.1%) .17 Carnett positive * 206 (22.4%) 715 (78%) <0.001† 202 (22%) 719 (78.1%) .47 137 (15%) 784 (85.1%) .01† 132 (14.3%) 789 (86%) .88 Bladder tenderness *  120 (29.4%) 288 (71%) .04† 106 (26%) 302 (74%) .06 82 (20.1%) 326 (80%) .03† 62 (15.2%) 346 (85%) .62 Pelvic floor tenderness * 323 (25%) 986 (75.3) .01† 291 (22.2%) 1018 (78%) .32 216 (16.5%) 1093 (83.5%) .46 190 (14.5%) 1119 (85.5%) .90 45  Depression * 220 (32%) 472 (68.2%) <0.001† 166 (24%) 526 (76%) .23 156 (22.5%) 536 (77.5%) <0.001† 118 (17.1%) 574 (83%) .01† Anxiety * 149 (30%) 349 (70.1%) .01† 121 (24.3%) 377 (75.7%) .26 96 (19.3%) 402 (81%) .064 85 (17.1%) 413 (83%) .04† Pain catastrophizing* 123 (33%) 251 (67.1%) <0.001† 96 (26%) 278 (74.3%) .10 80 (21.4%) 294 (77%) .01† 65 (17%) 309 (83%) .07 † Significant P value *Reported in number of patients and percentage in parentheses.46  2.3.3 Progestins: Table 2.6 summarizes the demographic characteristics of patients who reported LNG-IUD and dienogest (DNG) ineffectiveness and discontinuation due to side effects. Those who reported ineffectiveness tended to be younger, less likely to be married, and had lower education (P<0.05). While those who discontinued due to side effects were younger (P< 0.05).                    47  Table 2.6: Demographics in patients who reported using DNG and LNG-IUD ineffectiveness and side effects.  LNG-IUD ineffective LNG-IUD side effects DNG ineffective DNG side effects Yes (n=147) No (n=1293) P  Yes (n=113) No (n=1327) P  Yes (n=96) No (n=1344) P  Yes (n=82) No (n=1358) P  Age* 31.43± 6.7 34.1± 7.5 <0.001† 32.03± 6.4 34± 7.6 0.002† 31±7.4 34.1± 7.5 <0.001† 31.9±6.8 34± 7.5 0.01† BMI‡ 18.5 or below 4 (3%) 59 (5%)  3 (2.7%) 60 (5%)  4 (4.3%) 59 (5.4%)  6 (7.5%) 57 (4.3%)  18.5- 24.9 68 (49%) 714 (56.4%) .03† 64 (58.2%) 718 (55.4%) .12 43 (46%) 739 (94.5%) .09 44 (55%) 738 (56%) .18 25- 29.9 31 (22%) 282 (22.3%)  17 (15.5%) 296 (95%)  22 (23.4%) 291 (22.2%)  12 (15%) 301 (23%)  30 or above 37 (26.4%) 211 (17%)  26 (24%) 222 (17%)  25 (27%) 223 (17%)  18 (17.3%) 230 (22.5%)  48  Married‡ 50 (34%) 97 (66%) 0.01† 31 (27.4%) 82 (72.6%) <0.001† 30 (31.3%) 66 (69%) 0.01† 30 (37%) 52 (63.4%) 0.14 Smoker‡ 30 (20.4%) 117 (80%) 0.01† 21 (19%) 92 (81.4%) 0.11 11 (11.5%) 85 (88.5%) 0.64 11 (14%) 70 (86.4%) 1.00 Parous‡ 125 (85%) 22 (15%) 0.22 89 (79%) 24 (21.2%) 0.003† 85 (88.5%) 11 (11.5%) 1.00 72 (88%) 10 (12.2%) 0.86 Education‡ High school 23 (15.6%) 181 (14%)  14 (12.4%) 190 (14.4%)   20 (21%)  184 (13.8%)   13 (16%)  191 (14%)  College  105 (71.4%) 805 (63%) .02† 82 (72.6%) 828 (63%) .19 60 (62.5%) 850 (64%) .20 50 (5.5%) 860 (64%) .97 Graduate education 14 (9.5%) 254 (20%)  14 (12.4%) 254 (19%)  14 (14.6%) 254 (19%)  15 (18.5%) 253 (19%)  Other  5 (.3%) 44 (3%)  3 (.2%) 46 (3.2%)  2 (.1%) 47 (3.3%)  3 (3.7%) 46 (3.4%)  49  Income‡ 59.999 or less 74 (5.2%) 582 (45.3%) .26 61 (54%) 595 (45%) .08 60 (62.5%) 596 (45%) <0.001† 44 (54.3%) 612 (45.3%) .13 60.000 or more 73 (50%) 702 (56%)  52 (46%) 723 (55%)  36 (37.5%) 739 (55.4%)  37 (46%) 738 (55%)  † Significant P value. *Reported in means and standard deviation. ‡Reported in number of patients and percentage in parentheses.50  Table 2.7 shows pain and quality of life in patients who reported LNG-IUD and DNG ineffectiveness and side effects.  Patients who stated the LNG-IUD was ineffective reported worse chronic pelvic pain and quality-of-life, while those who stated the DNG was ineffective reported worse chronic pelvic pain, dysmenorrhea, and quality-of-life.  Patients with LNG-IUD discontinuation due to side-effects had worse dysmenorrhea, while patients with DNG discontinuation due to side-effects had worse chronic pelvic pain, dysmenorrhea, and quality-of-life.  Table 2.7: Pain levels and quality of life levels in patients who reported levonorgestrel IUD and dienogest ineffectiveness and side effects, shown in mean and standard deviation.  Ineffective Side effects LNG- IUD Yes  No  P value Yes  No  P value Dysmenorrhea* 7.4±3 7.1±3 .17 8.14±2.2 7±3 .001† Chronic pelvic pain* 7.2±2 6.6±2.3 .001† 6.7±2.2 6.7±2.3 .98 Quality of life* 24.2±9.4 21.3±10.4 .001† 22.3±9.5 21.5±10.4 .44 DNG  Dysmenorrhea* 7.9±3 7±3 .01† 7.99±3 7±3 .01† Chronic pelvic pain* 7.5±2 6.6±2.3 <0.001† 7.50±2 6.6±2.2 <0.001† Quality of life* 26.2±9 21.3±10.4 <0.001† 24.7±8.4 21.4±10.4 .001† † Significant P value. *Reported in means and standard deviation. 51  In terms of associated diagnoses, patients who reported LNG-IUD ineffectiveness were more likely to have pelvic floor tenderness and depression, while patients who discontinued LNG-IUD due to side effects were more likely to have bladder tenderness, depression and anxiety. Patients who reported DNG ineffectiveness were more likely to have abdominal wall tenderness, depression and pain catastrophizing, while patients who reported DNG side effects were more likely to have pelvic floor tenderness, depression, anxiety and pain catastrophizing (table 2.8).             52  Table 2.8: Association between levonorgestrel IUD and dienogest ineffectiveness or side effects and the underlying diagnoses. Diagnosis LNG-IUD ineffective LNG-IUD side effects DNG ineffective DNG side effects Yes (n=147) No (n=1293) P  Yes (n=113) Yes (n=147) No (n=1293) P  Yes (n=113) Yes (n=147) No (n=1293) P  Yes (n=113) Irritable bowel syndrome * 55 (10.3%) 481 (98.7%) 1.00 37 (7%) 499 (93.1%) .36 30 (5.6%) 507 (94.4%) .23 23 (4.3%) 513 (96%) .08 Painful bladder syndrome * 68 (10%) 610 (90%) .92 46 (6.8%) 632 (93.2%) .23 35 (5.2%) 643 (95%) .08 32 (5%) 646 (95.3%) .05 Carnett positive * 86 (9.3%) 835 (91%) .15 76 (8.3%) 845 (91.7%) .48 49 (5.3%) 872 (95%) .01† 46 (5%) 875 (95%) .15 Bladder tenderness *  52 (13%) 356 (87.3%) .05 42 (10.3%) 366 (90%) .04† 31 (7.6%) 377 (92.4%) .41 27 (6.6%) 381 (93.4%) .38 Pelvic floor tenderness * 125 (9.5%) 1184 (90.5%) .01† 100 (7.6%) 1209 (92.4%) .39 83 (6.3%) 1226 (93.7%) .14 69 (5.3%) 1240 (94%) .04† Depression * 88 (12.7%) 604 (87.3%) .003† 69 (10%) 632 (90%) .004† 61 (8.8%) 631 (91.2%) .002† 52 (7.5%) 640 (92.5%) .004† 53  Anxiety * 59 (12%) 439 (88.2%) .14 50 (10%) 448 (90%) .03† 39 (7.8%) 459 (92.2%) .22 42 (8.4%) 456 (92%) .002† Pain catastrophizing* 42 (11.2%) 332 (89%) .49 33 (8.8%) 341 (91.2%) .43 34 (9.1%) 340 (91%) .04† 33 (9%) 341 (91.2%) .004†  † Significant P value. *Reported in number of patients and percentage in parentheses.54  2.4 Discussion:  In this cohort, patients who reported ineffectiveness or discontinuation due to side-effects tended to be younger and have lower socioeconomic status. They also tended to have worse pain and quality-of-life, and higher frequency of non-gynecologic pain diagnoses. Several studies have evaluated the efficacy of cyclic and continuous CHCs in treating endometriosis- associated pain [68,69,73,75,76]. Although these studies concluded significant pain reduction in patients who used both forms of CHC, some cases withdrew from these studies due to inefficacy and side effects. Another prospective study compared between CHC and LNG-IUD effectiveness in reducing recurrence and pain relief and concluded that patients in the CHC group had larger reduction in their pain level, however patients at the LNG-IUD group reported higher rate of satisfaction with their treatment arm [138].  A retrospective study compared post-operative efficacy of DNG and LNG-IUD in treating endometriosis and concluded significant reduction in pain scores (evaluated via VAS) in both groups, with no difference between the two groups. Additionally, treatment discontinuation rate was significantly higher in the DNG group (26.9%) compared with LNG-IUD group (16.7%) which was due to treatment side effects [107]. Another prospective study assessing the efficacy and continuation rates of LNG-IUD in patients with endometriosis concluded an overall 56% continuation rate at the end of 3 years, and that most discontinuation took place within the first 12 months of treatment which was mainly due to side effects [105].   Generally, non-adherence is regarded as one of the main reasons for treatment inefficacy [8]. Drug cost is one of the reasons of non-adherence and a Canadian study concluded that female gender, having a chronic disease, living in British Columbia, low income, and lack of insurance to be risk factors for cost related non-adherence [139]. Other reasons for non-adherence could be 55  frustration due to the absence of immediate symptomatic control and knowing that hysterectomy is an option although it is not always effective for pelvic pain especially if the patient has chronic pain. It is important to note that in our questionnaire, we do not ask about the point of time of medication intake, so we do not know the duration of time between when they tried the hormonal medication and their current pain symptoms. In addition to worse pain and quality-of-life, we observed more psychological comorbidities in patients who reported ineffectiveness or discontinuation due to side-effects.  Higher pain levels, worse quality of life and psychological distress are closely integrated. A recent review suggested a higher incidence of psychopathological conditions in patients with endometriosis, which may amplify pain symptoms in these patients [140]. Another study indicated a close association between higher CPP levels and worse QOL levels, especially the psychological dimension [141]. Central sensitization of the nervous system may contribute to treatment ineffectiveness as it does not typically respond to hormonal therapy, thus higher pain levels and ineffective treatment may lead to worse QOL in these patients.  Indeed, we observed higher rates of non-gynecologic pain diagnoses such as abdominal wall pain and pelvic floor myalgia amongst the non-responders.  Pain catastrophizing could also play a role as higher levels are associated with higher pain levels and worse QOL [142]; and in our cohort, pain catastrophizing was significantly higher in non-responders. It is notable that in patients who discontinued due to side effects, the treatment might have been effective in treating their pain if they did not have to discontinue because of the side effects. One limitation to our study is the patient reported outcomes, and so we depend on patients’ subjective interpretation of inefficacy rather than objective measures. Neither duration of treatment nor other medication intake were recorded in our questionnaires, and thus we cannot 56  tell if the treatment was actually ineffective, the desired pain relief was not achieved yet, or drug efficacy was altered due to another drug interaction. Finally, we do not know which type of side-effect led to treatment discontinuation.    57  Chapter 3: Conclusion This thesis focused on patients’ prior response to medical treatment and investigated the association with patients’ current clinical presentation. In my study, I showed that patients who reported hormonal treatment was ineffective in treating their pain or discontinued due to side-effects, had higher pelvic pain severity compared with the rest of the cohort. In addition, these patients had worse quality of life, more psychological comorbidities, and non-gynecologic pain diagnoses.   3.1 Implications  My results identify a significant proportion of patients at a tertiary referral center who do not respond as desired under hormonal treatment use and their characteristics, which may help physicians identify patients at risk of treatment failure, such as those with psychological or other non-gynecological pain diagnoses. Proper counselling is a key tool for these patients and the possible factors that can alter their response, in addition to patient’s ability to afford the drug and compliance to long-term daily oral medication. As well, the association between treatment ineffectiveness and psychological conditions such as depression and anxiety sheds light on the importance of identifying psychological conditions which may possibly improve treatment response and improve the patient’s overall quality of life. Involvement of allied health professionals such as psychologists and physiotherapists in the management of patients if certain risk factors are identified, such as psychological symptoms or musculoskeletal pain, can be crucial for treatment success and pain management.  Furthermore, in this cohort, patients tend to have lower income compared to the rest of the clinic’s population. Closer attention needs to be paid to treatment affordability and insurance coverage to ensure maximum benefit. 58   3.2 Limitations The main limitation of my study is recall bias, where patients response to hormonal treatment was collected based on patient’s retrospective recall and subjective interpretation of ineffectiveness and side effects. Recall bias limits the validity and credibility of the results, however, I plan to correct for that in the future by prospective study. Due to the nature of data collection in this study, we do not have equal number of participants in each group. Moreover, the way this questionnaire was designed does not specify the time in a patient’s history where a certain drug was ineffective or caused side effects. In addition, the questionnaire did not have further questions on the inefficacy and side effects patients experienced, so we do not know how each patient defined ineffectiveness nor which side-effect caused discontinuation. Finally, these patients were recruited from a tertiary health care center, thus more likely to have worse pain and more comorbidities, which limits the generalizability of my results to the general population.  3.3 Future direction Ultimately, my goal is to classify patients according to their response to hormonal treatment into phenotypic groups: e.g. responders vs. non-responders, and those who cannot tolerate hormonal therapy due to side-effects. This can help understanding why some patients but not others respond in a certain way, which will optimize future treatment in these groups and ultimately improve patient’s quality of life. In reality, patients may present in more than one group (i.e. responder but having side effects). In such scenarios, focus should be shifted towards the most bothersome complaint and improving patient’s overall quality of life. 59  I would like to confirm my findings with a longitudinal study design to follow patients starting a new hormonal therapy over time. I would also include a more detailed questionnaire, including but not limited to the type of side effects experienced, duration/dates of treatment courses, and ask about any factors that may alter drug efficacy such as malabsorption, drug interactions, and dose optimization.  Newer medications were recently proposed to treat endometriosis pain, such as gonadotropin releasing hormone antagonists, selective estrogen receptor modulators, selective progesterone receptor modulators, and aromatase inhibitors [39–41]. I would like to include these medications in the study as well to compare their efficacy and tolerability to the first and second line of endometriosis pain treatment. As multidisciplinary management is effective and recommended for patients with endometriosis associated pain [52,55,56], and consulting clinical pharmacologists in patients who fail to respond to multiple hormonal treatment could be beneficial for treatment optimization. One of the most important steps in research is knowledge translation. As I have started this process by presenting abstracts at two conferences, I plan to share my results with to our patients at the Annual Celebration of Hope at BC Chronic Pelvic Pain Centre. 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Combined hormonal contraceptives (CHCs) are regarded as the first line of therapy in treating endometriosis-associated CPP [5,52,86]. They function via direct inhibition of endometriosis lesions and via inhibition of gonadal estrogen synthesis through a feedback mechanism on the hypothalamic-pituitary-gonadal axis. The resultant estrogen reduction decreases prostaglandin synthesis, which is a major component in the endometriotic inflammatory response [144]. Several studies have been performed to evaluate the effectiveness of CHCs for endometriosis and pelvic pain [60–63]. In a randomized controlled trial comparing the effectiveness of cyclic CHCs with placebo for four menstrual cycles, despite significant improvement of dysmenorrhea in the CHCs group, there was no significant improvement in the non-cyclic pelvic pain scores in the same group. In this trial, four patients (7.8%) discontinued the treatment due to side effects [63]. 83  Some studies have compared the efficacy of cyclic and continuous regimens, and there is evidence for benefit of continuous CHCs [68,69,75,145]. However, other randomized [76,145] and non-randomized [69,75] studies that investigated CHCs role in treating endometriosis-associated pain have reported participant withdrawal due to intolerability of side effects. As well, some studies reported patients changing the type of CHC because of menstrual cycle changes and side-effects [68,77]. In the current study, we investigated the prevalence of women reporting a history of CHC ineffectiveness for pain or CHC discontinuation due to side-effects, among women who attended a tertiary referral center for pelvic pain and endometriosis. We also determined whether CHC ineffectiveness or discontinuation due to side-effects were associated with CPP or other pelvic pain measures, as well as quality-of-life, psychological scores and underlying pain conditions.    A.2 Materials and methods A.2.1. Setting: This is a cross-sectional analysis of a prospective database at the BC Women’s Center for Pelvic Pain and Endometriosis, an interdisciplinary tertiary referral center in Vancouver, British Columbia, Canada.  This prospective database has been previously described in detail [55,56], and involves prospective consent followed by a series of online patient questionnaires completed prior to the initial visit, validated psychological and quality-of-life questionnaires, and real-time entry of data from the gynecologist assessment. Ethics approval was granted by the University of British Columbia (H11-02882).   84  A.2.2. Study population: In this study, we included participants who were referred or re-referred to our center between December 2013 and April 2015. Exclusion criteria was postmenopausal status.  A.2.3. Variables of interest: Participants were asked to retrospectively recall whether they have ever taken CHCs for treatment of their pain (including both past or current use), and whether the CHCs were taken cyclically and/or continuously.  For those who reported having taken CHC cyclically, participants were asked whether the CHCs were ineffective for their pain and/or whether the CHCs were discontinued due to side-effects. Similarly, for those who reported having taken CHC continuously, participants were asked whether the CHCs were ineffective for their pain and/or whether the CHCs were discontinued due to side-effects.     Thus, there were 4 variables of interest:  1) history of cyclical CHC ineffectiveness (yes/no); 2) history of cyclical CHC discontinuation due to side-effects (yes/no); 3) history of continuous CHC ineffectiveness (yes/no); 4) history of continuous CHC discontinuation due to side-effects (yes/no).  Based on the nature of the questions, it was possible for patients to have tried both cyclical or continuous CHCs, and to answer “yes” to both ineffectiveness and discontinuation due to side-effects.  Thus, a given patient could answer “yes” to 0 to 4 of the questions.    A.2.4. Analyses for primary and secondary outcomes: The primary outcome of chronic pelvic pain severity for the past three months was assessed using an 11-point numeric rating scale (0-10). Secondary outcomes were other pain symptoms in the past 3 months (dysmenorrhea, dyschezia, back pain, superficial and deep dyspareunia; 85  assessed using the same 11-point scale) and quality of life as measured by the pain subscale of the Endometriosis Health Profile 30 (EHP-30) [131].   Bivariate association was performed between each of the 4 variables of interest, and the primary and secondary outcomes. For the primary outcome, a logistic regression model was also developed, controlling for demographic factors.  A.2.5. Corollary analyses We also sought to determine whether the 4 variables of interest were associated with underlying conditions, which could explain the association with the primary/secondary outcomes. The underlying conditions were a previous surgical confirmation of endometriosis; diagnosis of irritable bowel syndrome using the Rome III criteria [136]; diagnosis of painful bladder syndrome using the criteria of the American Urological Association or International Continence Society [135]; abdominal wall pain, typically due to myofascial trigger points, and diagnosed by positive Carnett test [55]; bladder or pelvic floor tenderness on pelvic examination as a marker of pelvic floor myalgia [55]; and moderate depression assessed by Patient Health Questionnaire (PHQ-9) score ≥ 10 [132], moderate anxiety assessed by Generalized Anxiety Disorder (GAD-7) questionnaire score ≥ 10 [133], and catastrophizing assessed by the Pain Catastrophizing Scale (PCS) score ≥ 30 (75th centile) [134].   A.2.6. Statistics Analysis was done using SPSS software (SPSS, V22.0; IBM Corp, Armonk, NY). P value <.05 was considered statistically significant. Means are provided with standard deviation (SD), medians with ranges, and odds ratio with confidence interval.  Missing values were excluded 86  from the regression analysis if the proportion of missing values was < 5%. However, the proportion of missing values in anxiety, depression, and pain catastrophizing variables were 5.6% and thus were imputed as previously reported [55].  A.3 Results  A.3.1. Descriptive statistics A total of 656 patients from the registry met the study criteria. A detailed flow chart is presented in Figure A.1.  In the study sample, 362 (55.2%) reported prior use of cyclic CHCs, while 265 participants (40.7%) reported history of using continuous CHCs.   For the 4 variables of interest: a) 167 (25.5% of the study sample) reported cyclical CHC ineffectiveness; b) 139 (21.2%) reported cyclical CHC discontinuation due to side effects; c) 110 (16.8%) reported continuous CHC ineffectiveness; and d) 80 (12.2%) reported CHC discontinuation due to side effects (Figure A.1).  Demographic characteristics and comparisons are summarized in Table A.1.  Those who reported the cyclic CHCs to be ineffective were older (p = 0.010), less likely to be married (p = 0.005), and had significantly lower incomes (p = 0.002).  Those who reported the continuous CHCs to be ineffective were also significantly younger (p = 0.005) and had lower incomes (p < 0.001).  No differences were noted for those who reported discontinuing the cyclic or combined CHC due to side-effects (Table A.1).    87  Figure A.1: Flow chart that shows study participants according to the type of CHC used and the reported variables of interest (ineffectiveness, side effects).    Note that the sum does not add up to the total because patients could be in more than one category.     Study population n=656Cyclic CHCs n=362 (55.2%)Ineffective  n=167 (25.5%)Side effects n=139 (21.2%)Continuous CHCs n=265 (40.7%)Ineffective n=110 (16.8%)Side effects n=80 (12.2%)88  Table A.1: Demographic characteristics of included participants in the four groups of interest. Variable Cyclic CHC ineffective          Cyclic CHC side effects Continuous CHC ineffective Continuous CHC side effects Yes (n=167) No (n=195) P Yes (n=139) No (n=223) P Yes (n=110) No (n=157) P Yes (n=80) No (n=187) P  Age 31.6±6.8 33.5± 7.6 .01† 33.3±7 32.2± 7.4 .17 30.6 ± 6.5 33± 7.5 <0.001† 32.6 ± 7.3 31.8± 7.2 .38 BMI 25.4± 5.7 25.4± 5.9 .97 25.4± 6.2 25.3± 5.5 .88 25.7 ± 6 25.5± 5.7 .86 25.7 ± 5 25.6± 6.1 .87 Married 45 (27.8%) 81 (42.2%) <0.001† 52 (38%) 74 (34.1%) .49 30 (28%) 61 (39.6%) .06 30 (37.5%) 61 (33.7%) .32 Smoker  27 (16.7%) 24 (12.4%) .29 22 (16.1%) 29 (13.3%) .53 16 (15%) 22 (14.3%) 1.00 15 (18.8%) 23 (12.7%) .25 Parous 46 (67.6%) 53 (72.6%) .58 38 (69.1%) 61 (70.9%) .85 28 (65.1%) 42 (70%) .67 26 (76.5%) 44 (63.8%) .26 Education Some high school  5 (3.1%)  7 (3.6%)    4 (2.9%)  8 (3.7%)   4 (3.7%)  5 (2.2%)   1 (1.3%)  8 (4.4%)  89  High school 18 (11.1%) 15 (7.8%)  16 (11.7%) 17 (7.8%)  10 (9.3%) 18 (11.7%)  12 (15%) 16 (8.8%)  Some college 47 (29%) 47 (24.5%)  35 (25.5%) 59 (27.2%)  31 (29%) 38 (24.7%)  18 (22.5%) 51 (28.2%)  Graduated 2 year college 24 (14.8%) 29 (15.5%) .16 15 (10.9%) 38 (17.5%) .97 15 (14%) 22 (14.3%) .71 8 (10%) 29 (16%) .64 Graduated 4 year college 35 (21.6%) 46 (24%)  35 (25.5%) 46 (21.2%)  24 (22.4%) 33 (21.4%)  22 (27%) 35 (19.3%)  Post graduate 29 (18%) 41 (21.4%)  30 (21.9%) 40 (18.4%)  19 (17.8%) 21 (20%)  17 (21.3%) 33 (18.2%)  Other 4 (2.4%) 7 (3.6%)  2 (1.5%) 9 (4.1%)  4 (3.7%) 7 (4.5%)  2 (2.5%) 9 (5%)  Annual Income  Less than 20,000  24 (14.8%)  19 (10%)   19 (14%)  24 (11.1%)   20 (18.7%)  8 (5.2%)   10 (12.5%)  18 (10%)   20,000- 39,999 29 (18%) 32 (16.7%)  25 (18.2%) 36 (16.6%)  24 (22.4%) 24 (15.6%)  13 (16.3%) 35 (19.3%)  90  40,000- 59,999 33 (20.4%) 25 (13%) <0.001† 18 (13.1%) 40 (18.4%) .95 17 (15.9%) 27 (17.5%) <0.001† 16 (20%) 28 (15.5%) .43 60,000- 79,999 35 (21.6%) 35 (18.2%)  25 (18.2%) 45 (20.7%)  19 (17.8%) 26 (17%)  14 (17.5%) 31 (17.1%)  80,000- 99,999 19 (11.7%) 27 (14.1%)  19 (14%) 27 (12.4%)  12 (11.2%) 25 (16.2%)  13 (16.3%) 24 (13.3%)  100,000 or more 22 (13.6%) 54 (28.1%)  31 (22.6%) 45 (20.7%)  15 (14%) 44 (28.6%)  14 (17.5%) 45 (25%)   Mean +/- SD, or Number (%); † Significant P value. Proportions do not add up to 100% due to missing values. 91   A.3.2. Analyses for primary and secondary outcomes Associations between the 4 variables of interest, and the primary/secondary outcomes, are summarized in Table A.2. Those who reported the cyclic or continuous CHCs being ineffective had higher severity of chronic pelvic pain in the last 3 months (cyclic p = 0.008 and continuous p = 0.001) (Table A.3). Multiple logistic regression was performed, and showed that the association between chronic pelvic pain and CHC ineffectiveness was independent of demographic variables (age, marital status, and income) (Table A.4). Those who reported cyclic or continuous CHC discontinuation due to side-effects had poorer quality-of-life (cyclic p = 0.042, continuous p = 0.006) (Table A.2 and A.3). As no demographic variables were associated with CHC discontinuation due to side effects, no regression analysis was performed.  Other observations include cyclic CHC ineffectiveness associated with worse dysmenorrhea (p = 0.004); while continuous CHC discontinuation due to side-effects had less superficial dyspareunia (p = 0.041) (Table A.2 and A.3).       92  Table A.2: Various pain symptoms and quality of life levels in patients who discontinued cyclic CHCs.  Cyclic CHC Ineffective Side effects Yes (n=167) No (n=195) P Yes (n=139) No (n=223) P Dysmenorrhea 7.1± 2.5 6.8± 2.5 .43 7.4± 2.3 6.6± 2.6 <0.001 † Superficial dyspareunia 4.1± 3.2 3.8± 3.4 .42 3.6± 3.4 4.2± 3.2 .09 Deep dyspareunia 6.2± 3.2 5.9± 3.1 .28 6± 3.2 6± 3.1 .59 Dyschezia 4.4± 3 4.3± 3.2 .87 4.6± 3.1 4.2± 3.1 .24 Chronic pelvic pain 6.4± 3.1 5.5± 3.1 .01 † 6.0 ± 2.9 5.9± 3.2 .56 Back pain 5.5± 3.1 5.2± 2.9 .29 5.3± 2.9 5.3± 3.1 .99 Quality of life 48.8±24.4 47.9±23.6 .76 51.5± 22.9 46.2±24.4 .04 †  Mean +/- SD; † Significant P value     93  Table A.3: Various pain symptoms and quality of life levels in patients who discontinued continuous CHCs.  Continuous CHC Ineffective Side effects Yes (n=110) No (n=157) P Yes (n=80) No (n=187) P  Dysmenorrhea 7.15± 2.6 6.6± 2.7 .14 7.19± 2.4 6.6± 2.8 .13 Superficial dyspareunia 4.5± 3.4 3.9± 3.2 .20 3.5± 3.4 4.4± 3.2 .04 † Deep dyspareunia 6.7± 3 6.2± 3 .14 6.3± 3 6.5± 3 .72 Dyschezia 4.5± 3 4.3± 3.2 .54 4.5± 3 4.3± 3.2 .77 Chronic pelvic pain 6.8± 2.8 5.6± 3.2 <0.001 † 6.6± 2.8 6± 3.2 .47 Back pain 5.8± 2.3 5.2± 2.9 .16 5.6± 2.7 5.4± 3.1 .51 Quality of life 49.4± 24.4 47.4± 25.2 .53 54.2± 20.6 45.6± 26.1 <0.001 † Mean +/- SD; † Significant P value     94  Table A.4: Binary logistic regression for CHCs ineffectiveness. variable Odds ratio* 95% confidence interval P value Cyclic CHC ineffective Chronic pelvic pain ‡ 1.074 1.00- 1.15 0.05 Annual income 0.82 0.72- 0.93 <0.001 † Continuous CHC ineffective Chronic pelvic pain 1.12 1.02- 1.22 0.01 † Annual income 0.75 0.64- 0.88 <0.001 † *Odds ratio is derived from exponential (B) value; ‡ Odds ratio for each unit increase in level of pain on a scale of 0–10 † Significant P value  95  A.3.3. Corollary analyses In Table A.5, we show the associations between the 4 variables of interest and underlying conditions.  There were no associations with endometriosis, IBS, PBS, abdominal wall pain, or psychological measures. Only pelvic floor tenderness was significantly associated with cyclic and continuous CHC ineffectiveness (p < 0.05).                  96  Table A.5: Association between CHC ineffectiveness or side effects and the underlying diagnosis.  Diagnosis Cyclic CHC ineffective Cyclic CHC side effects Continuous CHC ineffective Continuous CHC side effects Yes (n=167) No (n=195) P Yes (n=139) No (n=223) P Yes (n=110) No (n=157) P Yes (n=80) No (n=187) P  Endometriosis 103 (61.7%) 28 (14.3%) .44 94 (67.6%) 17 (7.6%) .21 76 (69.1%) 19 (12.1%) .13 59 (73.7%) 7 (3.7%) .11 Irritable bowel syndrome 87 (52.1%) 80 (41%) .24 83 (59.7%) 56 (25.1%) .23 51 (46.4%) 59 (37.6%) .06 41 (51.2%) 39 (20.8%) .69 Painful bladder syndrome 67 (40.1%) 100 (51.3 %) .34 60 (43.2%) 79 (35.4%) 1.0 54 (49.1%) 56 (35.7%) .53 39 (48.8%) 41 (22%) .69 Carnett positive 76 (45.5%) 91 (46.7%) .16 62 (44.6%) 77 (34.5%) .38 50 (45.5%) 60 (38.2%) .26 35 (43.8%) 45 (24.1%) .59 Bladder tenderness 45 (26.9%) 122 (62.6%) .05 37 (27.4%) 98 (44%) .09 31 (28.2%) 78 (49.7%) .05 24 (30%) 54 (28.9%) .05 97  Pelvic floor tenderness 43 (25.7%) 124 (63.6%) .03† 49 (35.2%) 89 (40%) .24 42 (38.2%) 67 (42.7%) .04† 28 (35%) 50 (27%) .31 Depression  (PHQ-9 ≥ 10) 56 (33.5%) 111 (57%) .91 51 (36.7%) 88 (39.4%) .42 44 (40%) 66 (42%) .44 35 (43.8%) 45 (24.1%) .17 Anxiety (GAD-7 ≥ 10) 41 (24.6%) 126 (64.6%) 1.0 35 (25.2%) 104 (46.6%) .90 30 (27.3%) 80 (51%) .89 25 (31.3%) 55 (29.4%) .29 Pain catastrophizing scale ≥ 30  (75th centile) 44 (26.3%) 123 (63.1%) .39 39 (28.1%) 100 (45%) .17 27 (24.5%) 83 (53%) .28 21 (26.3%) 59 (31.5%) .19  Number (%); † Significant P value Proportions do not add up to 100% due to missing values.98  A.4 Discussion In this study, 16-25% of women stated that CHCs were ineffective for their pain, and 12-21% discontinued CHCs due to side-effects. Our results are consistent with the findings of Becker et al. [129] in a systematic review of endometriosis medical therapies, where they reported 5-24% discontinuation of CHCs.  In addition, we found that worse chronic pelvic pain severity was associated with a history of CHC ineffectiveness (cyclic or continuous), while poorer quality-of-life was associated with a history CHC discontinuation due to side-effects (cyclic or continuous). The association between CHC ineffectiveness and worse chronic pelvic pain may be due to the multifactorial pathophysiology of chronic pelvic pain, which includes nervous system and myofascial mechanisms [146] that would not be directly treated with CHCs.  Notably, we found that pelvic floor tenderness (as a marker of pelvic floor myalgia) was associated with CHC ineffectiveness. This points to the role of nervous system sensitization or myofascial contributors to chronic pelvic pain [55], and may explain why CHCs were ineffective in patients reporting more chronic pelvic pain. The association between CHC discontinuation due to side effects and poorer quality-of-life suggests that the CHC treatment regimen could have been effective for these patients, but they had to stop the CHC and thus lost the potential benefit which ultimately resulted in a worse quality of life. Alternatively, patients with more chronic pain and nervous system sensitization tend have side-effects with a variety of medications and environmental exposures, and they be also less likely to tolerate the side-effects of CHCs.   Another interesting observation was the association between CHC ineffectiveness and lower annual household income. Our study was conducted in a population with a universal province-wide health care plan, but not a universal pharmacare plan; and we do not know whether an 99  individual patient in the study paid for CHCs out of pocket or had coverage through third-party insurance. Several studies identified that female gender, lower income, chronic conditions, and increased drug cost or less insurance co-payment can significantly affect patient adherence to treatment [147–149]. In addition, a Canadian study identified living in British Columbia as a risk factor to lack of adherence to medications [139]. Another cross sectional study assessing the cost related to treatment non adherence in 11 developed countries concluded that Canada has the second highest national prevalence of cost related non adherence (the first being United States), although this study focused on patients older than 55 years [150].  It was also incidentally noted that those who reported continuous CHC discontinuation due to side effects had improved superficial dyspareunia. This may be due to the controversial putative association between CHCs and vulvodynia [151]. It is notable that for the cyclic CHCs discontinuation due to side-effects, there was also a trend to improved superficial dyspareunia but not reaching significance (p = 0.098).  This observation warrants more investigation. The main strengths of the study are the use of prospectively consented patients in a data registry. One limitation is that although patients were prospectively consented for inclusion in the registry, this study involves data from the patients’ retrospective recall. Another limitation is that sample size was too limited to analyze sub-groups, such as those women who reported both ineffectiveness and discontinuation due to side-effects. In addition, no data was collected on the type of side effects experienced by the patient, and the medication ineffectiveness was reported subjectively by the patient rather than using standardized criteria.  In our current research, we are now longitudinally following these patients to assess medication discontinuation prospectively.   100  Appendix B   Progestins use for endometriosis- associated chronic pelvic pain  B.1 Rationale As several progestin medications are available depending on its origin, testosterone or estrogen, we wanted to evaluate the efficacy and patterns of use of the lesser-used progestins, norethindrone and depot medroxyprogesterone acetate. B.2 Study sample Retrospective analysis of a prospective data registry (Endometriosis Pelvic Pain Interdisciplinary Cohort-EPPIC-ClinicalTrials.gov#NCT02911090). B.3 Results This cohort included 1440 participants that met our inclusion criteria. Of those, 181 (12.7%) reported prior use of depot medroxyprogesterone acetate, 76 (5.3%) reported ineffectiveness, while 100 (7%) discontinued due to side effects. In the norethindrone group, total of 110 (7.7%) used it, of these 49 (3.4%) reported ineffectiveness and 47 (3.3%) discontinued due to side effects intolerability. Patients who reported ineffectiveness in both groups were significantly younger, had higher chronic pelvic pain levels and poor quality of life (P<.05).  B.4 Discussion In both groups, sample sizes were small. However, there is evidence that there is more pain and poorer quality-of-life in women who reported ineffectiveness of norethindrone or depot medroxyprogesterone acetate, similar to the other progestins in Chapter 2 (dienogest and levonorgestrel IUD).   101  Appendix C  Gonadotropin releasing hormone analogue for endometriosis-associated chronic pelvic pain, patterns of use  C.1 Rationale Gonadotropin releasing hormone analogues are recommended as second line endometriosis associated pain treatment. Although several studies investigated their role in pain management (Table 1.5), few have reported on its tolerability by patients and patterns of use. C.2 Study sample  We retrospectively analyzed patients from the previously described prospective registry (Endometriosis Pelvic Pain Interdisciplinary Cohort-EPPIC-ClinicalTrials.gov#NCT02911090). C.3 Results In our cohort, 10% (143/1440) patients have ever used gonadotropin releasing hormone analogues. Of these, 41 (2.8%) reported ineffectiveness while 48 (3.3%) discontinued due to side effects intolerability.  Patients who reported ineffectiveness were more likely to have depression and anxiety, had higher levels of chronic pelvic pain, and more abdominal wall and pelvic floor tenderness (P<.05).  Patients who discontinued due to side effects intolerability were more likely to have depression and anxiety, lower education level, and had higher levels of deep dyspareunia and dychezia, and poorer quality of life. As well, this group were significantly more likely to have painful bladder syndrome, and abdominal and pelvic floor tenderness (P<.05).  C.4 Discussion Similar to CHC and progestins, patients who report GnRHa ineffectiveness or discontinuation due to side-effects tended to have worse pain and more non-gynecological pain diagnoses. 102  Appendix D  Corollary diagnoses Fisher’s exact test tables D.1 Cyclic ineffective   Ineffective: no Ineffective: yes P IBS: no 653 (61%) 251 (68%) .02 IBS: yes 418 (39%) 118 (32%)   Cyclic ineffective: no Cyclic ineffective: yes P PBS: no 387 (43%) 162 (50.5%) .02 PBS: yes 519 (57.3%) 159 (49.5%)   Ineffective: no Ineffective: yes P Carnett sign: negative 356 (33.2%) 163 (44.2%) <0.001  Carnett sign: positive 715 (66.8%) 206 (55.8%)   Ineffective: no Ineffective: yes P Bladder tenderness: no 783 (73%) 249 (67.5%) .04 Bladder tenderness: yes 288 (27%) 120 (32.5%)   Ineffective: no Ineffective: yes P Pelvic floor tenderness: negative 85 (8%) 46 (12.5%) .01 Pelvic floor tenderness: positive 986 (92%) 323 (87.5%)  103   Ineffective: no Ineffective: yes P depression: negative 599 (56%) 149 (40.4%) <0.001 depression: positive 472 (44%) 220 (59.6%)   Ineffective: no Ineffective: yes P anxiety: negative 722 (67.4%) 220 (59.6%) .01 anxiety sign: positive 349 (32.6%) 149 (40.4%)   Ineffective: no Ineffective: yes P Pain catastrophizing: negative 820 (76.6%) 256 (66.7%) <0.001 Pain catastrophizing: positive 251 (23.4%) 123 (33.3%)       D.2 Cyclic side effects    Ineffective: no Ineffective: yes P IBS: negative 675 (60.5%) 229 (70.5%) .001 IBS: positive 440 (39.5%) 96 (29.5%)  104   D.3 Continuous ineffective  Ineffective: no Ineffective: yes P PBS: negative 437 (43%) 112 (54.4%) .003 PBS: positive 584 (57%) 94 (45.6%)   Ineffective: no Ineffective: yes P Carnett sign: negative 415 (34.6%) 104 (43%) .01 Carnett sign: positive 784 (65.4%) 137 (57%)   Ineffective: no Ineffective: yes P Bladder tenderness: negative 873 (73%) 159 (66%) .03 Bladder tenderness: positive 326 (27%) 82 (34%)   Ineffective: no Ineffective: yes P depression: negative 663 (55%) 85 (35%) <0.001 depression: positive 536 (45%) 156 (65%)   Ineffective: no Ineffective: yes P Pain catastrophizing: negative 905 (75.5%) 161 (67%) .01 Pain catastrophizing: positive 294 (24.5%) 80 (33%)  105  D.4 Continuous side effects  Ineffective: no Ineffective: yes P anxiety: negative 819 (66.5%) 123 (59%) .04 anxiety: positive 413 (33.5%) 85 (41%)   Ineffective: no Ineffective: yes P depression: negative 658 (53%) 90 (43.3%) .01 depression: positive 574 (47%) 118 (57%)              106  D.5 LNG-IUD ineffective  Ineffective: no Ineffective: yes P Pelvic floor tenderness: negative 109 (8.4%) 22 (15%) .01 Pelvic floor tenderness: positive 1184 (91.6%) 125 (85%)   Ineffective: no Ineffective: yes P depression: negative 689 (53%) 59 (40%) .003 depression: positive 604 (47%) 88 (60%)   D.6 LNG-IUD side effects  Ineffective: no Ineffective: yes P Bladder tenderness: negative 961 (72%) 71 (63%) .040 Bladder tenderness: positive 366 (28%) 42 (37%)   Ineffective: no Ineffective: yes P depression: negative 704 (53%) 44 (39%) .004 depression: positive 623 (47%) 69 (61%)   Ineffective: no Ineffective: yes P anxiety: negative 879 (66%) 63 (56%) .03 anxiety: positive 448 (34%) 50 (44%) 107  D.7 DNG ineffective  Ineffective: no Ineffective: yes P Carnett sign: negative 472 (35%) 47 (49%) .01 Carnett sign: positive 872 (65%) 49 (51%)   Ineffective: no Ineffective: yes P depression: negative 713 (53%) 35 (36.5%) .002 depression: positive 631 (47%) 61 (63.5%)   Ineffective: no Ineffective: yes P Pain catastrophizing: negative 1004 (75%) 62 (65%) .04 Pain catastrophizing: positive 340 (25%) 34 (35.4%)  D.8 DNG side effects  Ineffective: no Ineffective: yes P Pelvic floor tenderness: negative 118 (9%) 13 (16%) .04 Pelvic floor tenderness: positive 1240 (91%) 69 (84%)   Ineffective: no Ineffective: yes P depression: negative 718 (53%) 30 (37%) .004 depression: positive 640 (47%) 52 (63%)  108    Ineffective: no Ineffective: yes P anxiety: negative 902 (66%) 40 (49%) .002 anxiety: positive 456 (34%) 42 (51%)    Ineffective: no Ineffective: yes P Pain catastrophizing: negative 1017 (75%) 49 (60%) .004 Pain catastrophizing: positive 341 (25%) 33 (40%)               109  Appendix E  Fisher’s exact test tables  Cyclic ineffectiveness No Yes P Married: no 552 (51.5%) 243 (66%) <0.001 Married: yes 519 (48.5%) 126 (34%)  Cyclic side effects No Yes P Married: no 605 (54%) 190 (58.5%) .18 Married: yes 510 (46%) 135 (41.5%)  Continuous ineffectiveness No Yes P Married: no 635 (53%) 160 (66.4%) <0.001 Married: yes 564 (47%) 81 (33.6%)  Continuous side effects No Yes P Married: no 674 (55%) 121 (58%) .37 Married: yes 558 (45%) 87 (42%)      110  LNG-IUD ineffectiveness No Yes P Married: no 698 (54%) 97 (66%) .01 Married: yes 595 (46%) 50 (34%)  LNG-IUD side effects No Yes P Married: no 713 (54%) 82 (73%) <0.001 Married: yes 614 (46%) 31 (27.4%)  Dienogest ineffectiveness No Yes P Married: no 729 (54%) 66 (69%) .01 Married: yes 615 (46%) 30 (31%)  Dienogest side effects No Yes P Married: no 743 (55%) 52 (63.4%) .14 Married: yes 615 (45%) 30 (36.6%)  

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