Paul Yong

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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BACKGROUND: More research is needed comparing post-surgical outcomes between patients who undergo hysterectomy for endometriosis with or without ovarian conservation. OBJECTIVE: To compare the rate of reoperation and use of other pain-related health services after hysterectomy for endometriosis, with or without ovarian conservationMETHODS: A population-based retrospective cohort study of 4489 patients aged 19-50 in British Columbia, Canada, undergoing hysterectomy for endometriosis between 2001 and 2016. Index surgeries were classified as: hysterectomy alone (conservation of both ovaries), hysterectomy with unilateral salpingoophorectomy (USO), or hysterectomy with bilateral salpingoophorectomy (BSO). Reoperation rate was the primary outcome. Secondary outcomes (measured at 3-12 months and 1-5 years after hysterectomy) included: physician visits for endometriosis and pelvic pain, prescriptions filled for opioids and hormonal suppression medications and hormone replacement therapy (HRT). RESULTS: 89.5% of patients remained reoperation free by the end of follow-up (median of 10 years, IQR = 6.1 to 14.3 years). Patients undergoing hysterectomy alone were more likely to undergo at least one reoperation compared to those having hysterectomy with BSO (13% vs 5%, p
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Background:IVF treatment has been used to transfer multiple embryos leading to multiple pregnancies which are known to be associated with increased maternal and perinatal complications. One question is whether IVF itself contributes to these risks.We compare the outcomes (maternal and perinatal) of IVF twin pregnancies with those of non-IVF twin pregnancies in the general population, in the province of British Columbia, Canada. We hypothesized twin pregnancies conceived by IVF are associated with a greater risk of maternal complications, abnormal labour and delivery events, and worse perinatal outcomes, compared with their non-IVF counterparts. Methods:An IVF twin pregnancy group (n = 161) was identified, in the former IVF Program of the University of British Columbia Centre for Reproductive Health (UBCCRH). We obtained these cases from the UBCCRH database between April 1, 1998, and March 31, 2010. A non-IVF twin pregnancy group was obtained by linking to the BC Perinatal Database to serve as a comparison group (n = 5525). Pregnancy outcomes and labour and delivery events were compared between IVF and non-IVF pregnancies using logistic and linear regression after adjustment for mothers' age, body mass index (BMI), and parity.Results:After adjustment for age, BMI, and parity, IVF twin pregnancies had higher rates of gestational hypertension, antepartum hemorrhage, gestational diabetes Mellitus, higher risks of C-section as the method of delivery and steroid use for lung maturation in IVF mothers. Also there were higher risks of IUGR and congenital anomalies in IVF babies, and IVF births had a lower birth weight, birth length, head circumference, and gestational age at birth.Conclusion:IVF twin pregnancies have an increased risk of some maternal complications, abnormal labour and delivery characteristics, and poorer perinatal outcomes, than naturally conceived twin pregnancies, even after adjustment for age, BMI, and parity. Further research is needed to clarify whether it is the infertility, maternal characteristics and co-morbidity associated with infertility, the IVF procedure or the potentially differential care of IVF patients that account for this increase in risk.

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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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Introduction: 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.Methods: 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.Results: 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.Conclusion: 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.

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Dyspareunia affects approximately 50% of people with endometriosis. Despite the prevalence of this symptom, it has been neglected in scientific contexts. Advancing the treatment of endometriosis-associated dyspareunia requires that it is adequately understood and measured in clinical research. This work therefore aims to provide a systematic description of dyspareunia, explore novel approaches to measurement, and makes recommendations for the development of an appropriate patient reported outcome measure. I conducted two studies exploring endometriosis-associated dyspareunia, the first of which was a qualitative description of sexual pain. 17 people with clinically-suspected or diagnosed endometriosis completed interviews about their experience of dyspareunia. Participants primarily experienced pain at the vaginal opening (n=7) and pain in the abdomen/pelvis (n=13). Pain at the vaginal opening began with initial penetration whereas deep pain was often triggered by full penetration or certain sexual positions. In general, participants describe superficial dyspareunia as pulling, burning or stinging and deep dyspareunia as sharp, stabbing, or cramping. Dyspareunia caused most participants to avoid or interrupt intercourse and many reported that the pain negatively affected their self-esteem, partner well-being, and/or relationships. The second study was a cross-sectional study that examined the relationship of superficial and deep dyspareunia with infertility concerns among 300 reproductive-aged participants with histologically-confirmed endometriosis. The odds of infertility concerns were not higher among women with more severe deep dyspareunia (OR=1.02, 95% CI: 0.95-1.09, P=.58). However, the odds of infertility concerns were higher among women with more severe superficial dyspareunia (OR=1.09, 95% CI: 1.02-1.16, P=.01); this relationship persisted after adjusting for potential confounders (AOR=1.14, 95% CI: 1.06-1.24, P<.001 additional="" analyses="" indicated="" that="" deep="" dyspareunia="" and="" superficial="" were="" different="" constructs.="" overall="" the="" results="" measures="" of="" endometriosis-associated="" sexual="" pain="" should="" separately="" quantify="" both="" dyspareunia.="" visual="" aids="" for="" item="" stems="" appropriate="" numeric="" response="" scales="" inclusion="" items="" about="" impact="" could="" improve="" measurement="" management="" this="" symptom.="">
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Assisted reproductive technologies (ARTs) are associated with a number of adverse pregnancy, neonatal, and long-term outcomes. One plausible explanation is that ART procedures may be causing alterations in epigenetic mechanisms, including the regulation of imprinted genes, that persist during development. Therefore, I investigated gene expression of the imprinted genes PLAGL1, CDKN1C, KCNQ1OT1, and H19 in cord blood from 24 IVF, 18 ICSI, 9 IUI, and 26 naturally conceived babies as well as genome-wide DNA methylation using Illumina’s EPIC methylation array in cord blood from 10 IVF, 9 ICSI, and 10 naturally conceived babies. All the samples were procured from healthy newborn singletons. No differences in the gene expression of the imprinted genes were observed across conception modes. The genome-wide DNA methylation analysis revealed an overall stability of DNA methylation following ART; however, a small number of CpG sites exhibited hypervariability in the ICSI (47 CpG sites) and the IVF (4 CpG sites) groups. Furthermore, the mCSEA method for detecting DMRs revealed 101 promoter associated DMRs in the ICSI group and 101 promoter associated DMRs in the IVF group. 35 DMRs overlapped between the ICSI and IVF groups, suggesting some regions may be susceptible to DNA methylation alterations following ART. Four imprinted gene DMRs were also found to overlap DMRs between conception modes. Overall this analysis revealed that a small number of genomic regions may be impacted by ART. These regions may be significant as genes associated with neurodevelopmental disorders, intrauterine programming of adult onset obesity, and male infertility were observed to be altered in both the IVF and ICSI groups. Although validation of these regions is required, this analysis provides support for ART impacting DNA methylation that persists to birth in genes related to adverse outcomes and mediating transmission of DNA methylation alterations from infertile parents to babies.

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Endometriosis affects 10% of reproductive-aged women and is the presence of ectopic endometrial glands and stroma. It is associated with different types of pain, such as dysmenorrhea, dyschezia, and deep dyspareunia. Deep dyspareunia affects approximately 50% of women with endometriosis. Previous research has suggested that, in addition to disease-specific factors (e.g., Stage), other factors such as comorbid conditions or central sensitization may also play a role in the etiology of deep dyspareunia. The thesis objective is to provide evidence for the role of these other factors in the etiology of deep dyspareunia in endometriosis. I propose that bladder/pelvic floor tenderness and painful bladder syndrome (PBS) are associated with an increased severity of deep dyspareunia in women with endometriosis, and that these factors may be related to central sensitization. In Aim 1, using data from a prospective registry, I found that bladder/pelvic floor tenderness (assess by physical exam) and PBS (diagnosed using established criteria) were independently associated with severity of deep dyspareunia in women with both Stage I/II endometriosis (AOR=1.94, 95% CI 1.11-3.38, p=0.019; AOR=1.99, 95% CI 1.15-3.44, p=0.013; respectively) and Stage III/IV (AOR=2.51, 95% CI 1.25-5.02, p=0.01; AOR=1.90, 95% CI 1.01-3.57, p=0.048; respectively). In Aim 2, by prospectively recruiting patients and measuring their pain-pressure thresholds (PPT), I determined that PPT at extra-pelvic sites were significantly associated with bladder/pelvic floor tenderness in women with endometriosis (t=2.9, p=0.007; t=2.3, p=0.029; respectively). In contrast, there was no association between PPT and PBS.In conclusion, I found that bladder/pelvic floor tenderness and PBS were associated with greater severity of deep dyspareunia, regardless of endometriosis stage. I also found evidence that bladder/pelvic floor tenderness is associated with lower PPT in women with endometriosis, which may indicate the presence of central sensitization. In contrast, PBS was not associated with changes in PPT, and thus may arise in endometriosis through mechanisms other than central sensitization. My findings point to a role for central sensitization, manifesting as bladder/pelvic floor tenderness, in some women with endometriosis-associated deep dyspareunia. Further research is needed to confirm these findings, and to incorporate measures of central sensitization into the clinical management of endometriosis.

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Endometriosis is a disease that affects almost 10% of reproductive-age women, where 50 % of these women have pelvic pain with sexual intercourse. Deep endometriosis is defined as an endometriotic lesion penetrating to a depth of 5 mm or more, and is characterized by both fibrosis (forming nodules) and invasion (into structures such as the colon). Other groups have found that increased plasminogen activator inhibitor-1 (PAI-1) or (SERPINE1) expression was associated with fibrosis and tumor invasion. In addition, a previous study found that the SERPINE1 4G allele (and thus increased gene expression) was associated with increased pain in women with endometriosis, and other work suggested that SERPINE1 may be implicated in local neurogenesis. The objective of this thesis is to determine whether PAI-1 expression is associated with a) deep infiltrating endometriosis; and b) deep dyspareunia. We propose that increased PAI-1 expression will be associated with deep infiltrating endometriosis, and increased pain in endometriosis via an increase in local nerve fibers. We utilized immunohistochemical analysis using a validated PAI-1 antibody. In the first cohort, we examined PAI-1 expression in deep infiltrating endometriosis and compared to endometrioma, superficial endometriosis, and eutopic endometrium. In the second cohort, we examined PAI-1 expression in cul-de-sac endometriosis from women with or without deep dyspareunia. We found higher expression of PAI-1 in deep infiltrating endometriosis (n = 10) compared to superficial endometriosis (n = 10) (p = 0.031) and eutopic endometrium (n = 10) (p = 0.002). In the second cohort, we found lower expression of PAI-1 in women with more severe deep dyspareunia (r = - 0.352, n =35, p = 0.038). However, there was no association between PAI-1 expression and local nerve bundle density. In conclusion, we observed higher PAI-1 expression in deep infiltrating endometriosis, but lower PAI-1 expression in endometriosis from women with deep dyspareunia. Further research is needed to clarify the complexities of PAI-1 expression in endometriosis.

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