Mohamed Bedaiwy

Endometriosis is a chronic, estrogen-mediated inflammatory condition associated with chronic pelvic pain and infertility. The condition affects up to 10% of reproductive aged women and is associated with significant impacts on quality of life, loss of productivity, and social isolation. Surgical intervention has been identified as an important tool in treatment of endometriosis, but the factors associated with treatment response are not clearly defined. Our current study aimed to address these issues by determining the impact of type of surgery, histology, and stage of endometriosis on surgical outcomes. We then evaluated whether conservative surgery for superficial peritoneal endometriosis resulted in positive impacts on pain and quality of life. Finally, we determined whether the characteristics of women undergoing hysterectomies before the age of 40 were different from those of women undergoing hysterectomies at age 40 or older and compared their surgical outcomes by age category. The first part of the thesis demonstrated that surgery was associated with improvement in all surgical outcomes regardless of type of surgery. Women undergoing hysterectomies demonstrated worse baseline quality of life scores but showed greater improvement in outcomes compared to conservative surgery. Stage and histology had little influence on outcomes. For the second part of our study, we found that surgery for superficial peritoneal endometriosis was associated with improvement in all outcomes except for superficial dyspareunia. Finally, the third part of study demonstrated that younger women undergoing hysterectomies tended to have earlier experiences of pain and increased likelihood of having comorbid conditions associated with central sensitization. Women 40 years of age demonstrated greater improvement in deep dyspareunia, while women above 40 had more improvement in depression. Overall, our study demonstrates that surgical intervention is associated with improvements in both pain and psychological scores. Future studies will expand on our findings through longer- follow-up and by linking our data to provincial administrative databases in order to look at outcomes such as reoperation rates. Our ultimate goal is to determine the predictors of successful surgical outcomes to create a predictive model for endometriosis-related pelvic pain.

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Unexplained recurrent pregnancy (uRPL) loss is a devastating and challenging condition for couples as well as clinicians. One of the greatest challenges is not being able to identify the baseline etiology of recurrent pregnancy losses (RPL) when all the routine and recommended investigations return normal or negative. Pregnancy losses that are not seen on the ultrasound or are confirmed only based on decreasing urine or serum beta-hCG’s are termed as non-visualized pregnancy losses (NVPLs). Routine evaluation of NVPLs is not recommended by the American Society for Reproductive Medicine (ASRM) guidelines. The first objective of my thesis was to evaluate how different types of miscarriages affect the rates of a successful pregnancy (ongoing pregnancy at or beyond 10 weeks gestation) among the uRPL group. The three different types of miscarriages include visualized pregnancy losses (VPL), NVPL, and a combination of both (mixed). The second objective was to assess the idea of stratifying uRPL women into Type 1 (age ≥35, NVPL) and Type 2 (age35, mixed, and VPL) groups and further estimate their chances of having a successful pregnancy. The data of 1311 RPL women was used from the BC Women’s Hospital, RPL clinic. For the first part, regression analysis was performed, comparing NVPL with VPL groups of uRPL women. The results showed that women with NVPL were more likely to have undergone therapeutic abortions in the past (AOR=3.274, 95% CI=1.425-7.523). The rate of successful pregnancy was lower among women in the NVPL group as compared to the VPL group (AOR=2.43 and 95% CI=1.33-4.42). In the second study, I found that only 8.2% of uRPL women were categorized as Type 1 and 32.3% as Type 2. The rate of successful pregnancy among Type 1 was 31.2% and 52.6% among Type 2 (p0.001). In conclusion, I observed a significant number of NVPLs among uRPL women. Women who had only NVPLs were more likely to experience a miscarriage at 10 weeks’ gestation compared with women with VPLs. Stratification of uRPL women into Type 1 and Type 2 groups might not be helpful and all the uRPL women should be managed irrespective of their age.

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Ectopic pregnancy (EP) is a life-threatening condition responsible for 6.5% of Canadian mothers’ death between 1993-2004. EP occurs when an embryo implants outside the uterine endometrium, commonly in the Fallopian tube (98%). Tubal EP often requires surgical intervention as a life-saving measure. Early and precise diagnosis allow many women to choose methotrexate, the only available medical option, for treatment. Methotrexate is effective in 70% of patients; however, they may require multiple treatments, suffer moderate-to-severe side effects, or experience sub-optimal responses. The remaining 30% fail to respond to the treatment.Gonadotropin-releasing hormone (GnRH) has an inducing effect on intrauterine placental cell invasion and human chorionic gonadotropin hormone (hCG) production. GnRH receptor (GnRH-R) antagonists have been used safely to treat endometriosis, chronic pelvic pain, and in the artificial fertilization techniques. For the first time, we separated primary trophoblast cells from tubal EP placentas. We validated their trophoblastic origin using trophoblast-validating markers. The preliminary findings showed that primary EP trophoblast cells express GnRH and GnRH receptor. Treating these cells with clinical GnRH-R antagonist, cetrorelix, suppressed their viability. We used primary trophoblast cells from tubal pregnancies, immortalized HTR-8/SVneo cell line, and placental villous explants established from the first-trimester human intrauterine placenta in this study. We investigated the effect of clinical GnRH-R antagonists, cetrorelix and ganirelix, on the invasion of different trophoblast models. Finding a safe, effective, and more tolerant medical treatment for tubal pregnancy will significantly improve women’s health and reduce healthcare-related costs.

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Symptomatic women with endometriosis may present with chronic pelvic pain (CPP) and infertility. Endometriosis leads to CPP through chronic inflammation, continuous peripheral nerve stimulation, and enhancement of central sensitization. The relationship between pregnancy and endometriosis is complex. Pregnancy has been proposed as a possible risk for developing CPP. However, amenorrhea has been thought to be protective against endometriosis. For fertility, endometriosis causes infertility mainly through distortion of reproductive anatomy with endometrioma and pelvic adhesions. Although endometrioma can be diagnosed with transvaginal ultrasound and sliding sign can evaluate adhesions in the posterior uterine compartment, the only way to estimate the pregnancy rate is by calculating the endometriosis fertility index (EFI). EFI calculation during laparoscopy provides a score between 0 and 10 (10 is associated with the best fertility prognosis while a score of 0 associated with the poorest fertility prognosis). In this thesis, I conducted two cross-sectional studies using a prospectively collected registry. In the first study, I compared the severity of pelvic pain between three groups of women: a group of nulligravid women (n=686), a group of parous women (n=371), and a group of women with a history of miscarriage or abortion (n=129). I found a higher number of women in the parous group had severe CPP. The nulligravid group had a higher rate of severe dysmenorrhea. Ordinal regression with backward elimination methods showed a strong association between parity and severe CPP (AOR= 1.448, 95%CI=1.092–1.918, P=0.010). In the second study, I divided infertile endometriosis patients into two groups based on the sliding sign results. The sliding sign is considered negative when the sliding motion is not observed between the colon and cervix or uterus. I found that participants with a negative sliding sign (n=26) had significantly lower total EFI scores and a lower score for each surgical factor than patients with positive sliding sign (n=60). Logistic regression showed that an EFI score of 7 can be predicted using the negative sliding sign and EFI historical factors, with a high sensitivity of 87.9% and specificity of 81.1%; the area under the curve was 0.93 (95% CI = 0.88–0.98).

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Endometriosis is a benign gynecological disease that affects up to 10% of women of reproductive age; however, the pathogenesis of endometriosis remains poorly understood. HOX genes encode transcription factors that play roles in regulating cell proliferation, differentiation, angiogenesis, adhesion and motility in adult tissues – key features of endometriosis. The aim of this study was to examine the localization of HOXB4, via immunohistochemistry (IHC), in both eutopic (EE) and ectopic endometrial tissues (deep infiltrating endometriosis (DIE) and endometriomas (Eoma)) from women with endometriosis and compare it to endometrial tissue from women with no history of endometriosis (EC). The localization of HOXB4 in these tissues was determined via immunohistochemistry (IHC) with a monoclonal HOXB4 antibody, where immunoreactivity was assessed by Histoscore (H-Score) method. HOXB4 protein was present in the endometrial glandular epithelial cells only. HOXB4 immunoreactivity in EC was significantly higher in the proliferative phase than in the secretory phase of the menstrual cycle; however, this difference was lost among the diseased groups (EE, Eoma and DIE). Interestingly, HOXB4 expression was significantly lower in the DIE lesions compared to matched eutopic endometrium and endometrioma /DIE lesions. After normalizing HOXB4 mRNA levels to endometrial epithelial cell content, consistent with IHC results, HOXB4 mRNA levels were significantly lower in the DIE groups when compared to EC and Eoma.On the whole, HOXB4 expression is reduced in DIE, but not endometrioma, and may be dysregulated in ectopic implants. During the menstrual cycle, the expression of HOXB4 in endometrial glandular epithelial cells is higher in the proliferative phase than the secretory phase in the normal eutopic endometrium. We here report for the first time the expression of HOXB4 localization and immunoreactivity not only in the normal eutopic endometrium but also in both eutopic and ectopic endometrial tissues in women with endometriosis.

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