Endometriosis is a chronic estrogen-dependent gynecological disease where endometrial cells implant at inappropriate sites causing significant pelvic pain, decreased quality of life, and often infertility. It affects 10% of women of reproductive age, and there is no minimally invasive diagnostic test. Consequently the time to diagnosis, which occurs during laparoscopic surgery followed by pathological confirmation of disease, is prolonged and exceeds 11 years. During this time, the disease often worsens and women thus experience avoidable morbidity. Additionally, endometriosis is a financial burden on the healthcare system; its annual cost was $69.4 billion (U.S.) and $1.8 billion (Canada) in 2009. For these reasons, identifying a clinical marker remains a top priority. Although multiple putative markers have been identified and reviewed, emerging evidence suggests a relationship between neurotrophins and endometriosis. The neurotrophins are growth factors recognized for promoting neuronal differentiation, growth, and maintenance. Recently, they have been shown to induce pathways central to endometriosis including proliferation, adhesion, angiogenesis and resistance to apoptosis, in cultured neurons, epithelial cells, fibroblasts, and cancer cell lines. Although two studies have suggested elevated concentrations of brain-derived neurotrophic factor (BDNF) in the plasma and eutopic endometrium of women with endometriosis, relatively little is known about uterine BDNF. Herein, we demonstrate the conservation of BDNF and its high affinity receptor in the mammalian uterus, and show the upregulation of BDNF and its low affinity receptor by estradiol in the mouse uterus. Encouraged by our results, we assessed circulating BDNF for its ability to differentiate between women with and without endometriosis, as excess estradiol in endometriotic lesions might increase BDNF in women with disease. Our results revealed that circulating BDNF concentrations were significantly higher in women with endometriosis, particularly those with Stage I and II disease compared to controls. Furthermore, women with endometriosis undergoing ovarian suppression had significantly lower circulating BDNF than women not undergoing treatment, suggesting that BDNF may provide an opportunity to monitor patient response to treatment. Taken together, the data herein advances our limited knowledge of uterine neurotrophins, and supports a link between BDNF and endometriosis. I therefore strongly suggest that BDNF is a useful clinical marker of endometriosis, and encourage additional research to determine its role in the pathophysiology of disease. / Thesis / Doctor of Philosophy (PhD) / Endometriosis is a chronic condition that affects over 10% of women of reproductive age. Women with endometriosis suffer from debilitating pelvic pain and it takes approximately 12 years before they are diagnosed during surgery. This is in part because there is no blood test to diagnose disease. We are interested in using a protein called brain-derived neurotrophic factor (BDNF) that is linked to several of the pathways that are disturbed in women with endometriosis as a means of determining whether or not a woman has endometriosis. The key goals of this thesis are to show that BDNF is a protein which is found in the uterus of many species, that it is controlled by estrogen, and that it might be useful in diagnosing endometriosis and monitoring how well a patient is responding to endometriosis treatment.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/18177 |
| Date | 11 1900 |
| Creators | Wessels, Jocelyn M. |
| Contributors | Foster, Warren G., Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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