Endometriosis is a common and poorly understood disease affecting millions of women around the world. The impact on fertility and pelvic pain is estimated to cost $22 billion dollars, but this does not include the costs to treat IBS, interstitial cystitis and the cost of failed Assisted Reproductive Technology (ART) cycles. It is estimated that 40% of failed ART cycles are due to undiagnosed endometriosis, and most women undertaking ART have never been tested. This proposal is based on established technology that detects all stages of endometriosis. Based on published results, women who over-express the oncogene BCL6 have a 47% reduction in live birth rate compared to women with normal BCL6. This proposal will develop this technology, validate these findings and pursue a less invasive test format. Aims including those in Phase I, which will validate and examine a second co-expressed biomarker, Sirtuin 1 (SIRT1) present in endometriosis cases at all phases of the menstrual cycle in women with documented endometriosis. This first phase will also study expression of SIRT1 and BCL6 in alternative tissue sources including blood, saliva, urine, and cervical mucous using ELISA technology. Aims in Phase II will examine expression of BCL6 and/or SIRT1 as predictors of pregnancy outcomes in at a major IVF center. In women who test positive for SIRT1/BCL6 with suspected endometriosis, a second multi-center study will examine whether suppression of endometriosis with a novel, newly approved GnRH agonist (Elagolix) followed by embryo transfer will improve outcomes. Finally, the team will develop, validate, and commercialize a reference laboratory test for endometriosis and endometrial receptivity using less invasive approaches for measuring SIRT or BCL6 based on Phase I results. The final validation of a reference laboratory test will involve prospective testing before laparoscopy for pelvic pain or infertility (cases and infertile controls) and for women with fertility undergoing tubal ligation for permanent sterilization (fertile controls). With this approach the sensitivity, specificity, and negative and positive predictive value can be defined. The goal for this project is to establish a validated new, less invasive, test for endometriosis by 2021 that will allow all physicians treating women to shorten the time to diagnosis for endometriosis in a variety of clinical settings including pelvic pain, infertility, irritable bowel syndrome and other pelvic complaints.
Public Health Relevance Statement: PROJECT NARRATIVE A validated test for endometriosis with clinical relevance is currently not available. Inflammation is a defining characteristic of endometriosis and is associated with pain and infertility, and directly promotes the expression of two co-expressed biomarker proteins, BCL6 and SIRT1 that are used for the diagnosis of endometriosis. These proteins directly alter the actions of the hormone progesterone, which is essential for pregnancy, contributing to the pathophysiology of this disease and the infertility that women with endometriosis experience. The goal of this project is to translate new discoveries based on these proteins into a rapid, less invasive test for endometriosis that will be available for all women.
NIH Spending Category: Chronic Pain; Clinical Research; Clinical Trials and Supportive Activities; Contraception/Reproduction; Endometriosis; Infertility; Pain Research; Prevention; Women's Health
Project Terms: Affect; aged; Agonist; Archives; Assisted Reproductive Technology; base; BCL6 gene; Benign; Biological Markers; Biopsy; Birth Rate; Blood; Cervical; Characteristics; chronic pelvic pain; Clinical; clinical application; clinically relevant; Consensus; cost; Data; Development; Diagnosis; diagnosis evaluation; Diagnostic tests; Disease; Dysmenorrhea; Early Diagnosis; Embryo Transfer; Endometrial; endometriosis; Enzyme-Linked Immunosorbent Assay; Estrogens; Evaluation; experience; Failure; Fertility; Functional disorder; Future; GNRH1 gene; Goals; Gonadotropin Releasing Hormone Inhibitor; Health Care Costs; Hormones; idiopathic infertility; improved; improved outcome; Individual; Infertility; Inflammation; International; Interstitial Cystitis; Intervention; Irritable Bowel Syndrome; Laboratories; Laparoscopy; Lesion; Live Birth; Marketing; Measures; Menstrual cycle; Methods; Mucous body substance; Multicenter Studies; novel; Oncogenes; Operative Surgical Procedures; Oral; Oral Contraceptives; Outcome; outcome prediction; overexpression; Pain; Patients; Pelvic Pain; Pelvis; performance tests; Phase; Physicians; Population; Predictive Value; Pregnancy; Pregnancy Outcome; Prevalence; Progesterone; proliferative phase Menstrual cycle; prospective; Prospective Studies; prospective test; protein biomarkers; Proteins; Publishing; Recurrence; reproductive; research clinical testing; Role; Saliva; Sensitivity and Specificity; SIRT1 gene; Source; specific biomarkers; Sterilization; success; Symptoms; Technology; Testing; Time; Tissues; Translating; Treatment outcome; Tubal Ligation; Urine; Validation; Woman
