The Effect of Long Acting GnRH Agonist Treatment on Mitochondrial Function

Endometriosis is an inflammation yet highly estrogen-dependent disease, which is characterized by the presence of endometriotic cells outside of uterus. It is one of the major causes of female infertility in Taiwan. Endometriosis is not a cancer but shows high ability in cell proliferation, migration/invasion and MMP activation. The most cited theory is retrograde menstruation from Sampson. The others theories are ceolomic metaplasia (Meyer’s theory), lymphatic and vascular spread (Halban’s theory), the implantation theory, and stem cell theory. But there is no single theory can explain clearly the pathophysiology of endometriosis. The mitochondria gene expression ratio was found significant higher than control in granulosa cells (GCs) from patients with endometriosis. Our previous studies showed the glutathione peroxidase activity in GCs of patients with endometriosis was significant lower than patients with male factor infertility. In addition, significantly higher oxidative damage was detected in endometriotic tissues than normal endometrium, including increased mitochondrial DNA (mtDNA) rearrangement, 8-OH deoxyguanosine (8-OH-dG), and lipoperoxide contents. Gonadotropin-releasing hormone agonist (GnRHa) therapy has been used to treat endometriosis implants by reduced estradiol production from ovary. Our preliminary data also demonstrated that GnRHa may up-regulate pro-apoptotic Bax gene and down-regulate of Bcl-2 and Mcl-1 genes to induce apoptosis of endometriotic tissues. Mitochondria not only regulates cell cycle and cell proliferation but also is essential site for steroidogenesis, however the mechanism and the role of mitochondria in endometriosis are still poorly understood. Therefore we conduct this 3-year project hopefully to achieve the following specific aims and anticipated results in order to understand the role of mitochondria in pathophysiology of endometriosis and to discover a new therapeutic approach to this disease. 1) To combine functional genomics, microRNA, proteomic approach to study the mitochondria gene expression pattern, copy numbers, and signal transduction in patients with endometriosis 2) To investigate alternation of mitochondria function by change of ATP synthesis, antioxidant enzyme activities, oxygen consumption rate (OCR), MDA production, ect in endometriotic tissue before and after GnRHa treatment. 3) To verify the difference of GnRH agonist and antagonist medication on mitochondria function in the cell apoptosis and progressiveness of endometriosis. 4) To translate and correlate the mitochondrial research with clinical pregnancy outcome following GnRHa treatment to set up a management protocol for patients with endometriosis.