Monitoring the progression of endometriosis using PET/CT imaging

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PROJECT SUMMARY Approximately 10% of sexually mature women are afflicted with endometriosis. Endometriosis occurs when the inner most lining of the uterus, the endometrium, is located ectopically. This disease can be debilitating and symptoms include painful periods, heavy and irregular menstruation, and subfertility. Based on size, location, spread, depth, and ovarian involvement, disease state can vary and is classified as different stages (i.e., I- minimal, II-mild, III-moderate, and IV-severe). Staging and a definitive diagnosis of endometriosis only occur through an exploratory laparoscopic surgery. Because of a hesitancy to perform and/or undergo an invasive surgery, treatment is often delayed four to eight years from clinical presentation. Further, despite decades of research, the etiology and pathophysiology of endometriosis has progressed little. Difficulty in identifying early- stage endometriotic lesions and the inability to monitor disease progression has likely hindered this research highlighting the need to develop a non-invasive tool to diagnosis endometriosis. While imaging modalities exist to identify late stage and deep infiltrating endometriosis [e.g., ultrasonography (US) and magnetic imaging resonance (MRI)], the resolution of detecting small, early stage lesions is equivocal. Therefore, the premise of this proposal is determine the efficacy in utilizing positron emission tomography (PET/CT) to identify endometriotic lesions. We will use radiotracers targeted to estradiol and progesterone receptors (ER and PGR, respectively) as contrast agents for PET/CT scans. Lesions express higher levels of ER and PGR compared to surrounding tissues because endometriosis is an estrogen-dependent disease and actions of estradiol include promoting not only its own receptor (i.e., ER), but also PGR. Although the ER radiotracer 16- α-18F-fluoro-17-β estradiol (FES) has been reported to identify deep infiltrating endometriosis, like US and MRI, it is uncertain whether FES can detect smaller lesions. This is likely due to the preferential binding of FES to ERα rather than ERβ. While some stages of endometriosis display elevated ERβ such as ovarian endometriomas, the ratio of ERα/ERβ in pelvic lesions is unclear. Therefore, we will use both FES and the PGR targeted radiotracer 21-18F-fluorofuranyl-norprogesterone (FFNP) to not only identify lesions, but also to determine each radiotracer’s ability to monitor lesion size over time in the following Specific Aims. In Aim 1, we will compare the uptake rates of FES and FFNP in mid- to late-stage lesions. For Aim 2, we will use small and newly developed lesions to identify the detection thresholds of each radiotracer. And finally, in Aim 3, we will regress mid- to late-stage lesions with letrozole, a common therapeutic for endometriosis to determine whether FES and FFNP can detect changes in lesion size over time. Collectively, this proposal aims to develop a non-invasive imaging tool to diagnosis and monitor the progression of endometriotic lesions. In doing so, we hope to substantially increase patient quality of life by substantially decreasing the delay to treatment. We also hope to drive research on endometriosis forward by developing a new technology to track lesions over time.