The Role of Low Testosterone in Perioperative Surgical Outcomes

Problem to Be Addressed Major abdominal surgery is associated with very high morbidity and mortality ranging from 2-18% with over 200,000 perioperative deaths annually in the United States (US).1, 2 Frailty, which consists of reduced muscle mass and strength (i.e. sarcopenia), bone density, and health related quality of life, is a key predictor of post-operative complication and mortality and is present in almost 90% of hospitalized older adults.3-6 Low testosterone (T) is a key determinant of frailty and is highly prevalent in older men – 30% of men over age 70 and 50% over age 80 have low T, thereby nominating it as an important pre-operative risk factor.8-15 However, the relationship between low T and frailty in the pre-operative setting, including its impact upon post-operative outcomes, remains unknown. Specific Aims and Experimental Design The objective of the proposed study is to evaluate low T as an essential predictor of perioperative morbidity and mortality. The central hypothesis is that a large proportion of older men undergoing major abdominal surgery have low T-associated frailty, and these men have higher risk of hospital readmission, surgical complication, and mortality. In Aim 1, we will prospectively measure serum T and frailty in the pre-operative setting. We will also identify barriers and challenges to broader implementation of preoperative serum T measurement and prehabilitation programs. In Aim 2, we will characterize the risk factors for pre-operative low T and frailty among men undergoing major surgery, utilizing two unique data sources - the Northwestern Enterprise Data Warehouse (EDW) and the Veterans Health Administration (VHA). We will also assess pre-operative frailty according to a validated metric, the Risk Analysis Index (RAI).21 In Aim 3, we will evaluate the relationship between T, frailty and post-operative outcomes including complications, hospital readmission, and mortality following surgery. Receiver operating characteristic (ROC) curves will compare the sensitivity and specificity of RAI-alone, T-alone, and RAI-T combination in predicting post-operative complications. Mentoring Plan Dr. Robert Brannigan will serve as the primary mentor for this project. He is an international thought leader on testosterone deficiency, and he was a panel member for the most recent AUA Guidelines on Testosterone Deficiency in 2018. Drs. Brannigan and Halpern have an existing mentorship relationship beginning with Dr. Halpern’s clinical fellowship in 2018, and they have published over 30 peer-reviewed manuscripts together. They share a clinical workspace and have academic offices in the same location. They will meet on a weekly basis for the duration of the two-year award period. Dr. Edward M. Schaeffer, Chair of the Department of Urology, will also serve as a primary mentor. Dr. Schaeffer also shares both clinical and academic spaces with Dr. Halpern, and the two will meet on a monthly basis for the duration of the award period. Potential Impact of Project on Urologic Research and on the Applicant’s Career Development This research is significant because it will improve pre-operative risk stratification to identify older men at high risk for adverse outcomes. This study will provide new knowledge through prospective characterization of perioperative hormonal and biophysiologic profiles of older men from diverse socioeconomic and healthcare settings and their relation to post-operative morbidity and mortality. This proposal is intended to support initial work that will serve as the basis for a career developm