Testosterone Levels in Men: Associations with Inflammation, Muscle Composition, and Hypogonadal Symptoms – Community-Based Studies

Abstract

The diagnosis of late-onset hypogonadism in men has increased markedly over the past two decades. While metabolic factors play a key role in these hormonal changes, their associations with sex hormones and subsequent clinical symptoms remains incompletely understood. This thesis investigates the interplay between specific metabolic factors and sex hormones, particularly testosterone, and explores how reduced testosterone levels associate with clinical manifestations. The thesis comprises four studies using data from two community-based cohorts: the Swedish Vara-Skövde study (Papers I and IV) and the U.S. Multi-Ethnic Study of Atherosclerosis (MESA; Papers II and III). Papers I and IV include longitudinal data from two examinations, conducted in 2002–2005 and 2012–2014, comprising 625 and 590 men. Papers II and III, based on MESA, used data collected between 2000-2005, including 3,091 and 878 men, respectively. In all studies, hormone levels were measured using validated immunoassay methods. Study III applied computed tomography scans to assess abdominal muscle composition while Study IV evaluated symptoms using the Aging Males’ Symptoms (AMS) questionnaire. In Study I, higher levels of the inflammatory marker high-sensitive C-reactive protein(hsCRP) were associated with lower testosterone levels and greater odds of biochemical hypogonadism ten years later, independent of confounders. Study II confirmed these findings in a larger multi-ethnic cohort, showing consistent inverse associations between inflammatory markers, including interleukin-6 and CRP, and testosterone levels in men. Significant associations were found between inflammatory markers and sex hormone-binding globulin (SHBG), although in opposite directions. In Study III, testosterone levels demonstrated diverse positive associations with both abdominal muscle area, index, and radiodensity, whereas estradiol was positively associated with abdominal muscle area and index. An inverse association was found between SHBG and abdominal muscle radiodensity. Study IV showed that men with low testosterone levels reported a higher overall symptom burden on the AMS scale, driven primarily by sexual symptoms. Moreover, methodological differences in immunoassays were found to influence the accuracy of current diagnostic thresholds. Collectively, these findings highlight a multifaceted interplay between metabolic factors and sex hormone levels, with a particular focus on testosterone, and its further association with clinical symptoms. These results provide novel insights that may further contribute to a more comprehensive understanding and improved clinical management of male health.