Insulin-like factor 3 (INSL3): a new parameter to assess Leydig cell functionality and primary hypogonadismus in the EMAS population.

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Insulin-like factor 3 (INSL3) is a constitutive product uniquely of the testicular Leydig cells. In adult men it is secreted into the blood in substantial amounts, thereby revealing the functional capacity of the Leydig cells in a way which is independent of testosterone and feedback via the HPG axis. It is thus an excellent and independent measure of Leydig cell capacity in health and disease, especially during aging. In collaboration with Professor Fred Wu from the University of Manchester and Coordinator of the EMAS (European Male Aging Study) project to research the physiology and clinical pathology of the aging European male, we plan to measure INSL3 in the two legs of the EMAS cohort (total ca. 6000 samples), allowing both cross-sectional as well as longitudinal correlation with the many biochemical and clinical parameters already obtained in this most extensive study of aging men from eight European centres. INSL3 measurement will not simply serve as an additional parameter, but will better help to define specific pathologies and clinically relevant groups of men.Hypoandrogenemia is at the core of pathologies associated with aging in men, however, testosterone as a clinical parameter is beset with many confounders, so that a hypogonadal causality in age-related symptoms is difficult to ascertain. Consequently, any recommendation for an androgen-based therapy is largely limited to a few extreme cases only. Because INSL3 is a robust and constitutive parameter which is largely independent of these androgen-related confounders, its measurement in the EMAS cohort will provide valuable insight into the role of testicular aging in the etiology of age-related pathologies such as metabolic syndrome or osteoporosis. The applicants draw on worldwide unique experience in the measurement of INSL3 in human (and animal) studies, and its clinical relevance.