Endocrine Abstracts

Insulin-like peptide 3 (INSL3) is produced by the mature Leydig cells of the adult testes and secreted into the bloodstream in a constitutive manner, where it represents an important biomarker of Leydig cell functional capacity. It specifically activates the G-protein-coupled receptor, RXFP2, which is expressed on Leydig cells themselves, on male germ cells, and on bone cells, where INSL3 promotes healthy bone physiology. Unlike testosterone, INSL3 exhibits negligible within-individual variance, although in a population circulating INSL3 may vary by up to 10-fold between individuals. By making use of the European Male Aging Study (EMAS) cohort we investigated the relationship between circulating INSL3 and the incidence of age-dependent morbidity, in comparison with total testosterone and other HPG axis parameters. Like testosterone, INSL3 is an index of hypogonadism and consequently, after correcting for age, correlates with conditions such as diabetes, cardiovascular disease, sexual function, hypertension, bone density, and frailty. Such associations may be due to the mutual relationships not only between INSL3 and testosterone, but also with BMI, or smoking. However, when multiple regression analysis was used to assess such relationships between morbidity in the second phase of the EMAS study and either INSL3 or testosterone in the same individuals in the first phase of the study, with blood samples collected 4 to 5 years previously, then INSL3 was significantly and independently predictive for 6 of the conditions later assessed, whereas testosterone was predictive for only 3 of these. Because of its low within-individual (though high between-individual) variance, even over long periods of time (several years at least), circulating INSL3 is an excellent biomarker for possible hypogonadism and dependent future conditions. Our current research is investigating the mechanisms behind these relationships and addressing the question why some individual men may have high or low INSL3 throughout their adult lives.