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Abstract
We aimed to clarify the nature of the relationship between testosterone and sex hormone binding globulin (SHBG) and improve our understanding of the relationship between testosterone, SHBG and obesity. We investigated the dynamics of the relationship between SHBG, total testosterone (total-T), and body mass index (BMI) throughout puberty (from 9 to 17 years of age) using longitudinal data obtained from 507 male adolescents, members of the the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The directionality of this relationship was explored using polygenic scores of SHBG and total-T and a two-sample Mendelian Randomization in male adults (from the UK Biobank). Wwe found a positive relationship between SHBG and total-T at 15 and 17 years of age but either no significant relationship or a negative relationship during the earlier time points. Such shifting relationships explained age-related changes in the association between total-T and BMI. Polygenic scores of SHBG and total-T in mediation analyses and the two-sample Mendelian Randomization in male adults provided evidence supporting the effect of SHBG on total-T but also a somewhat weaker effect of total-T on SHBG. Two-sample Mendelian Randomization (in male adults) showed the effect of BMI on SHBG but no effect of SHBG on BMI. These results clarify the nature and directionality of the relationship between testosterone and SHBG during human puberty and adulthood, and shed new light on their possible relationship with obesity.