A Shifting Relationship Between Sex Hormone-Binding Globulin and Total Testosterone Across Puberty in Boys

Abstract

Context: Sex hormone-binding globulin (SHBG) is associated with levels of total testosterone (total-T), and both total-T and SHBG are associated with obesity.

Objective: We aimed to clarify the nature of the relationship between testosterone and SHBG and improve our understanding of their relationships with obesity. We hypothesize that the hypothalamic-pituitary-gonadal axis contributes to the homeostasis of testosterone by increasing the production of gonadal testosterone through a feedback mechanism that might operate differently at different pubertal stages.

Methods: We investigated the dynamics of the relationship between SHBG, total-T, and body mass index (BMI) throughout puberty (from age 9 to 17) using longitudinal data obtained in 507 males. The directionality of this relationship was explored using polygenic scores of SHBG and total-T, and a two-sample Mendelian Randomization (MR) in male adults.

Results: Consistent with our hypothesis, we found positive relationships between SHBG and total-T at age 15 and 17 but either no 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 MR in male adults suggested an effect of SHBG on total-T but also a somewhat weaker effect of total-T on SHBG. Two-sample MR also showed an effect of BMI on SHBG but no effect of SHBG on BMI.

Conclusion: These results clarify the nature of the relationship between testosterone and SHBG during puberty and adulthood and shed new light on their possible relationship with obesity.

Keywords: ALSPAC; HPG axis; Mendelian randomization; body mass index; polygenic scores.