Sex hormone-binding globulin regulation of androgen bioactivity in vivo: Validation of the free hormone hypothesis

Michaël R. Laurent, Geoffrey L. Hammond, Marco Blokland, Ferran Jardí, Leen Antonio, Vanessa Dubois, Rougin Khalil, Saskia S. Sterk, Evelien Gielen, Brigitte Decallonne, Geert Carmeliet, Jean Marc Kaufman, Tom Fiers, Ilpo T. Huhtaniemi, Dirk Vanderschueren, Frank Claessens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

38 Citations (Scopus)

Abstract

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a ligand-dependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology.

Original languageEnglish
Article number35539
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016

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