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Sci Rep. 2016 Oct 17;6:35539. doi: 10.1038/srep35539.

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

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Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49 PO box 901, 3000 Leuven, Belgium.
Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49 PO box 7003, Leuven, Belgium.
Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, V6T 1Z3 Vancouver, B.C., Canada.
RIKILT, European Union Reference Laboratory for Residues, Wageningen UR, Akkermaalsbos 2, 6708WB Wageningen, The Netherlands.
Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49 PO box 902, 3000 Leuven, Belgium.
INSERM UMR1011, University of Lille and Institut Pasteur de Lille, Lille, France.
Laboratory for Hormonology and Department of Endocrinology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Rd, London, W12 0NN, United Kingdom.


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.

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