Androgens2016 Oral Communications (1) (17 abstracts)
Control of androgen bioactivity by sex hormone-binding globulin
Michael R Laurent 1, , Leen Antonio 1, , Marco H Blokland 4 , Saskia S Sterk 4 , Ferran Jardi 2 , V Dubois 5 , Jean-Mark Kaufman 6 , Tom Fiers 6 , Ilpo T Huhtaniemi 7 , Geoffrey T. Hammond 8 , Dirk Vanderschueren 3 & Frank Claessens 1
1Molecular Endocrinology Laboratory; 2Gerontology and Geriatrics; 3Clinical and Experimental Endocrinology, KU Leuven, Belgium; 4RIKILT-Institute of Food Safety, European Union Reference Laboratory for Residues, Wageningen UR, The Netherlands; 5Inserm UMR1011, Université de Lille, France; 6Laboratory for Hormonology, Department of Endocrinology, Ghent University Hospital, Belgium; 7Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, United Kingdom; 8Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
Sex hormone-binding globulin (SHBG) is a high-affinity binding protein for androgens and estrogens. According to the “free hormone hypothesis”, SHBG regulates the free sex steroid fraction and restricts androgen bioactivity. SHBG has also been independently associated with diabetes, osteoporosis etc., but whether this represents causality or residual confounding remains unconfirmed. We studied mice overexpressing human SHBG. Using multiligand liquid chromatography tandem mass spectrometry (LC-MS/MS) we show that total concentrations of testosterone, DHT and other circulating androgens are ~100-fold increased, whereas their urinary conjugation products were unaltered. Weights of androgen-sensitive organs (seminal vesicles and levator ani muscles) however were slightly (12–20%) but significantly (P<0.001) reduced, indicating suppressed androgen bioactivity in vivo. Also in an in vitro androgen reporter bioassay, SHBG suppressed androgen bioactivity. Total estradiol was also increased in male mice but remained strikingly low, indicating that the lack of circulating SHBG in male mice is only slightly responsible for their undetectable circulating estradiol levels. 3H-DHT- and T injections i.v. revealed that SHBG prolongs ligand circulatory half-life. In orchidectomized mice however, SHBG did not prolong the biological actions of androgens. Replacement experiments with anabolic testosterone doses showed that SHBG prevents hypertrophy of sex organ but not muscle, and restricts androgen entry into target tissues like bone. However, glucose sensitivity and bone mass were unaffected in SHBG-Tg mice. Despite 100-fold higher total androgen levels, their bioactivity is reduced in SHBG-Tg mice. This genetically modified mouse model however revealed no independent influence of SHBG on bone or metabolic outcomes.
Presenting Author: Frank Claessens, Molecular Endocrinology Laboratory, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Email: [email protected].
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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