Sex hormone-binding globulin
Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to sex hormones, to be specific, testosterone and estradiol. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin.
Transport of sex hormones
Testosterone and estradiol circulate in the bloodstream, bound mostly to SHBG and to some degree bound to serum albumin. Only a small fraction is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. The SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG. SHBG has a higher affinity for Dihydrotestosterone than for Testosterone or for Estradiol, making it essential in women for regulating the bio-availability of Dihydrotestosterone.
SHBG production
SHBG is produced mostly by the liver and is released into the bloodstream. Other sites that produce SHBG include the brain, uterus, testes, and placenta. Testes-produced SHBG is called androgen-binding protein. The gene for SHBG is located on chromosome 17.
Control
SHBG levels appear to be controlled by a delicate balance of enhancing and inhibiting factors. Its level is decreased by high levels of insulin and insulin-like growth factor 1 (IGF-1) (see:milk). Also, high androgen and transcortin levels decrease SHBG, whereas high growth hormone, estrogen, and thyroxine levels increase it.
However, recent evidence suggests that it is the liver's production of fats that reduces SHBG levels,[1][2] not any direct effect of insulin and specific genetic mechanisms that do this have been found.
Blood values
Reference ranges for blood tests for SHBG have been estimated to be:[3]
| Patient type |
Range |
| Adult female, premenopausal |
40 - 120 nmol/L |
| Adult female, postmenopausal |
28 - 112 nmol/L |
| Adult male |
20 - 60 nmol/L |
| Age 1 - 23 months |
60 - 252 nmol/L |
| Prepubertal (24m - 8y) |
72 - 220 nmol/L |
| Pubertal female |
36 - 125 nmol/L |
| Pubertal male |
16 - 100 nmol/L |
Conditions with high or low levels
Conditions with low SHBG include polycystic ovary syndrome, diabetes, and hypothyroidism. Conditions with high SHBG include pregnancy, hyperthyroidism, and anorexia nervosa.
Measurement of sex hormones
When determining levels of circulating estradiol or testosterone, either a total measurement that includes the "free" and the bound fractions could be done, or only the "free" hormone could be measured. A free androgen index expresses the ratio of testosterone to the sex hormone-binding globulin and can be used to summarize the activity of free testosterone.
The total testosterone is likely the most accurate measurement of testosterone levels and should always be measured at 8 o'clock in the morning. Sex hormone-binding globulin can be measured separate from the total fraction of testosterone.
See also
References
Further reading
- Hammond GL, Bocchinfuso WP (1996). "Sex hormone-binding globulin: gene organization and structure/function analyses". Horm. Res. 45 (3–5): 197–201. doi:10.1159/000184787. PMID 8964583.
- Rosner W, Hryb DJ, Khan MS, et al. (1999). "Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane". J. Steroid Biochem. Mol. Biol. 69 (1–6): 481–5. doi:10.1016/S0960-0760(99)00070-9. PMID 10419028.
- Power SG, Bocchinfuso WP, Pallesen M, et al. (1992). "Molecular analyses of a human sex hormone-binding globulin variant: evidence for an additional carbohydrate chain". J. Clin. Endocrinol. Metab. 75 (4): 1066–70. doi:10.1210/jc.75.4.1066. PMID 1400872.
- Bérubé D, Séralini GE, Gagné R, Hammond GL (1991). "Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12----p13)". Cytogenet. Cell Genet. 54 (1–2): 65–7. doi:10.1159/000132958. PMID 2249477.
- Gershagen S, Lundwall A, Fernlund P (1990). "Characterization of the human sex hormone binding globulin (SHBG) gene and demonstration of two transcripts in both liver and testis". Nucleic Acids Res. 17 (22): 9245–58. doi:10.1093/nar/17.22.9245. PMC 335128. PMID 2587256. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=335128.
- Hammond GL, Underhill DA, Rykse HM, Smith CL (1990). "The human sex hormone-binding globulin gene contains exons for androgen-binding protein and two other testicular messenger RNAs". Mol. Endocrinol. 3 (11): 1869–76. doi:10.1210/mend-3-11-1869. PMID 2608061.
- Que BG, Petra PH (1987). "Characterization of a cDNA coding for sex steroid-binding protein of human plasma". FEBS Lett. 219 (2): 405–9. doi:10.1016/0014-5793(87)80261-2. PMID 2956125.
- Gershagen S, Fernlund P, Lundwall A (1987). "A cDNA coding for human sex hormone binding globulin. Homology to vitamin K-dependent protein S". FEBS Lett. 220 (1): 129–35. doi:10.1016/0014-5793(87)80890-6. PMID 2956126.
- Walsh KA, Titani K, Takio K, et al. (1987). "Amino acid sequence of the sex steroid binding protein of human blood plasma". Biochemistry 25 (23): 7584–90. doi:10.1021/bi00371a048. PMID 3542030.
- Hammond GL, Underhill DA, Smith CL, et al. (1987). "The cDNA-deduced primary structure of human sex hormone-binding globulin and location of its steroid-binding domain". FEBS Lett. 215 (1): 100–4. doi:10.1016/0014-5793(87)80121-7. PMID 3569533.
- Hammond GL, Robinson PA, Sugino H, et al. (1986). "Physicochemical characteristics of human sex hormone binding globulin: evidence for two identical subunits". J. Steroid Biochem. 24 (4): 815–24. doi:10.1016/0022-4731(86)90442-5. PMID 3702459.
- Hardy DO, Cariño C, Catterall JF, Larrea F (1995). "Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects". J. Clin. Endocrinol. Metab. 80 (4): 1253–6. doi:10.1210/jc.80.4.1253. PMID 7714097.
- Cargill M, Altshuler D, Ireland J, et al. (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nat. Genet. 22 (3): 231–8. doi:10.1038/10290. PMID 10391209.
- Grishkovskaya I, Avvakumov GV, Sklenar G, et al. (2000). "Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain". EMBO J. 19 (4): 504–12. doi:10.1093/emboj/19.4.504. PMC 305588. PMID 10675319. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=305588.
- Hogeveen KN, Talikka M, Hammond GL (2001). "Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence". J. Biol. Chem. 276 (39): 36383–90. doi:10.1074/jbc.M104681200. PMID 11473114.
- Hryb DJ, Nakhla AM, Kahn SM, et al. (2002). "Sex hormone-binding globulin in the human prostate is locally synthesized and may act as an autocrine/paracrine effector". J. Biol. Chem. 277 (29): 26618–22. doi:10.1074/jbc.M202495200. PMID 12015315.
- Raineri M, Catalano MG, Hammond GL, et al. (2002). "O-Glycosylation of human sex hormone-binding globulin is essential for inhibition of estradiol-induced MCF-7 breast cancer cell proliferation". Mol. Cell. Endocrinol. 189 (1–2): 135–43. doi:10.1016/S0303-7207(01)00725-0. PMID 12039072.
- Grishkovskaya I, Avvakumov GV, Hammond GL, Muller YA (2002). "Resolution of a disordered region at the entrance of the human sex hormone-binding globulin steroid-binding site". J. Mol. Biol. 318 (3): 621–6. doi:10.1016/S0022-2836(02)00169-9. PMID 12054810.
- Thompson DJ, Healey CS, Baynes C, Kalmyrzaev B, et al. (2008). "Identification of common variants in the SHBG gene affecting sex hormone binding globulin levels and breast cancer risk in postmenopausal women". Cancer Epidemiol Biomarkers Prev. 17 (12): 3490–8. doi:10.1158/1055-9965.EPI-08-0734. PMC 2660245. PMID 19064566. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2660245.
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PDB gallery
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1d2s: CRYSTAL STRUCTURE OF THE N-TERMINAL LAMININ G-LIKE DOMAIN OF SHBG IN COMPLEX WITH DIHYDROTESTOSTERONE
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1f5f: CRYSTAL STRUCTURE OF THE N-TERMINAL G-DOMAIN OF SHBG IN COMPLEX WITH ZINC
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1kdk: THE STRUCTURE OF THE N-TERMINAL LG DOMAIN OF SHBG IN CRYSTALS SOAKED WITH EDTA
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1kdm: THE CRYSTAL STRUCTURE OF THE HUMAN SEX HORMONE-BINDING GLOBULIN (TETRAGONAL CRYSTAL FORM)
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1lhn: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 5ALPHA-ANDROSTANE-3BETA,17ALPHA-DIOL
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1lho: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 5ALPHA-ANDROSTANE-3BETA,17BETA-DIOL
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1lhu: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH ESTRADIOL
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1lhv: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH NORGESTREL
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1lhw: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 2-METHOXYESTRADIOL
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B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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see also disorders of globin and globulin proteins
B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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