Sex hormone-binding globulin

Sex hormone-binding globulin
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SHBG ; ABP; SBP; TEBG
External IDs OMIM: 182205 MGI: 98295 HomoloGene: 813 ChEMBL: 3305 GeneCards: SHBG Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 6462 20415
Ensembl ENSG00000129214 ENSMUSG00000005202
UniProt P04278 P97497
RefSeq (mRNA) NM_001040 NM_011367
RefSeq (protein) NP_001031 NP_035497
Location (UCSC) Chr 17:
7.61 – 7.63 Mb		 Chr 11:
69.61 – 69.62 Mb
PubMed search

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to the two sex hormones: androgen and estrogen. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds.[1]

Transport of sex hormones

Testosterone and estradiol circulate in the bloodstream, bound mostly to SHBG and to a lesser extent serum albumin and corticosteroid-binding globulin (CBG) (AKA transcortin). Only a very small fraction of about 1-2% is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG. The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone > androstenediol > estradiol > estrone.[2] DHEA is weakly bound to SHBG as well, but DHEA-S is not.[2] Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.[3]

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.[4] Testes-produced SHBG is called androgen-binding protein.

Gene

The gene for SHBG is called Shbg located on chromosome 17[4] on the short arm between the bands 17p12→p13.[5] Overlapping on the complimentary DNA strand is the gene for spermidine/spermine N1-acetyltransferase family member 2 (SAT2). Nearby are the genes for p53 and ATP1B2, and fragile X mental retardation, autosomal homolog 2 (FXR2) on the complimentary strand.[6] There are eight exons, of which exon 1 has three variations called 1L, 1T and 1N which are triggered by three promoters: PL, PT and PN respectively. SHBG comes with the 1L, 2, 3, 4, 5, 6, 7, and 8 exons connected together. A variation includes SHBG-T which is missing exon 7 but with exon 1T promoted by promoter PT on the opposite strand, which shared with that for SAT2.[7]

Polymorphisms

There are variations in the genetic material for this protein that have different effects. In humans common polymorphisms include the following:

Rs6259, also called Asp327Asn location 7633209 on Chromosome 17, results in there being an extra N-glycosilation site, and so an extra sugar can be attached. This results in a longer circulation half-life for the protein, and raised levels. A health effect is a lowered risk of endometrial cancer, and another is an increased risk of systemic lupus erythematosus.[8]

Rs6258 also called Ser156Pro is at position 7631360 on the Chromosome 17.

Rs727428 position 7634474 is in several percent of humans.[9]

(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.[10]

Promoter activation

The mechanism of activating the promoter for SHBG in the liver involves hepatocyte nuclear factor 4 alpha (HNF4A) binding to a DR1 like cis element which then stimulate production. Competing with HNF4A at a third site on the promter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then COUP-TF binds to the fist site and turns off production of SHBG.[1]

Protein

Sex hormone-binding globulin is homodimeric, meaning it has two identical peptide chains making up its structure. The amino acid sequence is the same as for androgen-binding protein but that has different oligosaccharides attached and is produced in testes.[4]

SHBG has two two laminin G-like domains which form pockets that bind hydrophobic molecules. The steroids are bound by the LG domain at the amino end of the protein.[1] Inside the pocket of the domain is a serine residue that attracts the two different types of steroids at different points, thus changing their orientation. Androgens bind at the C3 functiuonal groups on the A ring, and estrogens bind via a hydroxyl attached to C17 on the D ring. The two different orientations change a loop over the entrance to the pocket and the position of trp84 (in humans). Thus the whole protein signals what hormone it carries on its own surface.[1] The steroid binding LG domain is coded by exons 2 to 5.[1] A linker region joins the two LG domains together.[1]

When first produced the SHBG precursor has a leading signal peptide attached with 29 amino acids. The remaining peptide has 373 amino acids.[11] There are two sulfur bridges.

The sugars are attached at two different N-glycosilation points on apsparagine (351 and 367) and one O-glycosilation (7) point on threonine.[11]

Metals

A calcium ion is needed to link the two elements of the dimer together. Also a zinc ion is used to orient an otherwise disorganised part of the peptide chain.[1]

Control

SHBG has both enhancing and inhibiting hormonal influences. It decreases with high levels of insulin, growth hormone, insulin-like growth factor 1 (IGF-1), androgens, prolactin and transcortin. High estrogen, and thyroxine cause it to increase.

In an effort to explain obesity-related reductions in SHBG, recent evidence suggests sugar or monosaccharide-induced hepatic lipogenesis, hepatic lipids in general, and cytokines like TNF-alpha and Interleukin reduce SHBG, whereas insulin does not. As an example anti-psoriatic drugs that inhibit TNF-alpha cause an increase in SHBG. The common downstream mechanism for all of these, including the effect of thyroid hormones[12] was downregulation of HNF4, hepatocyte nuclear factor 4.[13][14][15][16][17]

Blood values

Reference ranges for blood tests for SHBG have been developed:[18]

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 associated with high or low levels

SHBG levels are decreased by androgens, administration of anabolic steroids,[19] polycystic ovary syndrome, hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[20] SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction of more than 50 percent increases SHBG, while lowering free and total testosterone and estradiol. DHEA-S, which lacks affinity for SHBG, is not affected by calorie restriction.[21] Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[22]

In the womb the human fetus has a low level of SHBG allowing increased activity of sex hormones. After birth, the SHBG level rises and remains at a high level throughout childhood. At puberty the SHBG level halves in girls and goes down to a quarter in boys.[1] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In pregnant women in the last two thirds of pregnancy the SHBG level escalates to five to ten times the usual level for a woman. A hypothesis is that this protects against the effect of hormone produced by the fetus.[1]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[1] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[1]

Measurement of sex hormones

When checking serum estradiol or testosterone, a total level that includes free and bound fractions can be assayed, or the free portion may be measured alone. A free androgen index expresses the ratio of testosterone to SHBG and can be used to summarize the activity of free testosterone. The best test for testosterone is the bioavailable testosterone. Sex hormone-binding globulin can be measured separate from the total fraction of testosterone.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Hammond GL (Sep 2011). "Diverse roles for sex hormone-binding globulin in reproduction". Biology of Reproduction 85 (3): 431–41. doi:10.1095/biolreprod.111.092593. PMID 21613632.
  2. 1 2 Somboonporn W, Davis SR (Jun 2004). "Testosterone effects on the breast: implications for testosterone therapy for women". Endocrine Reviews 25 (3): 374–88. doi:10.1210/er.2003-0016. PMID 15180949.
  3. ↑ Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 24 April 2001. ISBN 978-0-7817-1750-2. Retrieved 4 August 2012.
  4. 1 2 3 Hammond GL, Bocchinfuso WP (1996). "Sex hormone-binding globulin: gene organization and structure/function analyses". Hormone Research 45 (3-5): 197–201. doi:10.1159/000184787. PMID 8964583.
  5. ↑
    • 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)". Cytogenetics and Cell Genetics 54 (1-2): 65–7. doi:10.1159/000132958. PMID 2249477.
  6. ↑ Joseph DR (Jan 1998). "The rat androgen-binding protein (ABP/SHBG) gene contains triplet repeats similar to unstable triplets: evidence that the ABP/SHBG and the fragile X-related 2 genes overlap". Steroids 63 (1): 2–4. doi:10.1016/S0039-128X(97)00087-1. PMID 9437788.
  7. ↑ Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM (2009). "Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing". BMC Molecular Biology 10 (1): 37. doi:10.1186/1471-2199-10-37. PMC 2694190. PMID 19416531.
  8. ↑ Piotrowski P, Gasik R, Lianeri M, Cieślak D, Wudarski M, Hrycaj P, Łacki JK, Jagodziński PP (Jan 2010). "Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence". Molecular Biology Reports 37 (1): 235–9. doi:10.1007/s11033-009-9639-7. PMID 19649728.
  9. ↑ Svartberg J, Schirmer H, Wilsgaard T, Mathiesen EB, Njølstad I, Løchen ML, Jorde R (Mar 2014). "Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study". Andrology 2 (2): 212–8. doi:10.1111/j.2047-2927.2013.00174.x. PMID 24327369.
  10. ↑ Thompson DJ, Healey CS, Baynes C, Kalmyrzaev B, Ahmed S, Dowsett M, Folkerd E, Luben RN, Cox D, Ballinger D, Pharoah PD, Ponder BA, Dunning AM, Easton DF (Dec 2008). "Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women". Cancer Epidemiology, Biomarkers & Prevention 17 (12): 3490–8. doi:10.1158/1055-9965.EPI-08-0734. PMC 2660245. PMID 19064566.
  11. 1 2 Hammond, G.L.; D.A. Underhill; C.L. Smith; I.S. Goping; M.J. Harley; N.A. Musto; C.Y. Cheng; C.W. Bardin (1987). "The cDNA-deduced primary structure of human sex hormone-binding globulin and location of its steroid-binding domain". FEBS Letters 215 (1): 100–104. doi:10.1016/0014-5793(87)80121-7. ISSN 0014-5793.
  12. ↑ Selva DM, Hammond GL (Jul 2009). "Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha". Journal of Molecular Endocrinology 43 (1): 19–27. doi:10.1677/JME-09-0025. PMID 19336534.
  13. ↑ "Too much sugar turns off gene that controls the effects of sex steroids". PhysOrg.com. 2007-11-07. Retrieved 2008-02-10.
  14. ↑ Selva DM, Hogeveen KN, Innis SM, Hammond GL (Dec 2007). "Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene". The Journal of Clinical Investigation 117 (12): 3979–87. doi:10.1172/JCI32249. PMC 2066187. PMID 17992261.
  15. ↑ Simó R, Barbosa-Desongles A, Hernandez C, Selva DM (Nov 2012). "IL1β down-regulation of sex hormone-binding globulin production by decreasing HNF-4α via MEK-1/2 and JNK MAPK pathways". Molecular Endocrinology 26 (11): 1917–27. doi:10.1210/me.2012-1152. PMID 22902540.
  16. ↑ Simó R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM (Feb 2012). "Potential role of tumor necrosis factor-α in downregulating sex hormone-binding globulin". Diabetes 61 (2): 372–82. doi:10.2337/db11-0727. PMC 3266423. PMID 22210320.
  17. ↑ Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S (2012). "Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study". Cardiovascular Diabetology 11: 130. doi:10.1186/1475-2840-11-130. PMC 3537568. PMID 23066943.
  18. ↑ Unit Code 91215 at Mayo Clinic Medical Laboratories. Retrieved April 2011
  19. ↑ Ruokonen A, Alén M, Bolton N, Vihko R (Jul 1985). "Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man". Journal of Steroid Biochemistry 23 (1): 33–8. doi:10.1016/0022-4731(85)90257-2. PMID 3160892.
  20. ↑ Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S (Sep 2009). "Sex hormone-binding globulin and risk of type 2 diabetes in women and men". The New England Journal of Medicine 361 (12): 1152–63. doi:10.1056/NEJMoa0804381. PMC 2774225. PMID 19657112.
  21. ↑ Cangemi R, Friedmann AJ, Holloszy JO, Fontana L (Apr 2010). "Long-term effects of calorie restriction on serum sex-hormone concentrations in men". Aging Cell 9 (2): 236–42. doi:10.1111/j.1474-9726.2010.00553.x. PMC 3569090. PMID 20096034.
  22. ↑ Manni A, Pardridge WM, Cefalu W, Nisula BC, Bardin CW, Santner SJ, Santen RJ (Oct 1985). "Bioavailability of albumin-bound testosterone". The Journal of Clinical Endocrinology and Metabolism 61 (4): 705–10. doi:10.1210/jcem-61-4-705. PMID 4040924.

Further reading

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