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{{protein
{{Infobox gene}}
| Name = Sex hormone-binding globulin, Androgen-binding protein
 
| caption = Crystal structure of SHBG binding [[dihydrotestosterone]]. From {{PDB|1D2S}}.<ref name="pmid10675319">{{cite journal
'''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 hormone]]s such as [[progesterone]], [[cortisol]], and other [[corticosteroids]] are bound by [[transcortin]]. SHBG is found in all vertebrates apart from birds.<ref name="Hammond2011">{{cite journal | vauthors = Hammond GL | title = Diverse roles for sex hormone-binding globulin in reproduction | journal = Biology of Reproduction | volume = 85 | issue = 3 | pages = 431–41 | date = Sep 2011 | pmid = 21613632 | doi = 10.1095/biolreprod.111.092593 | pmc=4480437}}</ref>
|author=Grishkovskaya I, Avvakumov GV, Sklenar G, Dales D, Hammond GL, Muller YA
 
|title=Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain|journal=EMBO J|volume=19|issue=4|pages=504–12|year=2000|pmid=10675319|doi=10.1093/emboj/19.4.504|}}</ref>
| image = 92 1d2s-composite.jpg
| width =
| HGNCid = 10839
| Symbol = SHBG
| AltSymbols = ABP
| EntrezGene = 6462
| OMIM = 182205
| RefSeq = NM_001040
| UniProt = P04278
| PDB =
| ECnumber =
| Chromosome = 17
| Arm = p
| Band = 13
| LocusSupplementaryData = -p12
}}
{{SI}}
'''Sex hormone-binding globulin''' ('''SHBG''') is a [[glycoprotein]] that binds to [[sex hormones]], specifically [[testosterone]] and [[estradiol]]. Other steroid [[hormone]]s such as [[progesterone]], [[cortisol]], and other [[corticosteroids]] are bound by [[transcortin]].
==Transport of sex hormones==
==Transport of sex hormones==
These sex hormones 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 (biology)|cell]] and activate its [[Receptor (biochemistry)|receptor]]. The SHBG inhibits the function of these hormones. Thus bioavailability of sex hormones is influenced by the level of SHBG.
Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to [[serum albumin]] (~54%) and [[corticosteroid-binding globulin]] (CBG) (AKA transcortin), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1-2% is unbound, or "free," and thus biologically active and able to enter a [[Cell (biology)|cell]] and activate its [[Receptor (biochemistry)|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]].<ref name="pmid15180949">{{cite journal | vauthors = Somboonporn W, Davis SR | title = Testosterone effects on the breast: implications for testosterone therapy for women | journal = Endocrine Reviews | volume = 25 | issue = 3 | pages = 374–88 | date = Jun 2004 | pmid = 15180949 | doi = 10.1210/er.2003-0016 }}</ref> [[Dehydroepiandrosterone|DHEA]] is weakly bound to SHBG as well, but [[dehydroepiandrosterone sulfate|DHEA-S]] is not.<ref name="pmid15180949" /> [[Androstenedione]] is not bound to SHBG either, and is instead bound solely to albumin.<ref name="Principles and Practice of Endocrinology and Metabolism">{{cite book | title = Principles and Practice of Endocrinology and Metabolism | url = https://books.google.com/books?id=FVfzRvaucq8C | accessdate = 4 August 2012 | date = 24 April 2001 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-1750-2}}</ref>


==SHBG production==
==SHBG production==
SHBG is produced by the [[liver]] cells and is released into the bloodstream. Other sites that produce SHBG are the brain, uterus, and placenta and vagina. In addition SHBG is produced by the testes; testes-produced SHBG is also called [[androgen-binding protein]]. The [[gene]] for SHBG is located on [[chromosome]] 17.
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.<ref name=Hammond96/> Testes-produced SHBG is called [[androgen-binding protein]].
 
==Gene==
The [[gene]] for SHBG is called ''Shbg'' located on [[chromosome 17]]<ref name=Hammond96/> on the short arm between the bands 17p12→p13.<ref>* {{cite journal | vauthors = Bérubé D, Séralini GE, Gagné R, Hammond GL | title = Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12----p13) | journal = Cytogenetics and Cell Genetics | volume = 54 | issue = 1–2 | pages = 65–7 | year = 1991 | pmid = 2249477 | doi = 10.1159/000132958 }}</ref> 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.<ref name=Joseph>{{cite journal | vauthors = Joseph DR | title = 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 | journal = Steroids | volume = 63 | issue = 1 | pages = 2–4 | date = Jan 1998 | pmid = 9437788 | doi = 10.1016/S0039-128X(97)00087-1 }}</ref> There are eight exons, of which exon 1 has three variations called 1L, 1T and 1N which are triggered by three promoters: P<sub>L</sub>, P<sub>T</sub> and P<sub>N</sub> 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 P<sub>T</sub> on the opposite strand, which shared with that for SAT2.<ref name="Nakhla2009">{{cite journal | vauthors = Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM | title = Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing | journal = BMC Molecular Biology | volume = 10 | issue = 1 | pages = 37 | year = 2009 | pmid = 19416531 | pmc = 2694190 | doi = 10.1186/1471-2199-10-37 }}</ref>
 
===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]].<ref name="Piotrowski2009">{{cite journal | vauthors = Piotrowski P, Gasik R, Lianeri M, Cieślak D, Wudarski M, Hrycaj P, Łacki JK, Jagodziński PP | title = Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence | journal = Molecular Biology Reports | volume = 37 | issue = 1 | pages = 235–9 | date = Jan 2010 | pmid = 19649728 | doi = 10.1007/s11033-009-9639-7 }}</ref>
 
Rs6258 also called Ser156Pro is at position 7631360 on the Chromosome 17.
 
Rs727428 position 7634474 is in several percent of humans.<ref name="Svartberg2014">{{cite journal | vauthors = Svartberg J, Schirmer H, Wilsgaard T, Mathiesen EB, Njølstad I, Løchen ML, Jorde R | title = 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 | journal = Andrology | volume = 2 | issue = 2 | pages = 212–8 | date = Mar 2014 | pmid = 24327369 | doi = 10.1111/j.2047-2927.2013.00174.x }}</ref>
 
(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.<ref name="Thompson2008">{{cite journal | vauthors = 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 | title = Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 17 | issue = 12 | pages = 3490–8 | date = Dec 2008 | pmid = 19064566 | pmc = 2660245 | doi = 10.1158/1055-9965.EPI-08-0734 }}</ref>
 
==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 promoter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then [[COUP-TF]] binds to the first site and turns off production of SHBG.<ref name="Hammond2011" />
 
==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.<ref name=Hammond96>{{cite journal | vauthors = Hammond GL, Bocchinfuso WP | title = Sex hormone-binding globulin: gene organization and structure/function analyses | journal = Hormone Research | volume = 45 | issue = 3–5 | pages = 197–201 | year = 1996 | pmid = 8964583 | doi = 10.1159/000184787 }}</ref>
 
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.<ref name="Hammond2011"/> 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 functional 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.<ref name="Hammond2011"/> The steroid binding LG domain is coded by exons 2 to 5.<ref name="Hammond2011"/>  A linker region joins the two LG domains together.<ref name="Hammond2011"/>
 
When first produced the SHBG precursor has a leading signal peptide attached with 29 amino acids. The remaining peptide has 373 amino acids.<ref name="Hammond1987"/> There are two sulfur bridges.
 
The sugars are attached at two different [[N-glycosylation]] points on apsparagine (351 and 367)  and one [[O-glycosylation]] (7) point on threonine.<ref name="Hammond1987">{{cite journal|last=Hammond|first=G.L. |author2=D.A. Underhill |author3=C.L. Smith |author4=I.S. Goping |author5=M.J. Harley |author6=N.A. Musto |author7=C.Y. Cheng |author8=C.W. Bardin|year=1987|title=The cDNA-deduced primary structure of human sex hormone-binding globulin and location of its steroid-binding domain|journal=FEBS Letters|volume=215|issue=1|pages=100–104|issn=0014-5793|doi=10.1016/0014-5793(87)80121-7}}</ref>
 
===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.<ref name="Hammond2011"/>


==Control==
==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]]).  Also, high [[androgen]] levels decrease SHBG, while high [[estrogen]] and [[thyroxine]] levels increase it.
SHBG has both enhancing and inhibiting hormonal influences. It decreases with high levels of [[insulin]], [[growth hormone]], insulin-like growth factor 1 ([[IGF-1]]), [[androgen]]s, [[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 [[liver|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<ref name="pmid19336534">{{cite journal | vauthors = Selva DM, Hammond GL | title = Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha | journal = Journal of Molecular Endocrinology | volume = 43 | issue = 1 | pages = 19–27 | date = Jul 2009 | pmid = 19336534 | doi = 10.1677/JME-09-0025 }}</ref> was downregulation of HNF4, hepatocyte nuclear factor 4.<ref name="Sugar">{{cite web | url = http://www.physorg.com/news113902673.html | title = Too much sugar turns off gene that controls the effects of sex steroids | accessdate = 2008-02-10 | author = | authorlink = | date = 2007-11-07| work = | publisher = PhysOrg.com | pages = | archiveurl = | archivedate = | quote = }}</ref><ref name="pmid17992261">{{cite journal | vauthors = Selva DM, Hogeveen KN, Innis SM, Hammond GL | title = Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene | journal = The Journal of Clinical Investigation | volume = 117 | issue = 12 | pages = 3979–87 | date = Dec 2007 | pmid = 17992261 | pmc = 2066187 | doi = 10.1172/JCI32249 }}</ref><ref name="pmid22902540">{{cite journal | vauthors = Simó R, Barbosa-Desongles A, Hernandez C, Selva DM | title = IL1β down-regulation of sex hormone-binding globulin production by decreasing HNF-4α via MEK-1/2 and JNK MAPK pathways | journal = Molecular Endocrinology | volume = 26 | issue = 11 | pages = 1917–27 | date = Nov 2012 | pmid = 22902540 | doi = 10.1210/me.2012-1152 }}</ref><ref name="pmid22210320">{{cite journal | vauthors = Simó R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM | title = Potential role of tumor necrosis factor-α in downregulating sex hormone-binding globulin | journal = Diabetes | volume = 61 | issue = 2 | pages = 372–82 | date = Feb 2012 | pmid = 22210320 | pmc = 3266423 | doi = 10.2337/db11-0727 }}</ref><ref name="pmid23066943">{{cite journal | vauthors = Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S | title = Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study | journal = Cardiovascular Diabetology | volume = 11 | issue =  | pages = 130 | year = 2012 | pmid = 23066943 | pmc = 3537568 | doi = 10.1186/1475-2840-11-130 }}</ref>
 
==Blood values==
[[Reference ranges for blood tests]] for SHBG have been developed:<ref>[http://www.mayomedicallaboratories.com/test-catalog/print.php?unit_code=91215 Unit Code 91215] at [[Mayo Clinic]] Medical Laboratories. Retrieved April 2011</ref>
{|class="wikitable"
! 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==
{{expand section|date=June 2017| We need two different chapters - High and low.}}
SHBG levels are ''decreased'' by androgens, administration of [[anabolic steroid]]s,<ref name="pmid3160892">{{cite journal | vauthors = Ruokonen A, Alén M, Bolton N, Vihko R | title = Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man | journal = Journal of Steroid Biochemistry | volume = 23 | issue = 1 | pages = 33–8 | date = Jul 1985 | pmid = 3160892 | doi = 10.1016/0022-4731(85)90257-2 }}</ref> [[polycystic ovary syndrome]], [[hypothyroidism]], [[obesity]], [[Cushing's syndrome]], and [[acromegaly]]. Low SHBG levels increase the probability of [[Type 2 Diabetes]].<ref name="Ding2009">{{cite journal | vauthors = Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S | title = Sex hormone-binding globulin and risk of type 2 diabetes in women and men | journal = The New England Journal of Medicine | volume = 361 | issue = 12 | pages = 1152–63 | date = Sep 2009 | pmid = 19657112 | pmc = 2774225 | doi = 10.1056/NEJMoa0804381 }}</ref>  SHBG levels ''increase'' with estrogenic states ([[oral contraceptive]]s), [[pregnancy]], [[hyperthyroidism]], [[cirrhosis]], [[anorexia nervosa]], and certain [[drug]]s. 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.<ref name="pmid20096034">{{cite journal | vauthors = Cangemi R, Friedmann AJ, Holloszy JO, Fontana L | title = Long-term effects of calorie restriction on serum sex-hormone concentrations in men | journal = Aging Cell | volume = 9 | issue = 2 | pages = 236–42 | date = Apr 2010 | pmid = 20096034 | pmc = 3569090 | doi = 10.1111/j.1474-9726.2010.00553.x | url = https://dx.doi.org/10.1111/j.1474-9726.2010.00553.x }}</ref> [[Polycystic Ovarian Syndrome]] is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.<ref name="pmid4040924">{{cite journal | vauthors = Manni A, Pardridge WM, Cefalu W, Nisula BC, Bardin CW, Santner SJ, Santen RJ | title = Bioavailability of albumin-bound testosterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 61 | issue = 4 | pages = 705–10 | date = Oct 1985 | pmid = 4040924 | doi = 10.1210/jcem-61-4-705 }}</ref>


However, recent evidence suggests that it is the livers production of fats that reduces SHBG levels<ref>http://www.physorg.com/news113902673.html</ref>, not any direct effect of insulin and specific genetic mechanisms have been found that do this.
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.<ref name="Hammond2011"/> 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.<ref name="Hammond2011"/>


==Conditions with high or low levels==
Obese girls are more likely to have an early [[menarche]] due to lower levels of SHBG.<ref name="Hammond2011"/> Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to [[amenorrhea]].<ref name="Hammond2011"/>
Conditions with low SHBG include [[polycystic ovary syndrome]], [[diabetes]], and [[hypothyroidism]]. Conditions with high SHBG include [[pregnancy]], [[hyperthyroidism]], and [[anorexia nervosa]]. There has recently been research to link high SHBG levels with breast and testicular cancer as well.


==Measurement of sex hormones==
== Measurement of sex hormones ==
When determining levels of circulating estradiol or testosterone, either a total measurement could be done  that includes the "free" and the bound fractions, or only the "free" hormone could be measured.
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 separately from the total fraction of testosterone.
A [[free androgen index]] expresses the ratio of testosterone to the sex hormone binding globulin and can be used to summarise the activity of free testosterone.


==See also==
== References ==
* [[Androgen binding protein]]
{{Reflist|33em}}


==References==
== Further reading ==
{{Reflist}}
{{refbegin|33em}}
{{-}}
* {{cite journal | vauthors = Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA | title = Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 69 | issue = 1–6 | pages = 481–5 | year = 1999 | pmid = 10419028 | doi = 10.1016/S0960-0760(99)00070-9 }}
* {{cite journal | vauthors = Power SG, Bocchinfuso WP, Pallesen M, Warmels-Rodenhiser S, Van Baelen H, Hammond GL | title = Molecular analyses of a human sex hormone-binding globulin variant: evidence for an additional carbohydrate chain | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 75 | issue = 4 | pages = 1066–70 | date = Oct 1992 | pmid = 1400872 | doi = 10.1210/jcem.75.4.1400872 }}
* {{cite journal | vauthors = Gershagen S, Lundwall A, Fernlund P | title = Characterization of the human sex hormone binding globulin (SHBG) gene and demonstration of two transcripts in both liver and testis | journal = Nucleic Acids Research | volume = 17 | issue = 22 | pages = 9245–58 | date = Nov 1989 | pmid = 2587256 | pmc = 335128 | doi = 10.1093/nar/17.22.9245 }}
* {{cite journal | vauthors = Hammond GL, Underhill DA, Rykse HM, Smith CL | title = The human sex hormone-binding globulin gene contains exons for androgen-binding protein and two other testicular messenger RNAs | journal = Molecular Endocrinology | volume = 3 | issue = 11 | pages = 1869–76 | date = Nov 1989 | pmid = 2608061 | doi = 10.1210/mend-3-11-1869 }}
* {{cite journal | vauthors = Que BG, Petra PH | title = Characterization of a cDNA coding for sex steroid-binding protein of human plasma | journal = FEBS Letters | volume = 219 | issue = 2 | pages = 405–9 | date = Jul 1987 | pmid = 2956125 | doi = 10.1016/0014-5793(87)80261-2 }}
* {{cite journal | vauthors = Gershagen S, Fernlund P, Lundwall A | title = A cDNA coding for human sex hormone binding globulin. Homology to vitamin K-dependent protein S | journal = FEBS Letters | volume = 220 | issue = 1 | pages = 129–35 | date = Aug 1987 | pmid = 2956126 | doi = 10.1016/0014-5793(87)80890-6 }}
* {{cite journal | vauthors = Walsh KA, Titani K, Takio K, Kumar S, Hayes R, Petra PH | title = Amino acid sequence of the sex steroid binding protein of human blood plasma | journal = Biochemistry | volume = 25 | issue = 23 | pages = 7584–90 | date = Nov 1986 | pmid = 3542030 | doi = 10.1021/bi00371a048 }}
* {{cite journal | vauthors = Hammond GL, Robinson PA, Sugino H, Ward DN, Finne J | title = Physicochemical characteristics of human sex hormone binding globulin: evidence for two identical subunits | journal = Journal of Steroid Biochemistry | volume = 24 | issue = 4 | pages = 815–24 | date = Apr 1986 | pmid = 3702459 | doi = 10.1016/0022-4731(86)90442-5 }}
* {{cite journal | vauthors = Hardy DO, Cariño C, Catterall JF, Larrea F | title = Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 4 | pages = 1253–6 | date = Apr 1995 | pmid = 7714097 | doi = 10.1210/jc.80.4.1253 }}
* {{cite journal | vauthors = Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES | title = Characterization of single-nucleotide polymorphisms in coding regions of human genes | journal = Nature Genetics | volume = 22 | issue = 3 | pages = 231–8 | date = Jul 1999 | pmid = 10391209 | doi = 10.1038/10290 }}
* {{cite journal | vauthors = Grishkovskaya I, Avvakumov GV, Sklenar G, Dales D, Hammond GL, Muller YA | title = Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain | journal = The EMBO Journal | volume = 19 | issue = 4 | pages = 504–12 | date = Feb 2000 | pmid = 10675319 | pmc = 305588 | doi = 10.1093/emboj/19.4.504 }}
* {{cite journal | vauthors = Hogeveen KN, Talikka M, Hammond GL | title = Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence | journal = The Journal of Biological Chemistry | volume = 276 | issue = 39 | pages = 36383–90 | date = Sep 2001 | pmid = 11473114 | doi = 10.1074/jbc.M104681200 }}
* {{cite journal | vauthors = Hryb DJ, Nakhla AM, Kahn SM, St George J, Levy NC, Romas NA, Rosner W | title = Sex hormone-binding globulin in the human prostate is locally synthesized and may act as an autocrine/paracrine effector | journal = The Journal of Biological Chemistry | volume = 277 | issue = 29 | pages = 26618–22 | date = Jul 2002 | pmid = 12015315 | doi = 10.1074/jbc.M202495200 }}
* {{cite journal | vauthors = Raineri M, Catalano MG, Hammond GL, Avvakumov GV, Frairia R, Fortunati N | title = O-Glycosylation of human sex hormone-binding globulin is essential for inhibition of estradiol-induced MCF-7 breast cancer cell proliferation | journal = Molecular and Cellular Endocrinology | volume = 189 | issue = 1–2 | pages = 135–43 | date = Mar 2002 | pmid = 12039072 | doi = 10.1016/S0303-7207(01)00725-0 }}
* {{cite journal | vauthors = Grishkovskaya I, Avvakumov GV, Hammond GL, Muller YA | title = Resolution of a disordered region at the entrance of the human sex hormone-binding globulin steroid-binding site | journal = Journal of Molecular Biology | volume = 318 | issue = 3 | pages = 621–6 | date = May 2002 | pmid = 12054810 | doi = 10.1016/S0022-2836(02)00169-9 }}
* {{cite journal | vauthors = 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 | title = Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 17 | issue = 12 | pages = 3490–8 | date = Dec 2008 | pmid = 19064566 | pmc = 2660245 | doi = 10.1158/1055-9965.EPI-08-0734 }}
* {{cite web|url=http://www.snpedia.com/index.php/SHBG|title=SHBG - SNPedia|last=Trkiehl|year=2011|accessdate=13 July 2014}}
{{refend}}
 
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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, loosely bound mostly to serum albumin (~54%) and corticosteroid-binding globulin (CBG) (AKA transcortin), and to a lesser extent bound tightly to SHBG (~44%). 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 promoter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then COUP-TF binds to the first 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 functional 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-glycosylation points on apsparagine (351 and 367) and one O-glycosylation (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 separately from the total fraction of testosterone.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 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. PMC 4480437. PMID 21613632.
  2. ↑ 2.0 2.1 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. ↑ 4.0 4.1 4.2 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. ↑ 11.0 11.1 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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