Difference between revisions of "Sex hormone-binding globulin"

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{{protein
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{{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
 
|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
 
}}
 
'''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==
 
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.
 
  
==SHBG production==
+
'''Sex hormone-binding globulin''' ('''SHBG''') or '''sex steroid-binding globulin''' ('''SSBG''') is a [[glycoprotein]] that binds to [[androgen|androgens]] and [[estrogen|estrogens]]. 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 = September 2011 | pmid = 21613632 | pmc = 4480437 | doi = 10.1095/biolreprod.111.092593 }}</ref>
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.
 
  
==Control==
+
==Function==
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.
+
Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to [[serum albumin]] (~54%), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1 to 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 = June 2004 | pmid = 15180949 | doi = 10.1210/er.2003-0016 }}</ref> DHT binds to SHBG with about 5&nbsp;times the affinity of testosterone and about 20&nbsp;times the affinity of estradiol.<ref name="WintersHuhtaniemi2017" /> [[Dehydroepiandrosterone]] (DHEA) is weakly bound to SHBG, but [[dehydroepiandrosterone sulfate]] is not bound to SHBG.<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 | first1 =  K.L. | last1 = Becker | first2 = John P. | last2 = Bilezikian | first3 =  William J. | last3 = Bremner | first4 = Wellington | last4 = Hung | first5 = C. Ronald | last5 = Kahn | name-list-format = vanc | 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> [[Estrone sulfate]] and [[estriol]] are also poorly bound by SHBG.<ref name="Buchsbaum2012">{{cite book | vauthors =  Buchsbaum HJ | title = The Menopause|url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA62|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5525-3|pages=62–}}</ref> Less than 1% of [[progesterone]] is bound to SHBG.<ref name="FritzSperoff2012">{{cite book | first1 = Marc A. | last1 = Fritz | first2 = Leon | last2 = Speroff | name-list-format = vanc |title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA44|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=44–}}</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.
+
SHBG levels are usually about twice as high in women than in men.<ref name="WintersHuhtaniemi2017" /> In women, SHBG serves to limit exposure to both [[androgen]]s and [[estrogen]]s.<ref name="WintersHuhtaniemi2017" /> Low SHBG levels in women have been associated with [[hyperandrogenism]] and [[endometrial cancer]] due to heightened exposure to androgens and estrogens, respectively.<ref name="WintersHuhtaniemi2017" /> During [[pregnancy]], due to activation of SHBG production in the [[liver]] by high estrogen levels, SHBG levels increase by 5- to 10-fold.<ref name="WintersHuhtaniemi2017" /> The high SHBG levels during pregnancy may serve to protect the mother from exposure to [[fetus|fetal]] androgens that escape [[metabolism]] by the [[placenta]].<ref name="WintersHuhtaniemi2017" /> A [[case report]] of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.<ref name="WintersHuhtaniemi2017" />
  
==Conditions with high or low levels==
+
==Biochemistry==
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==
+
===Biosynthesis===
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.
+
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]].
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==
+
==Gene==
* [[Androgen binding protein]]
+
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 = January 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 | date = May 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 = January 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 = March 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 = December 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 | vauthors = Hammond GL, Underhill DA, Smith CL, Goping IS, Harley MJ, Musto NA, Cheng CY, Bardin CW | 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 = 100–4 | date = May 1987 | pmid = 3569533 | 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"/>
 +
 
 +
==Regulation==
 +
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]] levels 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 = July 2009 | pmid = 19336534 | doi = 10.1677/JME-09-0025 }}</ref> was downregulation of HNF4, hepatocyte nuclear factor 4.<ref name="Sugar">{{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 = December 2007 | pmid = 17992261 | pmc = 2066187 | doi = 10.1172/JCI32249 | laysummary = http://www.physorg.com/news113902673.html | laysource = PhysOrg.com }}</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 = November 2012 | pmid = 22902540 | pmc = 5416961 | 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 = February 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 | date = October 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] {{webarchive|url=https://web.archive.org/web/20110720111631/http://www.mayomedicallaboratories.com/test-catalog/print.php?unit_code=91215 |date=2011-07-20 }} at [[Mayo Clinic]] Medical Laboratories. Retrieved April 2011</ref>
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 +
{|class="wikitable"
 +
! Population !! Range
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|-
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| Adult female, premenopausal || 40–120 nmol/L
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|-
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| Adult female, postmenopausal || 28–112 nmol/L
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|-
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| Adult male || 20–60 nmol/L
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|-
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| Infant (1–23 months) || 60–252 nmol/L
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|-
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| Prepubertal (2 years–8 years) || 72–220 nmol/L
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|-
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| Pubertal female || 36–125 nmol/L
 +
|-
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| Pubertal male || 16–100 nmol/L
 +
|}
 +
 
 +
==Clinical significance==
 +
 
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===High or low levels===
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{{Expand section|date=June 2017| We need two different chapters - High and low.}}
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 +
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 = July 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 = September 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 = April 2010 | pmid = 20096034 | pmc = 3569090 | doi = 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 = October 1985 | pmid = 4040924 | doi = 10.1210/jcem-61-4-705 }}</ref>
 +
 
 +
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"/>
 +
 
 +
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"/>
 +
 
 +
===Type 2 diabetes===
 +
Reduced levels of SHBG and also certain [[gene polymorphism|polymorphisms]] of the SHBG gene are implicated in the development of [[insulin resistance]] and [[type 2 diabetes]].<ref name="Le12">{{cite journal | vauthors = Le TN, Nestler JE, Strauss JF, Wickham EP | title = Sex hormone-binding globulin and type 2 diabetes mellitus | journal = Trends in Endocrinology and Metabolism | volume = 23 | issue = 1 | pages = 32–40 | date = January 2012 | pmid = 22047952 | doi = 10.1016/j.tem.2011.09.005 | pmc = 3351377 }}</ref> Such effects apparently involve direct action at the cellular level where it became apparent that cell membranes of certain tissues contain specific high-affinity SHBG receptors.<ref name="Rosner10">{{cite journal | vauthors = Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA | title = Interactions of sex hormone-binding globulin with target cells | journal = Molecular and Cellular Endocrinology | volume = 316 | issue = 1 | pages = 79–85 | date = March 2010 | pmid = 19698759 | doi = 10.1016/j.mce.2009.08.009 }}</ref>
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 +
===Medications===
 +
[[Oral contraceptive]]s containing [[ethinylestradiol]] can increase SHBG levels by 2- to 4-fold and decrease free testosterone concentrations by 40 to 80% in women.<ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA157|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|page = 157 }}</ref> They can be used to treat [[symptom]]s of [[hyperandrogenism]] like [[acne]] and [[hirsutism]].<ref name="HumansOrganization2007" /><ref name="WintersHuhtaniemi2017" /> Some oral contraceptives, namely those containing high doses of ethinylestradiol (which have been discontinued and are no longer marketed), can increase SHBG levels by as much as 5- to 10-fold.<ref name="WintersHuhtaniemi2017">{{cite book | first1 = Stephen J. | last1 = Winters| first2 = Ilpo T. | last2 = Huhtaniemi | name-list-format = vanc | title = Male Hypogonadism: Basic, Clinical and Therapeutic Principles | url = https://books.google.com/books?id=UFi-DgAAQBAJ&pg=PA307 | date = 25 April 2017 | publisher = Humana Press | isbn = 978-3-319-53298-1 | page = 307}}</ref>
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 +
Some medications, such as certain [[anabolic steroid]]s like [[mesterolone]] and [[danazol]] and certain [[progestin]]s like [[levonorgestrel]] and [[norethisterone]], have high affinity for SHBG and can bind to it and displace [[endogenous]] [[steroid]]s from it, thereby increasing free concentrations of these endogenous steroids.<ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = J. Clin. Endocrinol. Metab. | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 | url = }}</ref><ref name="pmid6539197">{{cite journal | vauthors = Saartok T, Dahlberg E, Gustafsson JA | title = Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin | journal = Endocrinology | volume = 114 | issue = 6 | pages = 2100–6 | year = 1984 | pmid = 6539197 | doi = 10.1210/endo-114-6-2100 | url = }}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref> It has been estimated that therapeutic levels of danazol, [[methyltestosterone]], [[fluoxymesterone]], levonorgestrel, and norethisterone would respectively occupy or displace from testosterone 83–97%, 48–69%, 42–64%, 16–47%, and 4–39% of SHBG binding sites, while others with low affinity for SHBG such as [[ethinylestradiol]], [[cyproterone acetate]], and [[medroxyprogesterone acetate]] would occupy or displace from testosterone 1% or fewer SHBG binding sites.<ref name="pmid7195405" /><ref name="pmid7200170">{{cite journal | vauthors = Pugeat MM, Dunn JF, Rodbard D, Nisula BC | title = The significance of drug interactions with human TeBG and CBG under physiological conditions: a new approach | journal = J. Steroid Biochem. | volume = 15 | issue = | pages = 487–90 | date = December 1981 | pmid = 7200170 | doi = 10.1016/0022-4731(81)90319-8 | url = }}</ref>
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{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:675px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 70 medications for SHBG and CBG<ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = J. Clin. Endocrinol. Metab. | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 | url = }}</ref>
 +
|-
 +
! Compound || Structure || data-sort-type="number" | SHBG<br />{{abbr|RBA|Relative binding affinity}} (%) || data-sort-type="number" | SHBG<br />K (10<sup>6</sup> M<sup>−1</sup>) || data-sort-type="number" | CBG<br />{{abbr|RBA|Relative binding affinity}} (%) || data-sort-type="number" | CBG<br />K (10<sup>6</sup> M<sup>−1</sup>)
 +
|-
 +
| [[Aminoglutethimide]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Androstanolone]] || Steroidal || 220 || 5500 || 1.3 || 0.83
 +
|-
 +
| [[Betamethasone]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Cholecalciferol]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Cimetidine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Clomifene]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Hydrocortisone|Cortisol (hydrocortisone)]] || Steroidal || 0.13 || 1.6 || 100 || 76
 +
|-
 +
| [[Cortisone acetate]] || Steroidal || 0.10 || 1.2 || <0.1 || <0.1
 +
|-
 +
| [[Cyproterone acetate]] || Steroidal || 0.10 || 1.2 || <0.1 || <0.1
 +
|-
 +
| [[Danazol]] || Steroidal || 18 || 240 || 10 || 6.5
 +
|-
 +
| [[Dexamethasone]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Diazoxide]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Diethylstilbestrol]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Digitoxin]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Digoxin]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Dihydroxyphenylalanine|{{Small|DL}}-DOPA]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Dopamine (medication)|Dopamine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Enclomiphene]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Epinephrine (medication)|Epinephrine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Estradiol (medication)|Estradiol]] || Steroidal || 49 || 680 || <0.1 || <0.1
 +
|-
 +
| [[Estradiol benzoate]] || Steroidal || 0.70 || 8.6 || <0.1 || <0.1
 +
|-
 +
| [[Ethinylestradiol]] || Steroidal || 0.80 || 9.9 || <0.1 || <0.1
 +
|-
 +
| [[Ethisterone]] || Steroidal || 55 || 780 || 0.33 || 0.21
 +
|-
 +
| [[Fludrocortisone]] || Steroidal || <0.01 || <0.2 || 0.74 || 0.47
 +
|-
 +
| [[Fluoxymesterone]] || Steroidal || 4.8 || 60 || <0.1 || <0.1
 +
|-
 +
| [[Flutamide]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Homovanillic acid]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Hydrocortisone hemisuccinate]] || Steroidal || <0.01 || <0.2 || 8.7 || 5.6
 +
|-
 +
| [[Indometacin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Levonorgestrel]] || Steroidal || 31 || 420 || <0.1 || <0.1
 +
|-
 +
| [[Medroxyprogesterone]] || Steroidal || 0.15 || 1.9 || 13 || 8.1
 +
|-
 +
| [[Medroxyprogesterone acetate]] || Steroidal || 0.08 || 1.0 || 6.5 || 4.2
 +
|-
 +
| [[Melatonin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Mesterolone]] || Steroidal || 180 || 3600 || <0.1 || <0.1
 +
|-
 +
| [[Mestranol]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Methoxytryptophol]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Methyldopa]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Methylserotonin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Methyltestosterone]] || Steroidal || 39 || 530 || <0.1 || <0.1
 +
|-
 +
| [[Metiamide]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Metribolone]] || Steroidal || 1.7 || 21 || 0.36 || 0.23
 +
|-
 +
| [[Metyrapone]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Mexrenone]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Nafoxidine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Nandrolone]] || Steroidal || 5.8 || 72 || 0.10 || 0.63
 +
|-
 +
| [[Norepinephrine (medication)|Norepinephrine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Norethisterone]] || Steroidal || 11 || 140 || 0.28 || 0.18
 +
|-
 +
| [[Noretynodrel]] || Steroidal || 1.3 || 16 || 0.16 || 0.10
 +
|-
 +
| [[Normetanephrine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Phenytoin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Potassium canrenoate]] || Steroidal || 0.18 || 2.2 || 0.83 || 0.53
 +
|-
 +
| [[Prednisolone]] || Steroidal || 0.04 || 0.49 || 59 || 41
 +
|-
 +
| [[Prednisone]] || Steroidal || 0.17 || 2.1 || 5.0 || 3.2
 +
|-
 +
| [[Progesterone (medication)|Progesterone]] || Steroidal || 0.71 || 8.8 || 36 || 24
 +
|-
 +
| [[Promegestone]] || Steroidal || 0.007 || 0.09 || 0.40 || 0.25
 +
|-
 +
| [[Prorenone]] || Steroidal || 8.2 || 100 || <0.1 || <0.1
 +
|-
 +
| [[Reserpine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Rifampin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Serotonin]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Spironolactone]] || Steroidal || 0.03 || 0.37 || <0.1 || <0.1
 +
|-
 +
| [[Tamoxifen]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Testolactone]] || Steroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Testosterone (medication)|Testosterone]] || Steroidal || 100 || 1600 || 8.3 || 5.3
 +
|-
 +
| [[Testosterone enanthate]] || Steroidal || 0.007 || 0.086 || <0.1 || <0.1
 +
|-
 +
| data-sort-value="Thioprogesterone, 7α-" | [[7α-Thioprogesterone]] || Steroidal || 0.06 || 0.74 || 36 || 24
 +
|-
 +
| data-sort-value="Thiospironolactone, 7α-" | [[7α-Thiospironolactone]] || Steroidal || 0.59 || 7.3 || <0.1 || <0.1
 +
|-
 +
| [[Thyroxine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Triiodothyronine]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Trimethyltrienolone]] || Steroidal || 0.90 || 11 || 0.11 || 0.07
 +
|-
 +
| [[Vanillylmandelic acid]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|-
 +
| [[Zuclomifene]] || Nonsteroidal || <0.01 || <0.2 || <0.1 || <0.1
 +
|- class="sortbottom"
 +
| colspan="6" style="width: 1px;" | The reference [[ligand (biochemistry)|ligand]]s (100%) for the {{abbrlink|RBA|relative binding affinity}} (%) values were [[testosterone (medication)|testosterone]] for SHBG and [[hydrocortisone|cortisol]] for {{abbrlink|CBG|corticosteroid-binding globulin}}.
 +
|}
 +
 
 +
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:425px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 21 progestins for SHBG and CBG<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="BerginkLoonen1985">{{cite journal | vauthors = Bergink EW, Loonen PB, Kloosterboer HJ | title = Receptor binding of allylestrenol, a progestagen of the 19-nortestosterone series without androgenic properties | journal = Journal of Steroid Biochemistry | volume = 23 | issue = 2 | pages = 165–8 | date = August 1985 | pmid = 3928974 | doi = 10.1016/0022-4731(85)90232-8 }}</ref>
 +
|-
 +
! Progestogen || data-sort-type="number" | SHBG (%) || data-sort-type="number" | CBG (%)
 +
|-
 +
| [[17α-Allyl-19-nortestosterone]] || <1 || ?
 +
|-
 +
| [[Allylestrenol]] || <1 || ?
 +
|-
 +
| [[Chlormadinone acetate]] || <1 || <1
 +
|-
 +
| [[Cyproterone acetate]] || <1 || <1
 +
|-
 +
| [[Desogestrel]] || <1 || <1
 +
|-
 +
| [[Dienogest]] || <1 || <1
 +
|-
 +
| [[Drospirenone]] || <1 || <1
 +
|-
 +
| [[Etonogestrel]] || 15 || <1
 +
|-
 +
| [[Gestodene]] || 40 || <1
 +
|-
 +
| [[Levonorgestrel]] || 50 || <1
 +
|-
 +
| [[Medroxyprogesterone acetate]] || <1 || <1
 +
|-
 +
| [[Megestrol acetate]] || <1 || <1
 +
|-
 +
| [[Nomegestrol acetate]] || <1 || <1
 +
|-
 +
| [[Norelgestromin]] || <1 || ?
 +
|-
 +
| [[Norethisterone]] || 16 || <1
 +
|-
 +
| [[Noretynodrel]] || <1 || <1
 +
|-
 +
| [[Norgestimate]] || <1 || <1
 +
|-
 +
| [[Progesterone (medication)|Progesterone]] || <1 || 36
 +
|-
 +
| [[Promegestone]] || <1 || <1
 +
|-
 +
| [[Segesterone acetate]] || <1 || ?
 +
|-
 +
| [[Δ4-Tibolone|Δ<sup>4</sup>-Tibolone]] || 1 || <1
 +
|- class="sortbottom"
 +
| colspan="3" style="width: 1px;" | Values are {{abbrlink|RBAs|relative binding affinities}} (%). The reference [[ligand (biochemistry)|ligand]] (100%) for SHBG was [[dihydrotestosterone]] and for {{abbrlink|CBG|corticosteroid-binding globulin}} was [[cortisol]].
 +
|}
 +
 
 +
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:300px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 14 {{abbr|AAS|androgens/anabolic steroids}} for SHBG<ref name="pmid6539197">{{cite journal | vauthors = Saartok T, Dahlberg E, Gustafsson JA | title = Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin | journal = Endocrinology | volume = 114 | issue = 6 | pages = 2100–6 | year = 1984 | pmid = 6539197 | doi = 10.1210/endo-114-6-2100 | url = }}</ref>
 +
|-
 +
! Compound || data-sort-type="number" | SHBG (%)
 +
|-
 +
| [[5α-Androstane-3β,17β-diol]] || 17
 +
|-
 +
| [[5β-Androstane-3α,17β-diol]] || 5
 +
|-
 +
| [[Androstanolone|Dihydrotestosterone]] || 100
 +
|-
 +
| [[Ethylestrenol]] || <1
 +
|-
 +
| [[Fluoxymesterone]] || <1
 +
|-
 +
| [[Mesterolone]] || 440
 +
|-
 +
| [[Metandienone]] || 2
 +
|-
 +
| [[Metenolone]] || 3
 +
|-
 +
| [[Methyltestosterone]] || 5
 +
|-
 +
| [[Metribolone]] || <1
 +
|-
 +
| [[Nandrolone]] || 1
 +
|-
 +
| [[Oxymetholone]] || <1
 +
|-
 +
| [[Stanozolol]] || 1
 +
|-
 +
| [[Testosterone (medication)|Testosterone]] || 19
 +
|- class="sortbottom"
 +
| colspan="2" style="width: 1px;" | Values are {{abbrlink|RBAs|relative binding affinities}} (%). The reference [[ligand (biochemistry)|ligand]] (100%) for SHBG was [[dihydrotestosterone]].
 +
|}
 +
 
 +
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:300px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 41 steroids for SHBG<ref name="pmid7197818">{{cite journal | vauthors = Cunningham GR, Tindall DJ, Lobl TJ, Campbell JA, Means AR | title = Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP) | journal = Steroids | volume = 38 | issue = 3 | pages = 243–62 | date = September 1981 | pmid = 7197818 | doi = 10.1016/0039-128X(81)90061-1 | url = }}</ref>
 +
|-
 +
! Compound !! data-sort-type="number" | SHBG (%)
 +
|-
 +
| [[3β-Androstanediol]] || 100
 +
|-
 +
| [[Androstenediol]] || 77
 +
|-
 +
| [[Bolandiol]] || 24
 +
|-
 +
| [[5α-Dihydroethisterone|Dihydroethisterone]] || 100
 +
|-
 +
| [[5α-Dihydroethyltestosterone|Dihydroethyltestosterone]] || 18–21<!--Source reported both 18 and 21 for the same structure in different tables-->
 +
|-
 +
| [[5α-Dihydromethylandrostenediol|Dihydromethylandrostenediol]] || 77
 +
|-
 +
| [[5α-Dihydronandrolone|Dihydronandrolone]] || 44
 +
|-
 +
| [[Androstanolone|Dihydrotestosterone]] || 100
 +
|-
 +
| [[5α-Dihydrotrestolone|Dihydrotrestolone]] || 47
 +
|-
 +
| [[4,17α-Dimethyltestosterone]] || 97
 +
|-
 +
| [[Drostanolone]] || 39
 +
|-
 +
| [[Ethisterone]] || 92
 +
|-
 +
| [[Fluoxymesterone]] || 3
 +
|-
 +
| [[11-Ketodihydrotestosterone]] || 0
 +
|-
 +
| [[Medroxyprogesterone acetate]] || 16
 +
|-
 +
| [[Megestrol acetate]] || 0
 +
|-
 +
| [[Mestanolone]] || 84
 +
|-
 +
| [[Methasterone]] || 58
 +
|-
 +
| [[Methyl-1-testosterone]] || 69
 +
|-
 +
| [[Methylandrostenediol]] || 40
 +
|-
 +
| [[Methyltestosterone]] || 64
 +
|-
 +
| [[Mibolerone]] || 6
 +
|-
 +
| [[Nandrolone]] || 16
 +
|-
 +
| [[Nandrolone decanoate]] || 0
 +
|-
 +
| [[Nandrolone phenylpropionate]] || 0
 +
|-
 +
| [[Norethandrolone]] || 3
 +
|-
 +
| [[Norethisterone]] || 21
 +
|-
 +
| [[Normethandrone]] || 7
 +
|-
 +
| [[Oxandrolone]] || 0
 +
|-
 +
| [[Oxymetholone]] || 3
 +
|-
 +
| [[Progesterone (medication)|Progesterone]] || 13
 +
|-
 +
| [[Stanozolol]] || 36
 +
|-
 +
| [[1-Testosterone]] || 98
 +
|-
 +
| [[Testosterone (medication)|Testosterone]] || 82
 +
|-
 +
| [[Testosterone benzoate]] || 8
 +
|-
 +
| [[Testosterone cypionate]] || 6
 +
|-
 +
| [[Testosterone enanthate]] || 9
 +
|-
 +
| [[Δ4-Tibolone|Δ<sup>4</sup>-Tibolone]] || 8
 +
|-
 +
| [[Trestolone]] || 12
 +
|-
 +
| [[Trestolone enanthate]] || 12
 +
|-
 +
| [[Vinyltestosterone]] || 36
 +
|- class="sortbottom"
 +
| colspan="2" style="width: 1px;" | Values are {{abbrlink|RBAs|relative binding affinities}} (%). The reference [[ligand (biochemistry)|ligand]] (100%) for SHBG was [[dihydrotestosterone]].
 +
|}
 +
 
 +
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:300px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 11 steroids for SHBG and CBG<ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Res. | volume = 38 | issue = 11 Pt 2 | pages = 4186–98 | date = November 1978 | pmid = 359134 | doi = | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short}}</ref>
 +
|-
 +
! Compound || {{abbrlink|SHBG|Sex hormone-binding globulin}} (%) || {{abbrlink|CBG|Corticosteroid binding globulin}} (%)
 +
|-
 +
| [[Aldosterone]] || <0.2 || 6.0
 +
|-
 +
| [[Corticosterone]] || <0.2 || 107
 +
|-
 +
| [[Hydrocortisone|Cortisol]] || <0.2 || 100
 +
|-
 +
| [[Dexamethasone]] || <0.2 || <0.1
 +
|-
 +
| [[Androstanolone|Dihydrotestosterone]] || 100 || 0.8
 +
|-
 +
| [[Estradiol (medication)|Estradiol]] || 8.7 || <0.1
 +
|-
 +
| [[Metribolone]] || 0.2 || <0.1
 +
|-
 +
| [[Moxestrol]] || <0.2 || <0.1
 +
|-
 +
| [[Progesterone (medication)|Progesterone]] || <0.2 || 25
 +
|-
 +
| [[Promegestone]] || <0.2 || 0.9
 +
|-
 +
| [[Testosterone (medication)|Testosterone]] || 26 || 3
 +
|- class="sortbottom"
 +
| colspan="9" style="width: 1px;" | Values are {{abbrlink|RBAs|relative binding affinities}} (%). The reference [[ligand (biochemistry)|ligand]] (100%) for SHBG was [[dihydrotestosterone]] and for {{abbrlink|CBG|corticosteroid-binding globulin}} was [[cortisol]].
 +
|}
 +
 
 +
{| class="wikitable sortable mw-collapsible mw-collapsed" style="width:500px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | Affinities of 9 estrogens for SHBG<ref name="pmid16112947" /><ref name="LemkeWilliams2008">{{cite book|author1=Thomas L. Lemke|author2=David A. Williams|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1306|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1306–}}</ref>
 +
|-
 +
! Compound !! data-sort-type="number" | {{abbrlink|RBA|Relative binding affinity}} to<br />{{abbrlink|SHBG|sex hormone-binding globulin}} (%) !! data-sort-type="number" | Bound to<br />{{abbr|SHBG|sex hormone-binding globulin}} (%) !! data-sort-type="number" | Bound to<br />[[human serum albumin|albumin]] (%)
 +
|-
 +
| [[Estradiol (medication)|17β-Estradiol]] || 50 || 37 || 61
 +
|-
 +
| [[Estrone (medication)|Estrone]] || 12 || 16 || 80
 +
|-
 +
| [[Estriol (medication)|Estriol]] || 0.3 || 1 || 91
 +
|-
 +
| [[Estrone sulfate (medication)|Estrone sulfate]] || 0 || 0 || 99
 +
|-
 +
| [[17β-Dihydroequilin]] || 30 || ? || ?
 +
|-
 +
| [[Equilin]] || 8 || 26 || 13
 +
|-
 +
| [[17β-Dihydroequilin sulfate]] || 0 || ? || ?
 +
|-
 +
| [[Equilin sulfate]] || 0 || ? || ?
 +
|-
 +
| [[8,9-Dehydroestrone|Δ<sup>8</sup>-Estrone]] || ? || ? || ?
 +
|- class="sortbottom"
 +
| colspan="4" style="width: 1px;" | The reference [[ligand (biochemistry)|ligand]] (100%) for the SHBG {{abbrlink|RBA|relative binding affinity}} (%) values was [[testosterone (medication)|testosterone]].
 +
|}
 +
 
 +
==Endogenous steroids==
 +
 
 +
===Measurement===
 +
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.
 +
 
 +
===Affinity and binding===
 +
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:100%; text-align:left; margin-left:auto; margin-right:auto; border:none;"
 +
|+ class="nowrap" | {{Resize|105%|Affinities of endogenous steroids for SHBG and plasma protein binding<ref name="pmid7195404">{{cite journal | vauthors = Dunn JF, Nisula BC, Rodbard D | title = Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = J. Clin. Endocrinol. Metab. | volume = 53 | issue = 1 | pages = 58–68 | date = July 1981 | pmid = 7195404 | doi = 10.1210/jcem-53-1-58 | url = }}</ref>}}
 +
|-
 +
! rowspan="2" | Steroid !! colspan="2" | SHBG affinity !! colspan="5" | Plasma protein binding in men !! colspan="5" | Plasma protein binding in women (follicular phase)
 +
|-
 +
! {{abbr|RBA|Relative binding affinity}} (%) !! K (10<sup>6</sup> M<sup>−1</sup>) !! Total (nM) !! Unbound (%) !! SHBG (%) !! CBG (%) !! Albumin (%) !! Total (nM) !! Unbound (%) !! SHBG (%) !! CBG (%) !! Albumin (%)
 +
|-
 +
| [[Aldosterone]] || 0.017 || 0.21 || 0.35 || 37.1 || 0.10 || 21.2 || 41.6 || 0.24 || 36.8 || 0.23 || 21.9 || 41.2
 +
|-
 +
| data-sort-value="Androstanediol, 3α-" | [[3α-Androstanediol|3α&#8209;Androstanediol]] || 82 || 1300 || 0.41 || 0.85 || 13.7 || data-sort-value="0" | <0.1 || 85.5 || 0.068 || 0.71 || 27.9 || data-sort-value="0" | <0.1 || 71.4
 +
|-
 +
| [[Androstenediol]] || 97 || 1500 || 4.3 || 3.24 || 60.4 || data-sort-value="0" | <0.1 || 36.3 || 2.4 || 1.73 || 78.8 || data-sort-value="0" | <0.1 || 19.4
 +
|-
 +
| [[Androstenedione]] || 2.3 || 29 || 4.1 || 7.85 || 2.82 || 1.37 || 88.0 || 5.4 || 7.54 || 6.63 || 1.37 || 84.5
 +
|-
 +
| [[Androsterone]] || 1.1 || 14 || 2.0 || 4.22 || 0.73 || 0.52 || 94.5 || 1.5 || 4.18 || 1.77 || 0.54 || 93.5
 +
|-
 +
| [[Corticosterone]] || 0.18 || 2.2 || 12 || 3.39 || 0.09 || 77.5 || 19.0 || 7.0 || 3.28 || 0.22 || 78.1 || 18.4
 +
|-
 +
| [[Cortisol]] || 0.13 || 1.6 || 400 || 3.91 || 0.08 || 89.5 || 6.57 || 400 || 3.77 || 0.18 || 89.7 || 6.33
 +
|-
 +
| [[Cortisone]] || 0.22 || 2.7 || 72 || 16.2 || 0.54 || 38.0 || 45.3 || 54 || 15.8 || 1.30 || 38.6 || 44.3
 +
|-
 +
| [[Dehydroepiandrosterone]] || 5.3 || 66 || 24 || 4.13 || 3.38 || data-sort-value="0" | <0.1 || 92.4 || 17 || 3.93 || 7.88 || data-sort-value="0" | <0.1 || 88.1
 +
|-
 +
| data-sort-value="Deoxycorticosterone, 11-" | [[11-Deoxycorticosterone|11&#8209;Deoxycorticosterone]] || 1.9 || 24 || 0.20 || 2.69 || 0.80 || 36.4 || 60.1 || 0.12 || 2.62 || 1.91 || 36.9 || 58.6
 +
|-
 +
| data-sort-value="Deoxycortisol, 11-" | [[11-Deoxycortisol|11&#8209;Deoxycortisol]] || 1.3 || 16 || 1.4 || 3.37 || 0.67 || 77.1 || 18.9 || 0.60 || 3.24 || 1.57 || 77.1 || 18.1
 +
|-
 +
| [[Dihydrotestosterone]] || 220 || 5500 || 1.7 || 0.88 || 59.7 || 0.22 || 39.2 || 0.65 || 0.47 || 78.4 || 0.12 || 21.0
 +
|-
 +
| [[Estradiol]] || 49 || 680 || 0.084 || 2.32 || 19.6 || data-sort-value="0" | <0.1 || 78.0 || 0.29 || 1.81 || 37.3 || data-sort-value="0" | <0.1 || 60.8
 +
|-
 +
| [[Estriol]] || 0.35 || 4.3 || 0.037 || 8.15 || 0.44 || data-sort-value="0" | <0.2 || 91.3 || 0.10 || 8.10 || 1.06 || data-sort-value="0" | <0.2 || 90.7
 +
|-
 +
| [[Estrone]] || 12 || 150 || 0.081 || 3.96 || 7.37 || data-sort-value="0" | <0.1 || 88.6 || 0.23 || 3.58 || 16.3 || data-sort-value="0" | <0.1 || 80.1
 +
|-
 +
| [[Etiocholanolone]] || 0.11 || 1.4 || 1.3 || 8.15 || 0.14 || 0.44 || 91.3 || 1.2 || 8.13 || 0.35 || 0.46 || 91.1
 +
|-
 +
| [[Pregnenolone]] || 1.1 || 14 || 2.4 || 2.87 || 0.50 || 0.16 || 96.5 || 2.2 || 2.85 || 1.21 || 0.16 || 95.8
 +
|-
 +
| data-sort-value="Pregnenolone, 17α-Hydroxy" | [[17α-Hydroxypregnenolone|17α&#8209;Hydroxypregnenolone]] || 0.19 || 2.3 || 5.4 || 4.27 || 0.12 || data-sort-value="0" | <0.1 || 95.5 || 3.5 || 4.26 || 0.30 || data-sort-value="0" | <0.1 || 95.4
 +
|-
 +
| [[Progesterone]] || 0.71 || 8.8 || 0.57 || 2.39 || 0.26 || 17.2 || 80.1 || 0.65 || 2.36 || 0.63 || 17.7 || 79.3
 +
|-
 +
| data-sort-value="Progesterone, 17α-Hydroxy" | [[17α-Hydroxyprogesterone|17α&#8209;Hydroxyprogesterone]] || 0.8 || 9.9 || 5.4 || 2.50 || 0.31 || 41.3 || 55.9 || 1.8 || 2.44 || 0.73 || 42.1 || 54.7
 +
|-
 +
| [[Testosterone]] || 100 || 1600 || 23 || 2.23 || 44.3 || 3.56 || 49.9 || 1.3 || 1.36 || 66.0 || 2.26 || 30.4
 +
|- class="sortbottom"
 +
| colspan="13" style="width: 1px;" | In men, the concentrations of SHBG, CBG, and albumin were 28 nM, 0.7 μM, and 0.56 mM, respectively. In women, the concentrations of SHBG, CBG, and albumin were 37 nM, 0.7 μM, and 0.56 mM, respectively.
 +
|}
 +
 
 +
==Synonyms==
 +
SHBG has been known under a variety of different names including:<ref name="GeneCards">{{cite web | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SHBG | title = SHBG | work = GeneCards }}</ref><ref name="Westphal2012">{{cite book | chapter = Sex Steroid-Binding Protein | title = Steroid-Protein Interactions II | chapter-url = https://books.google.com/books?id=3DD6CAAAQBAJ&pg=PA198 | date = 6 December 2012 | publisher = Springer Science & Business Media | isbn = 978-3-642-82486-9 | page = 198 }}</ref><ref name="AcademicPress1994">{{cite book | editor-first = Gerald | editor-last = Litwack | first = Ulrich | last = Westphal | name-list-format = vanc | chapter = Structure, Function, and Regulation of Androgen-Binding Protein?Sex Hormone-Binding Globulin | title = Vitamins and Hormones: Steroids | chapter-url = https://books.google.com/books?id=ZBUjEoJu1MIC&pg=PA200|date=12 December 1994|publisher=Academic Press|isbn=978-0-08-086646-8 | pages = 200 }}</ref>
 +
 
 +
* Sex hormone-binding globulin (SHBG)
 +
* Sex steroid-binding globulin (SSBG, SBG)
 +
* Sex steroid-binding protein (SBP, SSBP)
 +
* Androgen-binding protein (ABP)
 +
* Estradiol-binding-protein (EBP)
 +
* Testosterone–estradiol binding globulin (TeBG, TEBG)
  
 
==References==
 
==References==
{{Reflist}}
+
{{Reflist|33em}}
{{-}}
+
 
 +
==Further reading==
 +
{{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 = October 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 = November 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 = November 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 = July 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 = August 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 = November 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 = April 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 = April 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 = July 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 = February 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 = September 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 = July 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 = March 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 = December 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}}
 +
 
 +
{{PDB Gallery|geneid=6462}}
 
{{Carrier proteins}}
 
{{Carrier proteins}}
 
{{Beta globulins}}
 
{{Beta globulins}}
 +
 
[[Category:Glycoproteins]]
 
[[Category:Glycoproteins]]
[[de:Sexualhormon-bindendes Globulin]]
 
[[pl:SHBG]]
 

Latest revision as of 08:10, 19 December 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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RefSeq (mRNA)

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RefSeq (protein)

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

Function

Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to serum albumin (~54%), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1 to 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] DHT binds to SHBG with about 5 times the affinity of testosterone and about 20 times the affinity of estradiol.[3] Dehydroepiandrosterone (DHEA) is weakly bound to SHBG, but dehydroepiandrosterone sulfate is not bound to SHBG.[2] Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.[4] Estrone sulfate and estriol are also poorly bound by SHBG.[5] Less than 1% of progesterone is bound to SHBG.[6]

SHBG levels are usually about twice as high in women than in men.[3] In women, SHBG serves to limit exposure to both androgens and estrogens.[3] Low SHBG levels in women have been associated with hyperandrogenism and endometrial cancer due to heightened exposure to androgens and estrogens, respectively.[3] During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by 5- to 10-fold.[3] The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta.[3] A case report of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.[3]

Biochemistry

Biosynthesis

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

Gene

The gene for SHBG is called Shbg located on chromosome 17[7] on the short arm between the bands 17p12→p13.[8] 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.[9] 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.[10]

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.[11]

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

Rs727428 position 7634474 is in several percent of humans.[12]

(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.[13]

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.[7]

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.[14] 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.[14]

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]

Regulation

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 levels 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[15] was downregulation of HNF4, hepatocyte nuclear factor 4.[16][17][18][19]

Blood values

Reference ranges for blood tests for SHBG have been developed:[20]

Population Range
Adult female, premenopausal 40–120 nmol/L
Adult female, postmenopausal 28–112 nmol/L
Adult male 20–60 nmol/L
Infant (1–23 months) 60–252 nmol/L
Prepubertal (2 years–8 years) 72–220 nmol/L
Pubertal female 36–125 nmol/L
Pubertal male 16–100 nmol/L

Clinical significance

High or low levels

SHBG levels are decreased by androgens, administration of anabolic steroids,[21] polycystic ovary syndrome, hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[22] 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.[23] Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[24]

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]

Type 2 diabetes

Reduced levels of SHBG and also certain polymorphisms of the SHBG gene are implicated in the development of insulin resistance and type 2 diabetes.[25] Such effects apparently involve direct action at the cellular level where it became apparent that cell membranes of certain tissues contain specific high-affinity SHBG receptors.[26]

Medications

Oral contraceptives containing ethinylestradiol can increase SHBG levels by 2- to 4-fold and decrease free testosterone concentrations by 40 to 80% in women.[27] They can be used to treat symptoms of hyperandrogenism like acne and hirsutism.[27][3] Some oral contraceptives, namely those containing high doses of ethinylestradiol (which have been discontinued and are no longer marketed), can increase SHBG levels by as much as 5- to 10-fold.[3]

Some medications, such as certain anabolic steroids like mesterolone and danazol and certain progestins like levonorgestrel and norethisterone, have high affinity for SHBG and can bind to it and displace endogenous steroids from it, thereby increasing free concentrations of these endogenous steroids.[28][29][30] It has been estimated that therapeutic levels of danazol, methyltestosterone, fluoxymesterone, levonorgestrel, and norethisterone would respectively occupy or displace from testosterone 83–97%, 48–69%, 42–64%, 16–47%, and 4–39% of SHBG binding sites, while others with low affinity for SHBG such as ethinylestradiol, cyproterone acetate, and medroxyprogesterone acetate would occupy or displace from testosterone 1% or fewer SHBG binding sites.[28][31]

Affinities of 70 medications for SHBG and CBG[28]
Compound Structure SHBG
RBA (%)
SHBG
K (106 M−1)
CBG
RBA (%)
CBG
K (106 M−1)
Aminoglutethimide Nonsteroidal <0.01 <0.2 <0.1 <0.1
Androstanolone Steroidal 220 5500 1.3 0.83
Betamethasone Steroidal <0.01 <0.2 <0.1 <0.1
Cholecalciferol Steroidal <0.01 <0.2 <0.1 <0.1
Cimetidine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Clomifene Nonsteroidal <0.01 <0.2 <0.1 <0.1
Cortisol (hydrocortisone) Steroidal 0.13 1.6 100 76
Cortisone acetate Steroidal 0.10 1.2 <0.1 <0.1
Cyproterone acetate Steroidal 0.10 1.2 <0.1 <0.1
Danazol Steroidal 18 240 10 6.5
Dexamethasone Steroidal <0.01 <0.2 <0.1 <0.1
Diazoxide Nonsteroidal <0.01 <0.2 <0.1 <0.1
Diethylstilbestrol Nonsteroidal <0.01 <0.2 <0.1 <0.1
Digitoxin Steroidal <0.01 <0.2 <0.1 <0.1
Digoxin Steroidal <0.01 <0.2 <0.1 <0.1
DL-DOPA Nonsteroidal <0.01 <0.2 <0.1 <0.1
Dopamine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Enclomiphene Nonsteroidal <0.01 <0.2 <0.1 <0.1
Epinephrine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Estradiol Steroidal 49 680 <0.1 <0.1
Estradiol benzoate Steroidal 0.70 8.6 <0.1 <0.1
Ethinylestradiol Steroidal 0.80 9.9 <0.1 <0.1
Ethisterone Steroidal 55 780 0.33 0.21
Fludrocortisone Steroidal <0.01 <0.2 0.74 0.47
Fluoxymesterone Steroidal 4.8 60 <0.1 <0.1
Flutamide Nonsteroidal <0.01 <0.2 <0.1 <0.1
Homovanillic acid Nonsteroidal <0.01 <0.2 <0.1 <0.1
Hydrocortisone hemisuccinate Steroidal <0.01 <0.2 8.7 5.6
Indometacin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Levonorgestrel Steroidal 31 420 <0.1 <0.1
Medroxyprogesterone Steroidal 0.15 1.9 13 8.1
Medroxyprogesterone acetate Steroidal 0.08 1.0 6.5 4.2
Melatonin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Mesterolone Steroidal 180 3600 <0.1 <0.1
Mestranol Steroidal <0.01 <0.2 <0.1 <0.1
Methoxytryptophol Nonsteroidal <0.01 <0.2 <0.1 <0.1
Methyldopa Nonsteroidal <0.01 <0.2 <0.1 <0.1
Methylserotonin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Methyltestosterone Steroidal 39 530 <0.1 <0.1
Metiamide Nonsteroidal <0.01 <0.2 <0.1 <0.1
Metribolone Steroidal 1.7 21 0.36 0.23
Metyrapone Nonsteroidal <0.01 <0.2 <0.1 <0.1
Mexrenone Steroidal <0.01 <0.2 <0.1 <0.1
Nafoxidine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nandrolone Steroidal 5.8 72 0.10 0.63
Norepinephrine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Norethisterone Steroidal 11 140 0.28 0.18
Noretynodrel Steroidal 1.3 16 0.16 0.10
Normetanephrine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Phenytoin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Potassium canrenoate Steroidal 0.18 2.2 0.83 0.53
Prednisolone Steroidal 0.04 0.49 59 41
Prednisone Steroidal 0.17 2.1 5.0 3.2
Progesterone Steroidal 0.71 8.8 36 24
Promegestone Steroidal 0.007 0.09 0.40 0.25
Prorenone Steroidal 8.2 100 <0.1 <0.1
Reserpine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Rifampin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Serotonin Nonsteroidal <0.01 <0.2 <0.1 <0.1
Spironolactone Steroidal 0.03 0.37 <0.1 <0.1
Tamoxifen Nonsteroidal <0.01 <0.2 <0.1 <0.1
Testolactone Steroidal <0.01 <0.2 <0.1 <0.1
Testosterone Steroidal 100 1600 8.3 5.3
Testosterone enanthate Steroidal 0.007 0.086 <0.1 <0.1
7α-Thioprogesterone Steroidal 0.06 0.74 36 24
7α-Thiospironolactone Steroidal 0.59 7.3 <0.1 <0.1
Thyroxine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Triiodothyronine Nonsteroidal <0.01 <0.2 <0.1 <0.1
Trimethyltrienolone Steroidal 0.90 11 0.11 0.07
Vanillylmandelic acid Nonsteroidal <0.01 <0.2 <0.1 <0.1
Zuclomifene Nonsteroidal <0.01 <0.2 <0.1 <0.1
The reference ligands (100%) for the RBA (%) values were testosterone for SHBG and cortisol for CBG.
Affinities of 21 progestins for SHBG and CBG[30][32]
Progestogen SHBG (%) CBG (%)
17α-Allyl-19-nortestosterone <1 ?
Allylestrenol <1 ?
Chlormadinone acetate <1 <1
Cyproterone acetate <1 <1
Desogestrel <1 <1
Dienogest <1 <1
Drospirenone <1 <1
Etonogestrel 15 <1
Gestodene 40 <1
Levonorgestrel 50 <1
Medroxyprogesterone acetate <1 <1
Megestrol acetate <1 <1
Nomegestrol acetate <1 <1
Norelgestromin <1 ?
Norethisterone 16 <1
Noretynodrel <1 <1
Norgestimate <1 <1
Progesterone <1 36
Promegestone <1 <1
Segesterone acetate <1 ?
Δ4-Tibolone 1 <1
Values are RBAs (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for CBG was cortisol.
Affinities of 14 AAS for SHBG[29]
Compound SHBG (%)
5α-Androstane-3β,17β-diol 17
5β-Androstane-3α,17β-diol 5
Dihydrotestosterone 100
Ethylestrenol <1
Fluoxymesterone <1
Mesterolone 440
Metandienone 2
Metenolone 3
Methyltestosterone 5
Metribolone <1
Nandrolone 1
Oxymetholone <1
Stanozolol 1
Testosterone 19
Values are RBAs (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 41 steroids for SHBG[33]
Compound SHBG (%)
3β-Androstanediol 100
Androstenediol 77
Bolandiol 24
Dihydroethisterone 100
Dihydroethyltestosterone 18–21
Dihydromethylandrostenediol 77
Dihydronandrolone 44
Dihydrotestosterone 100
Dihydrotrestolone 47
4,17α-Dimethyltestosterone 97
Drostanolone 39
Ethisterone 92
Fluoxymesterone 3
11-Ketodihydrotestosterone 0
Medroxyprogesterone acetate 16
Megestrol acetate 0
Mestanolone 84
Methasterone 58
Methyl-1-testosterone 69
Methylandrostenediol 40
Methyltestosterone 64
Mibolerone 6
Nandrolone 16
Nandrolone decanoate 0
Nandrolone phenylpropionate 0
Norethandrolone 3
Norethisterone 21
Normethandrone 7
Oxandrolone 0
Oxymetholone 3
Progesterone 13
Stanozolol 36
1-Testosterone 98
Testosterone 82
Testosterone benzoate 8
Testosterone cypionate 6
Testosterone enanthate 9
Δ4-Tibolone 8
Trestolone 12
Trestolone enanthate 12
Vinyltestosterone 36
Values are RBAs (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 11 steroids for SHBG and CBG[34]
Compound SHBG (%) CBG (%)
Aldosterone <0.2 6.0
Corticosterone <0.2 107
Cortisol <0.2 100
Dexamethasone <0.2 <0.1
Dihydrotestosterone 100 0.8
Estradiol 8.7 <0.1
Metribolone 0.2 <0.1
Moxestrol <0.2 <0.1
Progesterone <0.2 25
Promegestone <0.2 0.9
Testosterone 26 3
Values are RBAs (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for CBG was cortisol.
Affinities of 9 estrogens for SHBG[30][35]
Compound RBA to
SHBG (%)
Bound to
SHBG (%)
Bound to
albumin (%)
17β-Estradiol 50 37 61
Estrone 12 16 80
Estriol 0.3 1 91
Estrone sulfate 0 0 99
17β-Dihydroequilin 30 ? ?
Equilin 8 26 13
17β-Dihydroequilin sulfate 0 ? ?
Equilin sulfate 0 ? ?
Δ8-Estrone ? ? ?
The reference ligand (100%) for the SHBG RBA (%) values was testosterone.

Endogenous steroids

Measurement

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.

Affinity and binding

Affinities of endogenous steroids for SHBG and plasma protein binding[36]
Steroid SHBG affinity Plasma protein binding in men Plasma protein binding in women (follicular phase)
RBA (%) K (106 M−1) Total (nM) Unbound (%) SHBG (%) CBG (%) Albumin (%) Total (nM) Unbound (%) SHBG (%) CBG (%) Albumin (%)
Aldosterone 0.017 0.21 0.35 37.1 0.10 21.2 41.6 0.24 36.8 0.23 21.9 41.2
3α‑Androstanediol 82 1300 0.41 0.85 13.7 <0.1 85.5 0.068 0.71 27.9 <0.1 71.4
Androstenediol 97 1500 4.3 3.24 60.4 <0.1 36.3 2.4 1.73 78.8 <0.1 19.4
Androstenedione 2.3 29 4.1 7.85 2.82 1.37 88.0 5.4 7.54 6.63 1.37 84.5
Androsterone 1.1 14 2.0 4.22 0.73 0.52 94.5 1.5 4.18 1.77 0.54 93.5
Corticosterone 0.18 2.2 12 3.39 0.09 77.5 19.0 7.0 3.28 0.22 78.1 18.4
Cortisol 0.13 1.6 400 3.91 0.08 89.5 6.57 400 3.77 0.18 89.7 6.33
Cortisone 0.22 2.7 72 16.2 0.54 38.0 45.3 54 15.8 1.30 38.6 44.3
Dehydroepiandrosterone 5.3 66 24 4.13 3.38 <0.1 92.4 17 3.93 7.88 <0.1 88.1
11‑Deoxycorticosterone 1.9 24 0.20 2.69 0.80 36.4 60.1 0.12 2.62 1.91 36.9 58.6
11‑Deoxycortisol 1.3 16 1.4 3.37 0.67 77.1 18.9 0.60 3.24 1.57 77.1 18.1
Dihydrotestosterone 220 5500 1.7 0.88 59.7 0.22 39.2 0.65 0.47 78.4 0.12 21.0
Estradiol 49 680 0.084 2.32 19.6 <0.1 78.0 0.29 1.81 37.3 <0.1 60.8
Estriol 0.35 4.3 0.037 8.15 0.44 <0.2 91.3 0.10 8.10 1.06 <0.2 90.7
Estrone 12 150 0.081 3.96 7.37 <0.1 88.6 0.23 3.58 16.3 <0.1 80.1
Etiocholanolone 0.11 1.4 1.3 8.15 0.14 0.44 91.3 1.2 8.13 0.35 0.46 91.1
Pregnenolone 1.1 14 2.4 2.87 0.50 0.16 96.5 2.2 2.85 1.21 0.16 95.8
17α‑Hydroxypregnenolone 0.19 2.3 5.4 4.27 0.12 <0.1 95.5 3.5 4.26 0.30 <0.1 95.4
Progesterone 0.71 8.8 0.57 2.39 0.26 17.2 80.1 0.65 2.36 0.63 17.7 79.3
17α‑Hydroxyprogesterone 0.8 9.9 5.4 2.50 0.31 41.3 55.9 1.8 2.44 0.73 42.1 54.7
Testosterone 100 1600 23 2.23 44.3 3.56 49.9 1.3 1.36 66.0 2.26 30.4
In men, the concentrations of SHBG, CBG, and albumin were 28 nM, 0.7 μM, and 0.56 mM, respectively. In women, the concentrations of SHBG, CBG, and albumin were 37 nM, 0.7 μM, and 0.56 mM, respectively.

Synonyms

SHBG has been known under a variety of different names including:[37][38][39]

  • Sex hormone-binding globulin (SHBG)
  • Sex steroid-binding globulin (SSBG, SBG)
  • Sex steroid-binding protein (SBP, SSBP)
  • Androgen-binding protein (ABP)
  • Estradiol-binding-protein (EBP)
  • Testosterone–estradiol binding globulin (TeBG, TEBG)

References

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Further reading


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