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SHBG (sex hormone-binding globulin)

Written2010-11Nicoletta Fortunati, Maria Graziella Catalano
Lab Endocrinologia Oncologica, Dip Oncologia, AOU San Giovanni Battista & Dip Fisiopatologia Clinica, Universita di Torino, Via Genova 3, 10126 Torino, Italy

(Note : for Links provided by Atlas : click)


HGNC Alias symbABP
HGNC Alias nameandrogen binding protein
HGNC Previous namesex hormone-binding globulin
LocusID (NCBI) 6462
Atlas_Id 42286
Location 17p13.1  [Link to chromosome band 17p13]
Location_base_pair Starts at 7630135 and ends at 7633372 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SHBG.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DLG4 (17p13.1) / SHBG (17p13.1)
Note This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver; lately, it was recognized to be produced also by testis germ cells; the protein is now thought to participate in the regulation of steroid responses at cell level. The encoded protein in biological fluids is a dimer formed from identical or nearly identical monomers; in each monomer one steroid binding pocket has been recognized. SHBG binds androgen and estradiol with different affinity. Alternate promoters and several spliced transcripts were reported.


  Schematic representation of SHBG gene. Exons are represented by the blue boxes.
Description The human SHBG gene is located on the short arm of chromosome 17 (17pter-p12) and consists of eight exons.
Transcription Two major SHBG transcripts are known, each originating from a different promoter. The variant 1, which has also been referred to as SHBG-L, encodes the longest protein (isoform 1), while the variant 2 uses an alternate in-frame splice site in the 3' coding region compared to variant 1. These two transcripts differ in their 5' sequence and in the absence of exon 7 in the latter one.


Note 402 amino acids; 43779 Da each subunit: homodimer.
  Linear structure of SHBG protein. Location of glycosylation sites is shown by red lines.
Description SHBG is a homodimer; each monomer is constituted of 402 aa, molecular weight 43,7 kDa. The protein consists of a signal peptide (1-29 aa) and 2 laminin G-like domains (domain 1: 45-217 aa; domain 2: 224-390 aa). Each SHBG monomer has an O-linked oligosaccharide at Thr(36) and up to two N-linked oligosaccharides at Asn(380) and Asn(396).
Localisation SHBG is secreted by liver into the blood stream and it is synthesized by testis germ cells; it also recognizes a specific binding site located on membranes of sex steroid target cells (e.g. breast, prostate).
Function SHBG binds and carries sex steroids, regulating their biological active fraction; it also regulates sex steroid effects in target cells by direct action.
Homology Protein S, Gas6, laminin, agrin.


Note CCG-CTG; Pro-Leu156; reported in hyperandrogenism.
GAC-AAC; Asp-Asn327; reported in estrogen-dependent breast cancer.
(TAAAA)n promoter, n=6-11; n>8; reported in: polycystic ovary syndrome; CAD in postmenopausal women; reduced bone mineral density in men; metabolic syndrome.

Implicated in

Entity Breast cancer
Note Human serum sex hormone-binding globulin (SHBG) regulates the bioavailable fraction of circulating estradiol that is known to be a critical factor in breast cancer. In a case-controlled study within the European Prospective Investigation into Cancer and Nutrition (EPIC), SHBG levels in postmenopausal women who developed breast cancer were confirmed to be significantly lower compared with controls, while no significant difference was observed in premenopausal women.
SHBG has a direct effect in breast cancer cells; it interacts with membranes of these cells, initiates subsequently a specific intracellular pathway leading to cross-talk with the estradiol-activated pathway, finally inhibiting several effects of estradiol in breast cancer cells, e.g. cell proliferation.
The Asp327Asn polymorphism of SHBG gene is related to breast cancer risk. Cui et al. observed a significant association of the Asp327Asn polymorphism with reduced breast cancer risk and Becchis et al. reported a significantly higher frequency of the polymorphism in postmenopausal patients with ER-positive breast cancer than in ER-negative; more recently Costantino and co-workers suggested a protective role of this polymorphism since mutated SHBG is more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis, and this is due to the fact that D327N SHBG binds to MCF-7 cells to a greater extent than does wild type protein.
Entity Prostate cancer
Note Patients with prostate cancer showed lower SHBG levels than benign prostate hypertrophy patients and controls.
Alternative splicing of SHBG gene is more pronounced in LNCaP and MCF-7 cancer cell lines; at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7 were described.
SHBG might be a significant multivariate predictor of lymph node invasion in patients with prostate cancer. The use of preoperative serum SHBG could help to identify patients at risk of lymph node invasion.
Entity Type 2 diabetes mellitus
Note Epidemiological studies consistently show that circulating SHBG levels are lower in type 2 diabetes patients than in non-diabetic individuals.
Low circulating levels of SHBG are a strong predictor of the risk of type 2 diabetes in women and men.
Carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 and carriers of a rs6257 variant were associated with a risk of type 2 diabetes following their associated sex hormone-binding globulin levels.
Entity Insulin resistance and polycystic ovary syndrome (PCOS)
Note SHBG concentrations are inversely associated with insulin resistance, and in turn, with the risk of type 2 diabetes.
Women with polycystic ovary syndrome (PCOS) present low SHBG levels that are negatively correlated with body mass index and waist to hip ratio, and are, furthermore, associated with insulin resistance.


Note An X;17 translocation breakpoint was characterized in a 5-year-old female with hypomelanosis of Ito (HI) who exhibits characteristic hypopigmented lesions, psychomotor retardation, and choroid plexus papilloma. A chromosome-17-specific DNA fragment was isolated and used to identify cosmid clones crossing the translocation from chromosome 17p13. Exon trapping identified two known genes from chromosome 17: FMR1L2 (the fragile X mental retardation syndrome like protein 2) and SHBG (human sex hormone-binding globulin). Mapping the FMR1L2 and SHBG genes showed that neither gene was disrupted by the translocation.


The importance of the (TAAAA)n alleles at the SHBG gene promoter for the severity of coronary artery disease in postmenopausal women.
Alevizaki M, Saltiki K, Xita N, Cimponeriu A, Stamatelopoulos K, Mantzou E, Doukas C, Georgiou I.
Menopause. 2008 May-Jun;15(3):461-8.
PMID 18188141
Structural analyses of sex hormone-binding globulin reveal novel ligands and function.
Avvakumov GV, Cherkasov A, Muller YA, Hammond GL.
Mol Cell Endocrinol. 2010 Mar 5;316(1):13-23. Epub 2009 Sep 11. (REVIEW)
PMID 19748550
The additionally glycosylated variant of human sex hormone-binding globulin (SHBG) is linked to estrogen-dependence of breast cancer.
Becchis M, Frairia R, Ferrera P, Fazzari A, Ondei S, Alfarano A, Coluccia C, Biglia N, Sismondi P, Fortunati N.
Breast Cancer Res Treat. 1999 Mar;54(2):101-7.
PMID 10424400
Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells.
Catalano MG, Frairia R, Boccuzzi G, Fortunati N.
Mol Cell Endocrinol. 2005 Jan 31;230(1-2):31-7.
PMID 15664449
Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure.
Costantino L, Catalano MG, Frairia R, Carmazzi CM, Barbero M, Coluccia C, Donadio M, Genta F, Drogo M, Boccuzzi G, Fortunati N.
Breast Cancer Res Treat. 2009 Apr;114(3):449-56. Epub 2008 Apr 25.
PMID 18437557
Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene.
Cui Y, Shu XO, Cai Q, Jin F, Cheng JR, Cai H, Gao YT, Zheng W.
Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1096-101.
PMID 15894658
Sex hormone-binding globulin and risk of type 2 diabetes in women and men.
Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S.
N Engl J Med. 2009 Sep 17;361(12):1152-63. Epub 2009 Aug 5.
PMID 19657112
SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
Eriksson AL, Lorentzon M, Mellstrom D, Vandenput L, Swanson C, Andersson N, Hammond GL, Jakobsson J, Rane A, Orwoll ES, Ljunggren O, Johnell O, Labrie F, Windahl SH, Ohlsson C.
J Clin Endocrinol Metab. 2006 Dec;91(12):5029-37. Epub 2006 Aug 22.
PMID 16926255
Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer.
Fortunati N, Catalano MG, Boccuzzi G, Frairia R.
Mol Cell Endocrinol. 2010 Mar 5;316(1):86-92. Epub 2009 Sep 19. (REVIEW)
PMID 19770023
Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain.
Grishkovskaya I, Avvakumov GV, Sklenar G, Dales D, Hammond GL, Muller YA.
EMBO J. 2000 Feb 15;19(4):504-12.
PMID 10675319
Lipoproteins, sex hormones and inflammatory markers in association with prostate cancer.
Grosman H, Fabre B, Mesch V, Lopez MA, Schreier L, Mazza O, Berg G.
Aging Male. 2010 Jun;13(2):87-92.
PMID 19921964
Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.
Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL.
J Clin Invest. 2002 Apr;109(7):973-81.
PMID 11927624
Sequence and functional relationships between androgen-binding protein/sex hormone-binding globulin and its homologs protein S, Gas6, laminin, and agrin.
Joseph DR.
Steroids. 1997 Aug-Sep;62(8-9):578-88. (REVIEW)
PMID 9292933
Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).
Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, Bingham S, Boeing H, Bueno de Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A, van Gils CH, Gonzalez CA, Gurrea AB, Critselis E, Khaw KT, Krogh V, Lahmann PH, Nagel G, Olsen A, Onland-Moret NC, Overvad K, Palli D, Panico S, Peeters P, Quiros JR, Roddam A, Thiebaut A, Tjonneland A, Chirlaque MD, Trichopoulou A, Trichopoulos D, Tumino R, Vineis P, Norat T, Ferrari P, Slimani N, Riboli E.
J Natl Cancer Inst. 2005 May 18;97(10):755-65.
PMID 15900045
Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition.
Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, Dossus L, Lukanova A, Bingham S, Khaw KT, Allen NE, Bueno-de-Mesquita HB, van Gils CH, Grobbee D, Boeing H, Lahmann PH, Nagel G, Chang-Claude J, Clavel-Chapelon F, Fournier A, Thiebaut A, Gonzalez CA, Quiros JR, Tormo MJ, Ardanaz E, Amiano P, Krogh V, Palli D, Panico S, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Ferrari P, Norat T, Saracci R, Riboli E.
Endocr Relat Cancer. 2005 Dec;12(4):1071-82.
PMID 16322344
Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing.
Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM.
BMC Mol Biol. 2009 May 5;10:37.
PMID 19416531
Binding of an extracellular steroid-binding globulin to membranes and soluble receptors from human breast cancer cells (MCF-7 cells).
Porto CS, Musto NA, Bardin CW, Gunsalus GL.
Endocrinology. 1992 May;130(5):2931-6.
PMID 1315262
Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome.
Pugeat M, Nader N, Hogeveen K, Raverot G, Dechaud H, Grenot C.
Mol Cell Endocrinol. 2010 Mar 5;316(1):53-9. Epub 2009 Sep 26. (REVIEW)
PMID 19786070
Interactions of sex hormone-binding globulin with target cells.
Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA.
Mol Cell Endocrinol. 2010 Mar 5;316(1):79-85. Epub 2009 Aug 19. (REVIEW)
PMID 19698759
Sex hormone-binding globulin: a novel marker for nodal metastases prediction in prostate cancer patients undergoing extended pelvic lymph node dissection.
Salonia A, Briganti A, Gallina A, Karakiewicz P, Shariat S, Freschi M, Zanni G, Capitanio U, Bosi E, Rigatti P, Montorsi F.
Urology. 2009 Apr;73(4):850-5. Epub 2008 Nov 26.
PMID 19038425
A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis.
Selva DM, Hogeveen KN, Seguchi K, Tekpetey F, Hammond GL.
J Biol Chem. 2002 Nov 22;277(47):45291-8. Epub 2002 Sep 13.
PMID 12235141
The serum transport of steroid hormones.
Siiteri PK, Murai JT, Hammond GL, Nisker JA, Raymoure WJ, Kuhn RW.
Recent Prog Horm Res. 1982;38:457-510. (REVIEW)
PMID 6750727
Steroid-protein interactions II.
Westphal U.
Monogr Endocrinol. 1986;27:1-603.
PMID 2421156
The (TAAAA)n Polymorphism of the SHBG Gene in Men with the Metabolic Syndrome.
Xita N, Milionis HJ, Galidi A, Lazaros L, Katsoulis K, Elisaf MS, Georgiou I, Tsatsoulis A.
Exp Clin Endocrinol Diabetes. 2010 Aug 5. [Epub ahead of print]
PMID 20690069
Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels.
Xita N, Tsatsoulis A, Chatzikyriakidou A, Georgiou I.
J Clin Endocrinol Metab. 2003 Dec;88(12):5976-80.
PMID 14671199
Characterisation of X;17(q12;p13) translocation breakpoints in a female patient with hypomelanosis of Ito and choroid plexus papilloma.
Zajac V, Kirchhoff T, Levy ER, Horsley SW, Miller A, Steichen-Gersdorf E, Monaco AP.
Eur J Hum Genet. 1997 Mar-Apr;5(2):61-8.
PMID 9195154


This paper should be referenced as such :
Fortunati, N ; Catalano, MG
SHBG (sex hormone-binding globulin)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(7):582-585.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)SHBG   10839
Entrez_Gene (NCBI)SHBG    sex hormone binding globulin
GeneCards (Weizmann)SHBG
Ensembl hg19 (Hinxton)ENSG00000129214 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000129214 [Gene_View]  ENSG00000129214 [Sequence]  chr17:7630135-7633372 [Contig_View]  SHBG [Vega]
ICGC DataPortalENSG00000129214
Genatlas (Paris)SHBG
SOURCE (Princeton)SHBG
Genetics Home Reference (NIH)SHBG
Genomic and cartography
GoldenPath hg38 (UCSC)SHBG  -     chr17:7630135-7633372 +  17p13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SHBG  -     17p13.1   [Description]    (hg19-Feb_2009)
GoldenPathSHBG - 17p13.1 [CytoView hg19]  SHBG - 17p13.1 [CytoView hg38]
genome Data Viewer NCBISHBG [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK302603 BC069597 BC101785 BC112186 CD013955
RefSeq transcript (Entrez)NM_001040 NM_001146279 NM_001146280 NM_001146281 NM_001289113 NM_001289114 NM_001289115 NM_001289116
Consensus coding sequences : CCDS (NCBI)SHBG
Alternative Splicing GalleryENSG00000129214
Gene ExpressionSHBG [ NCBI-GEO ]   SHBG [ EBI - ARRAY_EXPRESS ]   SHBG [ SEEK ]   SHBG [ MEM ]
Gene Expression Viewer (FireBrowse)SHBG [ Firebrowse - Broad ]
GenevisibleExpression of SHBG in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6462
GTEX Portal (Tissue expression)SHBG
Human Protein AtlasENSG00000129214-SHBG [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04278   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP04278  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP04278
Domaine pattern : Prosite (Expaxy)LAM_G_DOMAIN (PS50025)   
Domains : Interpro (EBI)ConA-like_dom_sf    Laminin_G   
Domain families : Pfam (Sanger)Laminin_G_1 (PF00054)   
Domain families : Pfam (NCBI)pfam00054   
Domain families : Smart (EMBL)LamG (SM00282)  
Conserved Domain (NCBI)SHBG
PDB (RSDB)1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
PDB Europe1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
PDB (PDBSum)1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
PDB (IMB)1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
Structural Biology KnowledgeBase1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
SCOP (Structural Classification of Proteins)1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
CATH (Classification of proteins structures)1D2S    1F5F    1KDK    1KDM    1LHN    1LHO    1LHU    1LHV    1LHW    6PYA    6PYB    6PYF    6ULB   
AlphaFold pdb e-kbP04278   
Human Protein Atlas [tissue]ENSG00000129214-SHBG [tissue]
Protein Interaction databases
IntAct (EBI)P04278
Ontologies - Pathways
Ontology : AmiGOsteroid binding  androgen binding  protein binding  extracellular region  extracellular exosome  
Ontology : EGO-EBIsteroid binding  androgen binding  protein binding  extracellular region  extracellular exosome  
NDEx NetworkSHBG
Atlas of Cancer Signalling NetworkSHBG
Wikipedia pathwaysSHBG
Orthology - Evolution
GeneTree (enSembl)ENSG00000129214
Phylogenetic Trees/Animal Genes : TreeFamSHBG
Homologs : HomoloGeneSHBG
Homology/Alignments : Family Browser (UCSC)SHBG
Gene fusions - Rearrangements
Fusion : MitelmanDLG4/SHBG [17p13.1/17p13.1]  
Fusion : QuiverSHBG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSHBG [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SHBG
Exome Variant ServerSHBG
GNOMAD BrowserENSG00000129214
Varsome BrowserSHBG
Genomic Variants (DGV)SHBG [DGVbeta]
DECIPHERSHBG [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSHBG 
ICGC Data PortalSHBG 
TCGA Data PortalSHBG 
Broad Tumor PortalSHBG
OASIS PortalSHBG [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSHBG  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSHBG
Mutations and Diseases : HGMDSHBG
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutasearch SHBG
DgiDB (Drug Gene Interaction Database)SHBG
DoCM (Curated mutations)SHBG (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SHBG (select a term)
NCG6 (London) select SHBG
Cancer3DSHBG(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SHBG
NextProtP04278 [Medical]
Target ValidationSHBG
Huge Navigator SHBG [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDSHBG
Pharm GKB GenePA35745
Clinical trialSHBG
DataMed IndexSHBG
PubMed309 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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