Sex hormone-binding globulin explained

Androgen-binding protein, Sex hormone-binding globulin
Hgncid:10839
Symbol:SHBG
Altsymbols:ABP
Entrezgene:6462
Omim:182205
Refseq:NM_001040
Uniprot:P04278
Chromosome:17
Arm:p
Band:13
Locussupplementarydata:-p12

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding protein (ABP).[1]

Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds.[2]

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, the local bioavailability of sex hormones is influenced by the level of SHBG. Because SHBG binds to testosterone (T) and dihydrotestosterone (DHT), these hormones are made less lipophilic and become concentrated within the luminal fluid of the seminiferous tubules. The higher levels of these hormones enable spermatogenesis in the seminiferous tubules and sperm maturation in the epididymis. SHBG’s production is regulated under the influence of FSH[3] on Sertoli cells, enhanced by insulin, retinol, and testosterone.

The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone > androstenediol > estradiol > estrone.[4] DHT binds to SHBG with about 5 times the affinity of testosterone and about 20 times the affinity of estradiol. Dehydroepiandrosterone (DHEA) is weakly bound to SHBG, but dehydroepiandrosterone sulfate is not bound to SHBG. Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.[5] Estrone sulfate and estriol are also poorly bound by SHBG.[6] Less than 1% of progesterone is bound to SHBG.[7]

SHBG levels are usually about twice as high in women as in men. In women, SHBG serves to limit exposure to both androgens and estrogens. Low SHBG levels in women have been associated with hyperandrogenism and endometrial cancer due to heightened exposure to androgens and estrogens, respectively. During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by five-fold to ten-fold. The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta. A case report of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.[8]

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. Testes-produced SHBG is called androgen-binding protein.

Gene

The gene for SHBG is called Shbg located on chromosome 17 on the short arm between the bands 17p12→p13.[9] Overlapping on the complementary 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 complementary strand.[10] 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.[11]

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.[12]

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

Rs727428 position 7634474 is in several percent of humans.[13]

(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.[14]

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.

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.[15]

SHBG has 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.[2] 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.[2] The steroid binding LG domain is coded by exons 2 to 5.[2] A linker region joins the two LG domains together.[2]

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

The sugars are attached at two different N-glycosylation points on asparagine (351 and 367) and one O-glycosylation (7) point on threonine.[16]

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.[2]

Regulation

SHBG has both enhancing and inhibiting hormonal influences thus can be viewed as a hepatokine. 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[17] was downregulation of HNF4, hepatocyte nuclear factor 4.[18] [19] [20] [21]

Blood values

Reference ranges for blood tests for SHBG have been developed:[22] [23]

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,[24] polycystic ovary syndrome, hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[25] SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction increases SHBG in rodents and men, while lowering free and total testosterone and estradiol and having no effect on DHEA-S, which lacks affinity for SHBG.[26] Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[27]

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.[2] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In pregnant women in the third trimester of pregnancy the SHBG level escalates to five to ten times the usual level for a woman.[2] A hypothesis is that this protects against the effect of hormone produced by the fetus.[2]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[2] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[2]

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.[28] 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.[29]

Coagulation

SHBG is a useful correlate and indirect marker of estrogen-induced procoagulation and by extension thrombosis, for instance with birth control pills.[30] [31] [32]

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.[33] They can be used to treat symptoms of hyperandrogenism like acne and hirsutism. 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.[34]

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.[35] [36] [37] 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.[38]

Selective androgen receptor modulators (SARMs) also reduce SHBG.[39]

Affinities of 70 medications for SHBG and CBG[40]
Compound Structure data-sort-type="number" SHBG
(%) 		data-sort-type="number" SHBG
K (106 M−1) 		data-sort-type="number" CBG
(%) 		data-sort-type="number" CBG
K (106 M−1)
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 220 5500 1.3 0.83
Steroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 0.13 1.6 100 76
Steroidal 0.10 1.2 <0.1 <0.1
Steroidal 0.10 1.2 <0.1 <0.1
Steroidal 18 240 10 6.5
Steroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 49 680 <0.1 <0.1
Steroidal 0.70 8.6 <0.1 <0.1
Steroidal 0.80 9.9 <0.1 <0.1
Steroidal 55 780 0.33 0.21
Steroidal <0.01 <0.2 0.74 0.47
Steroidal 4.8 60 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 8.7 5.6
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 31 420 <0.1 <0.1
Steroidal 0.15 1.9 13 8.1
Steroidal 0.08 1.0 6.5 4.2
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 180 3600 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 39 530 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 1.7 21 0.36 0.23
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 5.8 72 0.10 0.63
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 11 140 0.28 0.18
Steroidal 1.3 16 0.16 0.10
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 0.18 2.2 0.83 0.53
Steroidal 0.04 0.49 59 41
Steroidal 0.17 2.1 5.0 3.2
Steroidal 0.71 8.8 36 24
Steroidal 0.007 0.09 0.40 0.25
Steroidal 8.2 100 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 0.03 0.37 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal <0.01 <0.2 <0.1 <0.1
Steroidal 100 1600 8.3 5.3
Steroidal 0.007 0.086 <0.1 <0.1
data-sort-value="Thioprogesterone, 7α-" Steroidal 0.06 0.74 36 24
data-sort-value="Thiospironolactone, 7α-" Steroidal 0.59 7.3 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Steroidal 0.90 11 0.11 0.07
Nonsteroidal <0.01 <0.2 <0.1 <0.1
Nonsteroidal <0.01 <0.2 <0.1 <0.1
The reference ligands (100%) for the (%) values were testosterone for SHBG and cortisol for .
Affinities of 21 progestins for SHBG and CBG[41]
Progestogen data-sort-type="number" SHBG (%) data-sort-type="number" CBG (%)
<1 ?
<1 ?
<1 <1
<1 <1
<1 <1
<1 <1
<1 <1
15 <1
40 <1
50 <1
<1 <1
<1 <1
<1 <1
<1 ?
16 <1
<1 <1
<1 <1
<1 36
<1 <1
<1 ?
1 <1
Values are (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for was cortisol.
Affinities of 14 for SHBG[42]
Compound data-sort-type="number" SHBG (%)
17
5
100
<1
<1
440
2
3
5
<1
1
<1
1
19
Values are (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 41 steroids for SHBG[43]
Compound data-sort-type="number" SHBG (%)
100
77
24
100
Dihydroethyltestosterone18–21
Dihydromethylandrostenediol77
44
100
Dihydrotrestolone47
4,17α-Dimethyltestosterone97
39
92
3
0
16
0
84
58
69
40
64
6
16
0
0
3
21
7
0
3
13
36
98
82
8
6
9
8
12
12
36
Values are (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 11 steroids for SHBG and CBG[44]
Compound (%) (%)
<0.2 6.0
<0.2 107
<0.2 100
<0.2 <0.1
100 0.8
8.7 <0.1
0.2 <0.1
<0.2 <0.1
<0.2 25
<0.2 0.9
26 3
Values are (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for was cortisol.
Affinities of 9 estrogens for SHBG[45]
Compound data-sort-type="number" to
(%) !		data-sort-type="number" Bound to
(%) !		data-sort-type="number" Bound to
albumin (%)
50 37 61
12 16 80
0.3 1 91
0 0 99
30 ? ?
8 26 13
0 ? ?
0 ? ?
? ? ?
The reference ligand (100%) for the SHBG (%) 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. Sex hormone-binding globulin can be measured separately from the total fraction of testosterone.

A free androgen index expresses the ratio of testosterone to SHBG and can be used to summarize the activity of free testosterone.

Affinity and binding

Steroid SHBG affinity Plasma protein binding in men Plasma protein binding in women (follicular phase)
(%) K (106 M−1) Total (nM) Unbound (%) SHBG (%) CBG (%) Albumin (%) Total (nM) Unbound (%) SHBG (%) CBG (%) Albumin (%)
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-" 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
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
2.3 29 4.1 7.85 2.82 1.37 88.0 5.4 7.54 6.63 1.37 84.5
1.1 14 2.0 4.22 0.73 0.52 94.5 1.5 4.18 1.77 0.54 93.5
0.18 2.2 12 3.39 0.09 77.5 19.0 7.0 3.28 0.22 78.1 18.4
0.13 1.6 400 3.91 0.08 89.5 6.57 400 3.77 0.18 89.7 6.33
0.22 2.7 72 16.2 0.54 38.0 45.3 54 15.8 1.30 38.6 44.3
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-" 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-" 1.3 16 1.4 3.37 0.67 77.1 18.9 0.60 3.24 1.57 77.1 18.1
220 5500 1.7 0.88 59.7 0.22 39.2 0.65 0.47 78.4 0.12 21.0
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
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
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
0.11 1.4 1.3 8.15 0.14 0.44 91.3 1.2 8.13 0.35 0.46 91.1
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" 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
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" 0.8 9.9 5.4 2.50 0.31 41.3 55.9 1.8 2.44 0.73 42.1 54.7
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:[46] [47] [48]

Further reading

Notes and References

  1. Bardin CW, Musto N, Gunsalus G, Kotite N, Cheng SL, Larrea F, Becker R . Extracellular androgen binding proteins . Annual Review of Physiology . 43 . 189–98 . 1981 . 7011179 . 10.1146/annurev.ph.43.030181.001201 .
  2. Hammond GL . Diverse roles for sex hormone-binding globulin in reproduction . Biology of Reproduction . 85 . 3 . 431–41 . September 2011 . 21613632 . 4480437 . 10.1095/biolreprod.111.092593 .
  3. Hansson V, Weddington SC, French FS, McLean W, Smith A, Nayfeh SN, Ritzén EM, Hagenäs L . Secretion and role of androgen-binding proteins in the testis and epididymis . Journal of Reproduction and Fertility. Supplement . 24 suppl . 17–33 . September 1976 . 1069850 .
  4. Somboonporn W, Davis SR . Testosterone effects on the breast: implications for testosterone therapy for women . Endocrine Reviews . 25 . 3 . 374–88 . June 2004 . 15180949 . 10.1210/er.2003-0016 . free .
  5. Book: Becker K, Bilezikian JP, Bremner WJ, Hung W, Kahn CR . Principles and Practice of Endocrinology and Metabolism . 4 August 2012 . 24 April 2001 . Lippincott Williams & Wilkins . 978-0-7817-1750-2.
  6. Book: Quirk Jr G, Wendel Jr GD. Biologic Effects of Natural and Synthetic Estrogens . Buchsbaum HJ . The Menopause. https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA62. 6 December 2012. Springer Science & Business Media. 978-1-4612-5525-3. 62–.
  7. Book: Fritz MA, Speroff L . Clinical Gynecologic Endocrinology and Infertility. 28 March 2012. Lippincott Williams & Wilkins. 978-1-4511-4847-3. 44–.
  8. Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL . Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction . J. Clin. Invest. . 109 . 7 . 973–81 . April 2002 . 11927624 . 150924 . 10.1172/JCI14060 .
    • Bérubé D, Séralini GE, Gagné R, Hammond GL . Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12----p13) . Cytogenetics and Cell Genetics . 54 . 1–2 . 65–7 . 1991 . 2249477 . 10.1159/000132958 .
  10. Joseph DR . The rat androgen-binding protein (ABP/SHBG) gene contains triplet repeats similar to unstable triplets: evidence that the ABP/SHBG and the fragile X-related 2 genes overlap . Steroids . 63 . 1 . 2–4 . January 1998 . 9437788 . 10.1016/S0039-128X(97)00087-1 . 12825993 .
  11. Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM . Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing . BMC Molecular Biology . 10 . 1 . 37 . May 2009 . 19416531 . 2694190 . 10.1186/1471-2199-10-37 . free .
  12. Piotrowski P, Gasik R, Lianeri M, Cieślak D, Wudarski M, Hrycaj P, Łacki JK, Jagodziński PP . Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence . Molecular Biology Reports . 37 . 1 . 235–9 . January 2010 . 19649728 . 10.1007/s11033-009-9639-7 . 38541900 .
  13. Svartberg J, Schirmer H, Wilsgaard T, Mathiesen EB, Njølstad I, Løchen ML, Jorde R . Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study . Andrology . 2 . 2 . 212–8 . March 2014 . 24327369 . 10.1111/j.2047-2927.2013.00174.x . 206007163 . free .
  14. 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 . Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women . Cancer Epidemiology, Biomarkers & Prevention . 17 . 12 . 3490–8 . December 2008 . 19064566 . 2660245 . 10.1158/1055-9965.EPI-08-0734 .
  15. Hammond GL, Bocchinfuso WP . Sex hormone-binding globulin: gene organization and structure/function analyses . Hormone Research . 45 . 3–5 . 197–201 . 1996 . 8964583 . 10.1159/000184787 .
  16. Hammond GL, Underhill DA, Smith CL, Goping IS, Harley MJ, Musto NA, Cheng CY, Bardin CW . The cDNA-deduced primary structure of human sex hormone-binding globulin and location of its steroid-binding domain . FEBS Letters . 215 . 1 . 100–4 . May 1987 . 3569533 . 10.1016/0014-5793(87)80121-7 . 1987FEBSL.215..100H . 23058156 .
  17. Selva DM, Hammond GL . Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha . Journal of Molecular Endocrinology . 43 . 1 . 19–27 . July 2009 . 19336534 . 10.1677/JME-09-0025 . free .
  18. Selva DM, Hogeveen KN, Innis SM, Hammond GL . Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene . The Journal of Clinical Investigation . 117 . 12 . 3979–87 . December 2007 . 17992261 . 2066187 . 10.1172/JCI32249.
  19. Simó R, Barbosa-Desongles A, Hernandez C, Selva DM . IL1β down-regulation of sex hormone-binding globulin production by decreasing HNF-4α via MEK-1/2 and JNK MAPK pathways . Molecular Endocrinology . 26 . 11 . 1917–27 . November 2012 . 22902540 . 5416961 . 10.1210/me.2012-1152 .
  20. Simó R, Barbosa-Desongles A, Lecube A, Hernandez C, Selva DM . Potential role of tumor necrosis factor-α in downregulating sex hormone-binding globulin . Diabetes . 61 . 2 . 372–82 . February 2012 . 22210320 . 3266423 . 10.2337/db11-0727 .
  21. Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S . Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study . Cardiovascular Diabetology . 11 . 130 . October 2012 . 23066943 . 3537568 . 10.1186/1475-2840-11-130 . free .
  22. http://www.mayomedicallaboratories.com/test-catalog/print.php?unit_code=91215 Unit Code 91215
  23. https://androgenhacker.com/lower-shbg#shbg-levels-by-age-chart
  24. Ruokonen A, Alén M, Bolton N, Vihko R . Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man . Journal of Steroid Biochemistry . 23 . 1 . 33–8 . July 1985 . 3160892 . 10.1016/0022-4731(85)90257-2 .
  25. Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S . Sex hormone-binding globulin and risk of type 2 diabetes in women and men . The New England Journal of Medicine . 361 . 12 . 1152–63 . September 2009 . 19657112 . 2774225 . 10.1056/NEJMoa0804381 .
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