Sex hormone-binding globulin

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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][2]

Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds.[3]

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[2] 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.[5] Dehydroepiandrosterone (DHEA) is weakly bound to SHBG, but dehydroepiandrosterone sulfate is not bound to SHBG.[4] Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.[6] Estrone sulfate and estriol are also poorly bound by SHBG.[7] Less than 1% of progesterone is bound to SHBG.[8]

SHBG levels are usually about twice as high in women as in men.[5] In women, SHBG serves to limit exposure to both androgens and estrogens.[5] Low SHBG levels in women have been associated with hyperandrogenism and endometrial cancer due to heightened exposure to androgens and estrogens, respectively.[5] During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by five-fold to ten-fold.[5] The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta.[5] A case report of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.[5][9]

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

Gene

The gene for SHBG is called Shbg, located on chromosome 17[10] on the short arm between the bands 17p12→p13.[11] 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.[12] 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.[13]

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-glycosylation site, and so an extra sugar can be attached. This results in a longer circulation half-life for the protein, and raised levels. Health effects include a lowered risk of endometrial cancer and an increased risk of systemic lupus erythematosus.[14]

Rs6258 also called Ser156Pro is at position 7631360 on chromosome 17.

Rs727428 position 7634474 is in several percent of humans.[15]

(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.[16]

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 stimulates production. Competing with HNF4A at a third site on the promoter is PPARG-2 which reduces copying the gene to RNA. If the HNF4A level is low, then COUP-TF binds to the first site and turns off production of SHBG.[3]

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 produced in testes, but with different oligosaccharides attached.[10]

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.[3] 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.[3] The steroid binding LG domain is coded by exons 2 to 5.[3] A linker region joins the two LG domains together.[3]

When first produced, the SHBG precursor has a leading signal peptide attached with 29 amino acids. The remaining peptide has 373 amino acids.[17] There are two sulfur bridges.

The sugars are attached at two different N-glycosylation points on asparagine (351 and 367) and one O-glycosylation point (7) on threonine.[17]

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.[3]

Regulation

SHBG has both enhancing and inhibiting hormonal influences and 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 interleukins reduce SHBG, whereas insulin does not. For 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,[18] was downregulation of hepatocyte nuclear factor 4 (HNF4).[19][20][21][22]

Blood values

Reference ranges for blood tests for SHBG have been developed:[23][24]

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 (2–8 years) 72–220 nmol/L
Pubertal female 36–125 nmol/L
Pubertal male 16–100 nmol/L

Clinical significance

High or low levels

File:Estrogen, progesterone, testosterone, and SHBG levels during pregnancy in women.png
Levels of sex hormones and SHBG during pregnancy in women.[25]
File:Sex hormone-binding globulin (SHBG) and estradiol levels during pregnancy in women.png
Levels of SHBG and estradiol during pregnancy in women.[26] For SHBG the lines are the mean and 95th percentile levels while the points are individual measurements.[26] For estradiol the line is the mean level.[26] The dashed parts of the lines are extrapolated.[26]
File:Sex hormone-binding globulin binding capacity during pregnancy in women.png
SHBG binding capacity during pregnancy in women.[27]

SHBG levels are decreased by androgens, administration of anabolic steroids,[28] polycystic ovary syndrome (PCOS), hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of type 2 diabetes.[29] 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.[30] PCOS is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[31]

In utero, 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.[3] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls.Template:Clarify In the third trimester of pregnancy, the SHBG level of the parent escalates to five to ten times the usual level for a woman.[3][5] A hypothesis is that this protects against the effect of hormone produced by the fetus.[3]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[3] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[3]

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.[32] 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.[33]

Coagulation

SHBG is a useful correlate and indirect marker of estrogen-induced procoagulation and by extension thrombosis, for instance with birth control pills.[34][35][36]

Medications

Oral contraceptives containing ethinylestradiol can increase SHBG levels 2- to 4-fold and decrease free testosterone concentrations by 40 to 80% in women.[37] They can be used to treat symptoms of hyperandrogenism like acne and hirsutism.[37][5] Some oral contraceptives, namely those containing high doses of ethinylestradiol (which have been discontinued and are no longer marketed), can increase SHBG levels as much as 5- to 10-fold.[5]

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.[38][39][40] 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][41]

Selective androgen receptor modulators (SARMs) also reduce SHBG.[42]

Affinities of 70 medications for SHBG and CBG[38]
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
DLScript error: No such module "Check for unknown parameters".-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 Template:Abbrlink (%) values were testosterone for SHBG and cortisol for Template:Abbrlink.
Affinities of 21 progestins for SHBG and CBG[40][43]
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 Template:Abbrlink (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for Template:Abbrlink was cortisol.
Affinities of 14 AAS for SHBG[39]
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 Template:Abbrlink (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 41 steroids for SHBG[44]
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 Template:Abbrlink (%). The reference ligand (100%) for SHBG was dihydrotestosterone.
Affinities of 11 steroids for SHBG and CBG[45]
Compound Template:Abbrlink (%) Template:Abbrlink (%)
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 Template:Abbrlink (%). The reference ligand (100%) for SHBG was dihydrotestosterone and for Template:Abbrlink was cortisol.
Affinities of 9 estrogens for SHBG[40][46]
Compound Template:Abbrlink to
Template:Abbrlink (%)		 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 Template:Abbrlink (%) 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

Template:Resize
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:[47][48][49]

  • 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

Template:Reflist

Further reading

Template:Refbegin

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Template:Refend

External links

Template:PDB Gallery Template:Carrier proteins Template:Beta globulins Template:Androgenics Template:Estrogenics

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  47. ↑ Script error: No such module "citation/CS1".
  48. ↑ Script error: No such module "citation/CS1".
  49. ↑ Script error: No such module "citation/CS1".
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