Sex hormone-binding globulin

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a is_associated_with::glycoprotein that binds to the two is_associated_with::sex hormones: is_associated_with::androgen and is_associated_with::estrogen. Other is_associated_with::steroid hormones such as is_associated_with::progesterone, is_associated_with::cortisol, and other is_associated_with::corticosteroids are bound by is_associated_with::transcortin. SHBG is found in all vertebrates apart from birds.

Transport of sex hormones
Testosterone and estradiol circulate in the bloodstream, bound mostly to SHBG and to a lesser extent is_associated_with::serum albumin and is_associated_with::corticosteroid-binding globulin (CBG) (AKA transcortin). Only a very small fraction of about 1-2% is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG. The relative binding affinity of various sex steroids for SHBG is is_associated_with::dihydrotestosterone (DHT) > is_associated_with::testosterone > is_associated_with::androstenediol > is_associated_with::estradiol > is_associated_with::estrone. DHEA is weakly bound to SHBG as well, but DHEA-S is not. is_associated_with::Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.

SHBG production
SHBG is produced mostly by the is_associated_with::liver and is released into the bloodstream. Other sites that produce SHBG include the brain, uterus, testes, and placenta. Testes-produced SHBG is called is_associated_with::androgen-binding protein.

Gene
The is_associated_with::gene for SHBG is called Shbg located on is_associated_with::chromosome 17 on the short arm between the bands 17p12→p13. Overlapping on the complimentary DNA strand is the gene for spermidine/spermine N1-acetyltransferase family member 2 (is_associated_with::SAT2). Nearby are the genes for is_associated_with::p53 and is_associated_with::ATP1B2, and is_associated_with::fragile X mental retardation, autosomal homolog 2 (FXR2) on the complimentary strand. 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.

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 is_associated_with::endometrial cancer, and another is an increased risk of is_associated_with::systemic lupus erythematosus.

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

Rs727428 position 7634474 is in several percent of humans.

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

Promoter activation
The mechanism of activating the promoter for SHBG in the liver involves is_associated_with::hepatocyte nuclear factor 4 alpha (is_associated_with::HNF4A) binding to a DR1 like cis element which then stimulate production. Competing with HNF4A at a third site on the promter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then is_associated_with::COUP-TF binds to the fist 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 is_associated_with::androgen-binding protein but that has different is_associated_with::oligosaccharides attached and is produced in testes.

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

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 is_associated_with::N-glycosilation points on apsparagine (351 and 367) and one is_associated_with::O-glycosilation (7) point on threonine.

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.

Control
SHBG has both enhancing and inhibiting hormonal influences. It decreases with high levels of is_associated_with::insulin, is_associated_with::growth hormone, insulin-like growth factor 1 (is_associated_with::IGF-1), is_associated_with::androgens, is_associated_with::prolactin and is_associated_with::transcortin. High is_associated_with::estrogen, and is_associated_with::thyroxine cause it to increase.

In an effort to explain obesity-related reductions in SHBG, recent evidence suggests sugar or monosaccharide-induced hepatic lipogenesis, hepatic lipids in general, and cytokines like TNF-alpha and Interleukin reduce SHBG, whereas insulin does not. As an example anti-psoriatic drugs that inhibit TNF-alpha cause an increase in SHBG. The common downstream mechanism for all of these, including the effect of thyroid hormones was downregulation of HNF4, hepatocyte nuclear factor 4.

Blood values
is_associated_with::Reference ranges for blood tests for SHBG have been developed:

Conditions associated with high or low levels
SHBG levels are decreased by androgens, administration of is_associated_with::anabolic steroids, is_associated_with::polycystic ovary syndrome, is_associated_with::hypothyroidism, is_associated_with::obesity, is_associated_with::Cushing's syndrome, and is_associated_with::acromegaly. Low SHBG levels increase the probability of is_associated_with::Type 2 Diabetes. SHBG levels increase with estrogenic states (is_associated_with::oral contraceptives), is_associated_with::pregnancy, is_associated_with::hyperthyroidism, is_associated_with::cirrhosis, is_associated_with::anorexia nervosa, and certain is_associated_with::drugs. Long-term is_associated_with::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. is_associated_with::Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.

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. The change at puberty is triggered by is_associated_with::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.

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

Measurement of sex hormones
When checking serum estradiol or testosterone, a total level that includes free and bound fractions can be assayed, or the free portion may be measured alone. A is_associated_with::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 separate from the total fraction of testosterone.