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.
The gene for SHBG is called Shbg located on 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 (SAT2). Nearby are the genes for p53 and ATP1B2, and 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.
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.
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.
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 promter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then COUP-TF binds to the fist site and turns off production of SHBG.
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.
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 N-glycosilation points on apsparagine (351 and 367) and one O-glycosilation (7) point on threonine.
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.
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.
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 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 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 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 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.
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