Sex hormone-binding globulin or sex steroid-binding globulin is a glycoprotein that binds to the
sex hormones, androgen and estrogen.
Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound
by 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 serum albumin and corticosteroid-binding
globulin.
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 dihydrotestosterone > testosterone
> androstenediol > estradiol > estrone.
DHEA is weakly bound to SHBG as well, but DHEA-S is not.
Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.
SHBG production 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.
Overlapping on the complimentary DNA strand is the gene for spermidine/spermine N1-acetyltransferase
family member 2.
Nearby are the genes for p53 and ATP1B2, and fragile X mental retardation, autosomal homolog
2 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 giuio include the folowing: 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.
Promoter activation The mechanism of activating the promoter for
SHBG in the liver involves hepatocyte nuclear factor 4 alpha 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.
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.
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.
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 and one O-glycosilation
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 insulin, growth hormone, insulin-like growth factor
1, androgens, prolactin and transcortin.
High estrogen, and 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 Reference ranges for blood tests for SHBG
have been estimated to be: Conditions associated with high or low levels
SHBG levels are decreased by androgens, administration of anabolic steroids, polycystic ovary syndrome,
hypothyroidism, obesity, Cushing's syndrome, and acromegaly.
Low SHBG levels increase the probability of Type 2 Diabetes.
SHBG levels increase with estrogenic states, pregnancy, hyperthyroidism, cirrhosis, anorexia
nervosa, and certain drugs.
Long-term 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.
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 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.
References
Further reading