biology

Sex hormone–binding globulin

Sex hormone–binding globulin is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Sex hormone–binding globulin rather than just read about it. In short: 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).

Key takeaways

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Reproduce the core statement of Sex hormone–binding globulin from memory before moving on to harder problems.

Reference excerpt

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

Function Testosterone and estradiol circulate in the bloodstream where 33-70% are loosely bound to serum albumin (depending on the sex and hormone), and most of the remaining is bound tightly to SHBG. Only a very small fraction of about 1 to 4% 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 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. 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. Estrone sulfate and estriol are also poorly bound by SHBG. Less than 1% of progesterone is bound to SHBG. 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.

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. 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. 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-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. Rs6258 also called Ser156Pro is at position 7631360 on 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 (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.

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. 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. 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. 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-glycosylation points on asparagine (351 and 367) and one O-glycosylation point (7) 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.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Sex hormone–binding globulin

Start with the simplest possible case. Write down what Sex hormone–binding globulin claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Sex hormone–binding globulin before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Sex hormone–binding globulin ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Sex hormone–binding globulin

In research: Sex hormone–binding globulin appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Sex hormone–binding globulin in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Sex hormone–binding globulin is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 17, Glycoproteins, so understanding it makes those chapters shorter.
In everyday life: Look for Sex hormone–binding globulin outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Sex hormone–binding globulin in 20 minutes

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Frequently asked questions

What is Sex hormone–binding globulin in simple terms?

Why does Sex hormone–binding globulin matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Sex hormone–binding globulin?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Sex hormone–binding globulin.