The many faces of hCG

One of the things that I find interesting about hCG is that there is more to it than meets the eye.
We often talk about hCG as though it's a single molecule when, in fact, there are lots of different
variants of hCG. Here's a quick summary of what those different molecules are all about.
1. Intact hCG: This is the variant that gets the job done. That is, it's the biologically active
form of the hormone that is made by the placenta. It's job is to keep the blood
progesterone concentrations high which is critical for maintaining pregnancy. It's made
up of two different protein subunits simply called alpha and beta. The alpha subunit isn't
unique to hCG because it's also part of three other completely different hormones: thyroid
stimulating hormone, follicle stimulating hormone, and luteinizing hormone. The beta
subunit is unique to just hCG (the other three hormones also have their own unique beta
subunit). A complete, intact hCG molecule is made when the alpha and beta subunits are
attached to each other. During pregnancy, most of the hCG in the blood is intact hCG.
2. Nicked hCG (hCGn): Nicked hCG is made when a chemical bond in part of the beta
subunit is broken. When that happens, the hormone loses is biological activity and the
alpha and beta subunits will often come apart. During pregnancy, nicked hCG makes up
about 10% of the total hCG in the blood.
3. Free Alpha Subunit of hCG (hCG): It goes without saying that this is the alpha
subunit all by itself. It has no biological activity. That is, it doesn't work and can't keep
blood progesterone levels high.
4. Free Beta Subunit of hCG (hCG): This variant of hCG is the free beta subunit without
the alpha subunit and it also lacks biological activity. During pregnancy, the free beta
subunit makes up about 1% of all the hCG in the blood. Also, this variant is sometimes
made by certain types of cancers.
5. Nicked Free Beta Subunit of hCG (hCGn): This is similar to hCGn (#2 above) yet
there is no alpha subunit attached to it and so it, too, has no activity.
6. Beta Core Fragment of hCG (hCGcf): This is the final breakdown product of hCG. It
is a small molecule that is made up of the center (core) part of the hCG beta subunit.
Like the other non-intact hCG variants, the beta core fragment is inactive. However,
unlike all of the other hCG forms that are present in both the blood and the urine of
pregnant women, the beta core fragment is only present in the urine. In fact, the urine of
pregnant women contains more beta core fragment than any of the other hCG variants.
7. Hyperglycosylated hCG (hCG-h): Intact hCG normally has carbohydrate (sugar)
molecules attached to it. Hyperglycosylated hCG is like intact hCG except it has even
more carbohydrate molecules attached. This hCG variant is the predominant form of
hCG produced during the first few weeks of pregnancy but it is nearly undetectable by
the end of the first trimester.

Here is a figure of the forms of hCG that contain all or part of the beta subunit (adapted
from Clin Chem 1997;43:2233-2243):

All of these forms of hCG (and probably others that we don't even know about) are produced
during pregnancy and can be detected in the blood and urine of pregnant women (hCGcf is only
in the urine). Future posts will discuss how these different hCG variants make detecting and
measuring hCG a bit of a challenge. Things are not always as straightforward as they seem!