Cortisol-binding globulin (CBG): what it is and why it changes cortisol results

Cortisol-binding globulin (CBG) is a protein made mainly in the liver that carries cortisol around your blood. Most of the cortisol in a blood sample is attached to it, so changes in CBG can move a standard cortisol result up or down without necessarily changing the cortisol your body can actually use.

That makes CBG a reason a result can look odd, and it is behind the difference between total and free cortisol. This page explains what CBG does, what affects it and what a rare inherited shortage looks like.

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What CBG does

MedlinePlus Genetics says CBG is produced mostly in the liver and attaches to cortisol. When cortisol is attached to CBG it is turned off. When cortisol is needed, CBG delivers it where it is needed and releases it, so it becomes active. In this way CBG regulates how much cortisol is available for use. MedlinePlus Genetics puts the share bound to CBG at about 80 to 90 percent.

A 2024 review in Endocrine Reviews gives a split: about 90 percent of serum cortisol is bound to CBG, 4 to 6 percent to other proteins such as albumin, and 4 to 6 percent circulates freely. The free fraction is what a “free cortisol” test is after. See free vs total cortisol.

Why CBG matters for test results

A standard blood cortisol test measures total cortisol, bound and free together. When CBG changes, the total moves with it. The Endocrine Reviews paper lists these effects:

What changes binding proteins	Effect on a total cortisol result
Oral estrogens, such as some birth control pills	CBG goes up, so total cortisol reads falsely high
Pregnancy, with its high estrogen	The same: falsely high total cortisol
Nephrotic syndrome, a kidney condition that loses protein	CBG is lost in the urine, so total cortisol is lower. It could lead to a false diagnosis of adrenal insufficiency after a stimulation test
Critical illness with low albumin	The review cites one study in which total cortisol was lower (435 against 633 nmol/L) but free cortisol was similar (140 against 143 nmol/L)

The paper adds that sex, temperature, critical illness, genetic variants, medicines and insulin sensitivity can all affect CBG.

The review says salivary cortisol and urinary free cortisol are not affected by CBG changes. It also says measuring free cortisol in blood was proposed for people whose total cortisol is near a diagnostic threshold or who have altered binding proteins. The ways to measure free cortisol directly (ultrafiltration, equilibrium dialysis and gel-filtration chromatography) are labor-intensive. Equations that estimate free cortisol can be inaccurate when albumin is low or CBG capacity is altered.

Clinicians plan around this when they choose and time tests. That is a plan for a prescriber to make. Don’t stop a birth control pill or any hormone medicine on your own. Tell whoever orders your test what you take. See birth control and cortisol and cortisol in pregnancy.

Is there a CBG blood test?

People do search for a “cortisol binding globulin blood test.” The sources used here don’t describe a CBG level as part of a routine cortisol work-up. They describe the workarounds above: free cortisol methods, saliva and urine samples, and clinical judgment about what is raising or lowering the total. If you think CBG explains your result, ask the clinician who ordered it whether a free cortisol or saliva test would answer the question better. See saliva, urine and hair cortisol tests.

CBG deficiency

CBG deficiency is a rare inherited condition. MedlinePlus Genetics says it is caused by changes in the SERPINA6 gene, which makes CBG. With less working CBG, people usually have more unbound cortisol, and the body compensates by making less, so total cortisol falls.

The signs are subtle, according to MedlinePlus Genetics. The most frequent is extreme tiredness, especially after physical exertion. Many people have unusually low blood pressure, and some have a fatty liver or chronic muscle pain. Features vary, even within a family, and some people have no symptoms and are found only because a relative is affected. Some people with CBG deficiency also have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Three cautions from the same source:

• It is thought to be rare, though because some people have mild or no symptoms it is probably underdiagnosed.
• It is unclear how the lower CBG and total cortisol lead to the symptoms. Some researchers think fatigue could result from chronic pain rather than from the disorder directly.
• It is reported to be recessive: both copies of the gene carry changes. Some people with only one changed copy may have fatigue or pain, and some with two have no features.

Tiredness is common and has many causes. A low total cortisol doesn’t mean you have CBG deficiency, and it doesn’t mean you have adrenal insufficiency either. A clinician sorts that out. For the usual causes of low cortisol, see low cortisol.

CBG is not SHBG

Searches for “CBG” sometimes get mixed up with SHBG, sex hormone-binding globulin. MedlinePlus says most testosterone in the blood is bound to proteins such as SHBG and albumin. That is a different protein with a different job, and it comes up in testosterone testing, not cortisol testing.

What to do with this

• If your cortisol result looks surprising, note what you take (especially estrogen-containing medicines), whether you are pregnant and whether you have a kidney or liver condition. These are the CBG-related factors in the sources used here.
• If your question is about free cortisol, ask what your lab reports, and check the order details before you buy.
• If you have symptoms, see a clinician. No cortisol or CBG result on its own settles whether you have a condition.

Questions people ask

What does cortisol-binding globulin do?

It carries cortisol in the blood and holds most of it in an inactive form, releasing it where it is needed.

Can birth control pills change a cortisol result?

MedlinePlus lists birth control pills among the things that can affect cortisol levels. The Endocrine Reviews paper explains one route: oral estrogens raise CBG and so raise total cortisol.

Is low CBG dangerous?

The sources used here describe CBG deficiency as having subtle signs such as tiredness, low blood pressure and pain. They don’t describe it as an emergency condition. Seek urgent care for the signs on the adrenal crisis page.

Keep reading

• Free and total cortisol

  What each measurement means and when it matters.

• Birth control and cortisol

  How oral estrogen can change a cortisol result.

• Saliva, urine and hair cortisol tests

  Other ways to measure cortisol.

• All adrenal and related tests

  ACTH, DHEA-S, aldosterone and more.