Corticosterone

Corticosterone is a glucocorticoid steroid hormone synthesized from cholesterol in the adrenal cortex.  It serves primarily as a precursor to aldosterone, a key regulator of blood pressure, and exhibits weak mineralocorticoid activity. 

Although corticosterone's glucocorticoid effects are much weaker than cortisol's, it still plays a role in anti-inflammatory actions, glucose metabolism, and HPA axis regulation. 

In humans, corticosterone is also an important marker for diagnosing conditions such as 11-beta hydroxylase deficiency and glucocorticoid-responsive hyperaldosteronism.

Accurate measurement of corticosterone is crucial for assessing adrenal function and stress responses. 

Common methods include blood, urine, and saliva testing, each with its own benefits and drawbacks. Blood tests provide a snapshot of total corticosterone levels, while urine tests offer a 24-hour integrated measure.  Saliva tests are non-invasive and reflect bioavailable hormone levels. 

Understanding corticosterone levels, alongside related biomarkers like ACTH, aldosterone, and cortisol, helps in diagnosing and managing adrenal disorders effectively.

Understanding Corticosterone

Corticosterone plays a pivotal role in the endocrine system, influencing various physiological processes. 

What is Corticosterone?  [1., 13.]

Corticosterone is a glucocorticoid steroid hormone that is synthesized from cholesterol in the zona fasciculata of the adrenal cortex.  

Corticosterone is produced via steroidogenesis.  Steroidogenesis is the biosynthetic process through which cholesterol is converted into steroid hormones.

The process begins with cholesterol's conversion to pregnenolone, catalyzed by the enzyme cytochrome P450scc (CYP11A1) within the mitochondria.  Pregnenolone is further processed by oxidative enzymes in both the mitochondria and endoplasmic reticulum to produce various steroids. 

For corticosterone specifically, pregnenolone is converted to progesterone, which is then hydroxylated by 21-hydroxylase to form 11-deoxycorticosterone.  11-Deoxycorticosterone is further processed by 11-beta hydroxylase to produce corticosterone.

Corticosterone Function: What Does Corticosterone Do in the Body?  [7., 13., 20.] 

Corticosterone is primarily recognized as a precursor for aldosterone, an important mineralocorticoid that regulates blood pressure.  [13.]  Corticosterone is converted to aldosterone by the enzyme 11-beta hydroxylase 2, a subtype of 11-beta hydroxylase.  [4.] 

As a direct precursor to aldosterone, corticosterone does have some weak mineralocorticoid activity, although much less than that of aldosterone.  [11.] 

In addition to its important role as a precursor for aldosterone, corticosterone has its own biological activity as a glucocorticoid, although it is much weaker than that of cortisol.  This is in contrast to steroidogenesis in rats: in rats, corticosterone is a main glucocorticoid so it exerts cortisol-like effects on their physiology.  

Corticosterone exerts anti-inflammatory actions similar to those of cortisol, although much more weakly.  [20.] 

Similarly, it may have the same effects on glucose metabolism, protein catabolism, HPA axis regulation and immunosuppression as cortisol, although its effects are much weaker than those of cortisol in humans.  [6., 9.]

Corticosterone can also have mineralocorticoid and glucocorticoid effects on the brain, at much lower levels than aldosterone and cortisol.  [5.] 

In humans, corticosterone is primarily considered a precursor to aldosterone as well as a marker of 11-beta hydroxylase deficiency.  [2.] 

Laboratory Testing for Corticosterone

Accurate measurement of corticosterone levels is essential for diagnosing and managing conditions related to adrenal function and stress responses.

Overview of Methods Used to Measure Corticosterone Levels

Corticosterone levels can be measured in blood, saliva, and urine, with blood being the most common medium. 

Blood Testing for Corticosterone

Blood testing for corticosterone involves drawing a blood sample from a vein, usually in the arm. This method measures the total corticosterone concentration in the bloodstream, providing a snapshot of cortisol levels at the time of the test.

Benefits:

• Widespread availability in medical facilities

• Accurate measurement of total corticosterone levels

• Considered the gold standard of corticosterone measurement, often used for diagnosis of 11-beta hydroxylase deficiency or glucocorticoid-responsive hyperaldosteronism, as well as a less-common version of congenital adrenal hyperplasia involving 11-beta hydroxylase deficiency.  [2.] 

Drawbacks:

• Requires venipuncture, which can be uncomfortable

• Corticosterone levels may fluctuate throughout the day and over the course of a woman’s menstrual cycle.  This may necessitate multiple blood draws, generally at least 2 within a 24 hour period (often at 8 am and 4 pm)

• Does not provide accurate reflection of free, or bioavailable, corticosterone levels 

Urine Testing for Corticosterone

Urine testing for corticosterone involves collecting a urine sample over a specified period, usually 24 hours, to measure the total corticosterone excretion. This method provides an integrated measure of corticosterone production over time and is less invasive than blood testing. 

Urine testing can also show cortisol, cortisone, and metabolized cortisol levels.  

Benefits:

• Non-invasive method

• Samples can be collected at home

• Demonstrates HPA axis function over 24 hours as well as glucocorticoid metabolism 

Drawbacks:

• Variations in urine volume and dilution can affect corticosterone concentrations

• Potential for incomplete sample collection, leading to inaccurate results

Saliva Testing for Corticosterone

Saliva testing for corticosterone involves collecting saliva samples at specific times throughout the day. 

Benefits:

• Non-invasive and painless sample collection

• Saliva testing provides the ability to assess free, or bioavailable, hormone levels

Drawbacks:

• Potential variability in saliva collection technique

Interpreting Corticosterone Test Results

Optimal Levels of Corticosterone

Optimal levels will vary depending on the laboratory and sample type used.  It is essential to contact the laboratory company used to determine their recommended reference ranges.  

As an example, one company reports a reference range in urine testing of:  10-47 ng/mg creatinine/day  [16.] 

Another company reports a reference range in salivary testing of: 11-66 pg/mL  [17.] 

Generally, optimal levels are well within the reference range, because higher or lower levels of corticosterone may affect blood pressure due to aldosterone production.

Clinical Significance of Elevated Corticosterone Levels  [8., 10., 14.]

Commonly, corticosterone testing is used to confirm rare aldosterone deficiency due to 18-hydroxylase deficiency, which shows elevated corticosterone levels.  [15.] 

Corticosterone levels are also typically elevated in cases of suspected or confirmed 11β-hydroxylase (CYP11B1) deficiency, as well as in glucocorticoid-responsive hyperaldosteronism, while they may be normal or only mildly elevated in aldosterone synthase (CYP11B2) deficiency.  In these settings, prompt assessment by an endocrinologist is recommended. 

Functionally, elevated corticosterone levels can also be seen in chronic stress.  [12.]  In this setting, they are associated with metabolic disturbances like insulin resistance, visceral adiposity, and impaired glucose tolerance that also are commonly seen in chronic stress. 

Because of its action as a mineralocorticoid, it may also contribute to cardiovascular complications such as hypertension and atherosclerosis. 

Clinical Significance of Decreased Corticosterone Levels

Decreased corticosterone levels should prompt further assessment by an endocrinologist, especially if other adrenal hormone levels are out of range, and/or if symptoms of hypoaldosteronism are present.  

Related Biomarkers and Additional Tests

To gain a comprehensive understanding of adrenal function and stress responses, it is often necessary to measure other related biomarkers alongside corticosterone. 

Overview of Other Biomarkers Closely Related to Corticosterone  [18., 19.]

• ACTH (Adrenocorticotropic Hormone): as the primary regulator of adrenal steroidogenesis, measuring ACTH levels can provide insight into the functional status of the hypothalamic-pituitary-adrenal (HPA) axis and its ability to stimulate corticosterone production 

• Aldosterone: testing aldosterone levels is important since corticosterone is a direct precursor for aldosterone synthesis. The corticosterone to aldosterone ratio can help evaluate the activity of the aldosterone synthase enzyme (CYP11B2) 

• Cortisol: in humans, cortisol is the primary glucocorticoid, while corticosterone is the major glucocorticoid in rodents. Measuring both can provide a comprehensive assessment of glucocorticoid status and HPA axis function 

• 11-Deoxycortisol: an intermediate in the biosynthetic pathway to cortisol and corticosterone. Elevated levels may indicate impaired 11β-hydroxylase (CYP11B1) activity, which can lead to accumulation of precursors like 11-deoxycortisol and corticosterone 

• 18-Oxocortisol and 18-Hydroxycortisol: these "hybrid" steroids have been shown to be useful biomarkers for distinguishing unilateral from bilateral aldosterone excess in primary aldosteronism 

• 11β-Hydroxyandrostenedione: this adrenal-derived androgen has been identified as a superior biomarker to cortisol for adrenal vein sampling data interpretation in primary aldosteronism 

• DHEA and DHEA-S: as adrenal androgens, their levels can provide additional information about adrenal function and HPA axis regulation, particularly in conditions like adrenal insufficiency 

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