Cortisol, Serum, LC-MS/MS
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Cortisol, the main glucocorticoid (representing 75%-95% of the plasma corticoids), plays a critical role in glucose metabolism and in the body's response to stress. Both hypercortisolism and hypocortisolism can cause disease.
Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin releasing hormone (CRH). CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (6-8 a.m.) and nadirs (11 p.m.) in plasma ACTH and cortisol levels.
The majority of cortisol circulates bound to corticosteroid-binding globulin and albumin. Normally, <5% of circulating cortisol is free (unbound). Free cortisol is the physiologically active form, and is filterable by the renal glomerulus.
Pathological hypercortisolism due to endogenous or exogenous glucocorticoids is termed Cushing syndrome. Signs and symptoms of pathological hypercortisolism may include central obesity, hypertension, hyperglycemia, hirsutism, muscle weakness, and osteoporosis. However, these symptoms and signs are not specific for pathological hypercortisolism. The majority of individuals with some or all of the symptoms and signs will not suffer from Cushing syndrome.
When Cushing syndrome is present, the most common cause is iatrogenic, due to repeated or prolonged administration of, mostly, synthetic corticosteroids. Spontaneous Cushing syndrome is less common and results from either primary adrenal disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the most frequently diagnosed subtype; most commonly seen in women in the third through fifth decades of life. The onset is insidious and usually occurs 2 to 5 years before a clinical diagnosis is made.
Hypocortisolism most commonly presents with nonspecific lassitude, weakness, hypotension, and weight loss. Depending on the cause, hyperpigmentation may be present. More advanced cases and patients submitted to physical stress (ie, infection, spontaneous or surgical trauma) also may present with abdominal pain, hyponatremia, hyperkalemia, hypoglycemia, and in extreme cases, cardiovascular shock and renal failure.
The more common causes of hypocortisolism are:
Primary adrenal insufficiency:
-Congenital adrenal hyperplasia, defects in enzymes involved in cortisol synthesis
Secondary adrenal insufficiency:
-Prior, prolonged corticosteroid therapy
See Steroid Pathways in Special Instructions.
Second-order testing when cortisol measurement by immunoassay (eg, CORT / Cortisol, Serum) gives results that are not consistent with clinical symptoms, or if patients are known to, or suspected of, taking exogenous synthetic steroids. For confirming the presence of synthetic steroids, order SGSS / Synthetic Glucocorticoid Screen, Serum.
An adjunct in the differential diagnosis of primary and secondary adrenal insufficiency
An adjunct in the differential diagnosis of Cushing syndrome
In primary adrenal insufficiency, adrenocorticotropic hormone (ACTH) levels are increased and cortisol levels are decreased; in secondary adrenal insufficiency both ACTH and cortisol levels are decreased.
When symptoms of glucocorticoid deficiency are present and the 8 a.m. plasma cortisol value is <10 mcg/dL (or the 24-hour urinary free cortisol value is <50 mcg/24 hours), further studies are needed to establish the diagnosis. The 3 most frequently used tests are the ACTH (cosyntropin) stimulation test, the metyrapone test, and insulin-induced hypoglycemia test. First, the basal plasma ACTH concentration should be measured and the short cosyntropin stimulation test performed.
Cushing syndrome is characterized by increased serum cortisol levels. However, the 24-hour urinary free cortisol excretion is the preferred screening test for Cushing syndrome, specifically CORTU / Cortisol, Free, 24 Hour, Urine that utilizes liquid chromatography-tandem mass spectrometry. A normal result makes the diagnosis unlikely.
Symptoms or signs of Cushing syndrome in a patient with low serum and urine cortisol levels suggest possible exogenous synthetic steroid effects.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
When patients are not taking or are not suspected to be taking exogenous glucocorticoids, the regular assay (CORT / Cortisol, Serum) should be used.
When cortisol assays are used for serial monitoring, the same methodology should be used throughout.
There is little, if any, value in an isolated p.m. serum cortisol measurement.
The most common cause of increased plasma cortisol levels in women is a high circulating concentration of estrogen (ie, estrogen therapy, pregnancy) resulting in increased concentration of corticosteroid-binding globulin. This does not result in an increase in the free, bioactive cortisol fraction. For this reason, measurement of 24-hour urinary free cortisol (CORTU / Cortisol, Free, 24 Hour, Urine) or demonstration of absent diurnal variation (ie, by midnight salivary cortisol measurement SALCT / Cortisol, Saliva) are the preferred means of diagnosing spontaneous Cushing syndrome.
Acute stress (including hospitalization and surgery), alcoholism, depression, and many drugs (ie, exogenous cortisones, anticonvulsants) can obliterate normal diurnal variation, affect response to suppression/stimulation tests, and cause elevated baseline levels.
Not recommended for evaluating response to metyrapone; DOC / 11-Deoxycortisol, Serum is more reliable.
A low plasma cortisol level does not give conclusive indication of congenital adrenal hyperplasia. DOC / 11-Deoxycortisol, Serum; OHPG / 17-Hydroxyprogesterone, Serum; and DHEA_ / Dehydroepiandrosterone (DHEA), Serum provide a more accurate and specific determination of the enzyme deficiency.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
5-25 mcg/dL (a.m.)
2-14 mcg/dL (p.m.)
Pediatric reference ranges are the same as adults, as confirmed by peer-reviewed literature.
Petersen KE: ACTH in normal children and children with pituitary and adrenal diseases. I. Measurement in plasma by radioimmunoassay-basal values. Acta Paediatr Scand 1981;70:341-345
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Lin CL, Wu TJ, Machacek DA, et al: Urinary free cortisol and cortisone determined by high-performance liquid chromatography in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1997;82:151-155
2. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 2001;30(3):729-747
3. Buchman Al: Side effects of corticosteroid therapy. J Clin Gastroenterol 2001;33(4):289-297
4. Dodds HM, Taylor PJ, Cannell GR, Pond SM: A high-performance liquid chromatography-electrospray-tandem mass spectrometry analysis of cortisol and metabolites in placental perfusate. Anal Biochem 1997;247:342-347