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ARTICLES Table of Contents   
Year : 2000  |  Volume : 2  |  Issue : 7  |  Page : 39-48
Clinical diagnosis of hyper- and hypocortisolism

Division of Endocrinology, Department of Internal Medicine, Klinikum Benjamin Franklin, Freie Universität Berlin, Germany

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The clinical correlate of chronic hypercortisolism is Cushing's syndrome (CS). After exclusion of an iatrogenic cause (glucocorticoid administration), two reliable laboratory methods for establishing the diagnosis are (i) measurement of "free" (unmetabolised) cortisol in a 24-hour urine (UFC) sample and (ii) the low-dose (1 or 1.5 mg) dexamethasone (Dex) test. For the latter, Dex is taken orally at midnight, and plasma cortisol is measured at 8 a.m. In normals and in the absence of CS, the morning cortisol (200-650 nmol/L) is suppressed to <80 nmol/L. In endogenous CS of all causes, cortisol suppression by Dex is absent or incomplete. In patients with severe mental depression or stress, suppression may also be incomplete ("false­positives"). However, UFC is normal or only slight increased in the latter group, while it is always markedly increased in clinically apparent CS. In CS, UFC rises proportionally more than plasma cortisol because the cortisol binding plasma protein (transcortin) can bind only about 500 nmol/L cortisol. Protein-bound cortisol is not excreted by the kidney.
After establishing the diagnosis CS, the differentiation between its pituitary (ca. 70%), adrenocortical (ca. 20%) or "ectopic" (ACTH production by non-pituitary tumours) (ca. 10%) origin is made by plasma ACTH measurement, a corticotropin releasing hormone injection
test (with plasma ACTH/cortisol measurement) and a high-dose Dex (8 mg or more) suppression test.
Chronic hypocorticolism can be primary (adrenal disease, Addison's disease) or secondary (pituitary or hypothalamic disorder). UFC measurement is not an established method for confirming hypocortisolism because most analytical methods are too unspecific and insensitive in the subnormal range. Low-normal or subnormal plasma cortisol plus elevated ACTH is the hallmark of Addison's disease. Injection of high doses of ACTH does not lead to a rise in plasma cortisol in these patients. A clearly subnormal cortisol plus low ACTH proves secondary hypocortisolism. Mild forms with low-normal plasma cortisol, however, are more difficult to prove. So-called "dynamic" tests stimulating the whole hypothalamo-pituitary­adrenal axis (insulin hypoglycemia test or metyrapone test) are necessary to confirm the diagnosis. Patients with hypocortisolism, depending on disease severity, must be treated permanently or only in stressful situations with hydrocortisone unless they may die after passing the clinical state of an "adrenal crisis".

Keywords: Hypercortisolism, Cushing′s syndrome, hypocortisolism, cortisol, laboratory methods

How to cite this article:
Oelkers W. Clinical diagnosis of hyper- and hypocortisolism. Noise Health 2000;2:39-48

How to cite this URL:
Oelkers W. Clinical diagnosis of hyper- and hypocortisolism. Noise Health [serial online] 2000 [cited 2022 Jul 1];2:39-48. Available from: https://www.noiseandhealth.org/text.asp?2000/2/7/39/31743

  Introduction Top

The hypothalamic - pituitary-adrenal axis has an important role in the body's ability to cope with stresses like infections, hypotension and surgery. The hypothalamus is subject to regulatory influences from other parts of the brain, especially the limbic system. The hypothalamic hormones corticotropin-releasing hormone and arginine-vasopressin are important stimulants of corticotropin secretion by the anterior pituitary. In this gland, the action of the hypothalamic hormones is amplified so that a much larger number of corticotropin molecules is secreted. Similarly, in the adrenal cortex the action of corticotropin is amplified; a plasma corticotropin concentration of approximately 5.5 pmol per litre results in a plasma cortisol concentration of approximately 550 nmol per litre. Only 5 to 10 percent of the plasma cortisol, however, is free; the majority is bound to cortisol-binding globulin. Cortisol is of vital importance for the metabolism of carbohydrates and protein and for the control of the immune system, and it controls the secretion of corticotropin, corticotropin­releasing hormone and vasopressin by a negative feedback inhibition mediated by glucocorticoid receptors. Corticotropin also stimulates adrenal androgens and, under short-term conditions, aldosterone.

Severe hypercortisolism, a disastrous catabolic disorder

Chronic hypercortisolism (Cushing's syndrome) results either from exogenous pharmacological glucocorticoid administration (e.g. in rheumatic disorders or asthma) or from endogenous hydrocortisone (= cortisol). The cortisol secretion rate in healthy subjects is between 10 and 15 mg per day (Esteban and Yergey, 1990). In patients with Cushing's syndrome, the cortisol secretion rate may be increased between 2-fold and 50-fold. Most cases of Cushing's syndrome are caused by ACTH overproduction due to either a pituitary micro- or macroadenoma (60­70% of all cases) or to "ectopic" ACTH by carcinomas or carcinoids in peripheral tissue, e.g., lung or thymus (about 5% of all cases). ACTH-independent Cushing's syndrome originates from primary overproduction of cortisol by adrenocortical tumors (adenomas or carcinomas) or from rare forms of primary adrenal hyperplasia (about 20% of all cases) (Trainer and Grossmann, 1991). Hypersecretion of cortisol leads to severe protein catabolism. Breakdown of muscle protein causes muscle atrophy and weakness, and the aliphatic amino acids set free by catabolism are converted to glucose in the liver (gluconeogenesis). An increase in glucose production stimulates insulin secretion, and insulin leads to lipogenesis, especially in the trunk, neck and face. Muscle atrophy in the extremities and increased fat apposition in the trunk leads to the typical aspect of patients with Cushing's syndrome. Furthermore, protein catabolism in the skeleton and skin leads to osteoporosis and increased bruisability of cutaneous vessels. The mineralocorticoid effect of cortisol in the kidney and an increased expression of catecholamine receptors in resistance blood vessels leads to arterial hypertension. The immune system is largely paralyzed in severe hypercortisolism. Therefore, patients are extremely susceptible to infections, and wound healing is poor. Clinical symptoms of Cushing's Syndrome are listed in [Table - 1]. Before surgical therapy of Cushing's syndrome was possible, most patients died within a few years of pneumonia or other infections.

Diagnostic tests for Cushing's syndrome Urinary free cortisol excretion rate

The best method for quantifying hypercortisolism would be measurement of the cortisol secretion rate. However, all available methods are not suited for clinical practice. A very good substitute is measurement of urinary free cortisol (UFC) i.e. the excretion of unmetabolised cortisol. The vast majority of cortisol is metabolised by the liver and excreted in the form of glucuronide conjugates. A large percentage of plasma cortisol is bound to a protein that is produced by the liver: transcortin. Transcortin binds about 500 nmol/l cortisol. With a normal range of total plasma cortisol between ca. 200-650 nmol/l in the early morning hours, an average of 95% of plasma cortisol is bound to transcortin. Only the remaining 5% is "free" and can be filtered by the kidney. Most of the filtered cortisol is reabsorbed in the renal tubules and only a small fraction of cortisol secreted is excreted as UFC. UFC is measured in a carefully collected 24-hour urine sample. The normal or reference range of UFC in clinical practice depends very much on the method of measurement. Urinary free steroids can be extracted with organic solvents and quantitated after separation by HPLC (Schoneshofer et al. 1980). The normal range of such a laborious method was between 30 and 150 nmol/day in our laboratory. After switching to a method including extraction of urine and direct radioimmunoassay of cortisol , the normal range was between 60 and 250 nmol/l. For plasma cortisol measurement, the central laboratory of our hospital successfully uses an chemoluminiscent assay that favorably compared to radioimmunoassay. For UFC, however, the "normal range" using the chemoluminiscent method was shifted up to 100­500 nmol/day. Such an unspecific method is not acceptable for research purposes. This shows that most UFC measurements used in clinical practice as well as in experimental and clinical research are not very specific. Nevertheless, most of these methods are suitable for estimating UFC in patients with hypercortisolism because of the cross-reacting material measured in addition to cortisol by using radioimmunoassays or immunofluorescent methods are unconjugated metabolites of cortisol, the urinary excretion of which is raised in parallel to cortisol in patients with endogenous hypercortisolism. While plasma cortisol exhibits large circadian variations, UFC is an integrated measure of cortisol secretion rate. The sensitivity of the UFC method in the diagnosis of Cushing's syndrome is between 95-100%. Elevations of UFC to more than the 3-fold upper normal limit are practically diagnostic of Cushing's syndrome if the patient at the time of urine collection was not severely ill (e.g. intensive care patients) or in severe stress. Slight increases in UFC may be due to stress, mild infections or pregnancy.

The dexamethasone suppression test

A second method for establishing the diagnosis of Cushing's syndrome is the low-dose dexamethasone suppression test. Dexamethasone is a halogenated cortisol derivative, the glucocorticoid potency of which is about 30 times higher than that of cortisol. One or 1.5 mg of dexamethasone administered orally at midnight leads to suppression of ACTH secretion, and the plasma cortisol at 8 a.m. is regularly depressed to <80 nmol/l in healthy subjects. Again, severe stress or mental depression may render ACTH and cortisol secretion less suppressible by low-dose dexamethasone. In patients with Cushing's syndrome of whatever cause, plasma cortisol suppression by low-dose dexamethasone is absent or incomplete (positive dexamethasone test). A positive dexamethasone test and a markedly increased UFC is diagnostic of Cushing's syndrome in patients who are not under severe stress (Kaye and Crapo, 1990).

Differential diagnosis of Cushing“s Syndrome and therapy

Once the diagnosis of Cushing's syndrome has been established, it is necessary to find out the cause of hypercortisolism. A detailed description of the methods for the differential diagnosis of Cushing's syndrome is outside the scope of this paper. Briefly, a single plasma ACTH determination at 8 a.m. distinguishes between ACTH-dependent and ACTH-independent Cushing's syndrome. In primary adrenal Cushing's syndrome, plasma ACTH, in contrast to cortisol, is unmeasurably low or at the lower limit of normal. In such cases, computerized tomography (CT) of the adrenals will demonstrate the causative lesion (adrenal adenoma, carcinoma or primary hyperplasia). In cases with normal or elevated plasma ACTH, the differential diagnosis between pituitary-caused Cushing's syndrome (also called Cushing's disease) and "ectopic" ACTH production is performed by applying the following methods:

1) A high dose (8 mg or more) dexamethasone suppression test. ACTH production by pituitary tumors is usually suppressible with very high doses of dexamethasone, while most ectopically ACTH producing tumors are absolutely resistant to dexamethasone. The suppressibility of ACTH is reflected by a decrease in plasma cortisol and UFC.

2) The corticotropin-releasing hormone (CRH) test. After intravenous injection of about 100 µg CRH, ACTH secretion by a pituitary tumor is stimulated in almost all cases (and so is plasma cortisol) [Figure - 1], while more than 90% of ectopically ACTH­secreting tumors are resistant to CRH.

3) ACTH measurement in the blood of the inferior petrosal sinus. The inferior petrosal sinus is a small vein that connects the pituitary venous plexus with the jugular vein. By introducing a catheter from the femoral vein through the jugular vein into the tiny inferior petrosal sinus, one can measure the concentration difference of ACTH between the petrosal sinus and a peripheral vein, which is high if a pituitary tumor is the source of ACTH but not so if an ectopic tumor, e.g. a bronchial carcinoid, secretes ACTH.

(Kaye and Crapo, 1990, Trainer and Grossmann,1991, Flack et al. 1992, Al-Saadi et al. 1998).

Surgery is the only curative therapy of Cushing's syndrome. Adrenal tumors are removed by conventional or minimally invasive (laparoscopic) surgery. Pituitary adenomas are removed by a microsurgical transphenoidal method (through the nose and the spenoidal sinus), while ectopically ACTH-secreting tumors are removed by conventional surgery. After successful complete removal of a cortisol­or ACTH-producing tumor, plasma and urinary cortisol falls to almost zero within a few hours, and the patient needs hydrocortisone substitution for some months or even up to three years until the hypothalamo-pituitary-adrenal axis has completely recovered from suppression by chronic hypercorticolism.

Hypocortisolism impairs stress tolerance and is life-threatening

Diseases that lead to destruction of the adrenal cortex itself lead to "primary adrenal insufficiency". Chronic primary adrenal insufficiency is also called Addison's disease. The production of cortisol, aldosterone and adrenal androgens and estrogens is progressively decreasing in this disorder. Since feedback inhibition of ACTH secretion by cortisol is decreasing gradually, ACTH hypersecretion occurs, and the remaining adrenocortical cells are maximally stimulated. ACTH hypersecretion leads to hyperpigmentation of the skin and mucous membranes. Almost all cells of the body possess glucocorticoid receptors, and glucocorticoids are universally important for substrate metabolism and generation of physical energy. It is therefore not surprising that patients with marked hypocortisolism are severely ill, suffering from tiredness, weakness, depression, anorexia, weight loss, low blood pressure and hypoglycemia. Other symptoms of hypercortisolism are listed in [Table - 2]. Patients with primary adrenal insufficiency must be treated with a glucocorticoid (hydrocortisone or prednisolone) plus a mineralocorticoid because aldosterone is also deficient. In contrast to patients with primary adrenal insufficiency those with hypothalamic or pituitary disorders leading to hypocortisolism (secondary adrenal insufficiency) have pale skin because of ACTH deficiency. The symptoms of hypocortisolism are usually milder than in primary adrenal insufficiency. One of the reasons for less severe symptoms is the fact that aldosterone, a product of the outer glomerular zone of the adrenal cortex, is secreted in almost normal amounts in patients with secondary adrenal insufficiency because the glomerular zone is mainly regulated by renin and angiotensin II rather than ACTH. Adrenal androgens and estrogens are also missing in secondary adrenal insufficiency because, like cortisol, they are regulated by ACTH. Patients with adrenal insufficiency (primary or secondary), who acquire an infection or are exposed to severe environmental stress, may die within a few days unless the diagnosis is made and high doses of glucocorticoids (plus sodium chloride and glucose) are administered.

Common causes of primary adrenal insufficiency are a chronic autoimmune adrenalitis, adrenal tuberculosis, the acquired immunodeficiency syndrome (AIDS) or adrenal metastases in patients with bronchial, renal or breast cancer. Common causes of secondary adrenal insufficiency are pituitary or hypothalamic tumors, inflammation of the pituitary (hypophysitis) or brain irradiation (Oelkers, 1996 a).

Diagnostic tests for hypocortisolism and therapy

In contrast to the diagnosis of hypercortisolism, the measurement of UFC is not a suitable and acknowledged test in cases where hypocortisolism is suspected. This is mainly due to the low specificity of most UFC methods and to the low sensitivity of UFC measurement in the low or low-normal range. We have recently compared standard tests for detecting secondary adrenal insufficiency with UFC measurements in 44 patients with pituitary tumors (Mayenknecht et al. 1998) and found the UFC method very unreliable showing low-normal or even mid­normal levels in several patients with hypocortisolism.

If adrenal insufficiency is only be excluded in a patient with tiredness and weakness, a morning plasma cortisol level (between 8 and 9 a.m.) should be measured. Cortisol levels at this time >500 nmol/l practically exclude adrenal insufficiency, while a level <100 nmol/l is almost diagnostic of adrenal insufficiency. In a patient with such a low plasma cortisol, measurement of ACTH in the same blood sample allows the distinction between primary (elevated ACTH) and secondary (normal or low ACTH) adrenal insufficiency (Oelkers et al. 1992). This is demonstrated in [Figure - 2]. All patients suspected of having adrenal insufficiency with morning plasma cortisol levels between 100 and 500 nmol/l require "dynamic" testing, i.e. administration of a stimulus that elicits a cortisol response that is compared to responses in a healthy population. In patients under suspicion of suffering from primary adrenal insufficiency (hyperpigmentation, hyperkalemia due to aldosterone deficiency) a corticotropin stimulation test should be performed. 250 µg of synthetic corticotropin or less are injected intravenously or intramuscularly, and plasma cortisol is determined before injection and 30 or 60 minutes after injection. If cortisol rises to a level >550 nmol/l, primary adrenal insufficiency is excluded. Usually, in patients with Addison's disease, plasma cortisol is not stimulated at all because the high endogenous ACTH level stimulate the adrenal cortex maximally.

The application of the corticotropin stimulation tests (either 250 µg or a lower dose) is problematic in patients suspected to have secondary adrenal insufficiency, because this test only measures the reactivity of the adrenal cortex to exogenous ACTH. In mild cases of secondary adrenal insufficiency, the adrenal cortex is not yet atrophic (atrophy of the adrenal cortex occurs in states of severe ACTH deficiency) and can still be stimulated to normal cortisol levels with corticotropin. Therefore, for the diagnosis of secondary adrenal insufficiency, tests are preferred that challenge the intactness of the whole hypothalamo-pituitary-adrenal axis. Such tests are the insulin-hypoglycemia test and the metyrapone test. After the administration of a small dose of insulin that lowers blood glucose to below 2.2 mmol/l, the normal hypothalamus releases large amounts of corticotropin releasing hormone and vasopressin that stimulate ACTH secretion, and ACTH stimulates the adrenal cortex. An increase of plasma cortisol to >550 nmol/l after insulin hypoglycemia proves the intactness of the whole hormonal axis and excludes secondary and primary adrenal insufficiency. Metyrapone is a chemical compound that inhibits the adrenocortical 11­hydroxylase, an enzyme that converts 11­deoxycortisol to cortisol. After administration of metyrapone at midnight, cortisol secretion falls. ACTH secretion is stimulated because of the diminished cortisol feedback, and the secretion of the cortisol precursor 11-deoxycortisol is greatly stimulated. 11-deoxycortisol is measured in a blood sample taken at 8 a.m., and an increase of this steroid to >200 nmol/l indicates the intactness of the hypothalamo-pituitary-adrenal axis.

Primary and secondary adrenal insufficiency can occur in all grades of severity, and there is no sharp dividing line between normalcy and adrenal insufficiency, be it primary or secondary. Therefore, the interpretation of the results of function tests needs some clinical experience.

The cut-off points used in this presentation are pragmatic. They are on the "safe side", and clinical judgment must be used in interpreting all tests (Oelkers, 1996 a, b). A synopsis of diagnostic tests for hyper- and hypo-cortisolism is given in [Table - 3].

Therapy of adrenal insufficiency consists in the substitution of the missing hormones. Patients who were bound to die without exception up to 60 years ago do nowadays have a normal life expectancy if the underlying disorder leading to adrenal failure is of benign nature. This has been one of the greatest triumphs of biochemistry and clinical medicine.[10]

  References Top

1.Al-Saadi N., Diederich S., Oelkers W. (1998) A very high dose dexamethasone suppression test for differential diagnosis of Cushing's syndrome. Clin Endocrinl. 48: 45­ 51  Back to cited text no. 1    
2.Esteban N. V., Yergey A. L. (1990) Cortisol production rates measured by chromatography/ mass spectrometry Steroids 55: 152-158  Back to cited text no. 2    
3.Flack M. R., Oldfield E. H., Cutler G. B., Zweig M. H., Malley J. D., Chrousos G. P., Loriaux D. L., Nieman L. K. (1992) Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann. Int. Med. 116: 211 - 217  Back to cited text no. 3    
4.Kaye T. B., Crapo L. (1990). The Cushing Syndrome: An update on diagnostic tests. Ann. Int. Med. 112: 434 - 444  Back to cited text no. 4    
5.Mayenknecht J., Diederich S., Bahr V., Plockinger U., Oelkers W. (1998) Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J. Clin. Endocrinol. Metab. 83: 1558 - 1562  Back to cited text no. 5    
6.Oelkers W. (1996a) Adrenal Insufficiency (review). N. Engl. J. Med. 335: 1206-1212  Back to cited text no. 6    
7.Oelkers W. (1996 b) Dose-response aspects in the clincal assessment of the hypothalamo-pituitary-adrenal axis, and the low-dose adrenocorticotropin test (review) Eur. J. Endocrinol. 135: 27- 33  Back to cited text no. 7    
8.Oelkers W., Diederich S., Bahr V (1992) Diagnosis and therapy surveillance in Addison's disease: Rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity and aldosterone. J. Clin. Endocrinol. Metab. 75: 259-264  Back to cited text no. 8    
9.Schoneshofer M., Fenner A., Altinok G., Dulce H. J. (1980). Specific and practicable assessment of urinary free cortisol by combination of automatic high-pressure chromatography and radioimmunoassay. Clin. Chim. Acta 106:63-73  Back to cited text no. 9    
10.Trainer P. J., Grossman A. (1991). The diagnosis and differential diagnosis of Cushing's syndrome. Clin. Endocrinol. 34: 317 - 330  Back to cited text no. 10    

Correspondence Address:
W Oelkers
Klinikum B.Franklin, Freie Universität Berlin, Hindenburgdamm 30 12200 Berlin
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Source of Support: None, Conflict of Interest: None

PMID: 12689470

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  [Figure - 1], [Figure - 2]

  [Table - 1], [Table - 2], [Table - 3]