INTRODUCTION — The clinical presentation of adrenal insufficiency is variable, depending on whether the onset is acute, leading to adrenal crisis, or chronic, with symptoms that are more insidious and vague. Therefore, the diagnosis of adrenal insufficiency depends upon a critical level of clinical suspicion. Adrenal crisis should be considered in any patient who presents with peripheral vascular collapse (vasodilatory shock), whether or not the patient is known to have adrenal insufficiency. Likewise, isolated corticotropin (ACTH) deficiency, although rare, should be considered in any patient who has unexplained severe hypoglycemia or hyponatremia. (See "Clinical manifestations of adrenal insufficiency in adults".)
GENERAL PRINCIPLES
Exogenous glucocorticoids — Prolonged administration of pharmacologic doses of synthetic glucocorticoids is by far the most common cause of corticotropin (ACTH) deficiency and consequent adrenal insufficiency. (See "Causes of primary adrenal insufficiency (Addison's disease)" and "Causes of secondary and tertiary adrenal insufficiency in adults".)
However, patients treated with glucocorticoid therapy rarely present with adrenal crisis, although sudden withdrawal of glucocorticoids can result in exacerbation of the disorder for which they were being given (eg, asthma, inflammatory disease, or organ transplantation), symptoms of glucocorticoid deficiency, or hypotension. (See "Clinical manifestations of adrenal insufficiency in adults".)
The principles involved in weaning patients from chronic high-dose glucocorticoid therapy are discussed elsewhere. (See "Glucocorticoid withdrawal".)
Critical illness — Subnormal corticosteroid production during critical illness in the absence of structural defects in the hypothalamic-pituitary-adrenal axis has been termed "functional adrenal insufficiency" or "relative adrenal insufficiency." There is currently no consensus on the diagnostic criteria for this entity. A detailed discussion of this issue is found separately. (See "Glucocorticoid therapy in septic shock in adults".)
Chronic versus acute adrenal insufficiency — The clinical diagnosis of chronic adrenal insufficiency is often more difficult than that of acute adrenal insufficiency. While the diagnosis may be obvious when classic symptoms and signs are present, early symptoms (such as fatigue and lassitude) are nonspecific. (See "Clinical manifestations of adrenal insufficiency in adults".)
As a result, the possible presence of adrenal insufficiency is sometimes overlooked while other possibilities are pursued:
●Weight loss and gastrointestinal complaints may raise suspicion of gastrointestinal malignancy.
●Cutaneous hyperpigmentation is not always present. Hyperpigmentation is absent in some patients with primary adrenal insufficiency and in all patients with secondary (pituitary) and tertiary (hypothalamic) adrenal insufficiency [1]. In addition, hyperpigmentation can be caused by antineoplastic, antimalarial, and other drugs, such as tetracyclines, phenothiazines, and zidovudine [2], and by heavy metals. The pigmentation of hemochromatosis is similar to that of adrenal insufficiency except that it seldom involves the mucous membranes.
●Patients with untreated adrenal insufficiency may have moderately elevated daytime serum thyroid-stimulating hormone (TSH) levels. Cortisol may play a role in regulating the normal circadian rhythm in TSH [3].
●In one study of 216 patients, 20 percent had symptoms for more than five years before diagnosis [4].
Even when the diagnosis appears obvious, endocrine evaluation is indicated to confirm the diagnosis and to determine the type of adrenal insufficiency and its cause (algorithm 1). However, therapy should be started before the diagnosis is established in an acutely ill patient with possible adrenal crisis.
LABORATORY DIAGNOSIS — Confirmation of the clinical diagnosis of adrenal insufficiency is a three-stage process [5]:
●Demonstrating inappropriately low cortisol secretion
●Determining whether the cortisol deficiency is dependent on or independent of corticotropin (ACTH) deficiency and evaluating mineralocorticoid secretion in patients without ACTH deficiency
●Seeking a treatable cause of the primary disorder (eg, infiltrative process involving the adrenal glands or a pituitary adenoma compromising normal pituitary function)
A scheme for establishing the diagnosis of adrenal insufficiency and determining its cause is shown in the figure (algorithm 2). Although laboratory testing is essential to confirm the diagnosis of adrenal insufficiency, both laboratory and patient errors can cause misleading results. One way to minimize these errors is to make certain that the different tests are internally consistent. (See "Basic principles in the laboratory evaluation of adrenocortical function".)
Further complicating the diagnosis is the fact that the most common cause of primary adrenal insufficiency, autoimmune adrenalitis, is a process that usually worsens over a period of many months or years. Two groups followed patients with adrenal autoantibodies but no evidence of adrenal insufficiency for three to five years and concluded that there were four stages in the development of adrenal insufficiency:
●Stage 1: High plasma renin activity and normal or low serum aldosterone
●Stage 2: Impaired serum cortisol response to ACTH stimulation
●Stage 3: Increased morning plasma ACTH with normal serum cortisol
●Stage 4: Low morning serum cortisol and overt clinical adrenal insufficiency [6-8]
Thus, by the time the patient has developed low serum cortisol concentrations, adrenal destruction is essentially complete.
Serum cortisol concentration — The diagnosis of adrenal insufficiency of any cause depends entirely upon the demonstration of inappropriately low cortisol production. Most tests use total serum cortisol as the diagnostic measurement. Caution should be taken in interpreting the results in patients with abnormalities of cortisol-binding globulin (CBG) or albumin, such as patients with cirrhosis or nephrotic syndrome, or those taking oral estrogens [9-11]. In these settings, decreased or increased levels may lead to an incorrect diagnosis. Salivary or serum free cortisol have been suggested as alternatives but are not widely available, and criteria for response have not been developed.
Morning serum cortisol concentration — In normal subjects, serum cortisol concentrations are higher in the early morning (about 6 AM), ranging from 10 to 20 mcg/dL (275 to 555 nmol/L), than at other times of the day. An early morning low serum cortisol concentration (less than 3 mcg/dL [80 nmol/L]) is strongly suggestive of adrenal insufficiency (algorithm 2) [12-15].
One report evaluated the utility of basal morning serum cortisol measurements in the diagnosis of adrenal insufficiency [16]. Values below 5 mcg/dL (138 nmol/L) had almost 100 percent specificity, but only 36 percent sensitivity (as defined by a subnormal serum cortisol response to insulin-induced hypoglycemia). Using a higher serum cortisol of 10 mcg/dL (275 nmol/L) as the criterion for adrenal insufficiency increased the sensitivity to 62 percent, but reduced the specificity to 77 percent. Thus, a low morning serum cortisol concentration alone is not a reliable predictor of deficient adrenal function.
Similar considerations apply to high serum cortisol values. A morning serum cortisol concentration of more than 15 mcg/dL (415 nmol/L) predicts a normal serum cortisol response to insulin-induced hypoglycemia or a short ACTH test in virtually all patients [12,16-19]. A morning serum cortisol greater than 18 mcg/dL is even more reassuring, and if increased CBG levels are not suspected (eg, patient is not on estrogen), then no further testing is required (algorithm 2).
However, occasional patients with partial secondary adrenal insufficiency (based on metyrapone or insulin tests, but with normal basal cortisol values) have had an inadequate clinical response to the stress of surgery or sepsis [20]. The overall clinical importance of these observations is not clear because the prevalence of the scenario is not known. Additionally, some studies suggest that normal subjects do not require elevated serum cortisol concentrations after a stress such as major abdominal surgery [20] to survive and recover from the surgery in a normal fashion [21-23].
Morning salivary cortisol concentration — Similarly, a salivary cortisol concentration at 8 AM above 5.8 ng/mL (16 nmol/L) excludes adrenal insufficiency, whereas a value below about 1.8 ng/mL (5 nmol/L) makes the probability of adrenal insufficiency high. The test has been used to screen for adrenal insufficiency, but has not been fully validated as the only diagnostic test. Patients in whom the clinical suspicion is higher or who have low or intermediate values require additional testing. (See "Measurement of cortisol in serum and saliva".)
Afternoon serum cortisol measurements — At 4 PM, normal serum cortisol concentrations range from 3 to 10 mcg/dL (85 to 275 nmol/L); concentrations are at their lowest (less than 5 mcg/dL [140 nmol/L]) one hour after the usual time of sleep, a manifestation of the circadian rhythm in ACTH secretion (figure 1) [24]. As a result, serum cortisol measurements at these times are of no value in establishing the diagnosis of adrenal insufficiency.
Urinary cortisol measurements — As with morning serum cortisol concentrations, basal urinary cortisol excretion is low in patients with severe adrenal insufficiency, but may be low-normal in patients with partial adrenal insufficiency. Thus, they cannot be used as a screening test for adrenal insufficiency. (See "Measurement of urinary excretion of endogenous and exogenous glucocorticoids".)
Subnormal response to acute ACTH stimulation — If it were possible to measure and obtain results of both serum cortisol and plasma ACTH immediately at the time of patient presentation, the diagnosis and cause of adrenal insufficiency could be established without delay in most cases (algorithm 2) [5]. (See "Measurement of ACTH, CRH, and other hypothalamic and pituitary peptides" and "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)
●If serum cortisol is inappropriately low and a simultaneous plasma ACTH concentration is very high, the patient has primary adrenal insufficiency (ie, primary adrenal disease) (algorithm 2). Plasma aldosterone and renin levels should also be determined if primary adrenal insufficiency is suspected.
●If both the serum cortisol and plasma ACTH concentrations are inappropriately low, the patient has secondary (ie, pituitary disease) or tertiary (hypothalamic disease) adrenal insufficiency (algorithm 2). Unfortunately, plasma ACTH results are usually not available immediately and it is important (as with the patient who presents in shock) to determine quickly whether primary adrenal insufficiency is the cause. This can be done indirectly by stimulating the adrenal gland with exogenous ACTH. It is useful to measure plasma ACTH and serum cortisol before injecting the ACTH; however, in the acute setting, the cortisol response will be used to make the diagnosis of adrenal insufficiency and a decision regarding ongoing treatment. The ACTH value, generally available later, can be used to establish the level of the defect.
Short ACTH stimulation tests — A short ACTH stimulation test should be performed in virtually all patients in whom the diagnosis of adrenal insufficiency is being considered, unless the diagnosis has been ruled out by a basal serum cortisol value in the upper end of the reference range or higher. The agent used is synthetic ACTH(1-24) (cosyntropin), which has the full biologic potency of native ACTH(1-39). In healthy individuals, cortisol responses are greatest in the morning, but in patients with adrenal insufficiency, the response to cosyntropin is the same in the morning and afternoon [25-27]. As a result, it is best to perform the test in the morning to avoid a falsely abnormal result in a healthy subject [28]. A standard high-dose and a low-dose test are available. For both tests, a subnormal response confirms the diagnosis of adrenal insufficiency, but further studies are necessary to establish the type and cause.
Details about performing the ACTH stimulation tests and interpreting their results are discussed in detail separately. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test", section on 'ACTH stimulation tests'.)
We agree with the Endocrine Society's 2016 Clinical Practice Guidelines and suggest the 250 mcg standard high-dose test [29].
Standard high-dose test (250 mcg) — A normal response to the high-dose (250 mcg as an intravenous [IV] bolus) ACTH stimulation test is a rise in serum cortisol concentration after either 30 or 60 minutes to a peak of ≥18 mcg/dL (500 nmol/L) (table 1) [26,30-32]. A normal response to the high-dose (250 mcg) ACTH stimulation test excludes primary adrenal insufficiency [33] and most patients with secondary adrenal insufficiency (algorithm 2).
Secondary adrenal insufficiency — In patients with recent onset ACTH deficiency (eg, within one to two weeks after pituitary surgery), the adrenal glands have not yet become completely atrophic and are still capable of responding to ACTH stimulation. The high-dose test performs well when it is performed at least four months after surgery, or nine months after radiation therapy. In one report, only 2 of 137 patients with 30-minute cortisol values between 18.2 and 22.7 mcg/dL (510 and 635 nmol/L, respectively) subsequently developed adrenal insufficiency [34]. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)
Other options include the insulin-induced hypoglycemia or the metyrapone test, although these are utilized less often. (See "Metyrapone stimulation tests" and "Insulin-induced hypoglycemia test".)
Adrenal crisis — In an acutely ill patient with possible adrenal crisis, therapy should be started before the diagnosis is established. It is essential that treatment of patients who present with acute adrenal insufficiency/possible adrenal crisis not be delayed while diagnostic tests are performed. Blood for serum cortisol and serum chemistry (electrolytes) should be drawn; some clinicians also draw and hold samples for later measurement of ACTH, renin, and aldosterone if the diagnosis of adrenal insufficiency is likely.
Therapy should be initiated immediately with intravenous saline and glucocorticoids. (See "Treatment of adrenal insufficiency in adults", section on 'Adrenal crisis'.)
The short ACTH stimulation test can be performed after initiation of glucocorticoid treatment provided that glucocorticoid therapy has not been given for more than a few days, after which it could begin to suppress the hypothalamic-pituitary-adrenal axis and compromise the adrenal response [35].
ESTABLISHING THE LEVEL OF DEFECT — It is important to determine whether the adrenal insufficiency is primary, secondary, or tertiary because it may be due to a disease that has other clinical ramifications, such as tuberculosis in primary adrenal insufficiency or a pituitary tumor in secondary adrenal insufficiency. Cortisol secretion is deficient in patients with primary adrenal insufficiency despite the fact that their ability to secrete corticotropin (ACTH) is intact. Conversely, patients with secondary or tertiary adrenal insufficiency have intrinsically normal but atrophic adrenal glands that are capable of producing cortisol but fail to do so because ACTH secretion is deficient. (See "Causes of secondary and tertiary adrenal insufficiency in adults".)
Basal plasma ACTH, renin, and aldosterone concentration — Measurement of the basal plasma ACTH concentration can usually distinguish between these disorders. Proper specimen collection and handling are important. (See "Measurement of ACTH, CRH, and other hypothalamic and pituitary peptides", section on 'Pitfalls in measurement'.)
When coupled with simultaneous measurement of basal serum cortisol, measurement of plasma ACTH may both confirm the diagnosis of adrenal insufficiency and establish its cause. This measurement can be done with the cortisol when the suspicion is high; alternatively, ACTH can be measured after the diagnosis is established. When there is no urgency in establishing the cause of adrenal insufficiency, as in patients with chronic mild symptoms and signs, treatment decisions may await the results of these tests.
The approach is somewhat different in previously undiagnosed patients who present in hypotensive crisis. These patients may have adrenal insufficiency or one of several other possible diagnoses. Furthermore, adrenal insufficiency, if present, may have been caused by infection, a bleeding diathesis, or metastatic disease that requires prompt diagnosis and treatment. In these patients, measurement of basal serum cortisol will potentially confirm the diagnosis.
While a basal plasma ACTH, renin, and aldosterone measurement may be ordered with the cortisol measurement, treatment must proceed immediately without waiting for the test results. Often resuscitation includes empiric hydrocortisone treatment so that the short ACTH stimulation test cannot be performed immediately. (See "Treatment of adrenal insufficiency in adults".)
●In primary adrenal insufficiency, the 8 AM plasma ACTH concentration is high, sometimes as high as or higher than 4000 pg/mL (880 pmol/L); these patients have mineralocorticoid deficiency in addition to cortisol deficiency, plasma renin concentration or activity will be elevated, while aldosterone levels will be low, with increased serum potassium and decreased serum sodium levels.
●In contrast, plasma ACTH concentrations are low or low normal in secondary or tertiary adrenal insufficiency. The normal value at 8 AM is usually between 20 and 52 pg/mL (4.5 and 12 pmol/L) in a two-site chemiluminescent assay. Plasma levels of renin and aldosterone are usually unaffected in secondary or tertiary adrenal insufficiency, but mineralocorticoid deficiency can sometimes occur after very prolonged deficiency of ACTH. Serum sodium is often decreased with normal serum potassium secondary to increased vasopressin levels resulting from its decreased inhibition by cortisol. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)
When to draw ACTH sample — Because glucocorticoid treatment can suppress ACTH secretion, blood samples for ACTH determination must be drawn before initiating glucocorticoid therapy or, in patients already being treated, at least 24 hours after the last dose of a short-acting glucocorticoid such as hydrocortisone and even longer after long-acting glucocorticoids such as dexamethasone. Clinical judgment must be used to determine whether or not this is safe.
If the patient has been on replacement long-acting glucocorticoid therapy, the steroid should be replaced with hydrocortisone for several days before measuring the morning plasma ACTH. If the sample is drawn in the proper setting and the ACTH assay is reliable, then this measurement by itself is sufficient to establish whether the adrenal insufficiency is primary [33].
Response to prolonged ACTH stimulation — Prolonged stimulation with exogenous ACTH also will distinguish between primary and secondary or tertiary adrenal insufficiency. The atrophic adrenal glands in secondary or tertiary adrenal insufficiency recover cortisol secretory capacity if chronically exposed to ACTH, whereas the adrenal glands in primary adrenal insufficiency are partially or completely destroyed, are already exposed to maximally stimulating levels of endogenous ACTH, and cannot respond to additional ACTH.
Because this test requires hospitalization and is more expensive than measurement of plasma ACTH, it is rarely used except in complicated clinical settings or when the ACTH or cortisol results are non-diagnostic. As an example, a patient treated for presumed adrenal insufficiency may have secondary adrenal insufficiency as a result of treatment. If the initial diagnosis is in question, a prolonged ACTH infusion may be used to differentiate between primary and secondary adrenal insufficiency, so that weaning of the glucocorticoid replacement might be considered. This test is reviewed in more detail separately. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)
Metyrapone tests — The metyrapone tests may be useful in occasional patients in whom partial ACTH deficiency is suspected, particularly in postoperative pituitary surgery patients and others with partial secondary adrenal insufficiency. Metyrapone blocks the final step in cortisol biosynthesis, resulting in reductions in cortisol secretion and the serum cortisol concentration, and stimulation of ACTH secretion in response to the decrease in cortisol negative feedback inhibition. The single-dose overnight metyrapone test is as reliable and quicker than the standard three-day test [36], and has the additional value of being apparently safe for outpatient use [37,38]. The longer test should not be performed in an outpatient in whom adrenal insufficiency is considered a possibility since it will worsen the degree of cortisol deficiency. (See "Metyrapone stimulation tests", section on 'Overnight, single-dose metyrapone test'.)
Metyrapone (Metopirone) is currently available in North America through its new distributor HRA Pharma (Paris, France) via its specialty pharmacy Direct Success Inc. with order forms available on the web (www.metopirone.us) or by phone at 1-855-674-7663; order forms can be faxed to 1-855-674-6767.
Hypocortisolemia is not as strong a stimulus to ACTH secretion as is stress such as that caused by hypoglycemia. As a result, the metyrapone test will detect partial ACTH deficiency that may be missed by the standard ACTH stimulation test [20] or the insulin-induced hypoglycemia test [39,40], which are more potent adrenal stimuli.
Insulin-induced hypoglycemia test — Although insulin-induced hypoglycemia is a valid and perhaps the most rational test of hypothalamic-pituitary-adrenal response to stress, there is little, if any, reason for performing the test except in patients with suspected recent ACTH deficiency or in patients with suspected growth hormone and ACTH deficiency. The test is safe, if a clinician is present, in patients with no history of seizures or cardiovascular or cerebrovascular disease, but otherwise should not be performed. Insulin (usually at a dose of 0.15 units/kg; in patients with low basal cortisol levels, the dose should be reduced to 0.1 units/kg) is given with the aim to achieve hypoglycemia of 35 mg/dL (1.9 mmol/L) or less. Cortisol concentrations are measured at 0, 30, and 45 minutes, even if glucose has been given to reduce symptoms of hypoglycemia. (See "Insulin-induced hypoglycemia test", section on 'Normal values'.)
Corticotropin-releasing hormone test — The differentiation between secondary and tertiary adrenal insufficiency can made by the administration of corticotropin-releasing hormone (CRH), although from a therapeutic standpoint this distinction is seldom important. There is little or no ACTH response in patients with secondary or pituitary-related adrenal insufficiency, whereas patients with tertiary disease due to lack of CRH from the hypothalamus usually have an exaggerated and prolonged ACTH response [41,42]. Other studies found a good concordance between the cortisol responses to insulin and CRH in patients suspected of having secondary adrenal insufficiency of any etiology, but criteria for interpretation differed [43,44]. Also, the CRH test is expensive and requires multiple blood samples. Thus, additional studies are needed to define the optimal test protocol and criteria for interpretation of the test in this setting. (See "Corticotropin-releasing hormone stimulation test".)
Which test? — None of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency in all patients and the results of different tests in a patient may be discordant. As an example, a patient with acute ACTH deficiency may have a normal response to a short ACTH stimulation test but subnormal responses to insulin-induced hypoglycemia or metyrapone, and a patient with partial ACTH deficiency may have a normal response to insulin-induced hypoglycemia but a subnormal response to metyrapone. Insulin induced-hypoglycemia may approximate most closely the hypothalamic-pituitary-adrenal activation that occurs during stress, but inducing hypoglycemia is potentially hazardous. Notwithstanding its limitations, the short high-dose ACTH test is probably the single best (and simplest) test for confirming a diagnosis of chronic secondary adrenal insufficiency [45]. The short low dose ACTH test or the metyrapone test may be substituted if new or recent onset ACTH deficiency is suspected.
DETERMINING THE ETIOLOGY — The approach to identifying the cause of adrenal insufficiency is different in primary versus secondary or tertiary disease. Pituitary computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in the latter to exclude a tumor or other mass lesion. Several other disorders, some of which are treatable, also can cause pituitary or hypothalamic disease. (See "Causes of hypopituitarism".)
Primary adrenal insufficiency — The patient's age and gender, the clinical setting (eg, anticoagulation or possible tuberculosis), and the presence of other autoimmune-mediated endocrine disorders are important in the evaluation of patients with primary adrenal insufficiency (algorithm 1) [7]. (See "Causes of primary adrenal insufficiency (Addison's disease)".)
Abdominal CT should be performed since it can detect enlarged adrenal glands or adrenal calcification; these findings eliminate autoimmune disease and suggest an infectious, hemorrhagic, or metastatic cause (algorithm 1) [46-51]. However, the absence of enlarged or calcified adrenal glands does not exclude tuberculosis as the cause. Measurement of antiphospholipid antibodies can be helpful when hemorrhage is present in a patient not receiving anticoagulants [52]. (See "Diagnosis of antiphospholipid syndrome".)
Patients presenting initially with tuberculous adrenal insufficiency almost always have obvious active tuberculosis elsewhere [46,53]. Chest radiograph, urine culture for Mycobacterium tuberculosis, and tuberculin skin testing should be performed if the diagnosis is not clear. Complement fixation titers for Histoplasma capsulatum should be obtained when appropriate.
CT-directed percutaneous fine needle aspiration of enlarged adrenal glands can establish the cause of the adrenal insufficiency [54,55]. It can, as an example, establish the presence of metastases from a previously unsuspected malignancy, especially small cell lung carcinoma or breast carcinoma. However, the availability of fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan to identify the source of metastasis has reduced the indications for adrenal fine needle aspiration. It is occasionally done as part of the staging of known carcinoma of the lung to plan treatment. However, the treatable causes of primary adrenal insufficiency can almost always be identified by other noninvasive means.
Autoimmune adrenal insufficiency — The diagnosis of autoimmune adrenal insufficiency is based upon the presence of associated autoimmune disorders and the exclusion of other causes. Measuring non-specific anti-adrenal antibodies in serum by indirect immunofluorescence is not useful for establishing the diagnosis. However, a promising strategy detects antibodies directed against 21-hydroxylase (P450c21), which is responsible for the first of the three hydroxylations needed to make cortisol (figure 2 and algorithm 1) [56]. In two studies, this assay identified nearly all patients with autoimmune adrenal insufficiency and was not positive in any patient with adrenoleukodystrophy-associated adrenal insufficiency [56,57]. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune adrenalitis' and "Pathogenesis of autoimmune adrenal insufficiency".)
In patients thought to have autoimmune primary adrenal insufficiency, the presence of other endocrine gland dysfunction should be sought by measuring serum calcium, phosphorus, glucose, and thyrotropin. Serum parathyroid hormone should be measured if the patient is hypocalcemic. Similarly, the possibility of hypogonadism should be investigated in women with oligomenorrhea or amenorrhea by measuring the serum follicle-stimulating hormone and luteinizing hormone and in possibly hypogonadal men by measuring serum testosterone and luteinizing hormone. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
Adrenoleukodystrophy — The presence of X-linked adrenoleukodystrophy and adrenomyeloneuropathy should be excluded in young men, particularly in boys less than 15 years of age, who have idiopathic adrenal insufficiency without accompanying neurologic symptoms (algorithm 1). It is estimated that approximately 8 percent of patients with this disorder have only adrenal involvement, while others may have early or preclinical disease when adrenal insufficiency is diagnosed. This disorder is discussed in detail separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Addison's disease (The Basics)" and "Patient education: Adrenal crisis (The Basics)")
●Beyond the Basics topics (see "Patient education: Adrenal insufficiency (Addison's disease) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●When to suspect the diagnosis – The diagnosis of adrenal insufficiency depends upon having an appropriate level of clinical suspicion. The clinical presentation of adrenal insufficiency is variable, depending on whether the onset is acute, leading to adrenal crisis, or chronic, with symptoms that are more insidious and vague. (See 'General principles' above and "Clinical manifestations of adrenal insufficiency in adults".)
•Adrenal crisis – Adrenal crisis should be considered in any patient who presents with peripheral vascular collapse (vasodilatory shock), whether or not the patient is known to have adrenal insufficiency.
•Chronic adrenal insufficiency – The clinical diagnosis of chronic adrenal insufficiency is often more difficult than that of acute adrenal insufficiency. Early symptoms (such as fatigue and lassitude) are nonspecific.
•Isolated ACTH deficiency – Isolated corticotropin (ACTH) deficiency, although rare, should be considered in any patient who has unexplained severe hypoglycemia or hyponatremia.
•Exogenous glucocorticoid use – Prolonged administration of pharmacologic doses of synthetic glucocorticoids is by far the most common cause of ACTH deficiency and consequent adrenal insufficiency. (See 'Exogenous glucocorticoids' above and "Causes of secondary and tertiary adrenal insufficiency in adults".)
Patients treated with glucocorticoid therapy rarely present with adrenal crisis, although sudden withdrawal of glucocorticoids can result in exacerbation of the disorder for which they were being given (eg, asthma, inflammatory disease, or organ transplantation), symptoms of glucocorticoid deficiency, or hypotension. (See "Clinical manifestations of adrenal insufficiency in adults".)
●Diagnostic evaluation – When evaluating the patient with possible adrenal insufficiency:
•Initial testing – For most patients, we suggest measuring 8 AM serum cortisol and plasma ACTH, and a high-dose 250 mcg ACTH stimulation test (table 1 and algorithm 2).
•Subsequent testing – If adrenal insufficiency is confirmed and ACTH levels are normal or high (ie, primary adrenal insufficiency is the diagnosis), further evaluation for mineralocorticoid deficiency should be performed (plasma renin activity [PRA] or renin concentration and serum aldosterone). (See 'Primary adrenal insufficiency' above.)
The underlying etiology of the adrenal insufficiency should then be determined (algorithm 1). (See 'Determining the etiology' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
