Division of Medical Sciences, University of Birmingham, Birmingham, UK (W Arlt MD); and Department of Medicine, Endocrine and Diabetes Unit, University of Wurzburg, Josef-Schneider Strasse 2, 97080, Wurzburg, Germany (Prof B Allolio MD)

Correspondence to: Prof Bruno Allolio (e-mail: allolio_b@klinik.uniwuerzburg.de).

Wiebke Arlt, Bruno Allolio

Adrenal insufficiency is caused by either primary adrenal failure (mostly due to autoimmune adrenalitis) or by hypothalamic-pituitary impairment of the corticotropic axis (predominantly due to pituitary disease). It is a rare disease, but is life threatening when overlooked. Main presenting symptoms such as fatigue, anorexia, and weight loss are nonspecific, thus diagnosis is often delayed. The diagnostic work-up is well established but some pitfalls remain, particularly in the identification of secondary adrenal insufficiency. Despite optimised life-saving glucocorticoid- replacement and mineralocorticoid-replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought. Dehydroepiandrosterone-replacement therapy has been introduced that could help to restore quality of life. Monitoring of glucocorticoid-replacement quality is hampered by lack of objective methods of assessment, and is therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a challenge, requiring an experienced specialist. However, all doctors should know how to diagnose and manage suspected acute adrenal failure.

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Search strategy

We searched Medline and PubMed for reviews and original articles related to adrenal insufficiency and published between 1966 and December, 2002. Keywords used included adrenal insufficiency and incidence, prevalence, cause, origin, diagnosis, function test, imaging, hydrocortisone, glucocorticoid, mineralocorticoid, dehydroepiandrosterone, management, treatment, therapy, replacement, surveillance, crisis, bone mineral density, quality of life, well-being, disablement, pregnancy, prognosis, morbidity, and mortality. Citations were chosen on the basis of relevance to the specific topics covered.

In 1855, Thomas Addison described a clinical syndrome characterised by wasting and hyperpigmentation, and identified its cause as destruction of the adrenal gland. However, life-saving glucocorticoid-replacement therapy for the condition did not become available until 1949, when Kendall, Sarett, and Reichstein first synthesised cortisone. Furthermore, despite this breakthrough, 150 years on there are still many advances and challenges with respect to the management of individuals with adrenal insufficiency.

Epidemiology

There are two types of adrenal insufficiency, primary and secondary (figure 1). Chronic primary adrenal insufficiency has a prevalence of 93-140 per million and an incidence of 4^.7-6^.2 per million in white populations.^1-4 These recent numbers are higher than those reported during the 1960s and 1970s,^5-6 despite a continuous decline in tuberculous adrenalitis in the developed world, suggesting an increasing incidence of autoimmune adrenalitis.^3,4 The age at diagnosis peaks in the fourth decade of life, with women more frequently affected than men.^1-4

Secondary adrenal insufficiency has an estimated prevalence of 150-280 per million,^3,7-10 and also affects women more frequently than men. Age at diagnosis peaks in the sixth decade of life.^8,9 Therapeutic glucocorticoid administration is thought to be the most common cause of secondary adrenal insufficiency, since chronic administration exogenous glucocorticoids induces atrophy of pituitary corticotroph cells. However, iatrogenic adrenal insufficiency becomes potentially relevant only during or after glucocorticoid withdrawal. Because iatrogenic adrenal insufficiency is transient in most cases,¹¹ we suspect its prevalence to be lower than that of endogenous adrenal insufficiency.

Cause

Primary adrenal insufficiency (panel 1)^12-38

During the times of Thomas Addison, tuberculous adrenalitis was by far the most prevalent cause of adrenal insufficiency and, in the developing world, it remains a major factor.³⁹ In active tuberculosis, the incidence of adrenal involvement is 5%.⁴⁰ In developed countries, 80-90% of patients with primary adrenal insufficiency have autoimmune adrenalitis, which can arise as isolated (40%; slight male preponderance) or as part of an autoimmune polyendocrine syndrome ([APS]; 60%; female preponderance).^12,41 APS type 1, also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), arises in up to 15% of patients with autoimmune adrenalitis. It is characterised by adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis with onset during childhood.^12,42 APECED might also comprise the autoimmune disorders seen in APS type 2, and in addition, childhood alopecia (40% of APECD patients), chronic active hepatitis (20%), and malabsorption (15%).¹² APECED is caused by mutations in the autoimmune regulator (AIRE) gene^13,14 and is inherited in an autosomal- recessive fashion. APS type 2 is the most frequently seen APS and comprises adrenal insufficiency and autoimmune thyroid disease. The clinical spectrum also includes primary gonadal failure, type 1 diabetes mellitus, and other autoimmune diseases such as vitiligo, chronic atrophic gastritis, or coeliac disease. APS type 2 occurs with autosomal-dominant inheritance with incomplete penetrance, and shows a strong association with HLA- DR3^12,43 and CTLA-4.^44,45 The combination of adrenal insufficiency with other autoimmune disorders, but without thyroid disease, is classified as APS type 4, and APS type 3 involves autoimmune thyroid disease but not adrenal insufficiency.

Primary and secondary adrenal insufficiency. CRH=corticotropin-releasing hormone.

X-linked adrenoleukodystrophy is caused by a mutation in the ABCD1 gene,⁴⁶ which encodes a peroxisomal membrane protein (adrenoleukodystrophy protein),⁴⁷ leading to accumulation of very-long-chain fatty acids (>24 carbon atoms). The clinical picture comprises adrenal insufficiency and neurological impairment due to white- matter demyelination. The two major forms are cerebral adrenoleukodystrophy (50% of cases; early childhood manifestation; rapid progression) and adrenomyelo- neuropathy (35% of cases; onset in early adulthood; slow progression) with restriction of demyelination to spinal cord and peripheral nerves.¹⁶ Adrenal insufficiency can precede the onset of neurological symptoms and is the sole manifestation of disease in 15% of cases.¹⁶

Other causes of primary adrenal insufficiency—eg, adrenal infiltration or haemorrhage—are rare. Congenital or neonatal primary adrenal insufficiency accounts for only 1% of all cases. However, the elucidation of the genetic basis of underlying diseases has emphasised the importance of specific genes for adrenal development and steroidogenesis (panel 1).

Secondary adrenal insufficiency (panel 2)^48-55

The most frequent cause of secondary adrenal insufficiency is a tumour of the hypothalamic-pituitary region, usually associated with panhypopituitarism caused by tumour growth or treatment with surgery or irradiation. Autoimmune lymphocytic hypophysitis is less frequent, mostly affecting women during or shortly after pregnancy. Isolated adrenocorticotropic hormone (ACTH) deficiency could also be of autoimmune origin since some patients concurrently have other autoimmune disorders, most frequently thyroid disease.⁴⁹ The differential diagnosis of postpartum autoimmune hypophysitis includes Sheehan’s syndrome, which results from pituitary apoplexy, mostly due to pronounced blood loss during delivery. Very rarely mutations of genes important for pituitary development or for synthesis and processing of the corticotropin precursor proopiomelanocortin cause secondary adrenal insufficiency (panel 2).

Pathophysiology and clinical presentation (panel 3)

Glucocorticoids are secreted from the adrenal zona fasciculata under the control of hypothalamic corticotropinreleasing hormone and pituitary corticotropin. Cortisol secretion is diurnal with maximum concentrations measured early in the morning and trough concentrations noted around midnight.⁵⁶ Mineralocorticoids are produced by the zona glomerulosa, mainly under the control of the renin- angiotensin system. Thus, mineralocorticoid secretion is preserved in secondary adrenal insufficiency. Dehydroepiandrosterone secretion by the zona reticularis is also diurnal and is acutely increased by ACTH. However, although cortisol secretion varies little throughout life, dehydroepiandrosterone secretion is age dependent, with an increase noted at age 6-10 years (adrenarche), which continues until age 20-30 years. Thereafter, dehydroepian- drosterone concentrations steadily fall. This pattern suggests the existence of ACTH-independent factors, controlling release of dehydroepiandrosterone.⁵⁷

Patients with acute adrenal insufficiency—ie, life- threatening adrenal crisis—typically present with severe hypotension or hypovolaemic shock, acute abdominal pain, vomiting, and often fever. Such individuals are, therefore, sometimes misdiagnosed as having an acute abdomen. In a series of 91 patients with Addison’s disease,⁵⁸ adrenal crisis led to the initial diagnosis of adrenal insufficiency in half of them. In children, acute adrenal insufficiency often presents as hypoglycaemic seizures. Deterioration of glycaemic control with recurrent hypoglycaemia can be the presenting sign of adrenal insufficiency in patients with pre-existing type 1 diabetes. In APS type 2, onset of autoimmune hyperthyroidism (or thyroxine replacement for newly diagnosed hypothyroidism) can precipitate adrenal crisis due to enhanced cortisol clearance.

The main symptom of chronic adrenal insufficiency is fatigue, accompanied by lack of stamina, loss of energy, reduced muscle strength, and increased irritability.

Additionally, chronic glucocorticoid deficiency leads to weight loss, nausea, and anorexia (anorexia or failure to thrive in children), and can account for muscle and joint pain. Unfortunately, most of these symptoms are non-specific. Thus, 50% of patients have signs and symptoms of Addison’s disease for more than 1 year before diagnosis is established.⁵⁸ In secondary adrenal insufficiency, diagnosis is generally prompted by a history of pituitary disease, but can also be delayed—eg, in isolated ACTH deficiency. A more specific sign of primary adrenal failure is hyperpigmentation, which is most pronounced in areas of the skin exposed to increased friction—eg, palmar creases, knuckles, scars, oral mucosa. Hyperpigmentation is caused by enhanced stimulation of skin MCl-receptor by ACTH and other pro-opiomelanocortin- related peptides. Accordingly, patients with secondary adrenal insufficiency often have pale, alabaster-coloured skin. Laboratory findings in glucocorticoid deficiency can include mild anaemia, lymphocytosis, and eosinophilia. Cortisol physiologically inhibits thyrotropin release. Thus, concentration of thyrotropin is often increased at initial diagnosis of primary adrenal insufficiency, but returns to normal during glucocorticoid replacement unless there is coincident autoimmune thyroid dysfunction.⁵⁹ In rare cases, glucocorticoid deficiency can result in hypercalcaemia, which is due to increased intestinal absorption and decreased renal excretion of calcium and generally coincides with autoimmune hyperthyroidism, facilitating calcium release from bone.⁶⁰

Mineralocorticoid deficiency, which is present only in primary adrenal insufficiency (figure 2), leads to dehydration and hypovolaemia, resulting in low blood pressure, postural hypotension, and sometimes even in prerenal failure. Deterioration can be sudden and is often due to exogenous stress such as infection or trauma. Combined mineralocorticoid and glucocorticoid replacement in primary disease reconstitutes the diurnal rhythm of blood pressure⁶¹ and reverses cardiac dysfunction.⁶² Glucocorticoids contribute to this improvement not only by mineralocorticoid receptor binding, but also by permissive effects on catecholamine action.⁶³ The latter could account for the relative unresponsiveness to catecholamines in patients with unrecognised adrenal crisis. Mineralocorticoid deficiency accounts for hyponatraemia (90% of patients with primary adrenal insufficiency), hyperkalaemia (65%), and salt craving (15%).^1,6 Low serum sodium values can also be present in secondary adrenal insufficiency due to syndrome of inappropriate antidiuretic hormone secretion, which results from the loss of physiological inhibition of pituitary vasopressin release by glucocorticoids.⁶⁴

Adrenal insufficiency inevitably leads to dehydro- epiandrosterone deficiency. Dehydroepiandrosterone is the major precursor of sex-steroid synthesis and loss of its production results in pronounced androgen deficiency in women. As a consequence, women with adrenal insufficiency frequently show loss of axillary and pubic hair (absence of pubarche in children), dry skin, and reduced libido. Dehydroepiandrosterone also exerts direct action as a neurosteroid with potential antidepressant properties.⁵⁷ Thus dehydroepiandrosterone deficiency could contribute to the impairment of wellbeing noted in patients with adrenal insufficiency despite adequate glucocorticoid and mineralocorticoid replacement.⁶⁵

Laboratory assessment of adrenal function (panel 4)

Concentrations of ACTH and cortisol vary throughout the day due to their closely related pulsatile release, which follows a diurnal rhythm. Therefore, the diagnostic usefulness of random samples is limited. Moreover, total cortisol, but not the biologically active free fraction, can increase as a result of hepatic cortisol-binding globulin production, which is increased, for example, by oestrogens.⁶⁶ Finally, differences in cortisol assays can affect normative data and interpretation of dynamic tests.⁶⁷

Primary adrenal insufficiency

The combined measurement of early morning serum cortisol and plasma ACTH separates patients with primary adrenal insufficiency from healthy individuals and from those with secondary disease.⁶⁸ Plasma ACTH is usually greatly increased and invariably higher than 22-0 pmol/L, with serum cortisol generally lower than the normal range (<165 nmol/L) but sometimes in the lower normal range. Serum aldosterone concentrations are subnormal or within the lower normal range, with plasma renin activity concurrently increased above the normal range.⁶⁸ In patients who have adrenal insufficiency, serum dehy- droepiandrosterone is consistently low,^69,70 and in women is often lower than the limit of detection.

The impaired ability of the adrenal cortex to respond to ACTH is readily demonstrated by the standard short corticotropin test,⁷¹ which involves measurement of serum cortisol before and after 30 or 60 min intravenous or intramuscular injection of 250 μg 1-24 ACTH.^66,72 In healthy individuals, this challenge leads to a physiological increase in serum cortisol to peak concentrations of greater than 500 nmol/L.⁶⁷ In those with primary adrenal insufficiency, in whom the adrenal cortex is already maximally stimulated by endogenous ACTH,⁶⁸ exogenous hormone administration usually does not evoke any further increase in serum cortisol.

Adrenal cortex autoantibodies or antibodies against 21-hydroxylase are present in more than 80% of patients with recent onset autoimmune adrenalitis.⁷³ Although 21-hydroxylase has been identified as the major autoantigen in autoimmune adrenalitis,⁷⁴ autoantibodies against other steroidogenic enzymes (P450scc, P450c17) and steroid-producing cell antibodies are present in some patients.¹² Measurement of autoantibodies is especially helpful in patients with isolated primary adrenal insufficiency and no family history of autoimmune disease. In APS type 2, autoimmune adrenalitis can be associated with autoimmune thyroid disease or type 1 diabetes, and screening for concomitant disease should involve measurement of thyrotropin and fasting glucose but not of other organ-related antibodies.

In boys and men with isolated primary adrenal insufficiency without unequivocal evidence of autoimmune adrenalitis, serum concentrations of very- long-chain fatty acids (chain length of ≥24 carbons; C26, C26/C22, and C24/C22 ratios) should be measured to exclude adrenoleukodystrophy or adrenomyeloneu- ropathy.¹⁶

Secondary adrenal insufficiency

Baseline hormone measurements differ little between patients with secondary adrenal insufficiency and healthy individuals.^16,68 However, a morning cortisol value below 100 nmol/L indicates adrenal insufficiency whereas a serum cortisol greater than 500 mmol/L is consistent with an intact hypothalmic-pituitary-adrenal axis.^72,75,76 Thus, in most instances, dynamic tests of the hypothalmic- pituitary-adrenal axis are required to establish a diagnosis of secondary adrenal insufficiency.

The insulin tolerance test⁷⁷ is regarded as the gold standard in the assessment of suspected secondary adrenal insufficiency, since hypoglycaemia (blood glucose <2-2 mmol/L) is a powerful stressor that results in rapid activation of the hypothalamic-pituitary-adrenal axis.⁶⁶ An intact axis is indicated by a peak cortisol of more than 500 nmol/L at any time during the test (panel 4).^78,79 Occasionally, however, a patient will pass the insulin tolerance test despite exhibiting clinical evidence for adrenal insufficiency that responds to hydrocortisone substitution.⁸⁰ A higher cut-off value (550 nmol/L) for peak cortisol in the insulin tolerance test could help to reduce misclassification.^79,81 During the test, close supervision is mandatory⁶⁶ and cardiovascular disease or history of seizures are contraindications.

Another diagnostic test is the overnight metyrapone test (metyrapone 30 mg/kg [maximum 3 g] administered with a snack at midnight).^82,83 Metyrapone inhibits adrenal 11β-hydroxylase—ie, the conversion of 11-deoxycortisol to cortisol. In healthy individuals, feedback activation of the hypothalmic-pituitary-adrenal axis increases serum 11-deoxycortisol, while serum cortisol remains at concentrations of less than 230 nmol/L. In patients with secondary adrenal insufficiency, however, 11-deoxycortisol does not exceed 200 nmol/L at 0800 h after metyrapone. Shortcomings of the test are limited availability of reliable 11-deoxycortisol assays and the need to order metyrapone directly from the manufacturer (Novartis, Basel, Switzerland). Since metyrapone can precipitate adrenal crisis in severe cortisol deficiency, a morning cortisol concentration of more than 200 nmol/L should be recorded before doing the test on an out patient basis.⁶⁶

Because both the insulin tolerance test and the metapyrone test pose a great burden to patients and doctors, there have been continuing efforts to replace these tests by more convenient ones.^78,84-86 Sustained secondary adrenal insufficiency leads to adrenal atrophy and also to reduced ACTH receptor expression in the adrenal gland, since ACTH up-regulates its own receptor.⁸⁷ Thus adrenal responsiveness to an acute exogenous ACTH challenge is impaired also in secondary disease, facilitating the use of the standard short corticotropin test for the assessment of axis integrity (panel 4). Several studies^72,88 have reported excellent agreement between peak cortisol concentrations in the standard short corticotropin test and in the insulin tolerance test. However, some patients with secondary adrenal insufficiency do pass the standard short corticotropin test but not the insulin tolerance test.^89-91 The use of a higher cut-off value (600 nmol/L) for passing the corticotropin test could keep to a minimum the risk of overlooking secondary disease.⁹² Thus the standard short corticotropin test obviates the insulin tolerance test in a substantial proportion of patients with suspected secondary adrenal insufficiency.

Since the administration of 250 μg 1-24 ACTH represents a massive supraphysiological challenge, a low-dose corticotropin test that uses only 1 μg ACTH has been proposed as a more sensitive test for the diagnosis of secondary adrenal insufficiency.^93,96 The test has been successfully used to monitor recovery of adrenal function after withdrawal of oral glucocorticoids¹¹ and to detect subtle impairment of adrenal reserve during inhaled steroid therapy.^97,98 However, the intravenous administration of 1 μg ACTH still results in hormone concentrations greater than those required for maximum cortisol release.⁹⁹ Accordingly, in healthy individuals, serum cortisol concentrations measured 30 min after the challenge do not differ between the standard short corticotropin test and the low-dose corticotropin test. Results of several studies, comparing the two tests for the assessment of patients with secondary adrenal insufficiency, have indicated a slightly improved sensitivity of the low-dose corticotropin test.^95,96 However, this advantage is offset by handling difficulties caused by the need to dilute the test amount from the commercially available 250 μg 1-24 ACTH ampoule and because of the potential binding of the hormone to the surface of injection devices.¹⁰⁰

Corticotropin releasing hormone has been used to differentiate hypothalamic from pituitary disease in secondary adrenal insufficiency. However, stimulation of the hormone is not of great help in actually diagnosing the condition, because individual responses to exogenous corticotropin releasing hormone are highly variable and cut-off values or even normal ranges are still not well defined.⁶⁶

Finally, a word of caution: none of the tests, including the insulin tolerance test, classify all patients correctly. Mild secondary adrenal insufficiency can pass as intact hypothalamic-pituitary-adrenal axis, and healthy individuals might fail any single test by a small margin. Thus, clinical judgment remains important. Persisting symptoms such as fatigue, myalgia, or reduced vitality should lead to reassessment.

Special diagnostic situations

Adrenal insufficiency after pituitary surgery

Screening for adrenal insufficiency with the standard short corticotropin test or with the low-dose corticotropin test should be done 4-6 weeks or more after surgery for pituitary surgery,^76,101 since adrenal atrophy can develop only gradually after onset of ACTH deficiency. Until then, patients with a morning cortisol not excluding secondary adrenal insufficiency (<450 nmol/L at 3 days and <350 nmo/L at 7 days after surgery) should receive hydrocortisone replacement, withheld for 24 h before scheduled testing of adrenal function.¹⁰² The impairment of other hormonal axes after pituitary surgery increases the likelihood of ACTH deficiency,¹⁰³ whereas isolated corticotropin deficiency is uncommon.

Adrenal insufficiency in critically ill patients

In critically ill patients, the corticotropic axis is greatly activated.^104,105 Moreover, patients in intensive care are less sensitive to dexamethasone suppression and achieve higher peak ACTH and cortisol concentrations after administration of corticotropin-releasing hormone.¹⁰⁶ Critically ill patients also have fairly low serum concentrations of aldosterone with concurrently raised plasma renin activity.¹⁰⁷ Cortisol concentrations correlate with illness-severity scores and are highest in individuals with the highest mortality.^106,108 However, cytokine activation might impair the adequate responsiveness of pituitary corticotrpic cells leading to secondary adrenal insufficiency in some patients with severe illness, thus putting them at risk of dying from adrenal crisis.

Chronic inhibition of cortisol production by etomidate has been associated with increased mortality in patients in intensive care.^36,37 Unfortunately, no consensus exists about how to diagnose adrenal insufficiency in these individuals.¹⁰⁹ In patients with primary or severe secondary adrenal insufficiency the standard short corticotropin test will establish a diagnosis by indicating a low baseline cortisol (<165 nmol/L) not responding to corticotropin (peak cortisol <500 nmol/L). However, partial secondary adrenal insufficiency might be present in some critically ill patients, characterised by a poor cortisol response (increment <248 nmol/L¹¹⁰) to ACTH despite normal baseline cortisol. These patients often present with catecholamine-dependent hypodynamic shock that responds to treatment with hydrocortisone.^109,111 Findings of a study showed decreased mortality in patients with septic shock and abnormal cortisol response in the standard short corticotropin test (increment <248 nmol/L) after treatment with replacement doses of hydrocortisone and fludrocor-tisone.¹¹²

We recommend that a random sample of serum cortisol and plasma ACTH is obtained from critically ill patients with suspected adrenal insufficiency followed by immediate hydrocortisone administration. Dependent on the results of these hormone measurements (serum cortisol >700 nmol/L rules out adrenal insufficiency) hydrocortisone therapy should be terminated or a more detailed assessment with the standard short corticotropin test undertaken.

Imaging

Adrenal imaging is not indicated in patients with an unequivocal diagnosis of autoimmune adrenalitis or adrenomyeloneuropathy. If infection, haemorrhage, infiltration, or neoplastic disease is suspected, abdominal CT scans should be done. In adrenal tuberculosis, bilateral enlargement is present in the subacute phase,¹¹³ whereas calcifications develop during later stages.¹¹⁴

In secondary adrenal insufficiency of unknown origin, MRI of the hypothalamic-pituitary region is the method of choice to reveal a space-occupying lesion. Only pituitary adenomas with a diameter of greater than 1 cm will cause secondary adrenal insufficiency; smaller microadenomas are coincident. Lymphocytic hypo- physitis might initially present as pituitary enlargement, sometimes leading to the misdiagnosis of a pituitary tumour, whereas the long-term course leads to pituitary atrophy and subsequent empty sella.

Mean age 51 (SD 14) years and mean duration of disease 10 (7) years.

Frequency of signs and symptoms during chronic replacement therapy for adrenal insufficiency in a series of our patients (n=53)

Treatment

Chronic replacement therapy

Glucocorticoid replacement is usually given in two or three daily doses, with a half to two-thirds of the daily dose administered in the morning to mimic the physiological cortisol secretion pattern. Findings of studies indicate that daily cortisol production rates vary between 5 mg/m² and 10 mg/m²,^115-118 equivalent to the oral administration of 15-25 mg hydrocortisone (cortisol) or 25^.0-37^.5 mg cortisone acetate.^119-120 Cortisone acetate requires conversion to cortisol by 11 p-hydroxysteroid dehydrogenase type 1. Administration of hydrocortisone or cortisone acetate results in peak serum cortisol concentrations that vary substantially between individuals but that are generally within the supraphysiological range, followed by a rapid decline to below 100 nmol/L 5-7 h after ingestion.^120-122 Whether a three-times-daily regimen of glucocorticoid administration should be preferred over a twice-daily one is not clear. The only study addressing this issue123 claimed improved effects of a three-times-daily regimen on measures of quality of life.¹²³ However, the number of patients included (seven) was small, with six switched from three times to twice daily, but only one from twice to three times daily. Furthermore, the intervention was open-label and not blinded. Additionally, the second dose in the twice-daily regimen was administered at 2000 h and thus is unusually late. In general, if a twice daily regimen is applied, the second dose should be administered about 6-8 h after the first. Long-acting glucocorticoids are also used for replacement (1 mg hydrocortisone=1^.6 mg cortisone acetate=0^.2 mg prednisolone=0^.05 mg dexamethasone). Prednisolone and dexamethasone have much longer biological half-lives than hydrocortisone and cortisone acetate, which could result in unfavourably high night-time glucocorticoid activity.

Treatment surveillance of chronic glucocorticoid replacement is mainly based on clinical grounds because no objective assessment has proven to be reliable for monitoring replacement quality. ACTH cannot be used as a criterion for glucocorticoid dose adjustment, since in primary adrenal insufficiency it is invariably high before the morning dose and rapidly declines with increasing cortisol concentrations after glucocorticoid ingestion.122,124 Aiming at morning ACTH values continuously within the normal range would, therefore, lead to chronic overreplacement. However, in case of reappearance of skin hyperpigmentation in primary adrenal insufficiency, concentrations of plasma ACTH should be measured.

Urinary 24 h free cortisol excretion has been advocated for monitoring replacement.^125,126 However, after exogenous glucocorticoid administration, urinary cortisol excretion shows considerable between-individual variability.¹²⁰ More importantly, after glucocorticoid absorption cortisolbinding globulin will be rapidly saturated,¹²⁷ resulting in transient but pronounced increases in renal cortisol excretion. Thus, one cannot refer to normal ranges for healthy individuals when judging urinary cortisol excretion during replacement therapy in adrenal insufficiency. However, in cases of suspected under-replacement—eg, due to non-adherence—urinary cortisol measurements could be helpful.

To measure a random serum cortisol without knowing the exact time of preceding glucocorticoid administration is not helpful in monitoring glucocorticoid replacement. Some researchers have suggested regular measurements of serum cortisol day curves during replacement therapy, aiming at serum cortisol concentrations within the normal range.^126,128 However, due to their pharmacokinetic properties, none of the exogenous glucocorticoids currently used is suitable to mimic the diurnal cortisol pattern noted in healthy individuals.

Thus, in the absence of objective variables to measure replacement quality, the doctor has to rely primarily on clinical judgment, taking into account signs and symptoms potentially suggestive of glucocorticoid overreplacement or under-replacement (table). Underreplacement bears the risk of incipient crisis and severe impairment of wellbeing. Conversely, chronic overreplacement can lead to substantial morbidity, including impaired glucose tolerance,¹²⁹ obesity, and osteoporosis.^130,131 With recommended replacement doses of 15-25 mg hydrocortisone osteoporosis is not to be expected.¹³² Therefore, bone-mineral-density measure-ments are not required for regular monitoring in adrenal insufficiency.

Mineralocorticoid replacement (only required in primary adrenal insufficiency) consists of oral administration of 0^.05-0^.2 mg fludrocortisone. Monitoring includes measurement of blood pressure, serum sodium, and potassium and plasma renin activity, aiming at concentrations within the middle or upper normal range (panel 5).⁶⁸ If primary hypertension develops during the long-term course of adrenal insufficiency, mineralocorticoid replacement can be gradually reduced, accompanied by monitoring of serum sodium and potassium. Glucocorticoids also contribute to the mineralocorticoid pool, since they bind to the mineralocorticoid receptor. However, excessive binding is prevented by 11 p-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone. With respect to mineralocorticoid potency, 20 mg hydrocortisone is equivalent to 0^.05 mg fludrocortisone.⁶⁸

Replacement of dehydroepiandrosterone has positive effects on wellbeing and mood in patients with primary and secondary adrenal insufficiency.^69,70,133 Treatment is hampered by the lack of pharmaceutically controlled preparations and larger-scale studies are underway. In the meantime, dehydroepiandrosterone should be reserved for patients whose wellbeing is greatly impaired despite optimimum glucocorticoid and mineralocor- ticoid replacement. Doses of 25-50 mg dehy- droepiandrosterone should be taken as one dose in the morning. Treatment surveillance should include measurement of serum dehydroepiandrosterone sulphate, aiming at the middle normal range for healthy young people (panel 5). Dose recommendations for elderly patients with adrenal insufficiency, who would physiologically experience an age-associated decline in serum dehydroepiandrosterone sulphate, remain to be established.

Prevention and management of adrenal crisis

In a series of 53 patients with chronic adrenal insufficiency, representing 511 replacement-years, we noted an overall risk of adrenal crisis needing hospital admission of 3^.3 per 100 years. Risk of crisis was much higher in primary adrenal insufficiency (3^.8 per 100 vs 2^.5 per 100 years) and in women (4^.4 per 100 vs .⁶ per 100 years) with the highest overall risk in women with autoimmune adrenalitis (6^.5 per 100 years). Most crises were due to glucocorticoid dose reduction or lack of stress-related dose adjustment by patients or family practitioners. Inappropriate stress-related glucocorticoid adjustment occurs more often in patients older than age 60 years.134 All patients and their partners should receive regular crisis prevention training, including verification of steroid emergency card or bracelet and instruction on stress-related glucocorticoid dose adjustment. Patients should add 5-10 mg hydrocortisone to their normal regimen shortly before strenuous activities—eg, hiking. More severe physical stress such as fever requires doubling of daily doses until recovery. In instances of vomiting or diarrhoea, glucocorticoids should be administered parenterally. Some doctors advocate a hydrocortisone emergency supply for rectal or parenteral self-administration.135,136 For major surgery, trauma, and diseases that require monitoring in intensive care, patients should receive intravenous infusions of 100-150 mg hydrocortisone in 5% glucose per 24 h. Results of some studies137,138 advocate lower doses (25-75 mg per 24 h) for minor or moderate surgical stress.

Management of acute adrenal crisis consists of immediate intravenous administration of 100 mg hydrocortisone followed by 100-200 mg per 24 h and continuous infusion of larger volumes of physiological saline solution (initially 1 L/h) under continuous cardiac monitoring. With daily hydrocortisone doses of 50 mg or more, mineralocorticoid replacement in primary adrenal insufficiency can be reduced because this dose is equivalent to 0-1 mg fludrocortisone.68 In case of newly diagnosed (or suspected) adrenal insufficiency, treatment must not be delayed by diagnostic work-up. Baseline blood samples for ascertainment of cortisol and ACTH (optional: plasma renin activity, aldosterone, dehydroepiandrosterone sulphate) should be drawn immediately before hydrocortisone administration.

Special therapeutic situations

Thyroid dysfunction

Hyperthyroidism increases cortisol clearance.¹²⁰ In patients with adrenal insufficiency and unresolved hyperthyroidism, glucocorticoid replacement should be doubled or tripled. To avoid adrenal crisis, thyroxine replacement for hypothyroidism should only be initiated after concomitant glucocorticoid deficiency has either been excluded or treated.

Pregnancy

Pregnancy is physiologically associated with a gradual increase in cortisol-binding globulin and, during the last term, also in free cortisol.¹³⁹ Serum progesterone concentrations also increase, exerting antimineralocorticoid action. Therefore, during the third trimester, hydrocortisone replacement should be increased by 50%. Mineralocorticoids should be adjusted according to blood pressure and serum potassium. Plasma renin activity cannot be used in monitoring because it physiologically increases during pregnancy.¹⁴⁰ Peripartum hydrocortisone replacement should follow the requirements for major surgery—ie, 100 mg per 24 h starting with labour and continuing until 48 h after delivery, followed by rapid tapering.

Drug interactions

Treatment of tuberculosis with rifampicin increases cortisol clearance¹⁴¹ but does not affect aldosterone clearance.¹⁴² Thus, glucocorticoid replacement should be doubled during rifampicin treatment.

Mitotane decreases bioavailable glucocorticoid concentrations because of an increase in cortisol-binding globulin and enhanced glucocorticoid metabolism. During chronic mitotane treatment—eg, in adrenal carcinoma— usual glucocorticoid replacement doses should, therefore, be doubled or tripled.³⁵

Quality of life, disablility, and prognosis

Prospective data¹⁰ indicate excess mortality in hypopituitarism, including secondary adrenal insufficiency, mainly due to vascular and respiratory disease. However, deficiencies of other hormonal axes could also contribute. Mortality in patients with primary adrenal insufficiency has not been studied. Nevertheless, life expectancy may be reduced as a consequence of unrecognised adrenal crisis, underlying illness—eg, adrenomyeloneuropathy—and other as yet unidentified causes.⁴

Despite adequate glucocorticoid and mineralocorticoid replacement, health-related quality of life is greatly impaired in patients with primary⁶⁵ and secondary adrenal insufficiency.¹⁴³ Predominant complaints are fatigue, lack of energy, depression, and anxiety.^65,69,70 In addition, affected women frequently complain about impaired libido. In a survey of 91 individuals, 50% of patients with primary adrenal insufficiency considered themselves unfit to work and 30% needed household help.¹⁴⁴ In another survey of 88 individuals the number of patients who received disablility pensions was two to three times higher than in the general population.⁶⁵ The adverse effect of chronic adrenal insufficiency on health-related quality of life is comparable to that of congestive heart failure.⁶⁵ However, fine-tuning of glucocorticoid replacement leaves only a narrow margin for improvement, and changes in timing or dose do not result in improved wellbeing.^145,146 Dehydroepiandrosterone replacement in adrenal insufficiency can improve wellbeing, mood,^69,70,133 and—in women—libido,⁶⁹ and opens up the prospect of improving quality of life for patients with chronic adrenal insufficiency.

Conflict of interest statement

W Arlt and B Allolio serve as consultants to Paladin Labs, Montreal, Canada, and to Euphar Corporation, Piacenza, Italy, which are both involved in the development of a pharmaceutically controlled dehydroepiandrosterone preparations.

Acknowledgments

W Arlt is a DFG Heisenberg Senior Clinical Fellow (Ar 310/3-1) and B Allolio is the recipient of DFG project grant Al 293/7-4. The funding source had no role in the writing of this Seminar.

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References

Kong MF, Jeffcoate W. Eighty-six cases of Addison’s disease. Clin Endocrinol (Oxf) 1994; 41: 757-61.  

Willis AC, Vince FP. The prevalence of Addison’s disease in Coventry, UK. Postgrad Med J 1997; 73: 286-88.  

Laureti S, Vecchi L, Santeusanio F, Falorni A. Is the prevalence of Addison’s disease underestimated? J Clin Endocrinol Metab 1999; 84: 1762.  

Lovas K, Husebye ES. High prevalence and increasing incidence of Addison’s disease in western Norway. Clin Endocrinol (Oxf) 2002; 56: 787-91.  

Mason AS, Meade TW, Lee JA, Morris JN. Epidemiological and clinical picture of Addison’s disease. Lancet 1968; 2: 744-7.  

Nerup J. Addison’s disease: clinical studies—a report of 108 cases. Acta Endocrinol (Copenh) 1974; 76: 127—41.  

Bates AS, Van’t Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996; 81: 1169-72.  

Nilsson B, Gustavasson-Kadaka E, Bengtsson BA, Jonsson B. Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality. J Clin Endocrinol Metab 2000; 85: 1420-25.  

Regal M, Paramo C, Sierra SM, Garcia-Mayor RV. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf) 2001; 55: 735-40.  

Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425-31.  

Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 2000; 355: 542-5.  

Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002; 23: 327-64.  

Nagamine K, Peterson P, Scott HS, et al. Positional cloning of the APECED gene. Nat Genet 1997; 17: 393-98.  

An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997; 17: 399-403.  

Findling JW, Buggy BP, Gilson IH, Brummitt CF, Bernstein BM, Raff H. Longitudinal evaluation of adrenocortical function in patients infected with the human immunodeficiency virus. J Clin Endocrinol Metab 1994; 79: 1091-96.  

Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997; 120: 1485-508.  

White PC, Dupont J, New MI, Leiberman E, Hochberg Z, Rosler A. A mutation in CYP11B1 (Arg-448—His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest 1991; 87: 1664-67.  

Rheaume E, Simard J, Morel Y, et al. Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene. Nat Genet 1992; 1: 239-45.  

Bose HS, Sugawara T, Strauss JF, 3rd, Miller WL. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 1996; 335: 1870-78.  

Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL. Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab 2001; 86: 3820-25.  

Wassif CA, Maslen C, Kachilele-Linjewile S, et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet 1998; 63: 55-62.  

Fitzky BU, Witsch-Baumgartner M, Erdel M, et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci USA 1998; 95: 8181-86.  

Zanaria E, Muscatelli F, Bardoni B, et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994; 372: 635-41.  

Francke U, Harper JF, Darras BT, et al. Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: molecular genetic evidence for deletions. Am J Hum Genet 1987; 40: 212-27.  

Achermann JC, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999; 22: 125-26.  

Vilain E, Le Merrer M, Lecointre C, et al. IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. J Clin Endocrinol Metab 1999; 84: 4335-40.  

Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol (Oxf) 1992; 37: 97-103.  

Boles RG, Roe T, Senadheera D, Mahnovski V, Wong LJ. Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease. Eur JPediatr 1998; 157: 643-7.  

Tsigos C, Arai K, Hung W, Chrousos GP. Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest 1993; 92: 2458-61.  

Weber A, Clark AJ. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet 1994; 3: 585-88.  

Tullio-Pelet A, Salomon R, Hadj-Rabia S, et al. Mutant WD-repeat protein in triple-A syndrome. Nat Genet 2000; 26: 332-35.  

Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet 2001; 10: 283-90.  

Satta MA, Corsello SM, Della Casa S, et al. Adrenal insufficiency as the first clinical manifestation of the primary antiphospholipid antibody syndrome. Clin Endocrinol (Oxf) 2000; 52: 123-26.  

Lutz A, Stojkovic M, Schmidt M, Arlt W, Allolio B, Reincke M. Adrenocortical function in patients with macrometastases of the adrenal gland. Eur J Endocrinol 2000; 143: 91-97.  

Robinson BG, Hales IB, Henniker AJ, et al. The effect of o,p'-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf) 1987; 27: 437-44.  

Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983; 1: 1270.  

Allolio B, Stuttmann R, Fischer H, Leonhard W, Winkelmann W. Long-term etomidate and adrenocortical suppression. Lancet 1983; 2: 626.  

Stein CA, Saville W, Yarchoan R, Broder S, Gelmann EP. Suramin and function of the adrenal cortex. Ann Intern Med 1986; 104: 286-87.  

Soule S. Addison’s disease in Africa: a teaching hospital experience. Clin Endocrinol (Oxf) 1999; 50: 115-20.  

Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf) 2001; 54: 633-39.  

Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60: 355-62.  

Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990; 322: 1829-36.  

Weetman AP. Autoimmunity to steroid-producing cells and familial polyendocrine autoimmunity. Baillieres Clin EndocrinolMetab 1995; 9: 157-74.  

Donner H, Braun J, Seidl C, et al. Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto’s thyroiditis and Addison’s disease. J Clin Endocrinol Metab 1997; 82: 4130-32.  

Kemp EH, Ajjan RA, Husebye ES, et al. A cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism is associated with autoimmune Addison’s disease in English patients. Clin Endocrinol (Oxf) 1998; 49: 609-13.  

Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993; 361: 726-30.  

Mosser J, Lutz Y, Stoeckel ME, et al. The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet 1994; 3: 265-71.  

Powrie JK, Powell M, Ayers AB, Lowy C, Sonksen PH. Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature. Clin Endocrinol (Oxf) 1995; 42: 315-22.  

Kasperlik-Zaluska AA, Czarnocka B, Czech W, et al. Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases. Clin Endocrinol (Oxf) 1998; 49: 779-83.  

Nussey SS, Soo SC, Gibson S, et al. Isolated congenital ACTH deficiency: a cleavage enzyme defect? Clin Endocrinol (Oxf) 1993; 39: 381-85.  

Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155-57.  

Wu W, Cogan JD, Pfaffle RW, et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18: 147-9.  

Thomas PQ, Dattani MT, Brickman JM, et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10: 39-45.  

Randeva HS, Schoebel J, Byrne J, Esiri M, Adams CB, Wass JA. Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol (Oxf) 1999; 51: 181-88.  

Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282: 671-76.  

Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab 1971; 33: 14-22.  

Allolio B, Arlt W. DHEA treatment: myth or reality? Trends Endocrinol Metab 2002; 13: 288.  

Zelissen PM. Addison patients in the Netherlands: medical report of the survey. The Hague: Dutch Addison Society, 1994.  

Hangaard J, Andersen M, Grodum E, Koldkjaer O, Hagen C. Pulsatile thyrotropin secretion in patients with Addison’s disease during variable glucocorticoid therapy. J Clin Endocrinol Metab 1996; 81: 2502-07.  

Vasikaran SD, Tallis GA, Braund WJ. Secondary hypoadrenalism presenting with hypercalcaemia. Clin Endocrinol (Oxf) 1994; 41: 261-64.  

Fallo F, Fanelli G, Cipolla A, Betterle C, Boscaro M, Sonino N. 24-hour blood pressure profile in Addison’s disease. Am J Hypertens 1994; 7: 1105-09.  

Fallo F, Betterle C, Budano S, Lupia M, Boscaro M, Sonino N. Regression of cardiac abnormalities after replacement therapy in Addison’s disease. Eur J Endocrinol 1999; 140: 425-28.  

Allolio B, Ehses W, Steffen HM, Muller R. Reduced lymphocyte beta 2-adrenoceptor density and impaired diastolic left ventricular function in patients with glucocorticoid deficiency. Clin Endocrinol (Oxf) 1994; 40: 769-75.  

Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989; 321: 492-96.  

Lovas K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf) 2002; 56: 581-88.  

Grinspoon SK, Biller BM. Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994; 79: 923-31.  

Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM. Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol (Oxf) 1998; 49: 287-92.  

Oelkers W, Diederich S, Bahr V. 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 1992; 75: 259-64.  

Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999; 341: 1013-20.  

Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000; 85: 4650-56.  

Wood JB, James VHT, Frankland AW, Landon J. A test of adrenocortical function. Lancet 1965; 1: 243-45.  

Stewart PM, Corrie J, Seckl JR, Edwards CR, Padfield PL. A rational approach for assessing the hypothalamo-pituitary-adrenal axis. Lancet 1988; 1: 1208-10.  

Betterle C, Volpato M, Pedini B, Chen S, Smith BR, Furmaniak J. Adrenal-cortex autoantibodies and steroid-producing cells autoantibodies in patients with Addison’s disease: comparison of immunofluorescence and immunoprecipitation assays. J Clin Endocrinol Metab 1999; 84: 618-22.  

Winqvist O, Karlsson FA, Kampe O. 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet 1992; 339: 1559-62.  

Hagg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 1987; 26: 221-26.  

Watts NB, Tindall GT. Rapid assessment of corticotropin reserve after pituitary surgery. JAMA 1988; 259: 708-11.  

Landon J, Greenwood FC, Stamp TCB, Wynn V. The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin and the comparison of this procedure with other tests of pituitary and adrenal function, 2: In hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 1966; 45: 437-48.  

Nelson JC, Tindall DJ Jr. A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH. Am J Med Sci 1978; 275: 165-72.  

Tuchelt H, Dekker K, Bahr V, Oelkers W. Dose-response relationship between plasma ACTH and serum cortisol in the insulin- hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease. Clin Endocrinol (Oxf) 2000; 53: 301-07.  

Tsatsoulis A, Shalet SM, Harrison J, Ratcliffe WA, Beardwell CG, Robinson EL. Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 1988; 28: 225-32.  

Stewart PM, Clark PM, Sheppard MC. Comparison of the short ACTH stimulation test with the insulin tolerance/glucagon test. Clin Endocrinol (Oxf) 1998; 48: 124-26.  

Dickstein G, Lahav M, Orr ZS. Single-dose metyrapone test at 06.00 h: an accurate method for assessment of pituitary-adrenal reserve. Acta Endocrinol (Copenh) 1986; 112: 28-34.  

Fiad TM, Kirby JM, Cunningham SK, McKenna TJ. The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 1994; 40: 603-09.  

Feek CM, Bevan JS, Ratcliffe JG, Gray CE, Blundell G. The short metyrapone test: comparison of the plasma ACTH response to metyrapone with the cortisol response to insulin-induced hypoglycaemia in patients with pituitary disease. Clin Endocrinol (Oxf) 1981; 15: 75-80.  

Courtney CH, McAllister AS, McCance DR, et al. The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery. Clin Endocrinol (Oxf) 2000; 53: 309-12.  

Lindholm J. The insulin hypoglycaemia test for the assessment of the hypothalamic-pituitary-adrenal function. Clin Endocrinol (Oxf) 2001; 54: 283-86.  

Lebrethon MC, Naville D, Begeot M, Saez JM. Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II. J Clin Invest 1994; 93: 1828-33.  

Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary- adrenocortical function. Clin Endocrinol (Oxf) 1987; 26: 53-59.  

Borst GC, Michenfelder HJ, O’Brian JT. Discordant cortisol response to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 1982; 306: 1462-64.  

Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276-79.  

Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996; 81: 285-90.  

Oelkers W. The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency. Eur J Endocrinol 1998; 139: 567-70.  

Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991; 72: 773-78.  

Tordjman K, Jaffe A, Grazas N, Apter C, Stern N. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995; 80: 1301-05.  

Thaler LM, Blevins LS Jr. The low dose (1-microg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998; 83: 2726-29.  

Tordjman K, Jaffe A, Trostanetsky Y, Greenman Y, Limor R, Stern N. Low-dose (1 microgram) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary- adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 microgram) test. Clin Endocrinol (Oxf) 2000; 52: 633-40.  

Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995; 80: 1243-6.  

Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab 2000; 85: 652-57.  

Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83: 1558-62.  

Murphy H, Livesey J, Espiner EA, Donald RA. The low dose ACTH test: a further word of caution. J Clin Endocrinol Metab 1998; 83: 712-13.  

Auchus RJ, Shewbridge RK, Shepherd MD. Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery? Clin Endocrinol (Oxf) 1997; 46: 21-27.  

Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab 2002; 87: 2745-50.  

Lange M, Svendsen OL, Skakkebaek NE, et al. An audit of the insulin-tolerance test in 255 patients with pituitary disease. Eur J Endocrinol 2002; 147: 41-47.  

Drucker D, McLaughlin J. Adrenocortical dysfunction in acute medical illness. Crit Care Med 1986; 14: 789-91.  

Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337: 1285-92.  

Reincke M, Allolio B, Wurth G, Winkelmann W. The hypothalamic- pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. J Clin Endocrinol Metab 1993; 77: 151-56.  

Findling JW, Waters VO, Raff H. The dissociation of renin and aldosterone during critical illness. J Clin Endocrinol Metab 1987; 64: 592-95.  

Jurney TH, Cockrell JL, Jr., Lindberg JS, Lamiell JM, Wade CE. Spectrum of serum cortisol response to ACTH in ICU patients: correlation with degree of illness and mortality. Chest 1987; 92:292-95.  

Beishuizen A, Thijs LG. Relative adrenal failure in intensive care: an identifiable problem requiring treatment? Best Pract Res Clin Endocrinol Metab 2001; 15: 513-31.  

Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991; 337: 582-83.  

Briegel J, Forst H, Kellermann W, Haller M, Peter K. Haemodynamic improvement in refractory septic shock with cortisol replacement therapy. Intensive Care Med 1992; 18: 318.  

Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.  

Kawashima A, Sandler CM, Fishman EK, et al. Spectrum of CT findings in nonmalignant disease of the adrenal gland. Radiographics 1998; 18: 393-Sawczuk IS, Reitelman C, Libby C, Grant D, Vita J, White RD. CT findings in Addison’s disease caused by tuberculosis. Urol Radiol 1986; 8: 44-45.  

Esteban NV, Loughlin T, Yergey AL, et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991; 72: 39-45.  

Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab 1993; 76: 1505-10.  

Kraan GP, Dullaart RP, Pratt JJ, Wolthers BG, Drayer NM, De Bruin R. The daily cortisol production reinvestigated in healthy men: the serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab 1998; 83: 1247-52.  

Brandon DD, Isabelle LM, Samuels MH, Kendall JW, Loriaux DL. Cortisol production rate measurement by stable isotope dilution using gas chromatography-negative ion chemical ionization mass spectrometry. Steroids 1999; 64: 372-78.  

Kehlet H, Binder C, Blichert-Toft M. Glucocorticoid maintenance therapy following adrenalectomy: assessment of dosage and preparation. Clin Endocrinol (Oxf) 1976; 5: 37—41.  

Allolio B, Kaulen D, Deuss U, Hipp FX, Winkelmann W. Comparison between hydrocortisone and cortisone acetate as replacement therapy in adrenocortical insufficiency. Akt Endokr Stoffw 1985; 6: 35-39.  

Barbato AL, Landau RL. Serum cortisol appearance-disappearance in adrenal insufficiency after oral cortisone acetate. Acta Endocrinol (Copenh) 1977; 84: 600-04.  

Feek CM, Ratcliffe JG, Seth J, Gray CE, Toft AD, Irvine WJ. Patterns of plasma cortisol and ACTH concentrations in patients with Addison’s disease treated with conventional corticosteroid replacement. Clin Endocrinol (Oxf) 1981; 14: 451-58.  

Groves RW, Toms GC, Houghton BJ, Monson JP. Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med 1988; 81: 514-16.  

Scott RS, Donald RA, Espiner EA. Plasma ACTH and cortisol profiles in Addisonian patients receiving conventional substitution therapy. Clin Endocrinol (Oxf) 1978; 9: 571-76.  

Burch WM. Urine free-cortisol determination: a useful tool in the management of chronic hypoadrenal states. JAMA 1982; 247: 2002-04.  

Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf) 1997; 46: 263-68.  

Monson JP. The assessment of glucocorticoid replacement therapy. Clin Endocrinol (Oxf) 1997; 46: 269-70.  

Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf) 1997; 46: 255-61.  

al-Shoumer KA, Beshyah SA, Niththyananthan R, Johnston DG. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clin Endocrinol (Oxf) 1995; 42: 85-90.  

Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med 1994; 120: 207-10.  

Florkowski CM, Holmes SJ, Elliot JR, Donald RA, Espiner EA. Bone mineral density is reduced in female but not male subjects with Addison’s disease. NZMedJ 1994; 107: 52-53.  

Braatvedt GD, Joyce M, Evans M, Clearwater J, Reid IR. Bone mineral density in patients with treated Addison’s disease. Osteoporos Int 1999; 10: 435-40.  

Johannsson G, Burman P, Wiren L, et al. Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen- deficient women: a placebo-controlled trial. J Clin Endocrinol Metab 2002; 87: 2046-52.  

Johannsson G, Burman P, Wiren L, et al. Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen- deficient women: a placebo-controlled trial. J Clin Endocrinol Metab 2002; 87: 2046-52.  

Braatvedt GD, Newrick PG, Corrall RJ. Patients’ self administration of hydrocortisone. BMJ 1990; 301: 1312.  

De Vroede M, Beukering R, Spit M, Jansen M. Rectal hydrocortisone during stress in patients with adrenal insufficiency. Arch Dis Child 1998; 78: 544-7.  

Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. Ann Surg 1994; 219: 416-25.  

Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery 1997; 121: 123-29.  

Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M, Schulte HM. Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing- hormone. Clin Endocrinol (Oxf) 1990; 33: 279-89.  

Diederich S, Bahr V, Oelkers W. Therapy of adrenal cortex insufficiency. Dtsch Med Wochenschr 1994; 119: 595-97.  

Maisey DN, Brown RC, Day JL. Rifampicin and cortisone replacement therapy. Lancet 1974; 2: 896-97.  

Schulte HM, Monig H, Benker G, Pagel H, Reinwein D, Ohnhaus EE. Pharmacokinetics of aldosterone in patients with Addison’s disease: effect of rifampicin treatment on glucocorticoid and mineralocorticoid metabolism. Clin Endocrinol (Oxf) 1987; 27: 655-62.  

Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA. Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf) 1994; 40: 111-16.  

Knapen MHJM, Puts PHM. Addison patients in the Netherlands: social report of the survey. The Hague: Dutch Addison Society, 1993.  

Riedel M, Wiese A, Schurmeyer TH, Brabant G. Quality of life in patients with Addison’s disease: effects of different cortisol replacement modes. Exp Clin Endocrinol 1993; 101: 106-11.  

Wichers M, Springer W, Bidlingmaier F, Klingmuller D. The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin Endocrinol (Oxf) 1999; 50: 759-65.