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ADRENAL INSUFFICIENCY Chapter 13 - Nicolas C. Nicolaides,MD, Evangelia Charmandari,MD George P.

Chrousos, MD
Introduction

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Adrenal insufficiency is a disorder first described by Thomas Addison in 1855, which is characterized by impaired adrenocortical function and decreased production of glucocorticoids, mineralocorticoids and/or adrenal androgens ( 1 ). Adrenal insufficiency can be caused by diseases affecting the adrenal cortex (primary), the pituitary gland and the secretion of adrenocorticotropic hormone (ACTH) (secondary), or the hypothalamus and the secretion of corticotropic-releasing hormone (CRH) (tertiary). This chapter will provide a brief overview of the etiology, clinical manifestations, diagnosis and treatment of adrenal insufficiency.

Causes of Adrenal Insufficiency
Causes of Primary Adrenal Insufficiency
The etiology of primary adrenal insufficiency has changed over time. Prior to 1920, the most common cause of primary adrenal insufficiency was tuberculosis, while since 1950, the majority of cases have been ascribed to autoimmune adrenalitis, either in isolation or in the context of complex polyglandular syndromes ( 2 ). Autoimmune adrenalitis : This condition is the result of an autoimmune process that destroys the adrenal cortex. Both humoral and cell-mediated immune mechanisms directed at the adrenal cortex are involved. The adrenals appear small and atrophic and the surrounding capsule is thickened. Antibodies that react with several steroidogenic enzymes, as well as all three zones of the adrenal cortex are detected in 60-75% of patients with autoimmune primary adrenal insufficiency, but only rarely in patients with other causes of adrenal insufficiency or normal subjects ( 3 , 4 ). Considerable progress has been made in identifying genetic factors that predispose to the development of autoimmune adrenal insufficiency ( 5 ). In addition to the well-known association of the HLA genotype DR3/4-DQB1*0302 with type 1 diabetes mellitus and adrenal insufficiency, a strong susceptibility for the latter was also found for the DR3-DQ2/DRB1*0404-DQ8 genotype, which predicted early onset of primary adrenal insufficiency ( 6 ). Moreover, a polymorphism of another major histocompatibility complex gene MICA5.1 was found to predispose subjects to the development of adrenal insufficiency ( 7 ). However, the role of these genetic factors in clinical practice has not been established. Autoimmune adrenalitis may present in isolation or may be accompanied by other diseases. Approximately 50% of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders ( 8 , 9 ), whereas patients with the more common autoimmune endocrine disorders, such as type 1 diabetes mellitus, chronic autoimmune thyroiditis, or Graves' disease, rarely develop adrenal insufficiency. The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune syndromes type I and II ( 10-12 ) ( Table 1 ). Table 1. Etiology of Adrenal Insufficiency

Primary Adrenal Insufficiency
Autoimmune (polyglandular failure) Tuberculosis Sarcoidosis, amyloidosis, hemochromatosis Hemorrhage (meningococcemia, anticoagulants, trauma) Fungal infections Metastatic neoplasia/infiltration Congenital adrenal hyperplasia Congenital adrenal hypoplasia Congenital unresponsiveness to ACTH (glucocorticoid deficiency, ACTH resistance) Adrenoleukodystrophy/Adrenomyeloneuropathy Aquired immynodeficiency syndrome Bilateral adrenalectomy Steroid synthesis inhibitors (e.g., metyrapone, ketoconazole, aminoglutethimide) Adrenolytic agents (o,p’DDD, suramin) Glucocorticoid antagonists (RU 486) Secondary and Tertiary Adrenal Insufficiency Following discontinuation of exogenous glucocorticoids or ACTH Following the cure of Cushing’s syndrome Pituitary and hypothalamic lesions Tumors Inflammation Infections Autoimmune lesions

Granulomatios infilitration Trauma Congenital aplasia, hypoplasia, dysplasia, ectopy Pituitary-hypothalamic surgery Pituitary-hypothalamic radiation Pituitary-hypothalamic hemorrhage (apoplexy) Acquired isolated ACTH deficiency Familial corticosteroid-binding-globulin deficiency Infectious adrenalitis : Many infectious agents may attack the adrenal gland and result in adrenal insufficiency, including tuberculosis (tuberculous adrenalitis), disseminated fungal infections and HIVassociated infections, such as adrenalitis due to cytomegalovirus and mycobacterium avium complex ( 13-15 ). Hemorrhagic infarction: Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency ( 16 , 17 ). The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen shows bilateral adrenal enlargement. Several coagulopathies and the heparin-induced thrombocytopenia syndrome have been associated with adrenal vein thrombosis and hemorrhage, while the primary antiphospholipid syndrome has been recognized as a major cause of adrenal hemorrhage ( 2 ). Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection ( 18 ). Adrenoleukodystrophy : This is an X-linked recessive disorder affecting 1 in 20.000 males ( 5 ). Adrenoleukodystrophy is characterized by spastic paralysis and adrenal insufficiency, usually beginning in infancy or childhood, and is caused by mutations in the ABCD1 gene, resulting in defective beta oxidation of very long chain fatty acids (VLCFAs) within peroxisomes. The abnormally high concentrations of VLCFAs in many organs, including the adrenal cortex, result in the clinical manifestations of this disorder ( 19 ). Drug-induced adrenal insufficiency : Drugs that may cause adrenal insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with limited pituitary and/or adrenal reserve, include aminoglutethimide (antiepileptic) ( 20 ), etomidate (anesthetic-sedative) ( 21 , 22 ), ketoconazole (antimycotic) ( 23 ) and metyrapone ( 24 ). Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, and rifampicin can also cause adrenal insufficiency in patients with limited pituitary or adrenal reserve, as well as those who are on replacement therapy with glucocorticoids ( 25 ). Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib) have been shown in animal studies to cause adrenal dysfunction and hemorrhage ( 26 ) .

Causes of Secondary and Tertiary Adrenal Insufficiency

such as anorexia. the clinical manifestations of the condition appear when the loss of the adrenocortical tissue of both glands is higher than 90% ( 2 ). bilateral adrenal infarction or hemorrhage. Pathophysiology of Secondary Adrenal Insufficiency ACTH deficiency leads to decreased secretion of cortisol and adrenal androgens. vomiting. It is rare in patients with secondary or tertiary adrenal insufficiency. leading to the clinical manifestations of the disease. and may be precipitated by a serious infection. In the early stages. acute stress. With further loss of adrenocortical tissue. The most common cause of secondary adrenal insufficiency is exogenous glucocorticoid administration therapy. tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. In the initial phase of chronic gradual destruction. With further loss of basal ACTH secretion. but more common in secondary adrenal insufficiency. abdominal pain. Hyperpigmentation due to chronic ACTH hypersecretion and weight loss are indicative of long-standing adrenal insufficiency. Hypoglycemia is a common manifestation in children and thin women with the disorder. all the above mentioned causes result in gradual destruction of the adrenal cortex. The main clinical manifestation of adrenal crisis is shock. basal cortisol secretion is decreased but aldosterone secretion by the zona glomerulosa is preserved. Hypoglycemia is rare in acute adrenal insufficiency. while additional symptoms and signs relating to the primary cause of adrenal insufficiency may also be present. 28 ). there is atrophy of zonae fasciculata and reticularis of the adrenal cortex. weakness. but patients may also have nonspecific symptoms. Consequently. The elevated plasma ACTH concentrations are responsible for the wellrecognised hyperpigmentation observed in these patients. However. On the other hand. The onset of adrenal insufficiency is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis ( 27 . PATHOPHYSIOLOGY OF ADRENAL INSUFFICIENCY Pathophysiology of Primary Adrenal Insufficiency In primary adrenal insufficiency. the adrenal reserve is decreased and although the basal steroid secretion is normal. any major or even minor stressor can precipitate an acute adrenal crisis. confusion or coma. lethargy. fatigue. even basal steroid secretion is decreased. . Adrenal Crisis: Adrenal crisis or acute adrenal insufficiency may complicate the course of chronic primary adrenal insufficiency. basal ACTH secretion is normal. while that of stress-induced is impaired ( 2 ). The most common causes of tertiary adrenal insufficiency are abrupt cessation of highdose glucocorticoid therapy and treatment of Cushing's syndrome ( 27 ). Low plasma cortisol concentrations result in the increase of production and secretion of ACTH due to decreased negative feedback inhibition ( 2 ). the secretion in response to stress is suboptimal. Clinical Manifestations of Adrenal Insufficiency The clinical manifestations of adrenal insufficiency depend upon the extent of loss of adrenal function and whether mineralocorticoid production is preserved. while mineralocorticoid production remains normal. Therefore.Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. nausea. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits ( Table 1 ).

Chronic Primary Adrenal Insufficiency: Patients with chronic primary adrenal insufficiency may have symptoms and signs of glucocorticoid. weakness. dehydration and hyperkalemia are not present. anorexia. nausea. However. but may be lownormal in patients with partial adrenal insufficiency. hence. hypotension. may also be present ( 27 .The major factor precipitating an adrenal crisis is mineralocorticoid deficiency and the main clinical problem is hypotension. mineralocorticoid. Basal urinary cortisol and 17hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency. determining whether the cortisol deficiency is secondary or primary and. 28 ). dependent or independent of ACTH deficiency. Secondary or Tertiary Adrenal Insufficiency: The clinical features of secondary or tertiary adrenal insufficiency are similar to those of primary adrenal insufficiency. headache or visual field defects. patients with secondary or tertiary adrenal insufficiency usually have normal mineralocorticoid function. Generally. ACTH Secretion : Inappropriately low serum cortisol concentrations in association with increased plasma ACTH concentrations determined simultaneously are suggestive of primary adrenal . given that the production of mineralococorticoids by the zona glomerulosa is mostly preserved. hyperkalemia. such as symptoms and signs of deficiency of other anterior pituitary hormones. and increasing the production and effects of prostacyclin and other vasodilatory hormones ( 30 . abdominal pain or diarrhea. Adrenal crisis can occur in patients receiving appropriate doses of glucocorticoid if their mineralocorticoid requirements are not met ( 29 ). glucocorticoid deficiency may also contribute to hypotension by decreasing vascular responsiveness to angiotensin II. while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. which may alternate with constipation. and loss of libido and amenorrhea in women ( 27 . Serum cortisol concentrations are normally highest in the early morning hours (04:00h – 08:00h) and increase further with stress. Diagnosis of Adrenal Insufficiency The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion. decreased axillary and pubic hair. autoimmune manifestations (vitiligo). The most common clinical manifestations of chronic primary adrenal insufficiency include general malaise. Hyponatremia and increased intravascular volume may be the result of “inappropriate” increase in vasopressin secretion. vomiting. whereas patients with secondary adrenal insufficiency and normal aldosterone secretion rarely present in adrenal crisis. norepinephrine and other vasoconstrictive hormones. Also. weight loss. and hypotension is less prominent. However. 31 ). and androgen deficiency. electrolyte abnormalities (hyponatremia. metabolic acidosis). fatigue. Hypoglycemia is more common in secondary adrenal insufficiency possibly due to concomitant growth hormone insufficiency and in isolated ACTH deficiency. baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency. 28 ). and detecting the cause of the disorder ( 27 . Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency ( 32 ). Cortisol Secretion : The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Clinical manifestations of a pituitary or hypothalamic tumor. By contrast. hyperpigmentation. 28 ). hyperpigmentation is not present because ACTH secretion is not increased. reducing the synthesis of renin substrate. The onset of chronic adrenal insufficiency is often insidious and the diagnosis may be difficult in the early stages of the disease.

this test may miss mild cases of adrenal insufficiency. i) High-Dose ACTH stimulation test: This test consists of determining serum cortisol responses immediately before and 30 and 60 minutes after the intravenous administration of 250 µg of cosyntropin. if secondary adrenal insufficiency is of recent onset. Prolonged ACTH Stimulation Tests: Prolonged ACTH stimulation tests are rarely performed because the history and physical examination. Therefore. Subsequently. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard high-dose test ( 38-42 ). +35 min. In these cases. recent studies have demonstrated that salivary cortisol concentrations perform equally well when measured in the high-dose ACTH stimulation test in patients with secondary adrenal insufficiency ( 47 ). when the endogenous secretion of ACTH is at its lowest. this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia ( 40 ). +40 min and +45 min after stimulation for determination of serum cortisol concentrations ( 28 ). since pharmacologic plasma ACTH concentrations can still be achieved by either route ( 34 ). +30 min. +25 min. The low dose of ACTH (1-24) (500 nanograms ACTH(124)/1. A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. which are often too high to detect cases of chronic partial and mild pituitary ACTH deficiency ( 33 ). In addition to serum cortisol concentrations. The advantage of the high-dose ACTH stimulation test is that the cosyntropin can be injected intravenously or intramuscularly. in early acute secondary or tertiary adrenal insufficiency. and subsequent measurement of serum cortisol concentrations at regular intervals. as in Sheehan syndrome. In normal subjects. The results might not be valid if it is performed at another time. Given that basal cortisol and ACTH secretion may be normal in partial adrenal insufficiency. stimulation tests of adrenocortical reserve must be performed in order to establish the diagnosis. the adrenal glands will have not yet atrophied. a lowdose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis ( 38 -40 ). However.73 m 2 ) is then administered as an intravenous bolus. and will still be capable of responding to ACTH stimulation normally. +15 min. Short ACTH stimulation tests: The short ACTH stimulation test assesses the capacity of the adrenal cortex to respond to ACTH and should be performed in all patients suspected of having adrenal insufficiency. the CRH test (see below) and/or the determination of cortisol . blood samples are collected at +10 min. ii) Low-Dose ACTH stimulation test: This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. a blood sample is collected for determination of basal cortisol concentrations.insufficiency. which has the full biologic potency of native ACTH (1-39) . This test should be performed at 14:00h. The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency ( 43-46 ). It involves the intravenous administration of synthetic ACTH (1-24) (cosyntropin). On the other hand. because it takes several days for the adrenal cortex to atrophy. Also. A rise in serum cortisol concentration at 30 minutes to a peak of 18 to 20 µg/dL (500 to 550 nmol/L) or more is considered a normal response to high-dose ACTH stimulation test ( 35-37 ) and excludes the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency. the test is not reliable. This dose of cosyntropin results in pharmacologic (supra-physiologic) plasma ACTH concentrations for the 60 min duration of the test. At 14:00h. +20 min. inappropriately low baseline morning cortisol and ACTH concentrations indicate secondary or tertiary disease.

In normal subjects. CRH Stimulation Test: This test is used to differentiate between secondary and tertiary adrenal insufficiency. Large volumes of normal saline solution should be given intravenously. the cause of the adrenal crisis should be sought and treated. the 24-hour urinary 17-OHCS excretion increases 3. whereas in primary adrenal insufficiency. and 24-hour urinary cortisol and 17-hydroxycorticoid (17-OHCS) concentrations before and after the infusion. except that 250 µg of ACTH (1-24) are infused for over 24 hours on two (or three) consecutive days ( 48 ). ii) Two-day ACTH Stimulation Test: The two-day ACTH stimulation test is similar to the eight-hour infusion test. The glucocorticoid deficiency should be treated by immediate intravenous administration of dexamethasone sodium phosphate or hydrocortisone sodium succinate. i. Initial treatment: The aim of initial management in adrenal crisis is to treat hypotension. Treatment of adrenal crisis: Adrenal crisis is a life-threatening emergency that requires immediate treatment. i) Eight-hour ACTH stimulation test: This test consists of administering 250 µg (40 IU) of cosyntropin intravenously as an infusion over eight hours. Prolonged stimulation with exogenous ACTH is used to differentiate between primary and secondary or tertiary adrenal insufficiency.and ACTH concentrations in association with the low-dose ACTH test may provide all necessary information. In secondary or tertiary adrenal insufficiency. In patients with secondary adrenal insufficiency. 52 ). If the diagnosis is suspected blood samples should be obtained for measurement of cortisol concentrations. TREATMENT OF ADRENAL INSUFFICIENCY Adrenal insufficiency is a potentially life-threatening condition. and exceed 25 g/dL (690 nmol/L) at 6-8 hours post-initiation of the infusion. the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH. parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral . the adrenal glands are partially or completely destroyed and do not respond to ACTH. Increases of these values in the 2-3 days of the test are indicative of a secondary/tertiary cause of adrenal insufficiency. and determining serum cortisol. In both conditions. cortisol concentrations are low at baseline and remain low after CRH administration. and to reverse the electrolyte abnormalities and cortisol deficiency. Subsequent treatment: Once the patient’s condition is stable and the diagnosis has been confirmed. 50 ). to correct hypovolemia. Additional investigations required to identify the cause of adrenal insufficiency vary depending on whether the disease is primary. or sooner if the patient presents in adrenal crisis ( 51. Dexamethasone may be preferred because it has long-duration of action and does not interfere with the measurements of serum or urinary steroids during subsequent ACTH stimulation tests. Once the initial treatment is offered. Serum cortisol concentrations reach 20 g/dL (550 nmol/L) at 30 to 60 min. secondary or tertiary. there is little or no ACTH response. Treatment should be initiated as soon as the diagnosis is confirmed.e..to 5-fold above the baseline. In primary adrenal insufficiency there is no or a minimal response of plasma or urinary cortisol and urinary 17-OHCS. whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH to CRH stimulation. which is not followed by an appropriate cortisol response ( 49 . This test may be helpful in distinguishing primary from secondary/tertiary adrenal insufficiency.

which has some mineralocorticoid activity. Treatment of Chronic Adrenal Insufficiency: One of the important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses ( 53 ). which should provide information on the diagnosis. methylprednisolone or dexamethasone in emergencies. Androgen replacement: In women. such as loss of lean body mass and bone density. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy. the medications and daily doses. high doses of glucocorticoid up to 10 times the daily production rate are required to avoid an adrenal crisis. intravascular volume depletion and hyperkalemia. Although the physiologic role of these androgens in women has not been fully elucidated. the dosage of glucocorticoid can be increased up to three times the usual maintenance dosage for three days. the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Mineralocorticoid replacement therapy: Mineralocorticoid replacement therapy is required to prevent sodium loss. the natural glucocorticoid. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be given in two to three divided doses. Depending on the nature and severity of the illness. as well as impaired quality of life ( 54 . Glucocorticoid replacement therapy: Patients with adrenal insufficiency should be treated with hydrocortisone. such as prednisolone. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range. The mineralocorticoid dose may have to be increased in the summer. prednisone or dexamethasone. The usual oral replacement dosages are 5-7. the need to increase the dose of glucocorticoid during minor or major stress and to inject hydrocortisone. and the maintenance dose can be resumed the third postoperative day.25-0. and gain of visceral fat.maintenance dose. Patients should understand the reason for life-long replacement therapy. This dose can be halved the second postoperative day. 57 ) but remains controversial ( 58 ).5 mg of prednisolone or prednisone or 0. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. A longer-acting synthetic glucocorticoid. Glucocorticoid replacement during minor illness or surgery: During minor illness or surgical procedures. Emergency precautions: Patients should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card. 55 ) were observed in patients treated with hydrocortisone. particularly if patients are exposed to temperatures above 29ºC (85ºF).75 mg of dexamethasone once daily. while patients receiving hydrocortisone. Patients should also have supplies of dexamethasone sodium phosphate and should be educated about how and when to administer them. may require lower doses. additional treatment may be required. and the physician involved in the patient’s management. It is given in the form of fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.1 mg daily. . their replacement is being increasingly considered in the treatment of adrenal insufficiency ( 56 . A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. may be employed but should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess. Glucocorticoid replacement during major illness or surgery: During major illness or surgery.

muscle weakness and depression. Cushing’s Syndrome Introduction Cushing’s Syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. some inflammatory factors may cause glucocorticoid resistance at the level of target cell. the metabolic upset of Cushing's syndrome is associated with a high mortality. secreted from the zona fasciculata and reticularis of the adrenal gland under the stimulus of adrenocorticotropin (ACTH) from the pituitary gland. Since the diagnosis of tissue glucocorticoid resistance remains difficult. more subtle excesses of cortisol may also have significant effects on glycaemic control and blood pressure. But.α ) or other peptides. Even now its investigation and management can vex the most experienced endocrinologist. known as corticostatins. Mineralocorticoid replacement is rarely required. Furthermore. the consensus statement recommends that hydrocortisone therapy should be given in patients with septic shock. glucocorticoid replacement is similar to that in primary adrenal insufficiency. and require careful interpretation. clinicians are now considering the diagnosis in its earlier manifestations. CRITICAL ILLNESS-RELATED CORTICOSTEROID INSUFFICIENCY Critical illness-related corticosteroid insufficiency (“relative adrenal insufficiency”) is a syndrome characterized by dysfunction of the HPA axis that occurs during critical illness ( 60 ). It may be difficult to miss the diagnosis in its most florid form. Yet. compete with ACTH for binding on its cognate receptor. components of oxidative stress and the impaired adrenal blood flow contribute to adrenal insufficiency. In its severe form and when untreated. Pathophysiology . this syndrome is the consequence of adrenal insufficiency combined with glucocorticoid resistance. ACTH in turn is secreted in . given the high prevalence of many of its non-specific symptoms such as obesity. and may therefore be an important cause of morbidity. On the other hand.Dehydroepiandrosterone may be beneficial in females with hypopituitarism in whom there was significant improvement in pubic hair development ( 59 ). however. measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose. Aetiology & Epidemiology In normal physiology the end product of the hypothalamo-pituitary-adrenal (HPA) axis is the glucocorticoid cortisol. particularly those who respond poorly to fluid resuscitation and vasopressing agents ( 60 ). such as cytokines (tumor necrosis. Treatment is often complex and may require all the modalities of surgery. signaling molecules. efforts have been made in order to establish a diagnostic workup for this syndrome. affecting vital steps of the glucocorticoid receptor signaling ( 66 ). Investigated mostly in cases of sepsis and septic shock ( 61-64 ). Strong inflammatory signals. The plethora of investigations often needed for the diagnosis and differential diagnosis has grown over the intervening century. Moreover. thus resulting in decreased cortisol production and secretion ( 65 ). It is now one hundred years since Harvey Cushing reported the classical clinical syndrome that bears his name. other neuropeptides. while replacement of other anterior pituitary deficits might be necessary. Treatment of chronic secondary and tertiary adrenal insufficiency: In chronic secondary or tertiary adrenal insufficiency. The American College of Critical Care Medicine suggests that the diagnosis is best made by a delta total serum cortisol of < 9 μ g/dL following intravenous administration of ACTH (1-24) in a dose of 250 μ g or a random total cortisol level of < 10 μ g/dL ( 60 ). radiotherapy and medical management.

This is the commonest cause of Cushing's syndrome seen in general clinical practice. The etiology of Cushing's syndrome can broadly be divided into two categories. It is almost always due to a monoclonal corticotroph adenoma (4.7).response to corticotropin releasing hormone (CRH) and vasopressin from the hypothalamus.00h. Cortisol exerts negative feedback control on both CRH and vasopressin in the hypothalamus. cortisol is secreted in a circadian rhythm. Cushing's Disease Pituitary-dependent Cushing's syndrome.00h-08. better known as Cushing's disease. True pituitary corticotroph carcinomas with extra-pituitary metatstases causing . together with loss of the normal feedback mechanism of the hypothalamo-pituitary-adrenal (HPA) axis.7 and 2. The majority of tumors are intrasellar microadenomas (<1 cm in diameter). administered in excessive quantities can give rise to exogenous Cushing's syndrome. which results in chronic exposure to excessive circulating cortisol levels and that gives rise to the clinical state of endogenous Cushing's syndrome (1). It is the loss of this circadian rhythm.3). levels fall during the day from a peak at 07.4 per million per year (2. accounting for 60-80% of all cases. ACTH-dependent and ACTH-independent (Table 1). and its existence is still debated. Although apparent nodular corticotroph hyperplasia (in the absense of an CRH-producting tumour) has been described. In normal individuals. and ACTH in the pituitary. and usually between the ages of 25 to 40 years of age. and extrasellar extension or invasion may occur. it is rare in large surgical series (6. Aetiology of Cushing's syndrome ACTH-dependent     Pituitary-dependent Cushing's syndrome (Cushing's disease) Ectopic ACTH syndrome Ectopic CRH syndrome Exogenous ACTH administration ACTH-independent        Adrenal adenoma Adrenal carcinoma ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) AIMAH secondary to abnormal hormone receptor expression/function Primary pigmented nodular adrenal disease (PPNAD). Table 1 .00h to a nadir at around midnight: they then begin to rise again at 02. although macroadenomas account for approximately 5-10% of tumors. Epidemiologic studies from Europe suggest an incidence of between 0. It presents much more commonly in women. is the most common at least in endocrine practice. associated with Carney complex or sporadic McCune-Albright syndrome Exogenous glucocorticoid administration ACTH-dependent Cushing's syndrome.5). Any of the numerous synthetic steroids that have glucocorticoid activity. usually due to treatment for chronic conditions such as asthma or rheumatological disease.

so -called "big" ACTH (14. The most frequent cause is probably small-cell lung carcinoma where it is estimated up to 12% of cases will have Cushing's syndrome (11). Bartholomew's Hospital 19692001 Site of secretion Bronchial carcinoid tumor Small cell lung carcinoma Medullary thyroid carcinoma Pancreatic carcinoid tumor Thymic carcinoid tumor Disseminated carcinoid tumor Mesothelioma Pancreatic carcinoma Colonic carcinoma Phaechromocytoma Gall bladder carcinoma Total 1 16 16 1 1 1 1 1 Female 11 1 Male 2 5 3 2 1 1 The mechanism by which these non-corticotroph tumours express the proopiomelanocortin (POMC) gene is not fully understood but may be related to hypomethylation of the POMC promotor in some tumours (12. As well as producing ACTH these tumours may also produce the precursor POMC. and usually presents after the age of 40 years.13). with just over 20 cases described in the literature (17). ACTH-independent Cushing Syndrome ACTH-independent causes of Cushing syndrome apart from exogenous glucocorticoids encompass a heterogeneous group of diseases. However.9). Table 2.Cushing's syndrome have also rarely been described (8. Despite much research the molecular pathogenesis of corticotroph adenomas remains unknown (10). Ectopic ACTH syndrome is more common in men. Ectopic ACTH syndrome & ectopic CRH tumors Ectopic sources of ACTH derive from a diverse group of tumor types. This may not be evident from series at endocrine centres where often more occult tumours are investigated (Table 2). which may potentially be helpful in the differential diagnosis of these tumors (16). The latter may lack some classic histological features of malignancy. assays for these are not routinely available in clinical practice. Isolated Ectopic CRH production is difficult to diagnose and exceedingly rare. but can usually be differentiated on the basis of weight (more than . and carcinoid tumours tend to predominate. Aetiology of the ectopic ACTH syndrome in patients seen at St.15). and other pre-ACTH peptides. The most common pathology is an adrenal adenoma or carcinoma.

angiotensin. and has a bimodal age distribution. Ectopic cortisol production by an ovarian carcinoma has been reported (35). The internodular cortex is usually atrophic (28). mitotic figures. Pseudo Cushing's syndrome . usually in the context of ACTH-dependent disease after adrenalectomy (31-34). necrosis. and other endocrine disorders (sexual precocity. or in association with the gonads may produce hypercortisolaemia. The normal adrenal cortex. It is one and a half times more common in women. Abnormal expression of vasopressin. Most cases of PPNAD occur as part of the Carney complex in association with a variety of other abnormalities. It is characterised by small or normal-size adrenal glands with cortical micronodules (average 2–3 mm) that may be dark or black in color. A missense mutation of the ACTH receptor resulting in its constitutive activation and ACTHindependent Cushing’s syndrome has also been reported (30). if this affects some adrenal cells the constitutive activation of adenylate cyclase leads to nodule formation and glucocorticoid excess. Other very rare causes of Cushing's syndrome have been reported: Adrenal rest tissue in the liver. leptin. glucagon. The best described example is fooddependent Cushing’s syndrome: in which ectopic gastric inhibitory peptide (GIP) receptors on the adrenal glands respond to GIP released after a meal causing hypercortisolaemia (21).2 per million per year (18). However. Leydig cell. and acromegaly). Sertoli cell. with peaks in childhood and adolescence and late in life (1. luteinizing hormone/human chorionic gonadotropin. AIMAH tissue may express more than one of these aberrant receptors (24). In one patient. This condition is caused by an activating mutation at codon 201 of the  -subunit of the G protein stimulating cyclic adenosine monophosphate (cAMP) formation. Most cases are sporadic. where the mutation is not present. Cushing’s syndrome due to bilateral nodular adrenal disease can also be an unusual feature of McCune-Albright syndrome (25). and endocrine dysfunction (usually precocious puberty). nuclear pleomorphism. and TSH have also been described and functionally linked to cortisol production (23). treatment with octreotide ameliorated the syndrome (22). becomes atrophic (27). but in a few cases the nodules have been shown to express increased numbers of receptors normally found on the adrenal gland. This occurs in a mosaic pattern in early embryogenesis (26).100g). The characteristic features are fibrous dysplasia of bone. Primary pigmented nodular adrenal disease (PPNAD). or adrenal rest tumors. is another rare form of Cushing’s syndrome. IL-1. mutations in PRKAR1A and also the phosphodiesterase 11A (PDE11A) gene have demonstrated (29). hyperpigmentation of the skin.  adrenergic. The tumor suppressor gene PRKAR1A (type 1A regulatory subunit of protein kinase A) has been shown to be mutated in approximately half of patients with Carney complex. In isolated PPNAD. ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) is a rare form of Cushing’s syndrome with sometimes huge nodular adrenal glands on imaging. The incidence of adrenal cancer is approximately 0. Adrenal adenoma occurs most often around 35 years of age and is significantly more common in women with an incidence of approximately 0.19). or ectopic receptors that then can stimulate cortisol production. skin or breast. and vascular or lymphatic invasion. In most the etiology is unknown. serotonin. but a few familial cases have been reported (20). café-au-lait skin pigmentation. including myxomas of the heart. otherwise known as micronodular adrenal disease. Cushing’s syndrome occurs in approximately 30% of cases of Carney Complex. in the adrenal beds.6 per million per year (18).

and temporal fossae. Sequential photographs of the patient over many years can be extremely helpful in demonstrating progression to a Cushingoid state. The distribution of fat can be useful as typically in Cushing's syndrome there is increased visceral adiposity giving rise to truncal obesity. skin thickness may be preserved in women with hyperandrogenaemia related to the Cushing's syndrome. The classical impression of the disease as the association of gross obesity of the trunk with wasting of the limbs. and it is useful to have a strategy looking for more specific clues when considering the diagnosis. reflecting increased androgens. associated with hyperpigmentation. or rising unaided from a squatting position. However. Clinical & Laboratory Features The clinical manifestations associated with hypercortisolaemia are variable and differ widely in severity. Typically seen on the abdomen. often with little or no weight gain and an absense of a gross Cushingoid appearance. hypertension and diabetes mellitus. When assessing for myopathy it is useful to ask questions about function typically affected by proximal muscle weakness such as climbing stairs or getting up from a chair. other forms of the ectopic ACTH syndrome. typically vertebral due to the preferential loss of trabecular bone induced by glucocorticoids. osteoporosis. but it is helpful to consider the age and gender of the patient as natural atrophy increases with age and female gender.Pseudo-Cushing's states are conditions in which a patient presents with clinical features suggestive of true Cushing's syndrome and with some biochemical evidence of hypercortisolaemia. depression. vertebral fractures. The rapid onset of the symptoms of profound weakness. as well as more typical terminal hair hirsuitism on the face and body. may be clinically indistinguishable from patients with other forms of hypercortisolism (40). supraclavicular . In addition. is rarely seen nowadays in its most obvious form. spontaneous bruising. muscle weakness. Purple coloured "Violaceous" striae greater than 1cm across are almost pathognomonic of Cushing's syndrome.37). Both settle after resolution of the pre-disposing condition. hypertension. Depression and alcohol abuse are the two most common such states (1). and should be differentiated from the typical healed silvery striae seen most commonly post-partum. or from a history of fractures. hirsuitism. Increased fine non-pigmented vellus hair on the upper cheeks or forehead may be seen in Cushing’s syndrome. they can also occur in other areas. Skin thickness is best tested over the dorsum of the hand. The pathophysiology has not clearly been established. dorsocervical area ("buffalo hump"). Severe hirsutism and virilisation strongly suggest an adrenal carcinoma (41). most often from small cell lung carcinoma. weight gain associated with growth retardation should highlight the possibility of the diagnosis (39). Many symptoms common in Cushing's syndrome including lethargy. Osteoporosis occurs in approximately 50% of adult patients (38) and can be gleaned from formal bone densitometry. particularly associated with carcinoid tumors. fat deposition in the face ("moon face"). In children. obesity. and thin skin and easy bruising (36. facial rounding and plethora. . and menstrual irregularity are also very common in the general population. is almost certainly due to the ectopic ACTH syndrome. Formal testing can be of leg extension whilst sitting. The signs that are most discriminatory are proximal myopathy. More commonly the clinical diagnosis may be more equivocal. hirsutism with frontal balding. Less wide and coloured striae are more commonly present.

it may also occur in approximately 10% of patients with Cushing’s disease. surgery and invasive investigative procedures results in a significant increased risk of thrombotic events in patients with Cushing's syndrome (58). Cyclicity can occur with all causes of Cushing’s syndrome (42). the hallmark of Cushing's syndrome is hypercortisolaemia. hypogonadotrophic hypogonadism is common and correlates with the degree of hypercortisolemia (45. and overt diabetes mellitus in 30% to 40% of patients. Hypercortisolism suppresses other pituitary hormones. Cushing’s syndrome is characterized by insulin resistance and hyperinsulinaemia with glucose intolerance evident in 20% to 30%.51).. the symptoms and signs waxing and waning according to the active periods of the disease. These markers and other cardiovascular risk factors such as hyperinsulinaemia continue to be present long after cure of the hypercortisolemia (59). Although. but there is a significantly increased prevalence of autoimmune thyroid disease in patients sucessfully treated for Cushing’s syndrome. There is reduced GH secretion during sleep and blunted GH responses to dynamic stimulation tests (48). In addition. There is an increase in total cholesterol and triglyceride levels. and von Willebrand factor. in the absence of clinical suspicion the yield is probably lower (55) (56). and reduces fibrinolytic activity. the coexistence of polycystic ovarian syndrome in Cushing’s syndrome is more common (47). However.releasing hormone and thyroid-stimulating hormone release has been shown to be disturbed and in particular the nocturnal surge of thyroid-stimulating hormone is lost (49). which inactivates cortisol to cortisone (43). This along with other risk factors such as obesity. including increased carotid artery intima-media thickness and atherosclerotic plaques. poorly-controlled patients with diabetes may have occult Cushing’s syndrome if fully investigated (54). In both men and women.46). It occurs when urine free cortisol excretion is greater than about 4100 nmol per day (44). Sympathetic autonomic function is also abnormal in patients with Cushing's syndrome (60). (52. other laboratory abnormalities may co-exist. These changes are multifactorial. with intermittent and variable cortisol secretion. although a more common feature of ectopic ACTH secretion.53). and therefore it is important to follow them with serial thyroid function tests (50. lipolysis. It has been suggested that as many as 2% of overweight. including cortisol effects on increased hepatic synthesis of very low density lipoprotein (VLDL). Patients may 'cycle in' or 'cycle out' over periods of months or years. These patients can cause particular diagnostic difficulty. and variable effect on high-density lipoprotein (HDL). and free fatty acid metabolism (57). Hypokalemic metabolic alkalosis is related to the degree of hypercortisolaemia and represents a mineralocorticoid action of cortisol at the renal tubule due to saturation of the enzyme 11  hydroxysteroid dehydrogenase type 2.they will need regular re-evaluation usually with urinary free cortisol or late-night salivary cortisol to allow full investigation at the appropriate time. as it is imperative that the diagnostic tests are performed in the presence of hypercortisolaemia to allow accurate interpretation. Therefore. fibrinogen.Some cases of ACTH-dependent Cushing's syndrome occur in a periodic or cyclical form. Thyrotropin. Hypercortisolaemia increases clotting factors including factor VIII. and patients exhibit direct markers of accelerated cardiovascular disease. This may not have a significant effect on free thyroid hormone levels during active hypercortisolaemia. if at presentation they are eucortisolaemic. and the ECG . The major cause of mortality in Cushing's disease is cardiovascular events.

Values greater than fourfold normal are rare except in Cushing's syndrome. Unbound cortisol is filtered by the kidney. Hence. and several completely normal collections make the diagnosis of Cushing's syndrome very unlikely. so as to avoid missing milder cases. and thus patients with marginally elevated levels require further investigation (1). within this series 11% had at least one of four UFC collections within the normal range. hypercortisolaemia together with the loss of the normal circadian rhythm of cortisol secretion. The 24 hour UFC is of little value in the differentiation from pseudo-Cushing's states (63. are the cardinal biochemical features of Cushing's syndrome. in all investigations relying on a serum cortisol assay that measures total cortisol.68). UFC measurement was shown to have a sensitivity of 95% for the diagnosis (62). It is important to realise that the validation of the published test criteria employed have been on specific assays. which overcomes the previous problem with conventional radioimmunoassay of cross-reactivity of some exogenous glucocorticoids and other structurally similar steroids (66). In a series of 146 patients with Cushing's syndrome. However. smoothing out the variations in cortisol during the day and night. Tests to confirm the diagnosis are based upon these principles. and should equal approximately 1g/ 24 hours in a 70kg patient (variations depend on muscle mass). tests of high sensitivity should be used initially. Biochemical confirmation of Cushing's syndrome As stated above. UFC measurements have a high sensitivity if collected correctly.performance liquid chromatography and cause falsely elevated results (67. 24-hour UFC collection produces an integrated measure of serum cortisol. In summary. which confirms the need for multiple collections. Urinary free cortisol Measurement of urinary free cortisol (UFC) is a non-invasive test that is widely used in the screening of Cushing's syndrome. We currently wait for a period of 6 weeks.abnormalities of a prolonged QTc dispersion (QTcd) and left ventricular hypertrophy have been identified as characteristic features in patients with Cushing's disease (61). This should not vary by more than 10% between collections in the same individual (41). To screen for Cushing's syndrome. hormone replacement therapy or the oral contraceptive pill should be stopped some time prior to investigation. digoxin and fenofibrate may coelute with cortisol during high. and written instructions must be given to the patient. In addition.64). The major drawback of the test is the potential for an inadequate 24-hour urine collection. and thus test responses should ideally be validated on the local assay used before the results can be interpreted in particular patients. For intermediate values the specificity is somewhat lower. Under normal conditions. Tests of high specificity can then be employed to exclude false positives. Thus. with the majority being reabsorbed in the tubules. creatinine excretion in the collection should be measured to assess completeness. 10% of plasma cortisol is 'free' or unbound and physiologically active. High-performance liquid chromatography or tandem mass spectrometry are now used to measure UFC. and disturbed feedback of the HPA axis. Drugs such as carbamazepine. although obesity per se does not appear to confound the results (65). and the remainder excreted unchanged. although it is likely that a shorter time off treatment may still be effective. Low-dose dexamethasone suppression test . Exogenous oestrogens will increase cortisol-binding globulin and therefore total cortisol levels. This is aided by supra-regional and nationwide inter-assay quality control assurance (1).

the increased suppression in some patients with Cushing's syndrome significantly decreases the sensitivity of the test (78). it offers a number of attractive advantages over blood collection.5mg 6 hourly (69). the simpler measurement of a single plasma or serum cortisol has been validated in various series and gives the test a sensitivity of between 95% and 100% (70-72).00h plasma cortisol after a single dose of 1mg dexamethasone taken at midnight (73). Although higher doses have been tried. phenobarbitone and rifampicin will reduce plasma dexamethasone concentrations (81). and with an extremely long duration of action. The original low-dose dexamethasone test (LDDST) described by Liddle in 1960 measured urinary 17-OHCS after 48 hours of dexamethasone 0.5mg or 2mg (77). Despite the greater simplicity of the overnight test. the specificity is greater for the 2 day test (95%-100%) compared to the overnight test (88%) (79). Late night salivary cortisol Salivary cortisol measurement accurately reflects the plasma free cortisol concentration. exogenous estrogens and the nephrotic syndrome) should also be excluded because these may result in false-positive and false-negative tests(82). phenytoin. It does not cross-react with most cortisol assays. Over the past decade there has been considerable increasing interest in this test. this measured a 09. and various diagnostic cutoffs have been used (74-76). Since then. Assays using a modification of the plasma cortisol radioimmunoassay. particularly in children. Hepatic enzyme inducers such as carbamazepine. Causes of increased or decreased corticosteroid-binding globulin (CBG) (such as pregnancy. it should be noted that the diagnostic value cut-off varies between studies because of different assays and the comparison groups studied.00h will rarely lead to the diagnosis being missed. In a comprehensive review of the LDDST. enzyme-linked immunosorbent assay. If the overnight test is used. However. to negative feedback. The overnight LDDST was first proposed by Nugent et al in 1965. between 0.This test works on the principle that in normal individuals administration of an exogenous glucocorticoid results in suppression of the HPA axis. However. Normal values also differ between adults and paediatric populations. In a recent meta-analysis of these studies. in adult patients the sensitivity and specificity of this test appears to be relatively consistent at different centres. Factors such as variable absorption and increased metabolism can influence dexamethasone test results. and overall is 92% and 96% respectively (83). at least partially. It should be noted that patients with PPNAD may show a paradoxical rise in cortisol levels to dexamethasone (80). both the original 2 day test and the overnight protocol appear to have comparable sensitivities (98%-100%) using the criteria of a post-dexamethasone serum cortisol of <50nmol/l (1.8 g/dL) (79). or liquid chromatography tandem mass spectrometry are now widely available. A history of symptoms of malabsorption and a careful drug history should be taken prior to using the test in a patient. we would still advocate the 48 hour test. whilst patients with Cushing's syndrome are resistant.8 g/dL) at 09. Dexamethasone is a synthetic glucocorticoid that is 30 times more potent than cortisol. and is thus considerably easier to perform. and the fact that salivary cortisol is stable for days at room temperature. and it has been evaluated at a large number of centres worldwide.5 and 2mg. Due to the simple non-invasive collection procedure which can conveniently be performed at home. we suggest that a dose of dexamethasone 1mg at midnight and a threshold of <50nmol/l (1. but false positives remain significant. Loss of the circadian rhythm of cortisol secretion by measuring night-time salivary cortisol can be utilised as a screening test for Cushing’s syndrome. even as an out-patient. and may be affected by other comorbidities such as . as long as written instructions are given to the patient. However. various doses have been suggested for the overnight test. There appears to be no advantage in discrimination between 1mg and 1. and will usually render the test uninterpretable.

dexamethasone 0. local normal ranges need to be validated based on the assay used and population studied.90). but false positive results do occur. An awake midnight cortisol of greater than 207 nmol/l (7 g/dL) shows 94% sensitivity and 100% specificity for the differentiation of Cushing's syndrome from pseudo-Cushing's states (94). particularly in the outpatient setting. The dexamethasone-CRH test In 1993 a combined dexamethasone-CRH (Dex-CRH) test was introduced for the difficult scenario of the differentiation of pseudo-Cushing’s states from true Cushing’s syndrome in patients with only mild hypercortisolemia and equivocal physical findings (63). The theory being that a small number of patients with Cushing's disease as well as normal individuals will show suppression to dexamethasone. and the desmopressin test (37)are not advocated. and should be asleep prior to venepuncture. Importantly. results from a number of other .diabetes (84). This has potential benefit in terms of convenience but requires further evaluation(87. the loperamide test (92) . in acute infection. However. it is a burdensome test that requires that the patient should have been an in-patient for at least 48 hours to allow acclimatisation to the hospital environment. and the dexamethasone-CRH test. Salivary cortisol has also been advocated as a sensitive tool to detect recurrence or treatment failure in patients post-pituitary surgery for Cushing's disease (89. this test performs less well in patients with subclinical Cushing's syndrome (86). ending 2 hours before administration of ovine CRH (1 µg/kg intravenously) to 58 adults with UFC less than 1000 nmol/day (360 µg/day).88). However.4 µg/dL) in all patients with pseudo-Cushing’s states and greater in all patients with Cushing’s syndrome. In the original description of the test. late-night salivary cortisol appears to be a useful and convenient screening test for Cushing's syndrome. A prospective follow-up study by the same group in 98 patients continued to show the test to have an impressive sensitivity and specificity of 99% and 96%. However. 2nd line tests In some patients with equivocal results other tests may be needed. and in the pseudo-Cushing's state associated with depression (93). The most useful of these are a midnight serum cortisol.8 g/dL) effectively excludes Cushing's syndrome (72). Less reliable tests such as the insulin tolerance test (91). The plasma cortisol value 15 minutes after CRH was less than 38 nmol/L (<1. Subsequent evaluation proved 39 to have Cushing’s syndrome and 19 to have a pseudo-Cushing’s state. particularly in the critically ill. all were correctly characterised after CRH. The patient should not be forewarned of the test. A single sleeping midnight plasma cortisol <50nmol/l (1. It is still useful as a second line test in cases of diagnostic difficulty. Midnight serum cortisol Before the introduction of salivary cortisol measurement a midnight serum cortisol was the only reliable method used to determine loss of the circadian rhythm of cortisol secretion. respectively (95). and the method by which the saliva is collected (85). In summary. heart failure. which must be performed within 5-10 minutes of waking the patient. but those with Cushing's disease should respond to CRH with a rise in ACTH and cortisol.5 mg every 6 hours was given for eight doses. Salivary rather than serum cortisol has been evaluated as the endpoint for the LDDST. in these two studies although eight of 59 patients with proven Cushing's disease showed suppression to dexamethasone. Not surprisingly.

Identifying the source in ACTH-dependent Cushing's syndrome . but a lack of ACTH response to the CRH test (see below) may be particularly helpful. Intermediate levels are less discriminatory. It is useful to duplicate this test because patients with ACTH-dependent Cushing’s disease have been shown to have on occasion ACTH levels less than 10 ng/L (2 pmol/L) on conventional radioimmunoassay (98). where adrenal enlargement is present in 70% of cases (105). Rapid collection and processing of the sample is essential as ACTH is susceptible to degradation by peptidases so that the sample must be kept in an ice water bath and centrifuged. different protocols and assays. and finally normal tissue (100). Some patients with Cushing's disease can also develop a degree of adrenal autonomy which can cause biochemical confusion (106). in these reports the specificity of the LDDST in 92 patients without Cushing's syndrome was 79%. and variable diagnostic thresholds. but the two can usually be distinguished by the ACTH level and the degree of adrenal enlargement. versus 70% for the Dex-CRH. different definitions of patients with pseudo-Cushing's. In PPNAD the adrenal glands appear normal or slightly lumpy from multiple small nodules but are not generally enlarged (102). Consistent ACTH measurements of less than 10 ng/L (2pmol/L) essentially confirm ACTH-independent Cushing's syndrome. Cushing's syndrome is ACTH-dependent. Bilateral adenomas can be present (101). the next step is to differentiate between ACTHdependent and ACTH-independent causes. if levels are consistently greater than 20 ng/L (4pmol/L).smaller studies have challenged the diagnostic utility of this test over the standard LDDST. It is perhaps not surprising that the diagnostic utility of the Dex-CRH has altered with further studies at more centers. adenoma. Adrenal tumours typically appear as a unilateral mass with an atrophic contralateral gland (101). High-resolution computed tomography (CT) scanning of the adrenal glands is the investigation of choice and is accurate for masses greater than 1 cm and allows evaluation of the contralateral gland (99). Investigating ACTH-independent Cushing's syndrome Imaging of the adrenal glands is the mainstay in differentiating between the various types of ACTHindependent Cushing's syndrome. the T2-weighted signal is progressively less intense in phaeochromocytoma. It is recommended that if this test is used. Conversely.104). aliquoted. Confusion can arise as the CT appearance of the adrenals in AIMAH may be similar to the appearance seen in ACTHdependent forms of Cushing's syndrome. AIMAH is characterized by bilaterally huge (>5 cm) adrenals with a nodular pattern (103. Exogenous administration of glucocorticoids results in adrenal atrophy and very small glands may be a clue as to this entity. Overall. In certain circumstances MRI may be useful for the differential diagnosis of adrenal masses. If the lesion is greater than 5 cm in diameter it should be considered to be malignant until proven otherwise. and imaging characteristics should not be relied upon. Modern two-site immunoradiometric assays are more sensitive than the older radioimmunoassays and therefore provide the best discrimination. and frozen within a few hours to avoid a spuriously low result. carcinoma. There are a number of reasons why there might be the case: variable dexamethasone metabolism in individuals. The sensitivity in 59 patients with Cushing's syndrome was 96% for the LDDST versus 98% for the Dex-CRH (96). The Differential Diagnosis of Cushing's syndrome Once Cushing's syndrome has been diagnosed. a dexamethasone level is measured at the time of CRH administration and the serum cortisol assay is accurate down to these low levels (97). Nowadays. It is important to stress that all investigations into the differential diagnosis of Cushing's syndrome must be carried out in the presence of hypercortisolaemia and it is useful to confirm this with concomitant UFC or late-night salivary cortisol. the simplest method of differentiation is the measurement of plasma ACTH.

This has been one of the most significant challenges in the investigation of Cushing's syndrome in the past. 92% had Cushing's disease. of the 85 women. A central (inferior petrosal) to peripheral plasma ACTH gradient of 2:1 or greater pre-CRH. although advances over the last 15 years have greatly improved our diagnostic capability. but there is considerable overlap of values. Serum cortisol levels during circadian studies in normal individuals and patients with ACTHdependent cushing's syndrome. and any investigation must improve on this pretest likelihood. producing poor discrimination (Fig 1) (107.110). and in our series of 115 patients with ACTH-dependent Cushing's syndrome. even before one starts investigation. In a normal individual. any test should ideally be set with 100% specificity for the diagnosis of Cushing's disease. Figure 1. This depends on gender. the serum cortisol level falls naturally during the day: in Cushing's syndrome this circadian rhytmicity is lost. this percentage was 77% in the 30 men (107). Cushing's disease accounts for by far the majority of cases of ACTH-dependent Cushing's syndrome. Invasive testing Bilateral inferior petrosal sinus sampling This is the "gold standard" test for distinguishing between Cushing's disease and an ectopic source of ACTH. between 85% and 90% in most series. However. the pretest probability that the patient with ACTH-dependent Cushing’s syndrome has Cushing's disease is very high. Levels of serum cortisol and ACTH tend to be higher in the ectopic ACTH syndrome.108). Therefore. as transsphenoidal pituitary surgery is widely accepted as the primary treatment of Cushing's disease. The procedure involves placement of sampling catheters in the inferior petrosal sinuses that drain the pituitary. testing should be designed to avoid inappropriate pituitary surgery in patients with ectopic ACTH production. it is now clear that false negative tests and to a smaller degree false positive test results do occur (111-113). In order to minimise these it is important to ensure the patient is actively hypercortisolaemic (as above) at the time of the study (114). Results from early series show these criteria to be 100% sensitive and specific for Cushing’s disease (109. and that catheter position is confirmed as bilateral and any anomalous venous drainage noted by venography . or a gradient of 3:1 post-CRH is consistent with Cushing's disease. However. Blood for measurement of ACTH is obtained simultaneously from each sinus and a peripheral vein at two time points before and at 3-5 minutes and possibly also 10 minutes after the administration of ovine or human CRH (IV 1 μg/kg or 100μg respectively). Thus.

although these are rare (<1%). the test achieves worse discrimination than the pretest probability of Cushing's disease.122. One case of CRH inducing pituitary apoplexy in a patient with Cushing’s disease has been reported (120). and then only as part of a combined testing strategy with the CRH test. Therefore. . Non-invasive tests High dose dexamethasone suppression test As with the LDDST. a recent study has shown that suppression to HDDST can be inferred by a > 30% suppression of serum cortisol to the 2-day LDDST (134).and post-CRH. There appears to be no discriminatory difference between ovine or human sequence CRH. and vice-versa. only about 80% of patients with Cushing's disease will show suppression of cortisol to less than 50% of the basal value and there are high number of false positives tests (~10-30%) seen in ectopic Cushing’s syndrome (128-130) (131-133). It should be noted that the procedure is technically difficult. Recent data suggest that where is CRH is unavailable desmopressin 10 μg may be used instead (116). BIPSS is also useful to lateralise microadenomas within the pituitary using the inferior petrosal sinus ACTH gradient (IPSG). Therefore. The HDDST’s role in the differential diagnosis of ACTH-dependent Cushing’s syndrome is based on the same premise: that most pituitary corticotroph tumors retain some albeit reduced responsiveness to negative glucocorticoid feedback. In these studies the diagnostic accuracy of localisation as assessed by operative outcome varied between 59% and 83%. the high dose dexamethasone suppression test (HDDST) was originally proposed by Liddle to differentiate between cortisol-secreting adrenal tumors and Cushing's disease (69). if there are any early warning signs of such events the procedure should be immediately halted. Sampling of the internal jugular veins is a simpler procedure but is not as sensitive as BIPSS (121). There appears to be no advantage in trying to sample the cavernous sinus. and should only be performed by radiologists experienced in the technique. whereas ectopic ACTH-secreting tumours like adrenal tumours typically do not. a situation where imaging is often negative (125).111. If a reversal of lateralisation is seen pre. For the diagnosis of Cushing's disease this test has a sensitivity of approximately 94% and a specificity fractionally short of 100%. we do not recommend routine use of the HDDST except when bilateral inferior petrosal sinus sampling is not available.123). Patients should be given heparin during sampling to prevent thrombotic events (119). Overall.before sampling (115). and local groin haematomas.4 being the criteria for lateralisation used in all large studies (110. and most have related to a particular type of catheter used (117) (118). The test is performed according to the same protocol as the LDDST either as 2mg 6 hourly for 2 days. The accuracy of lateralisation appears to be higher in children (90%). with a basal or post-CRH inter-sinus ratio of at least 1. the test cannot be relied upon (127). There is some discrepancy between studies as to whether CRH improves the predictive value of the test (126). although patients may experience brief facial flushing and a metallic taste in the mouth. More serious transient and permanent neurological sequelae have been reported. In addition. This is improved if venous drainage is assessed to be symmetric (124). including brainstem infarction. CRH itself is generally tolerated well. Shifting the criteria can only increase sensitivity with a loss of specificity. The most common complications are transient ear discomfort or pain.00h. or as an overnight using a single dose of 8mg of dexamethasone at 23.

yielding 98% to 100% sensitivity. our data show that if the maximal rise in cortisol is used the sensitivity falls to 71% (107). The sensitivity and specificity for the ACTH response were comparable for the two types of CRH (sensitivity: 85% vs 87% for oCRH and hCRH respectively). Conversely. The best ACTH response was a maximal rise of at least 105%. this may be related to the more rapid clearance of the human sequence by endogenous CRH-binding protein (136). and thus there is little consensus on a universal criterion for interpreting the test. Different centres have used differing protocols. an increase in ACTH by at least 35% from a mean basal (-5 and -1 minutes) to a mean of 15 and 30 minutes after oCRH in 100 patients with Cushing's disease and 16 patients with the ectopic ACTH syndrome gave the test a sensitivity of 93% for diagnosing Cushing’s disease. CRH either 1 µg/kg or 100 µg synthetic ovine (oCRH) or human sequence CRH (hCRH) is given as a bolus injection and the change in ACTH and cortisol measured. However. Human sequence CRH has qualitatively similar properties to oCRH. In a multicentre analysis from Italy. both hCRH or oCRH were used in 148 patients with Cushing's disease and 12 with the ectopic ACTH syndrome. particularly in a combined testing strategy with the HDDST or LDDST when diagnostic accuracy greater than that of either test alone.134. and an 88% to 100% specificity (129. it should be remembered that responses to both CRH and high-dose dexamethasone are more frequently discordant in Cushing's disease due to a macroadenoma (140). giving 70% sensitivity and 100% specificity (107). In the largest published series of the use of oCRH. A maximal 50% increase in ACTH and cortisol levels were considered as consistent with Cushing's disease. Testing with other peptides Both vasopressin and desmopressin (a synthetic long-acting vasopressin analogue without the V1mediated pressor effects) stimulate ACTH release in Cushing’s disease. while ectopic ACTH tumours lack CRH receptors and therefore do not respond to the agent. Indeed. The availability differs worldwide with oCRH predominant in North America but hCRH elsewhere. In summary. the sensitivity for the cortisol response was significantly greater with oCRH than with hCRH (sensitivity: 67% vs 50% for oCRH and hCRH respectively) (138). and caution should be exercised as there will undoubtedly be patients with the ectopic ACTH syndrome who respond outside these cut-offs. including type of CRH and sampling time-points. The authors do not report in this paper or an associated publication (19) whether time-point combinations other than the maximal were analysed for the rise in cortisol. although it is shorter acting with a slightly smaller rise in plasma cortisol and ACTH in normal and obese patients. However. excluding all patients with the ectopic ACTH syndrome and thus giving 100% specificity. These results again demonstrate that specific criteria need to be developed for each test.The CRH test The use of the CRH (corticotrophin-releasing hormone) test for the differential diagnosis of ACTHdependent Cushing's syndrome is based on the premise that pituitary corticotroph adenomas retain responsivity to CRH. and in those with Cushing's disease (135). probably through the . giving a sensitivity of 85% with 100% specificity. the best criterion to differentiate Cushing's disease from ectopic ACTH syndrome was a rise in cortisol of at least 14% from a mean basal (-15 and 0 minutes) to a mean of 15 and 30 minutes. and was 100% specific.139) Which cut-off to use should be evaluated at individual centres. and cannot readily be extrapolated from other similar but non-identical agents. The best cortisol criterion proved less discriminatory (137). in the largest series of the use of hCRH in 101 patients with Cushing's disease and 14 with the ectopic ACTH syndrome. the CRH test is a useful discriminator between causes of ACTH-dependent Cushing's syndrome.

and BIPSS to be of significant value in these patients (125). as noted above. The inferior discriminatory value of these stimulants is most likely due to the expression of both vasopressin and growth hormone secretagogue receptors by some ectopic ACTH-secreting tumours (148) (119). MRI can identify chest lesions that are not evident on CT scanning. Undoubedly this is a useful technique. 95% of microadenomas exhibit a hypointense signal with no post-gadolinium enhancement (Fig 2). Imaging Pituitary Imaging of the pituitary is an important part of the investigation of ACTH-dependent Cushing's syndrome to identify a possible pituitary lesion and to aid the surgeon during exploration. A combined desmopressin and hCRH stimulation test initially looked promising (146). but a further study of this combined test showed significant overlap in the responses (147). Modern MRI techniques using T1weighted spin echo and/or spoiled gradient recalled acquisition (SPGR) techniques will identify an adenoma in up to 80% of patients with Cushing’s disease (19. (111).151) . Fine-cut high-resolution CT scanning with both supine and prone images can help differentiate between tumors and vascular shadows (1). On MRI.corticotroph-specific V3 (or V1b) receptor. or to try and localise radiologically unidentified tumours (158). CT has a sensitivity of only approximately 40%-50% for identifying microadenomas. The majority of ectopic ACTH secreting tumours are of neuroendocrine origin and therefore may express somatostatin receptor subtypes. and is thus significantly inferior to MRI (sensitivity 50%-60%)(19. Other groups have found MRI less effective (156). and it should therefore be reserved for patients in whom MRI is contraindicated or unavailable. The most common site of the secretory lesion is the chest. in centres with no availability of CRH the desmopressin test may be an alternative. Hexarelin (a growth hormone secretagogue) stimulates ACTH release probably occurs through stimulation of vasopressin release in normal subjects (141).154). In addition. pre-gadolinium images are essential (152).155). Therefore the radiolabelled somatostatin analogue ( Inpentetreotide) scintigraphy may be useful to show either functionality of identified tumours. but in general patients should begin with imaging of the chest and abdomen with CT and/or MRI. and by stimulation of aberrant growth hormone secretagogue receptors in corticotroph tumors (142). however. Preoperative localisation to one side of the pituitary gland by MRI had been advocated as better than BIPSS with a positive predictive value of 93% (112.153. and although small cell lung carcinomas are generally easily visualised. Ectopic tumours Visualising an ectopic ACTH source can be a challenge. we have found MRI often to be unhelpful in the paediatric age group. but to date there are only sporadic reports that it identifies lesions not apparent using conventional imaging . and characteristically show a high signal on T2-weighted and short-inversiontime inversion-recovery images (STIR) (157). small bronchial carcinoid tumors that can be less than 1cm in diameter often prove more difficult. These peptides have been utilised in a similar manner to CRH to try and improve the differentiation of ACTH-dependent Cushing’s syndrome. the results must be used in conjunction with the biochemical assessment as approximately 10% of normal subjects may have pituitary incidentalomas on MRI (149). but have unfortunately proved inferior (143-145). However. bearing in mind likely sites (Table 2). Computerised tomography (CT) imaging typically shows a hypodense lesion that fails to enhance post-contrast. However. as the remaining 5% have an isointense signal post-gadolinium.150.

The procedure is not without risks. or radiological results are discordant or equivocal. The overall remission rate in various large series is in the order of 70%-75%.165). However. the LDDST. about 25% of these will have a recurrence by 10 years (166). but appears to offer prolonged remission in only around 50% of cases. BIPSS is recommended in cases of ACTH-dependent Cushing’s syndrome where the clinical. It is recommended that UFC (at least two measurements). There is limited data on endoscopic pituitary surgery for Cushing's syndrome although more centres are now offering this technique (170). In patients with discordant results second-line tests should be used as necessary for confirmation.9%. Treatment of Cushing’s syndrome Surgical Management Transphenoidal surgery Transsphenoidal surgery is widely regarded as the treatment of choice for Cushing’s disease (163). in many centres where BIPSS is available and validated.5% (164). a selective adenomectomy is performed. hopefully achieving cure without panhypopituitarism (168). Unless the tumours are metabolically active. which is not usually the case. and this emphasises the need for long term follow-up. However. Where remission is not achieved at the first operation.164.19. if somatostatin scintigraphy is positive. Investigative strategy for the diagnosis and differential diagnosis of Cushing’s syndrome There have been a number of international consensus statements published for the diagnosis and differential diagnosis of Cushing's syndrome.119). and with a high risk of hypopituitarism (169). the CRH test (combined with LDDST or HDDST). It does appear that it may be useful in patients with persistent or recurrent disease (171). the perioperative mortality was 1. The frequency of reported adverse events varies widely: diabetes insipidus (either temporary or .(159. and hence an ectopic source of ACTH. Abnormal results should be confirmed by one other of these tests. the latest on the diagnosis in 2008 (97. 18-flurodeoxyglucose positron-emission tomography (PET) does not generally offer any advantage over conventional CT or MRI (161) (162). low postoperative cortisol levels and long lasting adrenal insufficiency (167). or late night salivary cortisol (two measurements) are used as the first line screening test. histological confirmation of an ACTH-secreting tumor. Of the patients achieving remission. Where an adenoma is apparent at transsphenoidal exploration. a re-operation may be attempted. ACTH levels. Once the diagnosis of Cushing’s syndrome is unequivocal. and the surgeon may be guided by pre-operative imaging. although higher rates of approximately 90% can be achieved with microadenomas (6. However. together with appropriate imaging. and in the European Cushing’s disease survey group of 668 patients.160). a lesion of uncertain pathology is more likely to represent a neuroendocrine tumour. are the most useful non-invasive investigations to determine the aetiology. biochemical. a microadenoma detected by MRI. where no tumour is obvious a hemi-hypophysectomy as guided by the BIPSS results is often the best course of action. the practice is to use this test in almost all cases of ACTH-dependent Cushing’s syndrome. with other major complications occurring in 14. Prognostic markers of long term remission are patients aged over 25 years. lack of invasion of the dura or cavernous sinus.

They should also obtain a medical information bracelet or necklace that identifies this requirement (Medic Alert Foundation).172. However.178).) is probably the best indicator of the likelihood of long-term remission.m . If immediate surgical remission is not achieved at the first exploration.8%) (164. especially if previous diagnostic test results were indeterminate or conflicting. cortisol levels may sometimes gradually decline over 4-6 weeks reflecting either gradual infarction of remnant tumor or some degree of adrenal semiautonomy. however. They should be prescribed a 100-mg hydrocortisone (or other high dose glucocorticoid) intramuscular injection pack for emergency use. severe growth hormone deficiency (13%). Postoperative hypocortisolemia (<50 nmol/L [1. cerebrospinal fluid rhinorrhoea (4. The treatment options for patients with persistent Cushing’s disease include repeat surgery.6%-27. because later administration of glucocorticoids may result in disordered sleep.176). bleeding (1. Postoperative Evaluation and Management It is usual to give glucocorticoid cover for transsphenoidal surgery at initial daily doses of upto 400 mg hydrocortisone (4 mg dexamethasone). Patients who are hypocortisolaemic should be started on glucocorticoid replacement.173). the need to double the oral . Persistent cortisol levels greater than 140 nmol/L (>5µg/dL) six weeks after surgery require further investigation. Higher postoperative cortisol levels are more likely to be associated with failed surgery.177.m . or if no tumor was found on pathological examination. early repeat transsphenoidal surgery including the endoscopic technique may be worthwhile in a significant proportion of patients. tapering off within 1 to 3 days. Hydrocortisone 20 mg total daily dose in three divided doses is the preferred choice. detectable cortisol levels of less than 140 nmol/L (<5µg/dl) are also compatible with sustained remission (175.8 µg/dL] at 9:00 a.9%).179).3%-5%). radiation therapy. and meningitis (0-2. Persistent hypercortisolaemia after transsphenoidal exploration should prompt reevaluation of the diagnosis of Cushing’s disease. hypogonadism (14%-53%). Education should stress the need for compliance with the daily dose of glucocorticoid. (174). and the last 5mg dose should be taken no later than 6:00 p. Transsphenoidal surgery is also a useful procedure in patients with Nelson’s syndrome to reduce tumour size. at the expense of increased likelihood of hypopituitarism (169) (171. and adrenalectomy.) serum cortisol measurements are then obtained for 3 days starting 24 hours after the last glucocorticoid administration. Thromboprophylaxis with low molecular weight heparin should be used perioperatively in all surgical procedures for Cushing's syndrome (58). This low dose of hydrocortisone should be used to avoid long-term suppression of the HPA axis. Patients with cavernous sinus or dural invasion identified at the initial procedure are not candidates for repeat surgery to treat hypercortisolism and should receive radiation therapy. Morning (9:00 a.165. The largest dose (10mg) should be taken before getting out of bed. the rationale being that responsiveness may indicate residual tumor (19. and that failure to take or absorb the medication will lead to adrenal crisis and possibly death. Repeat sellar exploration is less likely to be helpful in patients with empty sella syndrome or very little pituitary tissue on MRI scans. during which time the patient should be observed for development of signs of adrenal insufficiency.m . The CRH test in the early postoperative period in patients with hypocortisolaemia and apparent "cure" may provide a useful index of the risk of recurrence of Cushing’s disease. and ameliorate hyperpigmentation. All patients receiving chronic glucocorticoid replacement therapy should be instructed that they are “dependent” on taking glucocorticoids as prescribed.permanent) (3%-46%). hypothyroidism (14%-40%).

m . The glucocorticoid dose should not be increased in the absence of intercurrent illness based on these symptoms alone. signs of adrenal insufficiency.m . Measurement of latenight salivary cortisol having omitted the afternoon dose of hydrocortisone may also be useful. diarrhea. Some of these symptoms have been related to high levels of circulating interleukin-6 (180). but the 9:00 a. . If it is used instead of the insulin tolerance test. but. If the cortisol is measurable.5 mg/day. If recurrent Cushing’s disease is diagnosed. indicating adequate reserve on modern assays (184). and nausea) during the postoperative months. Recovery of the HPA axis can be monitored by measurement of 9:00 a. initial testing at 6 to 9 months is reasonable (182). then recovery of the axis has not occurred and glucocorticoid replacement can be restarted. cortisol levels are above the lower limit of the normal range (200 nmol/L [7 µg/dL]). and that these are signs that indicate remission. the therapeutic options are the same as for persistent disease.dose for nausea. In the future modified release hydrocortisone may provide more physiological replacement (189).m . but there is some controversy as to its reliability in this situation (187. The patient should be told to expect desquamation of the skin. Investigation is warranted in a patient with these complaints or with recurrent physical signs characteristic of hypercortisolemia. Many centers use the cortisol response to 250 µg synthetic (1-24) ACTH as an alternative means of assessing HPA reserve (185. the hydrocortisone replacement dose should be adjusted down if weight loss has occured. even before physical and biochemical evidence are unequivocal. it is reasonable to taper and stop the hydrocortisone unless symptoms of adrenal insufficiency occur. Patients need to continue to be aware of the continuing need for additional glucocorticoids at times of stress or illness and should be given a supply of oral hydrocortisone and an intramuscular injection pack. For patients with detectable but low 9:00 a. and flu-like symptoms (malaise. adequate reserve of the HPA axis can be assessed using the insulin tolerance test (183). or severe medical stress. but there is a tradeoff between mirroring a normal physiologic rhythm as far as possible and the inconvenience of multiple dosing.186). serum cortisol after omission of hydrocortisone replacement.8 µg/dL]) before each dose is useful. ensuring that levels are always sufficient (>50 nmol/L [>1. Two late conundrums may arise: the questions of recurrence and permanent lack of recovery of the axis. anorexia. Most patients tolerate these symptoms of glucocorticoid withdrawal much better if they are forewarned and alerted to their positive nature. Patients who articulate that the Cushing’s syndrome has returned are often correct. Where recovery of the HPA axis is only partial on dynamic testing. trauma. If the cortisol is undetectable on 2 consecutive days. UFC can be measured initially on dexamethasone 0. Glucocorticoid replacement can be discontinued abruptly if the cortisol response is shown to be normal. such as vomiting. with a peak cortisol value of greater than 500 nmol/L (>18 µg/dL). joint aching. Assessment of adequate replacement of hydrocortisone dosing by measuring serum cortisol at various points throughout the day. cortisol levels. and a slightly lower dose may be given. electrolyte abnormalities. and fever. This may mean that the peak levels after each dose appear to be unphysiological. and postural hypotension should be excluded (181). ideally assessment of a cortisol circadian rhythm can be done as an inpatient having stopped the hydrocortisone completely. It should be remembered when investigating recurrence that longstanding ACTH stimulation by a pituitary adenoma causing macronodular adrenal hyperplasia may subsequently involve autonomous cortisol production (190). However. Because recovery after transsphenoidal surgery rarely occurs before 3 to 6 months and is common at 1 year. and the need for parenteral administration and medical evaluation during emesis. a 30-minute cortisol of greater than 600 nmol/L (>22 µg/dL) is probably more reliable (184). if not yet weaned from glucocorticoids.188).

This approach may require multiple operations to resect primary lesions. For these reasons. Laparoscopic adrenalectomy. and. either because they discover that this decreases the symptoms of glucocorticoid withdrawal or because they have increased the dose “for stress. hypertension. In adrenal adenomas cure following surgery in skilled hands approaches 100% (192). may be normalised during the postoperative period so that preoperative treatments for these need to reassessed. This may be due to injudicious fluid replacement or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) as is frequently seen after extensive gland exploration. particularly in young patients desiring fertility where there are concerns over radiotherapy induced hypopituitarism. occasionally. Its complication rate is lower than with the open approach. In adrenal cancer. requiring long-term treatment with a vasopressin analogue. including hypokalemia. It is advisable to withhold specific therapy unless the serum osmolality is greater than 295 mOsm/kg. These patients have a suppressed axis and very slow regression of Cushingoid features because of exogenous hypercortisolism. and hepatic. and the in-patient stay is significantly reduced (196). and increased . and glucose intolerance. thoracic. The patient who has a subnormal cortisol response to ACTH 2 years after transsphenoidal surgery (in the absence of overreplacement) is likely to proceed to life-long ACTH deficiency. the patient should be questioned about the actual dose of glucocorticoid that has been taken. A small minority of patients proceed to (apparently) permanent diabetes insipidus.If the UFC result is subnormal or low. and the urine output is greater than 200 mL/hour with an inappropriately low urine osmolality. Some glucocorticoid-induced abnormalities. They require education and support along with reduction in the daily dose of hydrocortisone to recommended levels. Often. intracranial metastases. it has the disadvantages of life long glucocorticoid and mineralocorticoid replacement therapy. and fluid intake should be restricted (191). However.” often without following strict guidelines. and is usually accompanied with adjuvant mitotane as discussed below. This is either unilateral in the case of an adrenal adenoma or carcinoma. assessment for deficiencies of other pituitary hormones should also be sought. Hyponatraemia may occur in as many as 20% of patients within 10 days of surgery. Bilateral adrenalectomy is also an important therapeutic option in patients with ACTH-dependent Cushing’s syndrome not cured by other techniques. both unilateral and bilateral. Ferring) 1 µg given subcutaneously will provide adequate vasopressin replacement for 12 hours or more. the serum sodium is greater than 145 mmol/L. has been shown in experienced hands to be a safe procedure and in many centres has become the approach of choice for non malignant disease. Post-operatively. Adrenalectomy Adrenalectomy is the treatment of choice for all cases ACTH-independent Cushing’s syndrome. local recurrences. and the appropriate replacement regimen initiated as necessary. more aggressive surgical approaches probably account for the increase in life span reported in this disease (194. Desmopressin (DDAVP. and is associated with low morbidity and mortality (193). Diuresis is common after transsphenoidal surgery and may result from intraoperative or glucocorticoidinduced fluid overload or may be due to diabetes insipidus. or bilateral in cases of bilateral hyperplasia. assessment of paired serum and urine osmolality and the serum sodium concentration is essential. patients take additional hydrocortisone.195).

the development of Nelson’s syndrome in patients with ACTH-secreting pituitary adenomas occurs in between 8% and 38% of cases (197). as it gives similar remission rates to primary transsphenoidal surgery (200). Radiotherapy Pituitary Conventional pituitary radiotherapy is delivered at a total dose of 4500 to 5000 cGy in 25 fractional doses over 35 days using a three-field (opposed lateral fields and vertex field) technique. This can take from between three months to two years (182). However. Remission usually occurs by two years although it can take considerably longer and patients should be reassessed at least yearly. Gamma knife radiosurgery is probably the most widely used of these techniques. The chance of developing Nelson’s syndrome appears to be greater if adrenalectomy is performed at a younger age. As adjunctive therapy after failed transsphenoidal surgery it achieves biochemical remission in about 55%. it is not clear whether the incidence is significantly greater than the background risk of developing such tumors (205. Primary pituitary radiotherapy for the treatment of Cushing’s disease has been shown to produce poor long-term remission rates of around 50% (202) (166). In addition. although followup times have not been as long as for conventional . such as in a lobectomy for a bronchial carcinoid tumour. In this situation bilateral adrenalectomy may be an option if medical management fails. This approach ensures that the daily dose to neural tissue does not exceed 180 cGy and avoids the complications of optic neuritis and cortical necrosis associated with larger total and fractional doses (201).197). There is some evidence of an increased risk of cerebrovascular complications. if significant metastatic disease is present. the chance of cure of Cushing’s syndrome is high. and if a pituitary adenoma is confirmed at previous pituitary surgery (166. especially whern imaging has originally not shown any clear tumour (199). it may be best to hold radiotherapy in reserve and undertake regular MRI scanning of the pituitary. Stereotactic conformal field planning is used to optimize the tumor dose and minimize radiation to other areas. The major side effect is other anterior pituitary hormone deficiency in over 50%. Although meningiomas and gliomas have been reported after pituitary radiotherapy. as a second line therapy to failed pituitary surgery better results are achieved with around 80% showing long-term remission as defined by the normalisation of the clinical state and biochemical parameters (203) (204). Surgery for the ectopic ACTH syndrome If the ectopic ACTH-secreting tumour is benign and amenable to surgical excision. It is not suitable for large lesions near the optic chiasm or optic nerves. The risk of optic neuropathy is low and probably less than 1% as long as low-dose fractions are used. which is of concern particularly in younger patients.206). Steriotactic radiotherapy has been less well investigated but has a number of theoretical advantages including reduction in risk of cerebrovascular disease. Patients after unilateral surgery will require glucocorticoid replacement whilst the suppressed HPA axis reawakens.peri-operative morbidity and mortality. but this should be reserved for selected cases. commonly growth hormone. Prophylactic pituitary radiotherapy probably reduces the risk of developing Nelson’s syndrome (198). with a lesser incidence of hypogonadism and hypothyroidism. surgery is not curative although it may still be of benefit in selected cases. However. In contrast. Others have advocated unilateral adrenalectomy plus pituitary irradiation as an alternative to bilateral adrenalectomy. Medical therapy is usually utilised in the interim.

radiotherapy (207). The fall in cortisol is rapid. but there are reports of some success in small numbers of patients (210). and therefore medical management is desirable pending reinvestigation. Radiosurgery of the pituitary gland using proton beams has similar efficacy as second line therapy (209). and thus can be utilised in all cases of hypercortisolemia regardless of cause. Metyrapone Metyrapone acts primarily to inhibit the enzyme 11β-hydroxylase. particularly in non-metastatic thoracic carcinoid tumours (214. It is the routine practice of many groups to pre-treat Cushing's syndrome patients prior to surgical treatment to reverse the hypercortisolaemia and its metabolic sequelae. there is no significant evidence that radiotherapy improves survival in adrenocortical carcinoma. medical therapy is helpful as a palliative modality in patients with metastatic disease causing Cushing's syndrome. Similarly. mitotane and in certain circumstances etomidate. Metyrapone has been used to good effect to reduce the hypercortisolaemia in patients with Cushing's syndrome from adrenal tumours. and Cushing's disease. medical management is often essential prior to (or long-term as an alternative to) bilateral adrenalectomy. It can also be used as salvage therapy in difficult tumours (208). ketoconazole. the ectopic ACTH syndrome. Maintenance therapy is 500-6000 mg/day in 3-4 divided doses daily. In . Adrenolytic Therapy These agents are primarily used as inhibitors of steroid biosynthesis in the adrenal cortex. although in the literature there are sporadic reports that it may be helpful adjuvant treatment to radical surgery in selected cases and will decrease local recurrence (211-213). It should be noted that there may be some cross-reactivity from 11-deoxycortisol with some cortisol radioimmunoassays: this may result in an unnecessary increase in the metyrapone dose and subsequent clinical hypoadrenalism (217). The most commonly used agents are metyrapone. It may not always be possible to identify the source of ACTH in certain cases of ACTHdependent Cushing's syndrome.215). Other Tumours Overall. with trough levels at 2 hours postdose. Finally. often with rapid improvement in the clinical features of Cushing's syndrome. In patients where surgery and/or radiotherapy has failed. and to hopefully reduce the complications of the definitive procedure. medical treatment is desirable in patients with Cushing's disease whilst waiting for pituitary radiotherapy to take effect. whilst in Cushing’s disease higher doses are often required. thus blocking the production of cortisol from 11-deoxycortisol in the adrenal gland (216). Local radiotherapy following surgical resection of an ectopic ACTH-secreting source may also be beneficial. In the former. Linear accelerator radiotherapy for Cushing’s disease is less well described. new hormone deficiencies are the major side-effect. Medical Management The role of medical treatment of Cushing’s syndrome is an important one. It is preferable to measure the serum cortisol via liquid chromatography tandem mass spectrometry in patients treated with metyrapone (218). patients can be very sensitive to low doses of this agent.As with other forms of radiotherapy. and in our unit we usually administer a test dose of 750mg with hourly cortisol estimation for 4 hours (219). The subsequent elevation of 11-deoxycortisol can be monitored in the serum of patients treated with metyrapone.

dizziness and gastrointestinal upset. and in 34 patients with Cushing's syndrome the mean total cholesterol was reduced from 6. It is an inhibitor of sex steroids production by its action on C17-20 lyase.232). with the incidence of serious hepatic injury at around 1 in 15. Conversely. It is also utilised in Cushing's syndrome of non-maliganant origin. It also inhibits 17-hydroxylase and 18-hydroxylase activity. At these lower doses the onset of the cortisol lowering effect takes longer (6-8 weeks) than with higher doses. it is hypoadrenalism that remains the most important potential problem. It has been used sucessfully to lower cortisol levels in patients with Cushing's syndrome of various aetiologies including adrenal carcinoma. It reduces cortisol and aldosterone production by blocking cholesterol side-chain cleavage and 11β-hydroxylase in the adrenal gland (235). particularly gastrointestinal (217. The principal side effect of ketoconazole is hepatotoxicity. but can require cessation of therapy (220). One major problem even with lose dose mitotane is the hypercholesterolaemia (principally an increase in LDL-cholesterol). and has a beneficial effect on endocrine hypersecretion in approximately 75% of patients (238). Hypokalaemia. thus reducing the incidence of side effects. which may be worsened with metyrapone. Due to its C17-20 lyase inhibition and consequent anti-androgenic properties. Reversible elevation of hepatic serum transaminases occurs in approximately 5%-10% of patients. and cortisol secretion by 11βhydroxylase inhibition (221-223).239). The hepatotoxicity appears to be idiosyncratic. It has also been reported to have a direct effect on ectopic ACTH secretion from a thymic carcinoid tumor (225). and one must always be wary of causing adrenal insufficiency (230. Triazole antifungals can also be effective. and in this regard lower doses can be utilised (up to 4 g/day versus 12 g/day). particularly LDL cholesterol (233).237).Cushing's disease this can be due to the compensatory rise in ACTH in patients not having received pituitary radiotherapy. an isomer of the insecticide DDD (belonging to the same family of chemicals as the insecticide DDT). Ketoconazole Ketoconazole is an imidazole derivative which was originally developed as an oral anti-fungal agent. The principal side-effects with metyrapone are hirsutism and acne (as predicted by the rise in adrenal androgens). and invasive ACTH-producing pituitary carcinoma. amongst other enzymes (224). was developed following the observation of adrenal atrophy in dogs administered DDD. and itraconazole. Mitotane Mitotane (o’p'DDD).1 to 5.0 mmol/l on ketoconazole (231). but has been reported within 7 days of the start of treatment in a patient with Cushing's syndrome (230). One further advantage of ketoconazole is its inhibition of cholesterol synthesis.000 patients (229). ketoconazole is particularly useful in female patients where hirsutism is an issue. gynaecomastia and reduced libido in male patients may be unacceptable and require alternative agents. . the ectopic ACTH syndrome. which appears to be due to the impairment of hepatic production of oxysterols. with doses required between 200-1200mg/day in up to 4 divided daily doses (226-228). and careful monitoring of treatment and education of the patient is required. Other adverse reactions of ketoconazole include skin rashes and gastrointestinal upset (231). Mitotane is used as a treatment for adrenal carcinoma and causes tumour regression and improved survival in some patients (236. However. Treatment for Cushing's syndrome is usually started at a dose of 200mg twice daily. such as fluconazole (234). with an onset of action that is slower than metyrapone. oedema and hypertension due to raised mineralocorticoids are infrequent (219).

has a similar inhibition of 17hydroxylase. However. Other side effects of mitotane include: neurological disturbance. Etomidate is an effective adrenolytic agent that acts rapidly. measurement of blood levels can allow dose titration and reduction as appropriate. a somatostatin analog with a broader spectrum of activity for somatostatin receptor sub-types. there has been renewed interest with the introduction of pasireotide (SOM230). there have been a number of case reports on the use of mitotane in successfully reducing hypercortisolaemia in seriously ill patients with either Cushing's disease or the ectopic ACTH syndrome (248-251). gynaecomastia in men. Recently. In the long-term. pasireotide 600µg injected twice daily for 15 days reduced UFC levels in 76% of 29 patients and normalised levels in 17% (254). although octreotide has been helpful in reducing ACTH and cortisol levels in selected case reports of ectopic ACTH-secreting tumours there has been much more limited success in patients with Cushing's syndrome probably through downregulation of receptor sub-type 2 in these tumors by hypercortisolaemia (252). simvastatin a HMG Co A reductase inhibitor. and 26% of patients on the 900µg twice daily dose. including type 5. Etomidate Etomidate is an imidazole-derived anaesthetic agent which was reported to have an adverse effect on adrenocortical function in 1983 (242).normally a brake on the enzyme HMG Co A reductase (240). However. In general. Since then. with a median UFC reduction of 48%. can reverse the hypercholesterolaemia. in this situation it may be life-saving. Pasireotide at a lower dose of 250µg three times daily has also been used in stepwise combination therapy with the dopamine agonist cabergoline (previously been demonstrated to have modest but . elevation of hepatic enzymes. its use has been limited outside of adrenal carcinoma.241). Compared to the other imidazole derivative ketoconazole.0mg/hour which is adjusted based on the serum cortisol levels. but is limited in its use by the fact it has to be given parenterally. as opposed to the preparation available in Europe which contains alcohol. This agent was shown in vitro to reduce human corticotroph proliferation and ACTH secretion (253). in which cases it has recently been shown to prolong life (237). It is usually given at a dose of 2. which is not downregulated during hypercortisolaemia. The preparation available in the USA contains the vehicle propylene glycol with the potential for nephrotoxicity.245).5 . etomidate more potently inhibits adrenocortical 11β-hydroxylase. and there have now been a number of clinical trials published. Patients who showed <50% reduction in UFC levels from baseline by month two were unlikely to show improvement by month six or 12. or recurrent Cushing's disease has presented 12 month results. Following their initial report in 1983 (246). but has less of an effect on C17-20 lyase (243). Allolio et al have shown that low-dose intravenous non-hypnotic etomidate (2. At six months there was a reduction in UFC levels in 91 of 103 evaluable patients. hypouricaemia. However.3.5mg/hour) normalised cortisol levels in 5 patients with Cushing's syndrome of various aetiologies (247). with 18% developing frank diabetes mellitus. At higher concentrations it also appears to have an effect on cholesterol side-chain cleavage (244. persistent. Other medical agents Somatostatin receptors have been demostrated on both corticotroph adenomas. A therapeutic level of 14-20 μg/ml has been recommended. and it or a similar agent should be used if necessary in patients treated with mitotane (240).6% of patients on the 600µg dose twice daily. Normalisation of UFC levels was achieved in 14. The most clinically relevant adverse events were hyperglycaemia (39%). In an initial phase II trial. and some ectopic ACTH-secreting tumours. A multicentre phase III dose-randomised trial in 162 patients with either new. and hypocortisolaemia (8%) (255). and a prolonged bleeding time (238.

others have found neither this somatostatin analog or pasireotide to be helpful in inducing a sustained response (272).276). However. This may be because doses used in the animal studies were much higher than the equivalent licensed dose in humans. We use the mean of five . The thiazolidinedione rosiglitazone. However.264). However. The further addition of ketoconazole in the remaining 8 patients induced normalisation of UFC levels in 6 of these. but recent evidence suggests it is also useful in selected aggressive pituitary tumors including corticotroph pituitary carcinomas (259. The addition of cabergoline normalised UFC levels in an additional 4 patients (24%). Although. inducing a rise in ACTH. and indeed for other reasons it has now been withdrawn from the market. to assess the effectiveness of treatment. we are not aware that the potential anti-secretory and anti-proliferative activities of this agent in Cushing’s syndrome has been investigated further. although the frequency of hyperglycaemia is a concern. specific receptor antagonists may prove to be useful (271a). results in human subjects with Cushing's disease have been disappointing (268-271). and in particular to avoid adrenal insufficiency.variable efficacy as monotherapy in Cushing's disease (256. Although octreotide has been shown to have cause a therapeutic reponse in GIP related AIMAH as mentioned above (22). it has proven effective in the treatment of hypercortisolaemia (275. β-adrenergic and LH/hCG receptors. and ketoconazole. It appears this is not specific to corticotroph adenomas. not all studies have confirmed this (263. In the rare causes of Cushing’s syndrome due to bilateral macronodular adrenal hyperplasia (AIMAH) and aberrant receptor expression of GIP. arginine-vasopressin (AVP) and hence cortisol (274). a PPAR-γ agonist. Retinoic acid has been found to inhibit ACTH-secretion and cell proliferation both in vitro in ACTHproducing tumor cell lines. In addition. the major drawback is the lack of biochemical markers to monitor over-treatment. and in vivo in nude mice (265). In humans. pasireotide monotherapy induced normalisation of UFC levels in 5 of 17 patients (29%). some reports suggested that response to temozolomide in pituitary tumors can be predicted by low expression of the DNA repair enzyme O6methylguanine-DNA-methyltransferase (MGMT) probably related to MGMT gene promotor methylation (261. the development of murine corticotroph tumours. generated by subcutaneous injection of ACTH-secreting AtT20 cells. Traditionally this chemotherapy agent has been used in the treatment of malignant gliomas. remission was achieved in 88% of patients using combination therapy out to 80 days treatment (258). Monitoring Treatment It is important to monitor all patients on medical therapy for Cushing’s syndrome.260). mifepristone blocks glucocorticoid-induced negative feedback at the hypothalamo-pituitary level. and cultured human corticotroph adenomas. the therapeutic response can usually be determined after three cycles of chemotherapy. Although. but also applies to other forms of pituitary tumor (267). has been shown in supra-pharmacological doses to suppress ACTH secretion in human and murine corticotroph tumor cells. Temozolomide is an oral alkylating prodrug that is converted in vivo to the DNA repair inhibitor dacarbazine. The glucocorticoid antagonist mifepristone (RU 486) is a potent antagonist of glucocorticoid and progesterone receptors (273).262). Therefore pasireotide represents an exciting potential new treatment for Cushing's disease. Its use cannot be recommended.257)). were prevented (266). Thus in total. and its long half-life and minimal agonist activity leaves the patient open to hypoadrenalism.

although its association with pre-eclampsia has been reported. Total serum cortisol levels increase in pregnancy. Glomerular filtration rates of less than 30 mL/min result in decreased cortisol excretion and spuriously low UFC values (281). The HDDST may be useful to distinguish these patients from Cushing's disease. The ACTH and cortisol responses to ovine CRH may be suppressed in patient with renal failure except for those undergoing continuous ambulatory peritoneal dialysis (282). hypertension and glucose intolerance. and the normal physiological changes in pregnancy. A mean serum cortisol between 150 and 300 nmol/l (5. probably reflecting increased induction of corticosteroid-binding globulin production by estrogen. ACTH levels are increased (280). beginning in the first trimester and peaking at 6 months. and its use in combination with the non-invasive tests above should be able to resolve most diagnostic issues. such as weight gain. and this range should be the aim of therapy. although adverse fetal outcomes may still persist: Medical treatment carries potential risk to the fetus and should be considered only as second line therapy when the benefit outweighs the risk. Although adrenal adenomas are often the cause of Cushing's syndrome in pregnancy (40-50%). This topic has been comprehensively reviewed by Lindsay and colleagues (299). ACTH levels may not be suppressed in these patients. Normal suppression to the overnight 1-mg LDDST is uncommon. . and there is no evidence of harm both in animal studies and the small number of pregnant patients studied with this drug. BIPSS with approriate additional radiation protection for the fetus should be reserved only for cases where diagnostic uncertainty remains. As mentioned above a liquid chromatography tandem mass spectrography cortisol assay is preferable in patients on metyrapone. striae. both maternal and fetal. Maternal hypercortisolism is associated with a poor outcome. with a decrease only after delivery.279). The metabolism of dexamethasone is normal in chronic renal failure. and then generally only as an interim measure. MRI without gadolinium enhancement is considered safe in the third trimester. and the 2-day LDDST does better in this regard (278. Metyrapone is probably the adrenolytic agent of choice. Ketoconazole has been utilised sucessfully in a small number of patients but is teratogenic in animals and therefore should be used with caution. thus definitive surgical treatment of adrenal or pituitary disease is recommended to achieve eucortisolemia. Cushing’s Syndrome in Pregnancy Cushing’s syndrome in pregnancy is fortunately rare in pregnancy but its diagnosis is challenging because of the symptoms and signs that are common to both conditions. The cortisol diurnal rhythm is maintained in pregnancy but with a higher nadir. fatigue. although others favour measurement of urinary free cortisol (UFC).serum cortisol measurements across the day.283). Cushing's syndrome in specific groups Chronic Renal Failure Cushing’s syndrome in the setting of chronic renal failure is poorly described but may pose diagnostic difficulties.5-11 ug/dl) corresponds to a normal cortisol production rate (277). In chronic renal failure plasma levels of cortisol are generally normal but with some radioimmunoassays may be increased (278. but the oral absorption can be altered in some patients There is reduced degree of suppression of cortisol by dexamethasone suggesting a prolonged half-life of cortisol. The second trimester is probably the safest time for operative intervention. UFC excretion is normal in the first trimester and then rises upto three-fold by term. The CRH test has also been used to identify patients with Cushing's disease. Suppression to dexamethasone testing is blunted. possibly due to placental CRH stimulation of the pituitary corticotrophs or placental ACTH secretion.

islet cell tumours and thymic carcinoids (308) illustrate this phenomenon. Bisphosphonate treatment may induce a more rapid improvement in bone mineral density (307).168. There is also some evidence that the outcome from Cushing's disease may be worse in males (302).300). The prognosis of the potentially malignant causes of Cushing's syndrome is more variable. has improved dramatically with effective surgical and medical treatments. compared with tumors from the same tissue that do not produce ACTH. There is some evidence that deficits in bone mass may be partially reversed after treatment of hypercortisolemia (305. it appear that after curative transsphenoidal surgery long-term mortality is not significantly different from that in the general population (18. Up to 82% of patients with small cell lung cancer and Cushing’s syndrome die within 2 weeks from the start of chemotherapy (11). This is perhaps not surprising given that increased cardiovascular risk markers and evidence of atherosclerotic disease persist when measured 5 years after remission of Cushing’s disease. Unfortunately. Tumors that produce ectopic ACTH tend to have a poorer prognosis.306). Adrenal cancer associated with Cushing's syndrome has an extremely poor prognosis. once a uniformly fatal illness. and hence it is important to aggressively treat associated conditions such as hypertension and diabetes (301). However. and should be considered (along with calcium and vitamin D supplements) in patients with osteoporosis. . in the long term this is only partially improved with treatment. another population based study suggested that mortality is marginally increased (3). and may not normalize (304). The affective and cognitive changes associated with Cushing’s syndrome are particularly slow to resolve.Prognosis The life expectancy of patients with non-malignant causes of Cushing's syndrome. Cushing's syndrome results in significant impairment in quality of life. From a number of studies in patients with Cushing’s disease treated in the era of transsphenoidal surgery. Small cell lung cancer. The outcome of paediatric Cushing’s disease is excellent if treated at centres with appropriate experience (285) (303).