 Cushing’s disease was first described as ‘polyglandular syndrome’ by Harvey Cushing in 1932.1 He called the condition ‘pituitary basophilism’. It represents the chronic exposure of tissue to increased plasma cortisol and causes a group of symptoms and signs that is called Cushing’s syndrome. Cushing’s syndrome is generally defined as pathological hypercortisolaemia.
There are several conditions that can cause this syndrome, including pituitary adenoma (Cushing’s disease), ectopic ACTH secretion, adrenal tumours, ectopic secretion of corticotrophin- releasing hormone, severe depression and chronic glucocorticoid treatment. Ideally, the physician should be able to determine the primary cause of the Cushing’s syndrome. Hypothalamic-Pituitary-Adrenal (HPA) AxisNormally the hypothalamus will produce and secrete a 41-amino acid peptide, called corticotrophin-releasing hormone (CRH). The paraventricular nucleus is the major location that regulates and secretes CRH.2 The CRH released enters the portal hypophyseal system, reaches the corticotroph cells at the anterior pituitary gland and binds to specific receptors. The ACTH then released is regulated by pulses of CRH secretion. In normal subjects, there are 12 to 40 pulses of ACTH secretion per day. The normal circadian rhythm is produced by the changing amplitude, but not frequency, of ACTH secretion.3 The ACTH itself is a 39-amino acid peptide product of enzymatic cleavage of a larger pro-hormone, called pro-opiomelanocortin. The ACTH enters the circulation and reaches the zona fascicularis of the adrenal gland, where it stimulates the release of cortisol. Cortisol has widespread actions involving the metabolism of carbohydrate, protein and lipid. It also influences most organ systems, including the cardiovascular, musculoskeletal, nervous and immune systems.4 Plasma ACTH and cortisol levels reach the highest point at the time of waking in the morning, between 6 am and 9 am, then decline during the day, with the lowest point being an hour or two after beginning sleep.3 Pathophysiology of Cushing’s DiseaseThe pituitary adenoma that causes Cushing’s disease is typically a microadenoma, smaller than 1 cm at its largest diameter. This microadenoma typically retains negative feedback by glucocorticoids, but it is set at a higher threshold for suppression. Regular doses of glucocorticoid cannot suppress ACTH production, but at higher doses the negative feedback will suppress ACTH production. This microadenoma also retains the expression of CRH receptors and the cellular process necessary to respond to CRH. Excessive production of ACTH by tumour cells leads to overproduction of cortisol by the adrenal cortex. The excessive ACTH will disrupt the normal cortisol rhythm, resulting in sustained hypercortisolaemia. (Figure 1) It is the excessive cortisol that causes the clinical manifestations of Cushing’s disease. Clinical PresentationAlmost all organ systems are affected by hypercortisolism, but the effects are not similar in all patients. Patients with Cushing’s syndrome usually have truncal obesity, with increased fat deposition over the abdomen and the dorsal cervical area—also known as a buffalo hump. (Figure 2) Abdominal fat deposition is associated with purple striae (stretch marks). Other features are ‘moon facies’, hirsutism, decreased fat in the limbs, thin skin and a bruising tendency, especially on the arm and hand. (Figure 3) The moon facies is caused by fat deposition in the cheeks and beneath the chin, which round out the face. Commonly, patients also have mood or psychiatric disorders such as depression. Other more general features include muscle weakness, hypertension and diabetes. Osteoporosis is caused by inhibition of calcium absorption and bone matrix formation by cortisol,5 with 25% to 40% of patients having pathological vertebral or rib fractures.6 Children with Cushing’s syndrome generally show a combination of obesity and growth arrest.7 Diagnostic ApproachEndocrine evaluation is the key to diagnosis in Cushing’s disease. Imaging studies help to localize the tumour, though sometimes the microadenoma is difficult to locate by imaging. The purpose of endocrine evaluation for Cushing’s syndrome is to establish the presence of hypercortisolaemia and the differential diagnosis of Cushing’s syndrome.  Establishing the Presence of Cushing’s Syndrome
Establishing the presence of hypercortisolism can be done in several ways, such as measurement of plasma cortisol from 6 am to 8 am and from 11 pm to 1 am; measurement of 24-hour urine-free cortisol (UFC); and 24-hour urine 17-hydroxy corticosteroids/ gm of urinary creatinine. It is also necessary to perform a low-dose (1 mg) overnight dexamethasone suppression test to assess the resistance of negative feedback. It is not necessary to perform all the tests if one already shows a significantly abnormal result. More than one test is required only when the results are doubtful and more information needs to be gathered to establish the diagnosis. Measurement of plasma cortisol is used in those above 3 years old, once the HPA axis is well established and the cortisol rhythm has become cyclic. Hypercortisolism is present when the level of evening cortisol is higher than 50% of the morning level. A UFC that is higher than 100 mg/ day confirms the presence of hypercortisolism. Daily UFC measurement is a very simple, cost-effective and accurate assessment to confirm the presence of hypercortisolism. False negatives of UFC after three measurements are rare, except in stress and chronic alcoholism. If the UFC level is not elevated above normal on repeat testing, at least two additional measurements should be made.8 Some obese patients with a body mass index >30 kg/m2 may have normal UFC. However, urine 17-hydroxy corticosteroid (OHCS), a metabolite derived from cortisol, may show elevation. To measure OHCS, 0.5 mg dexamethasone should be given orally every 6 hours for 2 days, starting at 6 am; 24-hour urine collections are obtained prior to dexamethasone administration and on the second day of dexamethasone administration. Normally, OHCS is less than 4 mg per 24 hours, whereas 95% of patients with Cushing’s syndrome will have higher OHCS.9 This test is not necessary for obese patients with significantly abnormal UFC. The low-dose overnight dexamethasone suppression test is done by using 1 mg dexamethasone given orally at 11 pm, and drawing serum cortisol the next day at 8 am. If cortisol <5 μg/dL is considered normal, 5 to 10 μg/dL is considered borderline, and retesting is necessary; >10 μg/dL suggests hypercortisolaemia.10 Establishing a Differential Diagnosis of Cushing’s SyndromePatients with excess cortisol secretion in the outpatient testing should be hospitalized for further evaluation. To differentiate Cushing’s disease from ectopic ACTH production and adrenal tumours, it is necessary to: Measure serum ACTH (usually low in adrenal tumours).
Perform an abdominal CT to rule out an adrenal tumour.
Carry out a high-dose dexamethasone suppression test; one-fifth of Cushing’s disease cases are not suppressed with high-dose dexamethasone.
Perform an overnight dexamethasone test: obtain a baseline 8 am plasma cortisol level, then give dexamethasone 8 mg orally at 11 pm and measure the plasma cortisol level the next morning at 8 am. In 95% of patients with Cushing’s disease, plasma cortisol levels are reduced to <50% of baseline, whereas in ectopic ACTH or adrenal tumours, it is usually unchanged.11
Metyrapone test: Give metyrapone 750 mg orally every 4 hours for 6 doses. Most patients with Cushing’s disease will have an OHCS rise in the urine of 70% above baseline, or increased serum 11-deoxycortisol 400-fold above baseline.11
CRH test: Patients with Cushing’s disease will usually respond to exogenous CRH 0.1 μg/kg intravenous bolus with even further increased plasma ACTH and cortisol levels. Ectopic ACTH and adrenal tumours do not respond to exogenous CRH.12
Inferior petrosal sinus sampling could help determine the likely side of the microadenoma within the pituitary. Fairly commonly, the adenoma cannot be seen on an MRI of the pituitary gland. Not all the above tests are required for every case. If the MRI does not show any pituitary abnormality, then we need to perform two or more tests to rule out ectopic production of ACTH. Cushing’s disease with normal MRI requires inferior petrosal sinus sampling before undergoing pituitary adenomectomy. ImagingA magnetic resonance imaging (MRI) scan focusing on the sellar region is the procedure of choice for detecting and localizing the pituitary adenoma. The MRI should be performed with and without contrast. Usually the pituitary adenoma will show less enhancement compared with the normal gland. Commonly, the microadenoma is so small that it is not clearly defined on MRI. Recently, the spoiled gradient recalled acquisition technique, using 1 mm non-overlapping cuts, has shown greater sensitivity than the conventional spin echo approach (sensitivity 80% vs 49%).13 However, the incidence of false positives was higher (4% vs 2%). Computed tomography (CT) scanning is sometimes used for patients with contraindications for MRI, such as in those with a pacemaker. A CT scan is far less sensitive than an MRI, but can still provide some detailed information such as aeration of the sphenoid, location of the carotid arteries, supra or parasellar extension if present, and location of any coexisting abnormality.
Treatment
SurgeryTransphenoidal microsurgical resection of the pituitary adenoma is the treatment of choice for Cushing’s disease. Adenomectomy should be directed according to MRI findings of whether the adenoma is on the left or right anterior lobe of the pituitary gland. Sometimes the adenoma is so small that it is not detected by MRI. A majority of Cushing’s disease with negative MRI will show lateralization from inferior petrosal sinus sampling, which should be use as guidance during pituitary adenomectomy. If it is doubtful intraoperatively, then careful complete bilateral exposure of the gland is necessary to identify the adenoma. Usually the adenoma is greywhite or grey-yellow in colour. The long-standing hypercortisolism feedback suppresses the hypothalamic CRH-producing cells and the secretion of ACTH by normal corticotroph cells, but does not suppress the ACTH secretion by tumour cells.  The HPA axis takes several months to recover after surgery; in the mean time, glucocorticoid replacement treatment is required for 6 months to 2 years for hypocortisolism. Figure 4 shows a patient waiting for the hypothalamic neurons to recover, the normal pituitary corticotroph cells to function, appropriate stimulation of the adrenal gland and a return to normal endogenous circadian cortisol secretion.The cure rate for microadenoma with surgery is higher (85%) compared with that of larger tumours.11 If the initial surgery fails, reassessment with more complete laboratory work is necessary, and sometimes a second surgery should be offered especially for younger patients to avoid early radiation. If the second surgery also fails, then other options of treatment should be initiated. Radiation therapyFractionated radiation of the sella after failed transphenoidal surgery can achieve biochemical remission in 80% of patients in 4 years.14 The effect of radiation takes place in a delayed fashion, from 6 months to years; medical therapy is, therefore, used to reduce adrenal production of glucocorticoids in the interim. Hypopituitarism is an anticipated side effect of radiation, usually occuring 5 to 10 years afterwards. Other disadvantages are injuries to the optic chiasm, induction of secondary neoplasm over the long term and occulomotor neuropathy. Medical therapyKetoconazole can block cortisol production by the adrenal cortex.15 It can induce remission of the signs and symptoms of Cushing’s disease whilst the patient awaits transphenoidal surgery or, more commonly, the effects of sella radiation. Its use is limited primarily by liver toxicity. AdrenalectomyBilateral adrenalectomy is limited to those patients in whom other treatments have failed. The problem with this procedure is the risk of developing Nelson’s syndrome, which occurs in 10% to 20% of patients after adrenalectomy for Cushing’s disease.16 In Cushing’s disease, ACTH is suppressed by negative feedback from the hypercortisolism, although ACTH secretion by tumour cells is not suppressed. After bilateral adrenalectomy, the ACTH level increases greatly, and some adenomata dramatically enlarge after correction of hypercortisolism. Nelson’s syndrome presents with hyperpigmentation associated with unbridled production of pro-opiomelanocortin, high levels of ACTH and melatonin-stimulating hormone, together with rapid growth of the pituitary adenoma. References1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull John Hopkins Hosp 1932;50:137–195. 2. Vale W, Spiess J, Rivier C, et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotrophin and beta-endorphine. Science 1981;213:1394–1397. 3. Veldhuis JD, Iranmanesh A, Johnson ML, Lizzaralde G. Twenty-four-hour rhythms in plasma concentrations of adrenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab 1990;71:1616–1623. 4. Loriaux DL, Cutler GB Jr. Diseases of the adrenal glands. In: Kohler PO, ed. Clinical Endocrinology. New York, US: John Wiley & Sons Inc; 1986:167–238. 5. Meunier PJ, Dempster DW, Edouard C, Chapuy MC, Arlot M, Charhon S. Bone histomorphometry in corticosteroidinduced osteoporosis and Cushing’s syndrome. Adv Exp Med Biol 1984;171:191–200. 6. Ross EJ, Marshall JP, Friedman M. Cushing’s syndrome: diagnostic criteria. Q J Med 1966;35:149–192. 7. Styne DM, Grumbach MM, Kaplan SL, Wilson CB, Conte FA. Treatment of Cushing’s disease in childhood and adolescence by transphenoidal microadenomectomy. New Engl J Med 1984;310:889–893. 8. Watts NB. Cushing’s syndrome: an update. Contemp Neurosurg 1995;17(18):1–7. 9. Yanovski JA, Cutler GB, Chrousos GP, et al. Corticotropin- Releasing Hormone Stimulation Following Low Dose Dexamethasone Administration: A new test to distinguish Cushing’s syndrome from Pseudo-Cushing’s states. JAMA 1993;269:2232–2238. 10. Tyrell JB, Aron DC, Forsham PH. Glucocorticoids and Adrenal Androgens. In: Greenspan FS, ed. Basic and Clinical Endocrinology. 3rd ed. Norwalk, Conn: Appleton & Lange; 1991:323-362. 11. Greenberg MS. Handbook of Neurosurgery. 5th ed. New York, US: Thieme; 2001;421-436. 12. Chrousos GP, Schulte HM, Oldfield EH, et al. The Corticotrophin-Releasing Factor Stimulation Test: an aid in the evaluation of patients with Cushing’s syndrome. N Engl J Med 1984;310:622–626. A complete list of references can be obtained upon request to the editor. About the Authors Dr July is Head of the Department of Neurosurgery at the Medical School of Universitas Pelita Harapan, and Staff Neurosurgeon at Siloam Hospital Lippo Karawaci, Tangerang, Indonesia. Dr Wahjoepramono is Dean of the Medical School of Universitas Pelita Harapan, and Chairman of Neurosurgical Service at Siloam Hospital Lippo Karawaci. E-mail: juliusjuly@yahoo.com | 
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