Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 I would paste the article, but it's huge. To get it, go to Lancet.com. Register (it's free) and search for Cushing's syndrome. The first article is a very good one published in March 2001. It details the types of tumors that don't secrete high levels of cortisol. It also describes how to test for those types of Cushings aka mild Cushings. It's detailed, but extremely clear. I don't see how any doctor can read this article and not understand how Cushings can be misdiagnosed. Also, Lancet is a very well thought of journal in the medical community. I hope this help someone. Ann Quote Link to comment Share on other sites More sharing options...
Guest Jean Ann Posted July 4, 2001 Report Share Posted July 4, 2001 Thanks Ann, I'm interested in reading it. -jean ann PS: I'm glad you redid your 24 hr urine with boric acid, don't forget to keep refrigerated. Quote Link to comment Share on other sites More sharing options...
Guest SuziQ2 Posted July 4, 2001 Report Share Posted July 4, 2001 It said I had to buy the article to read it or buy a subscription in order to read it. How did you read it without buying it or did you? If it's really good then I'll buy it. Quote Link to comment Share on other sites More sharing options...
Over 2000 Posts MaryOld Posted July 4, 2001 Over 2000 Posts Report Share Posted July 4, 2001 I just subscribed (free) but the article is ฟ. If you think it's worthwhile, I'll get a copy. Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 That's weird. ?I registered last night and I got it for free. ?I have printed it out and I cut and pasted it into my word processor. ?I can email it to anyone. ?kai@killerbytes.com It's about 27 pages long, I can post it if the forum allows that kind of length in posts. Sorry about the mixup. ?I would have never pointed you to a pay site. ?I don't know what happened. Ann (Edited by kai at 2:31 pm on July 4, 2001) Quote Link to comment Share on other sites More sharing options...
Over 2000 Posts MaryOld Posted July 4, 2001 Over 2000 Posts Report Share Posted July 4, 2001 I have no idea what length, if any, is the maximum for these boards. If it's too long, you could send it to me and I could post it on the website, possibly split up into several pages. Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 Well, I'll give it a try and see what happens. Hmmm. When I try to paste the whole thing, nothing happens. I'll try to do it in batches. olume?357,?Number?9258?? ??10?March?2001 ?Seminar Cushing's syndrome Marco Boscaro, Luisa Barzon, Francesco Fallo, Nicoletta Sonino Lancet 2001; 357: 783-91 ------------------------------------------------------------------------ Department of Medical and Surgical Sciences, Division of Endocrinology, University of Padova, Padova, Italy (M Boscaro MD, L Barzon MD, F Fallo MD, N Sonino MD) ------------------------------------------------------------------------ Correspondence to: Dr Marco Boscaro, Clinica di Endocrinologia, University of Ancona, Ospedale Generale Regionale di Torrette, 60100 Ancona, Italy (e-mail:clendo@popcsi.unian.it) Pathophysiology Epidemiology Diagnosis Differential diagnosis Imaging techniques Atypical clinical presentations and rare forms Pesudo-Cushing's syndrome Treatment of Cushing's disease Treatment of ectopic corticotropin or CRH syndromes Treatment of primary adrenal hypersecretion Quality of life Conclusion References Further reading During the past 30 years, there have been advances in understanding of the pathogenesis of Cushing's syndrome and in differential diagnosis of its various forms. Improved diagnostic tests and procedures have increased the ability to recognise even mild hypercortisolism and have provided the means to obtain an accurate diagnosis. Despite these advances, the occurrence of unusual clinical presentations and laboratory shortcomings may produce diagnostic problems and challenge clinical intuition. This article reviews recent pathogenic views, new tests, and new diagnostic problems in the evaluation of Cushing's syndrome. Atypical clinical presentations of hypercortisolism and some laboratory shortcomings that may confuse the diagnosis of Cushing's syndrome are also reported. Cushing's syndrome is a chronic glucocorticoid excess with various causes. Elucidation of the multiple pathogenetic mechanisms has greatly improved the management of this complex endocrine disorder. However, the syndrome is still associated with substantial morbidity and mortality, and from diagnosis to treatment it represents a challenge for the clinician. Pathophysiology Corticotropin-releasing hormone (CRH), synthesised in the hypothalamus, is the most potent regulator of corticotropin secretion. Corticotropin derives from a larger precursor pro-opiomelanocortin. Proteolysis occurs at pairs of basic aminoacids, generating several peptides, including ?-lipoprotein and ?-endorphin (the physiological roles of which are unclear) and corticotropin, which specifically stimulates the adrenal cortex.1 Cortisol, synthesised and secreted by the adrenal cortex, exerts negative feedback on pituitary corticotropin secretion. The pathogenetic mechanisms of Cushing's syndrome can be divided into those dependent and not dependent on corticotropin (panel 1).2 The most common form, which is termed Cushing's disease and accounts for 60-80% of cases in most series, is generally due to overproduction of corticotropin from a pituitary adenoma, in most cases a microadenoma (<1 cm in diameter).3 These tumours are of special interest in elucidation of the process of ontogenesis, because they show only mild abnormalities in comparison with normal corticotrophs. A mutation abnormality might give rise to a group of cells that are resistant to feedback effects and thus are reset to a higher concentration of cortisol in relation to corticotropin.4 Hyperplasia of pituitary corticotrophs has been described in a minority of patients in whom no tumour could be found.3,5 Stressful life events have been shown to have a pathogenetic role in hypothalamic-pituitary forms.6 Panel 1: Causes of hypercortisolism Corticotropin dependent Pituitary-dependent Cushing's syndrome (Cushing's disease) Ectopic corticotropin syndrome (bronchial, thymic, pancreatic carcinoids) Ectopic CRH syndrome Macronodular adrenal hyperplasia (autonomous) Iatrogenic: treatment with corticotropin or its analogues Corticotropin independent Adrenal adenoma Adrenal carcinoma Macronodular adrenal hyperplasia Micronodular adrenal hyperplasia (including the Carney complex) Adrenal hyperplasia caused by abnormal adrenal expression and function of receptors for various hormones (gastric inhibitory polypeptide, vasopressin, ?-adrenergic agonists, interleukin 1) Pseudo-Cushing's syndrome Major depressive disorder Alcoholism Ectopic production of corticotropin may derive from several types of tumours.7,8 Most patients with ectopic corticotropin syndrome have malignant tumours caused by small-cell lung carcinoma (overt ectopic corticotropin syndrome). Plasma corticotropin concentrations are high in many cases, causing hyperpigmentation. Hypertension, oedema, hypokalaemia, weakness, and glucose intolerance are generally present as manifestations of extremely high corticol concentrations. The typical Cushing's habitus is not present in many cases, whereas anorexia, weight loss, or other signs of malignant disease are common. Other cases of ectopic production of corticotropin are due to more indolent tumours, such as bronchial, thymic, and pancreatic carcinoids. This form of Cushing's syndrome may mimic pituitary-dependent hypercortisolism and is commonly misdiagnosed and mismanaged (occult ectopic corticotropin syndrome). The major problems arise because some of these tumours secrete amounts of corticotropin and similar compounds overlapping those observed in pituitary-dependent forms.9 In some cases, the ectopic corticotropin production has characteristics (such as dexamethasone suppressibility or responsiveness to CRH stimulation) typical of Cushing's disease.10 Moreover, some of these tumours secrete CRH with or without corticotropin,11 which can confuse diagnostic testing. Most ectopic tumours are benign, and some are so small that they are difficult to locate even with sophisticated morphological procedures; but there are also malignant and rapidly progressive cancers.12 Forms of autonomous adrenal hyperfunction include adrenocortical adenomas or carcinomas and the rarer primary nodular adrenal hyperplasia. However, the recent identification of several other forms of corticotropin-independent hypercortisolism has further complicated the pathogenesis of Cushing's syndrome (panel 1).2,13 An intriguing issue is the possibility that adrenal hyperplasia due to chronic stimulation by corticotropin or other factors may evolve towards autonomous nodular adrenal hyperplasia.14 At variance with this idea, some adrenal nodules decrease in size after removal of the pituitary adenoma, confirming that they are still under corticotropin control.15 About half the cases of bilateral micronodular hyperplasia, a rare cause of Cushing's syndrome, are in children and in adults younger than 30 years, whereas the other half occur as autosomal dominant disorders. This form, named Carney complex, is a genetic disorder linked to chromosomes 2p16 and 17q2.16,17 Adrenal masses discovered by imaging studies for unrelated reasons ('incidentalomas') in the vast majority of cases are non-hyperfunctioning adrenocortical adenomas. Their natural course is still under investigation; however, a minority of such lesions evolve towards overt Cushing's syndrome.18 Finally, iatrogenic or factitious Cushing's syndrome may be rarely associated with exogenous administration of corticotropin. Long-term treatment with glucocorticoids (eg, dexamethasone or prednisone) or, in rare cases, with megestrol acetate, may produce clinical features of hypercortisolism. Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 Next part: Note - the bolding is mine, I found this section to be particually important to us. Epidemiology Cushing's syndrome is rare. The estimated annual incidence of pituitary-dependent Cushing's disease is in the range of 0?1 to 1?0 new cases per 100 000,2,19 and that of Cushing's syndrome (benign and malignant tumours combined) is five to six times less.2 In most series, including our own (table), Cushing's disease accounts for about 70% of all cases of Cushing's syndrome, with the female to male ratio ranging from three to eight. Ectopic syndrome represents about 12% of cases. Corticotropin-independent causes of Cushing's syndrome include adrenal adenomas (10%) and carcinomas (8%). Such expected prevalence has to be taken into account in assessment of the power of available diagnostic tests. In our patients, age at diagnosis shows a peak in adult women ranging from 25 to 50 years. In children, primary adrenocortical tumours are more frequent than in adults and account for about 30% of cases. ------------------------------------------------------------------------ Sign/symptomFrequency (%) Truncal obesity96 Facial fullness82 Diabetes or glucose intolerance80 Gonadal dysfunction74 Hirsutism, acne72 Hypertension68 Muscle weakness64 Skin atrophy and bruising62 Mood disorders58 Osteoporosis38 Oedema18 Polydipsia, polyuria10 Fungal infections6 The mean age of the 239 female and 63 male patients was 38?4 years (SD 13?5; range 8-75). Signs and symptoms in our patients (n=302) ------------------------------------------------------------------------ Diagnosis Cushing's syndrome is characterised by an array of clinical features (table). The occurrence of any single feature ranges so widely among reported series that no single finding is necessary for diagnosis.19,20 Because clinical manifestations depend on both the degree and the duration of hypercortisolism, diagnostic difficulties arise at onset, when signs and symptoms are generally non-specific. However, certain features, such as weakness associated with proximal muscle wasting, skin atrophy, easy bruising after minor trauma, extensive ecchymoses, purple striae produced by the rapid enlargement of trunk and abdomen, hypertension, and psychological changes, strongly suggest hypercortisolism. On the other hand, some patients present with only isolated symptoms. Even the most common findings, such as truncal obesity and hypertension, may be lacking in some cases.21 The presence of only a few symptoms common to other disorders may be deceptive, and Cushing's syndrome can be misdiagnosed for a long time and patients treated in rheumatological, psychiatric, or other clinics before the correct diagnosis is achieved. Atypical clinical presentations or forms of pseudo-Cushing's syndrome further complicate the diagnosis. Routine chemistry abnormalities associated with hypercortisolism include neutrophilic leucocytosis, hyperglycaemia, hypokalaemia, hypercholesterolaemia, and hypercoagulable state.22 The lack of classic features of hypercortisolism in children may delay the diagnosis and treatment. Because high glucocorticoid concentrations strongly interfere with growth,23 all children with higher than normal weight and stunted linear growth should be investigated. Various tests proposed in the past three decades have been extensively reviewed, and their diagnostic accuracy discussed in detail.20,24,25 Both 24 h urinary free cortisol assay and the overnight 1 mg dexamethasone suppression test are suggested for screening of hypercortisolism (figure). Assessment of Cushing's syndrome Urinary free cortisol Measurement of urinary free cortisol has the advantages of simplicity and ability to provide an integrated measure of cortisol throughout 24 h.24 The sensitivity is 95-100% and the specificity 94-98%.20 Owing to the possibility of inaccurate urine collections and the variability of cortisol secretion from day to day, three 24 h urine specimens collected on an outpatient basis are commonly needed. To assess the adequacy of 24 h collection, creatinine should be also measured, because daily creatinine excretion varies by less than 10% from day to day. Because urinary free cortisol measurements are not valid in patients with renal failure and glomerular filtration rate below 30 mL/min, renal function should be verified before testing. Low-dose dexamethasone suppression tests In patients with very high urinary free cortisol, these tests add no further useful information. <b>They should be reserved for patients with mild hypercortisolism or suspected pseudo-Cushing's syndrome.</b> The overnight 1 mg dexamethasone suppression test (1 mg at 2300 h or 0000 h) may exclude the presence of Cushing's syndrome when morning concentrations of plasma cortisol are below 50 nmol/L. These strict criteria allow adequate sensitivity (98-100%),26 although the low specificity limits the test's clinical usefulness. <b>Higher cut-off values can result in a substantial number of false-negative responses, because some patients with mild Cushing's disease show unusual sensitivity to dexamethason suppression.</b> In the 2-day test, a normal response is a morning plasma cortisol concentration below 50 nmol/L after the patient has taken eight doses of 0?5 mg dexamethasone, with intervals of 6 h. This test, which showed sensitivity and specificity of 97-100%,26 can be carried out in inpatients or outpatients if adequate written instructions are provided. These strict criteria allow exclusion of patients with obesity or pseudo-Cushing's syndrome, but interfering conditions should be considered. There may be no suppression in patients with psychiatric illness, alcoholism, stress, high concentrations of corticosteroid-binding globulin (ie, pregnancy, oestrogen treatment), glucocorticoid resistance, decreased absorption of dexamethasone, those taking drugs that stimulate enzyme activity in the liver (phenobarbital, phenytoin), those presenting with abnormal cortisol metabolism, and those unable to follow directions. False-negative tests can occur in chronic renal failure and in hypothyroidism. Salivary cortisol Cortisol concentration in saliva is highly correlated with free cortisol in plasma and may distinguish patients with Cushing's syndrome from normal individuals when tested in late evening (at 2300 h) samples. Saliva can be easily collected at home several times to assess cortisol production over long periods.25 Midnight plasma cortisol In patients in hospital, a single cortisol measurement on blood taken during sleep at midnight indicates the presence of Cushing's syndrome when values are greater than 50 nmol/L with sensitivity of 100%.26 <b>New tests Special tests have been introduced lately to distinguish normal individuals and those with pseudo-Cushing's from patients with mild Cushing's disease. With a 48 h low-dose dexamethasone suppression test followed by CRH stimulation, plasma cortisol remains suppressed in normal people and those with pseudo-Cushing's syndrome (depression and alcoholism) but not in Cushing's disease.25 Dexamethasone (0?5 mg every 6 h) is administered eight times starting at 1200 h, then CRH (1 ?g/kg) is given intravenously at 0800 h (2 h after the last dexamethasone dose). In normal or pseudo-Cushing's individuals, the cortisol concentration does not rise above 39 nmol/L after CRH, whereas it does in those with Cushing's syndrome.25 Intravenous administration of desmopressin, a drug mainly used to treat central diabetes insipidus, does not consistently increase corticotropin secretion in normal people but it does in patients with pituitary-dependent Cushing's disease. In a recent study,27 100% of patients with Cushing's disease responded to desmopressin, so this drug is a promising first-line diagnostic tool. Moreover, the test was useful also in the postoperative assessment and follow-up of these patients. Despite early interest in this test for differential diagnosis of corticotropin-dependent Cushing's syndrome, there have been reports of ectopic corticotropin-secreting tumours that responded to desmopressin.25 Newell-Price and co-workers investigated the administration of desmopressin (10 ?g) with or without CRH (100 ?g).28 Patients with ectopic corticotropin production responded to the combined test, but the response was significantly lower than in patients with Cushing's disease. These new tests can give useful information when baseline results are not straightforward.25</b> The availability of stable isotopes that allow sophisticated measurement of cortisol production rates by infusion of tracer amounts of cortisol isotopes does not seem to offer any diagnostic advantage.29 (Edited by kai at 7:32 pm on July 4, 2001) Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 Part 3: Differential diagnosis Corticotropin assay Corticotropin measurement represents the first step and the best way to distinguish corticotropin-dependent from corticotropin-independent hypercortisolism. Concentrations below the limit of detection at 0900 h indicate autonomous adrenal hyperfunction. The higher the plasma corticotropin concentration, the more likely is an ectopic source of the hormone, particularly a small-cell lung carcinoma. In active Cushing's disease, plasma corticotropin at 0900 h may be within the normal range, and there may be a significant overlap between concentrations seen with pituitary adenomas and 'occult' ectopic corticotropin-secreting tumours. The immunoradiometric assay, which shows high sensitivity and low detection limits,30 is widely used but it does not recognise some biologically active variants of corticotropin from ectopic sources. The less specific radioimmunoassay is more effective in measurement of circulating corticotropin-like forms. High-dose dexamethasone suppression test Owing to the low sensitivity and specificity of the original criteria for cortisol suppression, new criteria (ie, suppression of urinary free cortisol to less than 10% of baseline for pituitary-dependent Cushing's disease) have been proposed, by which the high-dose dexamethasone suppression test reaches sensitivity of 70% and specificity of 100%. Together with CRH stimulation, this test is the most useful in distinguishing pituitary from ectopic corticotropin-dependent Cushing's syndrome. Suppression with a very high dose of dexamethasone (32 mg in 24 h) has been reported to be more effective, and it has been recommended in 'non-suppressible' pituitary-dependent Cushing's syndrome.31 CRH stimulation test Most pituitary but not ectopic corticotropin-secreting tumours have CRH receptors and show exaggerated corticotopin and cortisol responses to CRH administration. Diagnostic sensitivity and specificity are 93% and 100%, respectively, when the response of corticotropin to CRH stimulation of more than 35% is taken as positive.32 The largest published series report only the use of ovine CRH, and there have been no large studies with human CRH.33 Although this test is thought, together with the high-dose dexamethasone suppression test, to be the most useful in diagnosing ectopic corticotropin production, there are cases of ectopic production showing responsiveness to CRH stimulation.25 Moreover, some of these patients may respond also to high-dose dexamethasone suppression, leading to a mistaken diagnosis of pituitary-dependent Cushing's disease. CRH testing in combination with other peptides (eg, vasopressin) may represent an improvement over the standard CRH test; however, the data are scanty.24 Negative results may also be due to mistakes in handling of CRH. The lyophilised peptide easily deteriorates if not carefully diluted immediately before testing. Inferior petrosal sinus sampling This approach allows the determination of the site of a corticotropin-secreting lesion (pituitary versus ectopic).10,25,34 A ratio of central to peripheral corticotropin of more than 2?0, after CRH stimulation, has sensitivity of 95-97% and specificity of 100% in diagnosing pituitary-dependent Cushing's disease.35 Potential pitfalls of the method are the presence of non-pituitary neoplasms secreting CRH alone or with corticotropin, or very rare disorders such as an ectopic corticotropin-secreting adenoma localised within the sphenoid sinus producing a central to peripheral gradient similar to that of a pituitary-dependent form.25 This procedure may also help to localise the side of corticotropin-secreting pituitary adenoma. A gradient across left and right sides of greater than 1?4 can predict the exact localisation of corticotropin hypersecretion with accuracy ranging from 5% to 100%.25 However, an intersinus corticotropin gradient may be lacking in cases of adenoma located in the median wedge of the adenohypophysis and primary diffuse corticotroph cell hyperplasia without adenoma. Moreover, anatomical variability in number and size of anastomic vessels may also confuse the results.36 The great variability in results may relate to the expertise of the team doing the test.37 Although the associated morbidity seems to be low,38 the test requires experienced teams in specialised centres and should be reserved only for patients in whom diagnostic doubts persist after the more common testing. Imaging techniques Imaging techniques are required for localisation of pituitary or ectopic corticotropin-producing tumours and adrenal masses. Because of their small size, 40-50% of pituitary corticotropin-secreting tumours are not recognised preoperatively despite use of sophisticated methods such as magnetic resonance imaging (MRI) with gadolinium enhancement. By contrast, substantial numbers of the general population have asymptomatic non-secreting microadenomas (pituitary incidentalomas) revealed by MRI.34 Therefore, morphological localisation of the pituitary tumour is useful only to confirm the diagnosis of Cushing's disease previously made by hormonal testing. At adrenal level, in the majority of patients with corticotropin-dependent Cushing's syndrome, computed tomography (CT) shows bilateral adrenal enlargement, with nodular adrenal hyperplasia in 10-15%, and in up to 30% the adrenal glands are of normal size. In patients in whom an adrenal tumour is suspected, CT or MRI confirms the diagnosis, easily localises the mass, and may help to distinguish benign and malignant forms.38 Patients with suspected ectopic corticotropin production should be studied by accurate chest and abdominal CT or MRI. Most of these tumours are of neuroendocrine origin and may present with high expression of somatostatin receptors.12 Advanced scintigraphic methods with radiopharmaceuticals such as indium-111-labelled pentreotide are able to visualise only tumours bearing sst2 (and sst3 and sst5) somatostatin receptor subtypes.39 In the near future, the development of new classes of radiolabelled somatostatin subtype-selective analogues should improve scintigraphic localisation of ectopic corticotropin-secreting tumours. At present, 111In-pentreotide scintigraphy could be combined with conventional radiography to improve the accuracy of localisation of these tumours. The radio-labelled cholesterol scintiscan provides morphofunctional information complementary to anatomical imaging and is useful in assessment of malignant disease.40 Positron-emission tomography has gained clinical acceptance in oncology and can be used to differentiate malignant and benign adrenal masses as well as metastatic lesions41 and to identify ectopic corticotropin-producing neuroendocrine tumours (unpublished). Atypical clinical presentations and rare forms <b>Intermittent hypercortisolism Cortisol hypersecretion with periodicity, varying from a few days to months,42 may be observed in Cushing's syndrome of pituitary, adrenal, or ectopic origin. Episodes of active hypercortisolism are separated by periods of normal pituitary-adrenal function of varying length as shown by frequent measurements of salivary cortisol in the late evening25 or tests of urinary free cortisol. For a cost-effective approach, patients can be tested only when they note something wrong, such as swelling, or some clinical signs become apparent. </b> Adrenal incidentalomas 1-8% of normal individuals have non-functioning adrenal adenomas, some of which are large enough to be easily recognised by abdominal CT scan. Therefore, a substantial proportion of people who undergo assessment for Cushing's syndrome may be found to have an 'incidentaloma' (ie, an incidentally discovered adrenal mass) that has no relevance to the cortisol overproduction. In these cases, adrenocortical scintigraphy, in additional to hormonal testing, is a useful tool. Bilateral uptake of radiolabelled cholesterol may indicate corticotropin-dependent hypercortisolism, despite the presence of an adrenal mass.40 Pigmented micronodular adrenal hyperplasia In this disorder, the adrenal glands appear of normal size on CT, but on surgical examination show many small nodular brown or black lesions. Clinical features may include myxomas of the heart, blue naevi, pigmented lentigines, endocrine tumours, and peripheral-nerve tumours.16 Diagnosis may be achieved by a careful clinical examination and, if necessary, by accurate thin-section CT or MRI of the adrenal glands. Some patients show on dexamethasone suppression tests a paradoxical cortisol increase. <b>Abnormal sensitivity to glucocorticoids Clinical and laboratory features of Cushing's syndrome have been reported in rare cases of patients with normal, low, or undetectable cortisol concentrations.43 The pathophysiology of these forms, due to abnormal sensitivity to glucocorticoid activity or to increased glucocorticoid receptor numbers, is still under investigation. Clinical and laboratory features are similar to those of patients given doses of synthetic glucocorticoids (factitious hypercortisolism).44 A meticulous search for synthetic glucocorticoids in urine by gas chromatography or by high-performance liquid chromatography may be required in the differential diagnosis.</b> Pesudo-Cushing's syndrome Obesity Although not generally accepted as a cause of pseudo-Cushing's syndrome, obesity is the most frequent reason for investigation for Cushing's syndrome. With use of the low-dose dexamethasone suppression and urinary free cortisol tests, Cushing's syndrome can be confidently excluded in the vast majority of patients. Depression Patients with major depression can show some hormonal features of Cushing's syndrome.45 However, in most cases cortisol hypersecretion is negligible, and only occasional patients in whom severe depression coexists with other symptoms (obesity, hypertension, diabetes) might be mistakenly thought to have Cushing's syndrome with secondary depression.2 In depressed patients, a cortisol response to insulin-induced hypoglycaemia or lack of response to the low-dose dexamethasone suppression and CRH test may exclude Cushing's syndrome.20 Alcoholism Alcohol excess can produce in some people clinical features identical to those of Cushing's syndrome.46 This picture may be associated with abnormalities of cortisol secretion (loss of circadian rhythm). The exact mechanism by which alcohol influences cortisol secretion is still unclear. One hypothesis is that alcohol activates the hypothalamic-pituitary-adrenal axis by increasing the production and secretion of CRH.46 Normalisation of clinical and hormonal features after ethanol withdrawal is the simplest way to avoid a false diagnosis. HIV infection Pseudo-Cushing's syndrome has been described in HIV-infected patients. This form, in which cortisol concentrations are normal and adequately suppressed by dexamethasone, seems to be due to antiviral therapies.47 Treatment of Cushing's disease Trans-sphenoidal selective adenomectomy This operation is the most widely accepted primary therapy for Cushing's disease. Surgical skill and experience are the most important factors for a high success rate. In most centres with special interest in this illness, acceptable results with total remission rates of 80-90% have been achieved for tumours confined to the sella.2,3,34,48 The criteria for cure should be undetectable plasma cortisol concentration postoperatively. Less strict criteria result in higher rates of apparent cure but higher rates of recurrence. Patients require glucocorticoid-replacement therapy (20-30 mg hydrocortisone daily) from the time of surgery until recovery of the hypothalamic-pituitary-adrenal axis, which is 4-12 months after surgery in most cases. Relapse is defined as recurrence of both clinical and biochemical characteristics of Cushing's syndrome more than 6 months after cure. The main argument for the choice of surgery instead of radiotherapy in recurrences is the possibility of leaving pituitary function intact in most of the cases. However, the results of a second trans-sphenoidal operation in recurrences have been disappointing in most series, with a success rate of 22-64%.49 Thus, in recurrences, surgical treatment should be considered only for patients with clear morphological signs of pituitary tumour. Use of intraoperative ultrasonography to localise pituitary adenomas in Cushing's disease improved surgical outcome in a recent study.50 Owing to their hypercoagulable state,22 patients with Cushing's syndrome undergoing any type of surgery should receive heparin prophylaxis. Pituitary irradiation For adults not cured by trans-sphenoidal surgery and judged not suitable for a second operation at pituitary level, pituitary irradiation is the most appropriate choice as second-line treatment. In the series of Estrada and colleagues,51 83% of patients had remission after radiotherapy. The remissions began 6-60 months after irradiation, but in most cases remission occurred within 2 years of treatment. The only side-effect noted was the development of variable degrees of hypopituitarism in 15 of 30 patients. Radiotherapy, as first treatment, may be used in adult patients in whom high surgical risks or low compliance exclude any surgical approach: remission is obtained in about 55% of these patients.48 Radiosurgery with the 'photon knife' or 'gamma knife' in experienced hands implies low risks, but its effectiveness in large series has still to be proved.52 Bilateral adrenalectomy Bilateral adrenalectomy, which provides the definitive cure in patients for whom cure is not achieved with surgery, radiation, or both, necessitates lifelong continuous monitoring of glucocorticoid and mineralo-corticoid replacement therapy. Glucocorticoid replacement is 20-30 mg hydrocortisone daily in most cases. Mineralocorticoid replacement with 9-fludrocortisone (50-100 ?g daily) should be started as soon as intravenous saline is discontinued. Laparoscopic bilateral adrenalectomy may be a valid therapeutic option.53 However, the benefits must be weighed against the risk of Nelson's syndrome and other drawbacks. In our experience,48 about 25% of the patients who underwent bilateral adrenalectomy developed Nelson's syndrome (dark skin pigmentation, very high corticotropin concentrations, and radiological evidence of pituitary adenoma). Such a proportion is consistent with those reported previously, though rates vary across series and with duration of follow-up.50,54 Variability may also depend on the criteria for tumour aggressiveness, because there is no consensus definition of Nelson's syndrome. Prognostic risk factors Survival analysis has been used to assess long-term outcome in Cushing's disease in multicentre55 and single-centre48 studies. In the latter, the estimated cumulative proportion of 79 patients remaining in remission after successful pituitary surgery was 99% after 2 years and 74% after 10 years. Of eight factors examined, statistical significance was found for age, clinical severity, presence of major depression, urinary free cortisol concentrations before and after treatment, and post-treatment corticotropin concentrations. Predictive factors for success of pituitary surgery were also assessed. Surgical failure was significantly associated with the lack of neuroradiological or surgical evidence of pituitary adenoma, a clinical picture noted as severe, and the presence of major depression.48 In patients with Cushing's disease who underwent bilateral adrenalectomy, two risk factors were associated with the occurrence of Nelson's syndrome: high pretreatment urinary cortisol and the presence of pituitary adenoma. None of our 15 patients without adenoma in the pituitary developed Nelson's syndrome.48 Like others, we did not detect a protective effect of pituitary irradiation before bilateral adrenalectomy for this complication. However, Jenkins and colleagues56 recommended its use because the frequency of Nelson's syndrome was lowered by prophylactic pituitary radiotherapy in their sample. Medical treatment Many drugs have been used in the treatment of pituitary-dependent Cushing's disease (panel 2). They act at hypothalamic-pituitary level and decrease corticotropin secretion, inhibit cortisol synthesis at adrenal level, or compete with cortisol at the receptor level.57 The neuromodulatory compounds used so far have shown real clinical efficacy only rarely when used as sole treatment, whereas inhibitors of steroid synthesis are effective in most cases in a dose-dependent manner. Through their ability to correct hypercortisolism and its severe complications quickly, they are suitable for critical cases and in preparation for surgery, for patients treated with pituitary irradiation, and whenever a definitive treatment is delayed. Practical guidelines for medical treatment may be summarised as follows. Panel 2: Medical treatment of Cushing's disease Compounds acting at hypothalamic-pituitary level Serotonin antagonists (cyproheptadine, metergoline, ketanserin, ritanserin) Dopamine agonists (bromocriptine, lisuride) GABA agonists (sodium valproate) Somatostatin analogues (octreotide) Compounds acting on adrenal glands Mitotane Metyrapone Aminoglutethimide Ketoconazole Etomidate Trilostane Compounds acting at receptor level Glucocorticoid antagonists (mifepristone) First, drugs acting at the hypothalamic-pituitary level (serotonin antagonists, dopamine agonists, GABA agonists) are rarely effective. Unfortunately, no predictive criteria for therapeutic outcome can be given, because the response to acute testing may be misleading. A treatment trial of at least 2 weeks with measurements of corticotropin and urinary free cortisol is needed to assess the responsiveness.57 Bromocriptine, cyproheptadine, sodium valproate, ritanserin, and ketanserin have all been reported to work only occasionally.58-61 Second, the most common inhibitors of steroid biosynthesis in clinical use are: mitotane, metyrapone, aminoglutethimide, and ketoconazole (panel 2). The mode of action of mitotane seems to be multifactorial, but the other inhibitors of steroidogenesis that have found most practical clinical application all interfere with reactions catalysed by cytochrome P450. This mechanism of action has little selectivity and extra-adrenal effects are likely.57 Daily doses should be titrated to maintain urinary cortisol in the normal range, avoiding excessive suppression of adrenal function and the need for glucocorticoid replacement. Patients should be watched for possible adrenal insufficiency and specific toxic effects. Mitotane has been extensively used in all forms of hypercortisolism. The mechanisms of action involve adrenocorticolytic effects, modifications of steroid peripheral metabolism, and direct inhibition of steroid biosynthesis. Extensive metabolism is required for this drug to be active, and it takes several weeks to reduce cortisol secretion. The daily doses currently used for the treatment of Cushing's disease range from 2 g to 4 g, and the monitoring of urinary free cortisol is the best index of response. Replacement therapy requirements are higher than usual, due to interference of hormone-binding proteins. Metyrapone has been used in the management of various types of Cushing's syndrome.57 Side-effects due to increased concentrations of androgens (acne, hirsutism) and 11-deoxycorticosterone (hypokalaemia, oedema) as a consequence of 11?/18-hydroxylase inhibition, may be reversed by addition of low doses of aminoglutethimide (a more toxic agent) with predominant inhibition on the cholesterol side-chain cleavage complex.62 Ketaconazole is effective as a single agent and at lower doses than the other inhibitors of steroid synthesis. By inhibition of cholesterol side-chain cleavage and 17-hydroxylase/17-20-lyase activities, it can have favourable effects on hirsutism, but its androgenic effects may be disturbing.63 In most cases, 600-800 mg daily is needed to keep urinary cortisol concentrations within the upper normal limits (to avoid the risk of adrenal insufficiency). According to the effect on adrenal enzymes, a suitable combination would be with low-dose aminoglutethimide, but the association with metyrapone might cause mineralocorticoid hypertension (by accumulation of 11?/18-hydroxylase precursors). By contrast with mitotane, which causes hypercholes-terolaemia, ketoconazole interferes with the conversion of lanosterol to cholesterol, leading to low cholesterol concentrations. The occurrence of idiosyncratic hepatotoxic effects may be a limiting factor in its use.64 Third, mifepristone is the first potent glucocorticoid antagonist available for clinical use that has affinity for glucocorticoid receptors and very little agonist effect. Only a few patients with Cushing's syndrome have been treated with this drug. Clinical improvement was obtained at high doses (up to 20 mg/kg daily) in forms of hypercortisolism other than pituitary-dependent Cushing's disease. As a result of treatment, cortisol concentrations tend to increase, and therefore monitoring relies only on looking for clinical signs of hypoadrenalism as a marker of overtreatment.57 Finally, combined treatments may increase the likelihood of effectiveness.57 In pituitary-dependent Cushing's disease, there is no treatment strategy valid for all cases. The various therapeutic tools should be selected according to the drug's properties and the particular clinical situation of each patient. Treatment of ectopic corticotropin or CRH syndromes Surgical tumour excision completely cures hypercortisolism, removing the source of ectopic corticotropin or CRH and thereby curing the metabolic disorder. In many patients in whom tumours are not surgically resectable (occult and malignant metastatic). the hypercortisolism can be controlled by inhibitors of steroid biosynthesis. Somatostatin analogues rapidly decrease ectopic corticotropin secretion by some tumours; however, not all ectopic corticotropin-secreting tumours are responsive to this treatment (lack of somatostatin receptors).57 In patients with severe hypercortisolism due to metastatic malignant tumours or undiagnosed ectopic sources, bilateral adrenalectomy remains the only rational treatment. Laparoscopic bilateral adrenalectomy65 seems to be a safe and effective procedure, which can be undertaken more easily in patients with the ectopic corticotropin syndrome, in whom good control of cortisol concentrations is not obtainable with drugs. Treatment of primary adrenal hypersecretion In all cases of autonomous corticotropin-independent Cushing's syndrome, adrenalectomy is necessary (unilateral adrenalectomy in the case of an adrenal adenoma or carcinoma; total bilateral adrenalectomy in the cases of bilateral micronodular or macronodular adrenal hyperplasia). Laparoscopic adrenalectomy has gained wide acceptance as the procedure of choice for resection of most adrenal tumours.65 The cure rate by surgical removal of adrenal glands is virtually 100%. After unilateral adrenalectomy for an adrenal adenoma, patients need glucocorticoid replacement for several months until hypothalamic-pituitary-adrenal function recovers. After bilateral adrenalectomy, patients need lifelong steroid replacement therapy with both glucocorticoids and mineralocorticoids. Patients with carcinomas almost invariably have progression of disease. In these cases, mitotane alone or in combination with chemotherapy is generally used. This drug, at doses of 2-10 g daily, has been extensively used for the treatment of metastatic adrenocortical carcinoma. Although this drug may offer patients a hope of cure, it is merely palliative in residual or recurrent disease. Quality of life Quality of life in Cushing's syndrome may be seriously compromised even when patients are apparently doing well in hormonal terms during medical management or replacement therapy.66 Indeed, this endocrine disorder has profound physical and emotional effects, beyond the well-known psychopathology associated with hypercor-tisolaemic states.67 Full recovery may be very slow to take place, and help should be provided to overcome as much as possible the neuropsychological (cognitive and emotional) and physical (osteoporosis, hypertension, hypopituitarism) residual impairments. The speed with which psychosomatic recovery occurs may depend on various factors, such as properly individualised glucocorticoid and other hormone replacement (when indicated). Assessment of psychological wellbeing and functional capacity should, therefore, be added to traditional hormonal and clinical variables.68 Conclusion Cushing's syndrome remains one of the most complex endocrine syndromes. A simplified flow-chart is provided in the figure. The correct assessment of Cushing's syndrome depends on the exact knowledge of its various forms and attention to the pitfalls in the diagnostic evaluation. The choice of tests, the integrity of the specimens, the quality of the measurements, and a close dialogue among clinicians and laboratory are key factors for optimum care of the patients. The treatment of choice is surgery in most cases, in the attempt to eliminate completely the cause of hypercortisolism while minimising the chance of an endocrine deficiency. (Edited by kai at 7:36 pm on July 4, 2001) Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 Here are the references, if your docs want to see them. References 1Smith AI, Funder JW. Proopiomelanocortin processing in the pituitary, central nervous system and peripheral tissues. ?Endocr Rev?1988;?9:?159-79.?[PubMed] 2Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, Foster DW, Kronemberg HM, Larsen PR, eds. Williams textbook of endocrinology, 9th edn. Philadelphia: W B Saunders, 1998: 517-664. 3Mampalam TJ, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing's disease: a report of 216 cases. ?Ann Intern Med?1988;?109:?487-93.?[PubMed] 4Dahia PLM, Grossman AB. The molecular pathogenesis of corticotroph tumours. ?Endocr Rev?1999;?20:?136-55.?[PubMed] 5Kruse A, Kliniken L, Holck S, Lindholm J. Pituitary histology in Cushing's disease. ?Clin Endocrinol ?1992;?37:?254-59.?[PubMed] 6Sonino N, Fava GA, Boscaro M. A role for life events in the pathogenesis of Cushing's disease. ?Clin Endocrinol?1993;?38:?261-64.?[PubMed] 7Becker M, Aron DC. Ectopic ACTH syndrome and CRH-mediated Cushing's syndrome. ?Endocrinol Metab Clin North Am?1994;?23:?585-606.?[PubMed] 8Wigg SJ, Ehrlich AR, Fuller PJ. Cushing's syndrome secondary to ectopic ACTH secretion from metastatic breast carcinoma. ?Clin Endocrinol?1999;?50:?675-78.?[PubMed] 9White A. Gibson A. ACTH precursors: biological significance and clinical relevance. ?Clin Endocrinol?1998;?48:?251-55.?[PubMed] 10Perry LA, Grossman AB. The role of the laboratory in the diagnosis of Cushing's syndrome. ?Ann Clin Biochem?1997;?34:?345-59.?[PubMed] 11Carey RM, Vrma SK, Drake CRJ, et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome: a clinical, morphologic, and biochemical study. ?N Engl J Med?1984;?311:?13-20.?[PubMed] 12de Herder WW, Lamberts SWJ. Tumour localization. The ectopic ACTH syndrome. ?J Clin Endocrinol Metab?1999;?84:?1184-85.?[PubMed] 13Bornstein SR, Chrousos GP. Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. ?J Clin Endocrinol Metab?1999;?84:?1729-36.?[PubMed] 14Hermus AR, Pieters GF, Smals AC, Pesman GJ, Lamberts SW. Transition from pituitary-dependent to adrenal-dependent Cushing's syndrome. ?N Engl J Med ?1988;?318:?966-70.?[PubMed] 15Aron DC, Findling JW, Fitzgerald PA, et al. Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome: report of two cases and review of the literature. ?Am J Med?1981;?71:?302-06.?[PubMed] 16Stratakis CA, Carney JA, Lin JP, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2. ?J Clin Invest?1996;?97:?599-607.?[PubMed] 17Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. ?Nat Genet?2000;?26:?89-92.?[PubMed] 18Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta A, Boscaro M. Risk factors and long-term follow-up of adrenal incidentalomas. ?J Clin Endocrinol Metab?1999;?84:?520-26.?[PubMed] 19Bertagna X, Raux-Demay MC, Guilhaume B, Girhard F, Luton JP. Cushing's disease. In: Melmed S, ed. The pituitary. Oxford: Blackwell Science, 1995; 478-545. 20Crapo L. Cushing's syndrome: a review of diagnostic tests. ?Metabolism?1979;?28:?955-77.?[PubMed] 21Ross EJ, Linch DC. Cushing's syndrome-killing disease: disciminatory value of signs and symptoms aiding early diagnosis. ?Lancet ?1982;?2:?646-49.?[PubMed] 22Casonato A, Pontara E, Boscaro M, et al. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing's syndrome. ?Blood Coag Fibrinol?1999;?10:?145-51.?[PubMed] 23Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing's syndrome in children and adolescents. ?N Engl J Med?1994;?331:?629-36.?[PubMed] 24Newell-Price J, Grossman A. Diagnosis and management of Cushing's syndrome. ?Lancet ?1999;?353:?2087-88.?[Text] 25Boscaro M, Barzon L, Sonino N. The diagnosis of Cushing's syndrome: atypical presentations and laboratory shortcomings. ?Arch Intern Med?2000;?160:?3045-53.?[PubMed] 26Newell-Price JDL, Trainer PJ, Besser GM, Grossman AB. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. ?Endocr Rev?1998;?19:?647-72.?[PubMed] 27Colombo P, Dall'Asta C, Barbetta L, Re T, Passini E, Faglia G, Ambrosi B. Usefulness of the desmopressin test in the postoperative evaluation of patients with Cushing's disease. ?Eur J Endocrinol?200;?143:?227-34.?[PubMed] 28Newell-Price J, Perry L, Medba HD, et al. A combined test using desmopressin and corticotropin releasing hormone in the differential diagnosis of Cushing's syndrome. ?J Clin Endocrinol Metab?1997;?82:?176-81.?[PubMed] 29Samuels MH, Brandon DD, Isabelle LL, et al. Cortisol production rates in subjects with suspected Cushing's syndrome: assessment by stable isotopic dilution methodology and comparison to other diagnostic methods. ?J Clin Endocrinol Metab?2000;?85:?22-28.?[PubMed] 30Kertesz G, Boucier B, Cailla H, Jean F. Immunoradiometric assay of succinylated corticotropin: an improved method for quantification of ACTH. ?Clin Chem?1998;?44:?78-85.?[PubMed] 31Al-Saadi N, Diederich S, Oelkers W. A very high dose dexamethasone suppression test for differential diagnosis of Cushing's syndrome. ?Clin Endocrinol?1998;?48:?45-51.?[PubMed] 32Nieman LK, Oldfield EH, Wesley R, et al. A simplified morning ovine corticotropin-releasing hormone stimulation test for differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. ?J Clin Endocrinol Metab?1993;?77:?1308-12.?[PubMed] 33Trainer PJ, Faria M, Newell-Price J, et al. A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis. ?J Clin Endocrinol Metabol?1995;?80:?412-17.?[PubMed] 34Freda PU, Wardlaw SL. Diagnosis and treatment of pituitary tumors. ?J Clin Endocrinol Metab?1999;?84:?3859-66.?[PubMed] 35Kaltsas GA, Giannulis MG, Newell-Price JDC, et al. A critical analysis of the value of simultaneous inferior petrosal sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome. ?J Clin Endocrinol Metab?1999;?84:?487-92.?[PubMed] 36Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK. The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing's disease. ?J Clin Endocrinol Metab?1999;?84:?533-40.?[PubMed] 37Findling JW. Inferior petrosal sinus sampling: pros and cons; when and where. ?J Endocrinol Invest?2000;?23:?193-95.?[PubMed] 38Kaltsas GA, Newell-Price JDC, Trainer PJ, Besser GM, Grossman AB. Complications of inferior petrosal sinus sampling. J Clin Endocrinol Metab 2000; 85: 1741. 39Tabarin A, Valli N, Chanson P, et al. Usefulness of somatostatin receptor scintigraphy in patients with occult ectopic adrenocorticotropin syndrome. ?J Clin Endocrinol Metab?1999;?84:?1193-202.?[PubMed] 40Barzon L, Scaroni C, Sonino N, et al. Incidentally discovered adenal tumors: endocrine and scintigraphic correlates. ?J Clin Endocrinol Metab ?1998;?83:?55-62.?[PubMed] 41Hoh CK, Schiepers C, Seltzer MA, et al. PET in oncology: will it replace the other modalities? ?Semin Nucl Med?1997;?27:?94-106.?[PubMed] 42Walker AB, Leese GP, Vora JP. Diagnostic difficulties in periodic Cushing's syndrome. ?Postgrad Med J?1997;?73:?426-28.?[PubMed] 43Newfield RS, Kalaitzoglou G, Licholai T, et al. Normocortisolemic Cushing's syndrome initially presenting with increased glucocorticoid receptor number. ?J Clin Endocrinol Metab?2000;?85:?14-21.?[PubMed] 44Cizza G, Nieman LK, Doppman JL, et al. Factitious Cushing's syndrome. ?J Clin Endocrinol Metab?1996;?10:?3573-77.?[PubMed] 45Plotsky PM, Owerns MJ, Nemeroff CB. Psychoneuroendocrinology of depression: hypothalamic-pituitary-adrenal axis. ?Psychiatr Clin North Am?1998;?21:?293-307.?[PubMed] 46Groote Veldman R, Meinders AE. On the mechanism of alcohol-induced pseudo-Cushing's syndrome. ?Endocr Rev?1996;?17:?262-68.?[PubMed] 47Miller KK, Daly PA, Sentochnik D, et al. Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients. ?Clin Infect Dis?1998;?27:?68-72.?[PubMed] 48Sonino N, Zielezny M, Fava GA, Fallo F, Boscaro M. Risk factors and long-term outcome in pituitary-dependent Cushing's disease. ?J Clin Endocrinol Metab?1996;?81:?2647-52.?[PubMed] 49Luedecke DK. Transnasal microsurgery of Cushing's disease: overview including personal experience with 256 patients. ?Pathol Res Pract ?1991;?187:?608-12.?[PubMed] 50Watson JC, Shawaker TH, Nieman LK, De Vroom HL, Doppman JL, Oldfield E. Localization of pituitary adenomas by using intraoperative ultrasound in patients with Cushing's disease and no demonstrable pituitary tumor on magnetic resonance imaging. ?J Neurosurg?1998;?89:?927-32.?[PubMed] 51Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. ?N Engl J Med?1997;?336:?172-77.?[PubMed] 52Morange Ramos I, Regis J, Dufour H, et al. Gamma-knife surgery for secreting pituitary adenomas. ?Acta Neurochir (Wien)?1998;?140:?437-43.?[PubMed] 53Lanzi R, Montorsi F, Losa M, et al. Laparoscopic bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal surgery. ?Surgery?1998;?123:?144-50.?[PubMed] 54Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P. Patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease. ?J Clin Endocrinol Metab?1994;?79:?887-89.?[PubMed] 55Bochicchio D, Losa M, Buchfelder M and the European Cushing's disease survey study group. Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by the European Cushing's disease survey group. ?J Clin Endocrinol Metab?1995;?80:?3114-20.?[PubMed] 56Jenkins PJ, Trainer PJ, Plowman PN, et al. The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome.?J Clin Endocrinol Metab?1995;?80:?165-71.?[PubMed] 57Sonino N, Boscaro M. Medical therapy for Cushing's disease. ?Endocrinol Metab Clin North Am?1999;?28:?211-22.?[PubMed] 58Hale AC, Coates PJ, Doniach I, et al. A bromocriptine-responsive corticotroph adenoma secreting alpha-MSH in a patient with Cushing's disease. ?Clin Endocrinol (Oxf)?1988;?28:?215-23.?[PubMed] 59Van Waveren Hogervorst CO, Koppeschaar HPF, Zelissen PMJ, et al. Cortisol secretory patterns in Cushing's disease and response to cyproheptadine treatment.?J Clin Endocrinol Metab?1996;?81:?652-55.?[PubMed] 60Beckers A, Stevenert A, Pirens G, et al. Cyclic Cushing's disease and its successful control under sodium valproate. ?J Endocrinol Invest ?1990;?13:?923-25.?[PubMed] 61Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M. Effect of the serotonin antagonists ritanserin and ketanserin in Cushing's disease. ?Pituitary?2000;?3:?55-59.?[PubMed] 62Sonino N, Boscaro M, Ambroso G, Merola G, Mantero F. Prolonged treatment of Cushing's disease with metyrapone and aminoglutethimide. ?IRCS Med Sci?1986;?14:?485-86.?[PubMed] 63Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. ?Clin Endocrinol (Oxf)?1991;?35:?347-52.?[PubMed] 64Sonino N. The use of ketoconazole as an inhibitor of steroid production. ?N Engl J Med?1987;?317:?812-18.?[PubMed] 65Henry JF, Defechereux T, Raffaelli M, Lubrano D, Gramatica L. Complications of laparoscopic adrenalectomy: results of 169 consecutive procedures. ?World J Surg?2000;?24:?1342-46.?[PubMed] 66Sonino N, Fava GA. Psychosomatic aspects of Cushing's disease. ?Psychother Psychosom?1998;?67:?140-46.?[PubMed] 67Sonino N, Fava GA. Psychiatric disorders associated with Cushing's syndrome: epidemiology, pathophysiology and treatment. CNS Drugs (in press). 68Sonino N, Boscaro M, Fallo F, Fava GA. A clinical index for rating severity in Cushing's syndrome. ?Psychother Psychosom?2000;?69:?216-20.?[PubMed] Further reading Pathophysiology Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X. Monoclonality of corticotroph macroadenomas in Cushing's disease. ?J Clin Endocrinol Metab ?1992;?75:?472-75.?[PubMed] Lacroix A, Bolt? E, Tremblay J, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion: a new case of Cushing's syndrome. ?N Engl J Med ?1992;?327:?974-80.?[PubMed] Orth DN. Corticotropin-releasing hormone in humans. ?Endocr Rev ?1992;?13:?164-91.?[PubMed] Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, Gaillard RC. Food-dependent Cushing's syndrome: possible involvement of leptin in cortisol hypersecretion. ?J Clin Endocrinol Metab ?1999;?84:?3817-22.?[PubMed] Quddusi S, Browne P, Toivola B, Hirsch IB. Cushing's syndrome due to surreptitious glucocorticoid administration. ?Arch Intern Med ?1998;?158:?294-96.?[PubMed] Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing's syndrome. ?Horm Metab Res ?1998;?30:?456-63.?[PubMed] Wajchenberg BL, Mendonca BB, Liberman B, et al. Ectopic adrenocorticotropic hormone syndrome. ?Endocr Rev ?1994;?15:?752-87.?[PubMed] Wulffraat NM, Drexhage HA, Wiersinga WM, van der Gaag RD, Jeukcken P, Mol JA. Immunoglobulins of patients with Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis. ?J Clin Endocrinol Metab ?1988;?66:?301-07.?[PubMed] Clinical Fava GA. Affective disorders and endocrine disease: new insights from psychosomatic studies. ?Psychosomatics ?1994;?35:?341-53.?[PubMed] Sarlis NJ, Chanock SJ, Nieman LK. Cortisolemic indexes predict severe infections in Cushing's syndrome due to ectopic production of adrenocorticotropin. ?J Clin Endocrinol Metab ?2000;?85:?42-47.?[PubMed] Sarlis NJ, Chrousos GP, Doppman JL, Carney JA, Stratakis CA. Primary pigmented nodular adrenocortical disease: reevaluation of a patient with Carney complex 27 years after unilateral adrenalectomy. ?J Clin Endocrinol Metab ?1997;?82:?1274-78.?[PubMed] Schlechte JA, Sherman B, Bfohl B. A comparison of adrenal cortical function in patients with depressive illness and Cushing's disease. ?Horm Res ?1986;?23:?1-8.?[PubMed] Diagnosis and differential diagnosis Findling JW, Raff H. Newer diagnostic techniques and problems in Cushing's disease. ?Endocrinol Metab Clin North Am ?1999;?28:?191-210.?[PubMed] Katz J, Bouloux PM. Cushing's: how to make the diagnosis. ?Practitioner ?1999;?243:?118-22.?[PubMed] Martinelli CE, Sader SL, Oliveira EB, Daneluzzi JC, Moreira AC. Salivary cortisol for screening of Cushing's syndrome in children. ?Clin Endocrinol (Oxf) ?1999;?51:?67-71.?[PubMed] Meier CA, Biller BMK. Clinical and biochemical evaluation of Cushing's syndrome. ?Endocrinol Metab Clin North Am ?1997;?26:?741-61.?[PubMed] Papanicolau DA, Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. A single midnight serum cortisol measurement distinguishes Cushing's syndrome from pseudo-Cushing's states. ?J Clin Endocrinol Metab ?1998;?83:?1163-67.?[PubMed] Ross RJM, Trainer PJ. Endocrine investigation: Cushing's syndrome. ?Clin Endocrinol (Oxf) ?1998;?49:?153-55.?[PubMed] Tsigos C, Chrousos GP. Differential diagnosis and management of Cushing's syndrome. ?Annu Rev Med ?1996;?47:?443-61.?[PubMed] Therapy Chapuis Y, Inabnet B, Abboud B, et al. Bilateral video-endoscopic adrenalectomy in Cushing's disease. Experience in 24 patients. ?Ann Chir ?1998;?52:?350-56.?[PubMed] Flitsch J, Ludecke DK, Knappe UJ, Sager W. Correlates of long-term hypocortisolism after transsphenoidal microsurgery for Cushing's disease. ?Exp Clin Endocrinol Diabetes ?1999;?107:?183-89.?[PubMed] Luedecke DK, Knappe UJ, Glagla G. Cushing's disease: surgical results and prognosis. In: Landolt AM, Vance ML, Reilly PL, eds. Pituitary adenomas. Edinburgh: Churchill Livingstone, 1996: 353-61. Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ. Long-term results of total adrenalectomy for Cushing's disease. ?World J Surg ?2000;?24:?108-13.?[PubMed] Semple PL, Laws ER Jr. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing's disease. ?J Neurosurg ?1999;?91:?175-79.?[PubMed] Swearingen B, Biller BM, Baker FG 2nd, et al. Long-term mortality after transsphenoidal surgery for Cushing's disease. ?Ann Intern Med ?1999;?130:?821-24.?[PubMed] Wooten MD, King DK. Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review or the literature. ?Cancer ?1993;?72:?3145-55.?[PubMed] Quality of life Sonino N, Fava GA. Psychological aspects of endocrine disease. ?Clin Endocrinol ?1998;?49:?1-7.?[PubMed] Quote Link to comment Share on other sites More sharing options...
Guest kai Posted July 4, 2001 Report Share Posted July 4, 2001 P.S. If your doctors want the hard copy, go to your local library and request the March 2001 issue of the Lancet Journal. Most libraries can get it from a larger library or a college library. If any of you live near a med school or a college, go to their library and ask to make a copy of the article. My school, CU Boulder, has the journal in our library. Good luck everyone! Quote Link to comment Share on other sites More sharing options...
Guest Michelle Posted July 5, 2001 Report Share Posted July 5, 2001 Thanks Kai! I will take it with to the endo (unfortunately I can only see her in August ) Michelle Pretoria, South Africa Quote Link to comment Share on other sites More sharing options...
Guest Lorrie Posted July 13, 2001 Report Share Posted July 13, 2001 Ann, What a fantastic article! Thanks for taking the time to share it with us! Quote Link to comment Share on other sites More sharing options...
Guest Dot Posted July 15, 2001 Report Share Posted July 15, 2001 Hi Shauna, Is this the test that you had the one under the new tests part of Kai's article? thanks Dot Quote Link to comment Share on other sites More sharing options...
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