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ABSTRACT: With adequate dose titration, pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients.
The aim of the study was to investigate the efficacy of cabergoline monotherapy and pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial.
We measured the change in serum IGF-I.
After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monotherapy did not significantly reduce IGF-I (454 ± 219 baseline vs. 389 ± 192 ng/ml cabergoline), although two patients did normalize IGF-I. The addition of 10 mg pegvisomant daily for 12 wk significantly reduced IGF-I (389 ± 192 ng/ml cabergoline vs. 229 ± 101 ng/ml combination), and 68% achieved a normal IGF-I. Twelve weeks after cabergoline withdrawal, while continuing to receive pegvisomant 10 mg, only 26% of patients maintained an IGF-I within the reference range (229 ± 101 ng/ml combination vs. 305 ± 177 ng/ml pegvisomant). There were no significant changes in liver transaminases or glucose metabolism throughout the study.
These data suggest that combination treatment with cabergoline and pegvisomant is more effective at reducing IGF-I levels than either cabergoline or pegvisomant monotherapy.
The Journal of clinical endocrinology and metabolism 01/2012; 97(4):1187-93. · 6.50 Impact Factor
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B M K Biller,
A B Grossman,
P M Stewart,
S Melmed,
X Bertagna,
J Bertherat,
M Buchfelder,
A Colao,
A R Hermus,
L J Hofland, [......],
J R Lindsay, J Newell-Price,
L K Nieman,
S Petersenn,
N Sonino,
G K Stalla,
B Swearingen,
M L Vance,
J A H Wass,
M Boscaro
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ABSTRACT: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder.
Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations.
Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.
Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.
ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.
Journal of Clinical Endocrinology & Metabolism 08/2008; 93(7):2454-62. · 6.50 Impact Factor
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J S Bevan, J Newell-Price,
J A H Wass,
S L Atkin,
P M Bouloux,
J Chapman,
J R E Davis,
T A Howlett,
H S Randeva,
P M Stewart,
A Viswanath
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ABSTRACT: The introduction of ready-to-use lanreotide Autogel has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety.
Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel at their established dose. Effects were monitored for up to 40 weeks.
Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel (60, 90 or 120 mg) for > or = 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study.
All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%-99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study.
Patients with acromegaly or their partners were able to administer lanreotide Autogel injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients.
Clinical Endocrinology 03/2008; 68(3):343-9. · 3.17 Impact Factor
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ABSTRACT: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced.
To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)).
Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls.
Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls.
For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.
Clinical Endocrinology 02/2008; 68(1):130-5. · 3.17 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-gamma agonists have been proposed as therapy to lower plasma ACTH in Cushing's disease. Cyclical secretion of ACTH may, however, explain some of the responses seen. Patients with Nelson's syndrome have persistently high levels of ACTH and may be a better model for examining new therapies to elevated ACTH levels.
The objective of the study was to assess whether high-dose rosiglitazone therapy reduces circulating ACTH levels in Nelson's syndrome, a model of ACTH hypersecretion for which no established medical therapy exists.
The design was an open-label, prospective, nonrandomized study over 14 wk.
The study was conducted at a university teaching hospital.
Six patients with Nelson's syndrome participated in the study.
Patients were assessed at -2, 0, 4, 8, and 12 wk. Rosiglitazone 12 mg/d was administered between 0 and 8 wk. PPAR-gamma immunoreactivity was assessed in pathological tissue.
Plasma ACTH was measured before (0830 h) and 120 min after morning dosing with hydrocortisone (HC).
One female withdrew prior to commencing therapy for personal reasons. There was no evidence that ACTH levels changed over time (P = 0.864). The average ACTH level was 1187 ng/liter (95% confidence interval 928-1446) for patients before the HC dose and 432 ng/liter (95% confidence interval 172-692) after the HC dose. PPAR-gamma immunoreactivity was positive in three ACTH-secreting tumors available.
Rosiglitazone 12 mg/d did not change circulating ACTH over time, despite PPAR-gamma receptor expression in the tumor tissue. However, this does not preclude the possibility that other patients may respond or that higher doses of rosiglitazone or more potent agonists might prove useful treatment.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(5):1758-63. · 6.50 Impact Factor
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ABSTRACT: Conventional hydrocortisone therapy in adrenal insufficiency cannot provide physiological replacement. We have explored the potential of circadian delivery of hydrocortisone as proof of concept for such therapy delivered in modified-release tablet formulation.
We investigated whether the circadian intravenous infusion of hydrocortisone could improve control of ACTH and androgen levels. Two healthy subjects, two patients with Addison's disease and two patients with congenital adrenal hyperplasia (CAH) were studied.
In patients on thrice daily oral hydrocortisone, peak serum cortisol levels were higher than in normal subjects and overnight levels were very low. Patients had very high plasma ACTH levels before their morning dose of hydrocortisone, both at the beginning and at the end of their conventional oral therapy: mean +/- SEM 311.8 +/- 123.2 and 311.2 +/- 85.4 ng/l, respectively. In the patients with CAH, serum 17-hydroxyprogesterone levels were also elevated: 550 and 642 nmol/l at the beginning and 550 and 777 nmol/l at the end of conventional treatment, respectively. The overall 24-h mean cortisol levels were similar for conventional oral hydrocortisone and the circadian infusion. At 0700 h, ACTH levels were much higher on conventional treatment than after circadian infusion: mean +/- SEM 311.2 +/- 85.4 vs. 70.5 +/- 45.0 ng/l, respectively (P < 0.05). The same pattern was observed in 17-hydroxyprogesterone levels, which were 550 and 777 nmol/l after conventional treatment and 3 and 64 nmol/l after circadian infusion.
In patients with poor biochemical control of Addison's disease and CAH, a 24-h circadian infusion of hydrocortisone can decrease morning ACTH and 17-hydroxyprogesterone levels to near normal.
Clinical Endocrinology 08/2006; 65(1):45-50. · 3.17 Impact Factor
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ABSTRACT: Diabetic and endocrine emergencies are traditionally treated by the acute medical admitting team or accident and emergency department staff. Most will see diabetic emergencies on a regular basis, as they are common and both type 1 and type 2 disease are increasing in prevalence. Diabetic emergencies are usually easily treated and the patients discharged. However, it is vital not to become complacent as these disorders can lead to death. It is particularly important to follow local guidance and to involve the diabetes team both during and after each episode. Recently it has become clear that about 30% of patients admitted with acute coronary syndrome (including infarction) have either diabetes or "stress hyperglycaemia"; evidence suggests that these patients should be treated not only as a cardiac emergency but also as a diabetic one. Thus, every patient with acute coronary syndrome or acute myocardial infarction needs diabetes to be excluded. The other endocrine emergencies are less common, but in some ways more important simply because of their rarity. A high level of suspicion is often required to make a diagnosis, although some, such as myxoedema coma, are usually obvious. Treatment must be started before the diagnosis can be confirmed. Guidance on making the diagnosis and initiating treatment should be made available on the local NHS intranet for non-endocrinologists to access; and where possible expert advice made available by telephone. The basic management steps in the common diabetic and endocrine emergencies are outlined; this is not a complete list, but rather an insight for those involved in non-selected emergency admissions.
Postgraduate Medical Journal 10/2004; 80(947):506-15. · 1.94 Impact Factor
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G Arnaldi,
A Angeli,
A B Atkinson,
X Bertagna,
F Cavagnini,
G P Chrousos,
G A Fava,
J W Findling,
R C Gaillard,
A B Grossman,
B Kola,
A Lacroix,
T Mancini,
F Mantero, J Newell-Price,
L K Nieman,
N Sonino,
M L Vance,
A Giustina,
M Boscaro
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ABSTRACT: In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.
Journal of Clinical Endocrinology & Metabolism 01/2004; 88(12):5593-602. · 6.50 Impact Factor
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J Newell-Price
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ABSTRACT: Proopiomelanocortin gene (POMC) is recognised as playing an important role in the regulation of the hypothalamo-pituitary-adrenal axis, adrenal development and obesity. POMC is activated in ACTH-dependent Cushing's syndrome. The syndrome may occur when the highly tIssue-specific 5' promoter of human POMC is activated in pituitary and non-pituitary sites. Whilst the factors involved in transcription in the corticotrophs of the anterior pituitary gland are becoming well delineated, the mechanism of activation in non-pituitary sites is not fully understood. This promoter is embedded within a defined CpG island, and, in contrast to somatically expressed CpG island promoters reported to date, is methylated in normal non-expressing tIssues, but is specifically unmethylated in expressing tIssues, tumours and the POMC-expressing DMS-79 small-cell lung cancer cell line. Methylation in vitro is sufficient for silencing of expression. In particular, methylation near the response element for the tIssue-specific POMC activator PTX1, diminishes POMC expression. Sites outside the PTX1 response element may be important for binding, and this may have implications for pituitary development. DMS-79 cells lack POMC-demethylating activity, implying that the methylation and expression patterns are likely to be set early or prior to neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy. It is conceivable that in POMC neurons of the hypothalamus the POMC promoter is subject to a variable density of methylation with clear implications for the signalling of satiety and obesity.
Journal of Endocrinology 07/2003; 177(3):365-72. · 3.55 Impact Factor
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ABSTRACT: Misuse of opioids is associated with abnormalities of pituitary function. Patients with chronic pain frequently complain of fatigue and undergo endocrine testing. To test whether oral opioid treatment causes abnormal pituitary function we prospectively assessed pituitary function in 37 patients with chronic pain who were receiving either oral opioid analgesia or non-opioid analgesia. Oral opioid treatment was not associated with abnormal pituitary function although a few patients had abnormal results mainly related to obesity. Our results suggest that patients with chronic pain who have abnormal endocrine results should have a complete assessment, since abnormal test results cannot be attributed to their analgesia.
The Lancet 07/2003; 361(9376):2203-4. · 38.28 Impact Factor
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ABSTRACT: The diagnosis and differential diagnosis of Cushing's syndrome remains a considerable challenge in clinical endocrinology. Investigation is a two-step process, involving first diagnosis followed by differential diagnosis. Traditionally diagnosis has relied upon urinary free cortisol (UFC) collection, low-dose dexamethasone-testing, and assessment of midnight cortisol. More recently, differentiation between mild disease and pseudo-Cushing's states has been achieved using dexamethasone-suppressed corticotropin releasing hormone (CRH) and desmopressin tests. Refinements of tests used for differential diagnosis have been made including optimized response criteria for ovine and human sequence CRH tests, desmopressin tests, GHBP-testing and testing with combinations of peptides. Despite improvements in these non-invasive tests use of inferior petrosal or cavernous sinus sampling is frequently required. Imaging is guided by biochemical assessment. MRI is the investigation of choice for Cushing's disease, but is often negative. Scintigraphic investigation using radionucleotide-labeled agonists for receptors commonly expressed by neuroendocrine tumors the investigation of occult ACTH-dependent disease remains disappointing. In this review we critically analyze the tests used for this most challenging of clinical conditions.
Minerva endocrinologica 07/2002; 27(2):95-118. · 0.98 Impact Factor
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ABSTRACT: The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.
Journal of Clinical Endocrinology & Metabolism 05/2002; 87(4):1640-5. · 6.50 Impact Factor
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ABSTRACT: The diagnosis of Cushing's syndrome remains one of the most challenging tasks in clinical neuroendocrinology. The diagnostic procedure can be divided into two distinct steps: diagnosis of the neuroendocrine disorder and differential diagnosis of the precise aetiology. The goal of the first laboratory tests is to obtain biochemical proof of Cushing's syndrome. Patients with Cushing's syndrome are relatively insensitive to glucocorticoid feedback and exhibit an oversecretion of cortisol devoid of a circadian cycle. In our experience, a low-dose dexamethasone suppression test provides the most reliable confirmation of steroid resistance, a cortisol level of<50 nmol/l at 9 a.m. having 98% sensitivity. A cortisol level below 50 nmol/l at midnight rules out active Cushing's syndrome with, in our experience, 100% sensitivity and a specificity depending on numerous other variables. A very high level of free urinary corticol can be a useful sign. After having established the diagnosis of Cushing's syndrome, a persistently low level of ACTH (<10 pg/ml), or preferentially an undetectable level unresponsive to CRH (100 microgram iv), is suggestive of an ACTH-independent disorder, and consequently of primary adrenal disease. The precise location of the lesion can identified with CT or MRI imaging, generally prior to surgical cure. If the ACTH level is detectable, patients with pituitary Cushing's syndrome, or Cushing's disease, should be differentiated from those with ectopic ACTH secretion. The secreting tumour may be difficult to localise and diagnosis is never 100% sure with dynamic tests. Catheterisation of the petrosal sinus with CRH stimulation provides the best sensitivity for differentiating the two aetiologies. We consider a central to peripheral gradient of>3 to confirm the pituitary origin of the disorder with a 98% sensitivity. Chest or abdominal CT can be helpful to identify an ectopic tumour but very small tumours may go undetected. MRI can detect 60 or 70% of all pituitary adenomas but is virtually non-contributive to the diagnosis of Cushing's disease in children.
Annales d Endocrinologie 05/2001; 62(2):173-9. · 0.74 Impact Factor
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ABSTRACT: Ectopic secretion of ACTH, from sites such as small cell lung cancer (SCLC), results in severe Cushing's syndrome. ACTH is cleaved from POMC. The syndrome may occur when the highly tissue-specific promoter of the human POMC gene (POMC) is activated. The mechanism of activation is not fully understood. This promoter is embedded within a defined CpG island, and CpG islands are usually considered to be unmethylated in all tissues. We demonstrate that much of this CpG island is methylated in normal nonexpressing tissues, in contrast to somatically expressed CpG island promoters reported to date, and is specifically unmethylated in expressing tissues, tumors, and the POMC-expressing DMS-79 SCLC cell line. A narrow 100-bp region is free of methylation in all tissues. E2F factors binding to the upstream domain IV region of the promoter have been shown to be involved in the expression of POMC in SCLC. We show that these sites are methylated in normal nonexpressing tissues, which will prevent binding of E2F, but are unmethylated in expressing tissue. Methylation in vitro is sufficient for silencing of expression, which is not reversed by treatment with Trichostatin A, suggesting that inhibition of expression may be mediated by means other than recruitment of histone deacetylase activity. The DMS-79 cells lack POMC demethylating activity, implying that the methylation and expression patterns are likely to be set early or before neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy.
Molecular Endocrinology 03/2001; 15(2):338-48. · 4.54 Impact Factor
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The Lancet 07/1999; 353(9170):2087-8. · 38.28 Impact Factor
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ABSTRACT: Major depression is associated with significant disturbance in hypothalamic-pituitary-adrenal axis functioning, including blunted release of ACTH in response to CRH infusion. Eight melancholic depressives and eight matched healthy comparison subjects underwent, in random order, the following challenges: placebo, CRH, CRH + DDAVP. Blood for ACTH and cortisol estimation was drawn at -15, 0, 15, 30, 45, 60, 90, and 120 min. A blunted release of ACTH, in response to CRH challenge, was observed in depression (P < 0.01), whereas maximal cortisol responses in both groups were similar, despite elevated baseline levels in depression (P < 0.05). The combined CRH/DDAVP infusion produced similar ACTH and cortisol release in both groups. These results suggest that melancholic depression is associated with enhanced pituitary vasopressinergic responsivity.
Journal of Clinical Endocrinology & Metabolism 06/1999; 84(6):2238-40. · 6.50 Impact Factor
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ABSTRACT: Computed tomography (CT) evaluation of the thymus and anterior mediastinum is an important aspect of the investigation of patients with ACTH-dependent Cushing's syndrome in order to exclude an ACTH-secreting carcinoid tumor. We have reviewed the CT imaging of the thymus and anterior mediastinum in a series of 85 patients (55 females; median age 41, range 7-77 yr) with active Cushing's syndrome as there are few data on the range of appearances in hypercortisolemic states. One patient had a thymic carcinoid tumor (24 x 18 mm). Of the others, 28/84 (33%) patients showed thymic remnant tissue, consisting of either nodule(s) at least 5 mm diameter (n = 21, mean diameters 12.5 +/- 5 x 9.6 +/- 4 mm), or triangular bilobed glands (n = 7, mean thickness of the body, right and left limbs 25 +/- 7, 14 +/- 3, and 12 +/- 5 mm). Thymic involution appeared in 56/84 (67%) patients, ranging from small nodule(s) of less than 5mm diameter to linear soft tissue strands and complete fatty replacement. Patients with thymic remnant tissue were younger than those with thymic involution (P < 0.05). The thymic carcinoid tumor could be distinguished from remnant tissue on the basis of age and size. The presence of anterior mediastinal nodule(s) in hypercortisolemia need not imply the presence of a thymic carcinoid tumor, although in older patients this should arouse suspicion.
Journal of Clinical Endocrinology & Metabolism 03/1999; 84(2):602-5. · 6.50 Impact Factor
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ABSTRACT: Cushing's syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.
Hormone Research 02/1999; 51 Suppl 3:81-94. · 2.48 Impact Factor
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Endocrine Reviews 11/1998; 19(5):647-72. · 19.93 Impact Factor
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J Newell-Price
Clinical Endocrinology 09/1997; 47(2):173-4. · 3.17 Impact Factor
