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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress-related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

Gastrinoma; Insulinoma; Pancreatic neuroendocrine tumour Gastrinoma; Insulinoma; Tumor neuroendocrino pancreático Gastrinoma; Insulinoma; Tumor neuroendocrí pancreàtic Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1–3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Background The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. Methods Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. Results We included 114 consecutive patients (74 women; age at baseline 54.5 ± 12.7 years [mean ± SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 ± 46 (mean ± SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. Conclusion Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction.

Objective Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR), and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up. Design Prospective study in a tertiary hospital. Patients and Measurements Seventy-one patients with AI, (51 non-functioning [NFAI], 20 ACS), and 5.54±1.7 year follow-up underwent testing for autonomous cortisol secretion, Oral Glucose Tolerance Test to determine IR indices and adrenal imaging. Results At follow-up, 16/51 (31%) NFAI patients converted to ACS, while 2 with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9.8% NFAI and 15% ACS, respectively) and 14 IR (17.6% NFAI and 25% ACS, respectively). Adenoma size increased from 2.1±0.8 to 2.3±0.8cm, whereas IR correlated with post-dexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Ν-UFC), to H-UFC, to C-ACS and ACS patients. Conclusions New-onset ACS developed in 31% patients with NFAI whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients. This article is protected by copyright. All rights reserved.

Polycystic ovarian syndrome (PCOS) is a heterogenous disorder associated with clinical, endocrine and ultrasonographic features that can also be encountered in a number of other diseases. It has traditionally been suggested that prolactin excess, enzymatic steroidogenic abnormalities and thyroid disorders need to be excluded before a diagnosis of PCOS is made. However, there is paucity of data regarding the prevalence of PCOS phenotype in some of these disorders, whereas other endocrine diseases that exhibit PCOS-like features may elude diagnosis and proper management if not considered. This article reviews the data of currently included entities that exhibit a PCOS phenotype and those that potentially need to be looked for, and attempts to identify specific features that distinguish them from idiopathic PCOS.

Background Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background. Design We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/PGLs as well as currently established and evolving therapies. Results Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B (SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/PGLs along with evolving molecular markers such as miRNAs and SNAIL. Conventional imaging is used for tumour localization, whereas 18F-FDG-PET for staging of metastatic PCs/PGLs especially those related to SDHB gene mutations. In addition, 68 Ga-DOTATATE PET/CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with 131I-MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice. Conclusions Metastatic PCs/PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future.

Background and Aims Sweet's syndrome or acute febrile neutrophilic dermatosis is characterized by fever, leukocytosis and tender erythematous plaques, which show infiltration by mature neutrophils on histological examination. Pulmonary involvement is rare in Sweet's syndrome. Method We describe the case of a 17-year-old man with a myelodysplastic syndrome following therapy for Hodgkin's lymphoma who developed Sweet's syndrome and cryptogenic organizing pneumonia. In addition, we conducted a review of the related English literature. Results Literature review yielded six similar reports of biopsy-proven cryptogenic organizing pneumonia associated with Sweet's syndrome. We present the clinical and laboratory characteristics, as well as the response to treatment, of all cases of cryptogenic organizing pneumonia reported in patients with Sweet's syndrome. Conclusions Cryptogenic organizing pneumonia is a rare manifestation of Sweet's syndrome, which may be complicated by respiratory failure. Prompt treatment with corticosteroids usually leads to clinical and radiographic improvement.

Background The prevalence of primary aldosteronism (PA) in hypertensive patients varies according to diagnostic testing and ascertained normal cut-offs. The aim of this case–control study was to confirm the high prevalence of PA in a large hypertensive population and evaluate the antihypertensive effect of mineralocorticoid receptor antagonists (MRA) treatment. Material and methods We investigated 327 hypertensive and 90 matched normotensive subjects with normal adrenal imaging. Serum aldosterone (ALD), active renin (REN) levels and aldosterone/active renin (ALD/REN) ratio were measured before and after a combined sodium chloride, fludrocortisone and dexamethasone suppression test (FDST). Post-FDST values were compared to cut-offs obtained from controls (post-FDST ALD 2·96 ng/dL and post-FDST ALD/REN 0·93 ng/dL/μU/mL). PA patients received MRA treatment. Results By applying the combination of post-FDST ALD levels and ALD/REN ratio, 28·7% of the hypertensive patients had PA. There was a positive, albeit weak, correlation between systolic (SBP) and diastolic blood pressure (DBP) and ALD levels and/or ALD/REN ratio after the FDST (P

Eur J Clin Invest 2012; 42 (11): 1165–1172 Abstract Background Adrenal incidentalomas (AI) are associated with several parameters of the metabolic syndrome (MS). Although nonalcoholic fatty liver disease (NAFLD) is considered a cardiometabolic risk factor, no data exist on its prevalence and clinical relevance in AI. The aim was to investigate the presence of MS and NAFLD in AI subjects. Patients and Methods Fifty-six AI subjects and 30 age-, sex- and body mass index (BMI)-matched controls were evaluated. All subjects underwent abdominal computerized tomography scan and hepatic and spleen attenuation measurements. The presence of NAFLD was defined as a mean hepatic minus mean spleen attenuation difference (ΔL−ΔS)

Eur J Clin Invest 2012; 42 (3): 275–281 Abstract Background Acromegaly is well known to induce hypertrophic and hyperplastic changes in various organs and is commonly accompanied by arterial hypertension. In our study, we assess the adrenal morphology and function in a series of patients with acromegaly and possible associations with the activity of the disease and arterial hypertension. Materials and methods Sixty patients with acromegaly, admitted to two endocrinology departments in the time period 2005–2010, were studied prospectively. Basal IGF-1 and growth hormone levels after oral glucose tolerance test were used to assess the disease activity. All subjects underwent adrenal CT scan, basal adrenal hormonal investigation and evaluation with 24-h urinary free cortisol and cortisol levels following low-dose dexamethasone suppression test. In 33 acromegalics, the ‘modified’ saline infusion test (MSI), i.e. saline infusion after dexamethasone administration, was performed to identify autonomous aldosterone (ALD) secretion. Results Abnormal adrenal morphology was present in 48% of our patients, and a significant association was found between the presence of arterial hypertension and adrenal morphology. Among patients with adrenal morphological changes, 55% exhibited no adrenal secretory hyperactivity, 34% autonomous cortisol, 7% ALD and 4% combined autonomous cortisol and ALD secretion, when applying recently proposed modified cut-off levels compared to widely used criteria. An increased prevalence of autonomous ALD secretion was shown among the subgroup of patients with acromegaly tested with MSI. Conclusions This study provides evidence of an increased prevalence of anatomic and functional adrenal alterations in patients with acromegaly; further studies will clarify the importance of evaluating these subjects with baseline hormonal investigation along with dynamic testing and modified cut-offs.

Summary Objective To investigate autonomous cortisol and aldosterone secretion and insulin resistance (IR) indices, in patients with incidentally discovered bilateral adrenal lesions (BA). Patients Thirty-six patients with BA, 113 patients with unilateral adrenal incidentalomas (UA) and 89 healthy subjects (C) with normal adrenal imaging. Measurements All participants underwent adrenal imaging, baseline biochemical and hormonal measurements and the following investigations on consecutive days: (i) A 2-h oral glucose tolerance test (OGTT) (75 g) with glucose and insulin measurements every 30 min. (ii) An adrenocorticotrophin (ACTH) stimulation test with intravenous (i.v.) bolus administration of 250 μg of ACTH (1–24) and measurement of serum cortisol and aldosterone before and after 30 and 60 min. (iii) A low-dose dexamethasone suppression test (LDDST) (0·5 mg of dexamethasone every 6-h for 2 days) with cortisol measurement 6 h after the last dexamethasone dose and (iv) A NaCl (0·9%) postdexamethasone saline infusion test (PD-SIT) (2 l of NaCl 0·9% iv in 4 h) following the LDDST, with aldosterone measurement at the end of the test. Results Cortisol and aldosterone cut-offs based on the mean + 2 SD values obtained from the C group following the LDDST and PD-SITs were calculated (34·11 nm and 74·83 pm, respectively). Based on the above cut-offs, autonomous cortisol and aldosterone secretion was found in 42·5 and 15·9% of patients with UA, and in 41·7 and 19·4% of patients with BA, respectively. In addition, 17·7% of patients with UA and 19·4% of patients with BA had concomitant autonomous cortisol and aldosterone secretion. Cortisol and aldosterone levels following the LDDST and PD-SIT were significantly higher in the BA compared to the UA group, respectively. Furthermore, patients with BA had more pronounced glucose levels and insulin resistance (IR) indices compared to patients with UA. Conclusions Patients with BA have more pronounced autonomous cortisol and aldosterone secretion and glucose metabolism alterations than patients with UA. Further studies are needed to evaluate the potential long-term consequences of these findings.

Eur J Clin Invest 2012; 42 (1): 86–94 Abstract Background Hyperandrogenism refers to classical androgen-dependent signs such as hirsutism, acne and androgenetic alopecia. Hirsutism is the main hyperandrogenic symptom, defined as an excess of body hair in the androgen-sensitive skin regions of the women. In this review, we attempt to focus on the pathogenesis of hirsutism related to disorders other than polycystic ovary syndrome (PCOS). Also, we will discuss their clinical and biochemical features as well as therapeutic options. Design Several original articles, meta-analysis and reviews have been screened in the field of hirsutism and hyperandrogenic disorders. Results Current English literature including our studies suggests that PCOS is the most common cause of hirsutism. The most important purpose for investigation is to identify those women with androgen-secreting tumours because of their life-threatening potential. In approximately 1–8% of the women with hirsutism, the underlying cause is nonclassical adrenal hyperplasia because of 21-hydroxylase deficiency. Depending on ethnicity and the geographic area, idiopathic hirsutism constitutes 5–17% of the patients with hirsutism. Approximately 3% of hyperandrogenic women were observed to suffer from hyperandrogenic-insulin-resistant acanthosis nigricans syndrome. More rare causes are glucocorticoid resistance syndrome, hyperprolactinemia, acromegaly, Cushing’s syndrome and some drugs. Specific causes of hirsutism such as Cushing’s syndrome and adrenal/ovarian tumours should be treated specifically. In other patients, pharmacological approach is the mainstay of therapy. Conclusions A number of patients presenting with hirsutism and exhibiting similar features to PCOS may have other underlying diagnoses. Unlike PCOS, some of these disorders can occasionally be life threatening and require prompt diagnosis and treatment.

This retrospective study evaluated bone mineral density (BMD) and bone turnover in adults with LCH. Twenty-five adult patients and 25 matched controls were evaluated with BMD measurement and indices of bone metabolism. A BMD value below the expected range for age (Z-score ≤ - 2.0) was found in 20% of patients; in particular, all postmenopausal women and men over 50-years had either osteoporosis or osteopenia. Patients with active disease had significantly lower Z-scores compared to patients with inactive disease and controls. Reduced bone turnover was found in all 14 patients treated with chemotherapy. No fractures due to osteoporosis were identified during 305.15 patient-years of follow-up.

Eur J Clin Invest 2011; 41 (11): 1227–1236 Abstract Background Previous studies based on standard endocrine testing have generally shown a low prevalence of primary aldosteronism, a form of autonomous aldosterone secretion (AAS), in hypertensive individuals. The purpose of this case–control study was to evaluate whether use of appropriately defined controls and combined testing reveal previously undetected AAS in hypertensives. Materials and methods We investigated aldosterone secretion in 180 hypertensives with (n = 44) and without (n = 136) adrenal adenomas on computerized tomography (CT) and 72 matched nonhypertensive individuals with normal adrenal CT. Serum aldosterone and active renin were measured, and the aldosterone/active renin ratio was calculated before and after a modified fludrocortisone-suppression test (FST).In the latter, to eliminate any stimulatory effect of endogenous stress-induced adrenocorticotrophin hormone on aldosterone secretion, we administered 1 mg of dexamethasone on the last day of the classical FST fludrocortisone/dexamethasone suppression test (FDST). Results Using the 97·5 percentiles of serum aldosterone (74 pM L−1) and the aldosterone/renin ratio (32 pM L−1 mU−1 L−1) values obtained from the controls following the FDST, normal cut-off values indicative of adequate aldosterone suppression were established. Using the combination of these cut-offs, the estimated prevalence of AAS in patients with hypertension was 31%. Multiple linear regression analysis revealed a significant correlation between systolic and/or diastolic arterial blood pressure and the aldosterone value (P

OBJECTIVE Hypercortisolaemia is associated with an increased risk of cardiovascular disease (CVD), either through a direct action on the myocardium or by increased traditional cardiovascular risk factors. The aim of this study was to investigate whether the alterations in the ECG in Cushing's disease (CD) are predictable from risk factor analysis alone. DESIGN In 79 patients with a diagnosis of CD, retrospectively recruited, ECG features [corrected for heart rate QT (QTc), QTc dispersion (QTcd), left ventricular hypertrophy (ECG-LVH), right ventricular hypertrophy (ECG-RVH)], systolic (SBP) and diastolic (DBP) blood pressure were assessed. Biochemical, hormonal (cortisol at 09·00 h or cortisol day curve, CDC) and carbohydrate abnormalities (CHA), history of hypertension and cardiovascular disease were recorded. For comparison reasons, a group of 42 healthy subjects matched for gender, age and body mass index previously subjected to ECG assessment were selected. RESULTS In patients with CD, we noted the following prevalence: metabolic syndrome 39%, hypertension 81%, CVD 21·5%, hypercholesterolaemia 37%, hypertriglyceridaemia 29%, CHA 41%, but a history of cardiac dysrhythmia was only noted in a single patient. No difference in QTc or QTcd was shown between patients with normal or low potassium levels. QTcd >50 ms was associated with both increased ECG-LVH and ECG-RVH. When compared to the control group, patients had longer QTcd (P < 0·001), more prevalent LVH (P < 0·001) and RVH (P = 0·001), and higher SBP and DBP (P < 0·001), but similar QTc. Both CD and ECG evidence of LVH predicted prolonged QTcd, but the association of CD with a prolonged QTcd was independent of other risk factors, including hypertension. CONCLUSIONS Prolonged QTcd in association with ECG evidence of LVH appears to be the specific feature of CD. This may be relevant in the choice of medical therapy for CD and for consideration of treatment of the comorbidities that are associated with hypercortisolaemia.

Eur J Clin Invest 2011; 41 (5): 552–560 Abstract Background The term adrenal incidentaloma (AI) indicates an adrenal mass lesion > 1 cm in diameter discovered during testing for conditions unrelated to adrenal disease. The overall prevalence of these lesions ranges between 3% and 10%. Their incidence increases with age, and it is clinically important to identify AI associated with hormonal activity and/or malignant potential. Design A detailed Medline search of all English language articles related to AI was carried out, and the clinical implications related to their hormonal activity and malignant potential are discussed. Results The subclinical hypercortisolism observed in a significant percentage of patients with AI is associated with some of the detrimental effects of continuous autonomous cortisol secretion, including a higher prevalence of hypertension, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus and an increased risk for osteoporotic fractures. However, it remains to be proven whether treatment to reverse subtle glucocorticoid excess is beneficial. Clinically silent phaeochromocytomas and primary adrenal cancer are conditions associated with significantly high morbidity and mortality and require urgent treatment, while the prevalence and clinical significance of autonomous mineralocorticoid secretion are less clearly defined. Size and radiological features are the main predictors of malignant potential. Conclusions Patients harbouring AI should be evaluated for the possibility of malignancy and/or subclinical hypercortisolism which is associated with cardiovascular risk and bone loss. However, in the absence of prospective controlled studies correlating biochemical activity with end-organ complications, the long-term consequences of AI remain uncertain and their management remains largely pragmatic.

Background To identify a serum prolactin (PRL) cut‐off value indicative of a PRL‐producing adenoma in women with Polycystic Ovarian Syndrome (PCOS) and hyperprolactinemia and characterize such patients. Materials and methods In the present retrospective case‐control study the medical records of 528 PCOS women were reviewed. Pituitary magnetic resonance imaging (MRI) was performed in PCOS patients with PRL levels ≥94.0 ng/mL and/or symptoms suspicious of a pituitary adenoma (PA). Prolactinoma diagnosis was made in the presence of an MRI‐identifiable PA with biochemical and radiological response to dopamine agonists. Receiver operating characteristic (ROC) curve analysis was performed to determine a serum PRL threshold that could identify hyperprolactinemic PCOS subjects with prolactinomas. Clinical, metabolic and endocrine parameters were also analysed. Results Among 528 patients with PCOS, 60 (11.4%) had elevated PRL levels. Of 44 (73.3%) patients who had pituitary imaging, 19 had PAs, 18 normal MRI and 7 other abnormalities. Patients harboring prolactinomas had significantly higher PRL levels compared to patients without adenomas (median PRL 95.4 vs. 49.2 ng/mL, p

Fatigue is a frequent reason for seeking medical attention. Endocrine dysfunction is a common etiology of fatigue. In fact, thyroid function is usually one of the first explanations on the list of possible diagnoses. The symptoms associated with endocrinopathies are frequently "nonspecific," and psychiatric disease or psychological disorders need to be differentiated. Often, this can be accomplished using biological measures of hormone function, such as measures of thyroid, pituitary, parathyroid, and adrenal hormone levels. The field of endocrinology is highly dependent on an algorithmic approach to differential diagnosis using hormone levels as the guide. The use of self-reports helps identify at-risk patients, and raises suspicions about whether there is an abnormality, but diagnosis is dependent on laboratory values. Metabolic abnormalities, such as hyper- or hypoglycemia, dyslipidemia, and gonadal dysfunction can also contribute to fatigue. A better understanding of the interactions among hormones, their releasing factors, and regulation of inflammation will help identify abnormalities early and help distinguish endocrinopathies from other causes of fatigue. Early identification of these abnormalities may reduce end-organ damage and improve treatment strategies.

Summary Background Previous retrospective studies have suggested that women with acromegaly may present with menstrual irregularity and symptoms/signs of hyperandogenism, a phenotype similar to that of the polycystic ovary syndrome (PCOS). Objective The aim of this study was to investigate prospectively the presence of the PCOS phenotype (PCOSP) and polycystic ovaries (PCO) on ultrasonography in women with active acromegaly. Design Women within the reproductive age range (21–43 years) with active acromegaly of recent onset and/or previous surgical and/or medical therapy were studied. Main outcome measures Subjects underwent a physical examination; fasting bloods for androgens, pituitary hormones and metabolic parameters; an oral glucose tolerance test (OGTT) to estimate disease activity and insulin resistance; and a transvaginal ultrasound. Results Six women had newly diagnosed acromegaly, and eight still had active disease following previous surgical and/or medical treatment. Seven women were found to have PCO and six fulfilled the criteria for PCOSP; six of these women, five with PCOSP, had a pituitary macroadenoma. Women with PCOSP had significantly increased mean ovarian volumes and characteristic ovarian morphology compared to women without PCOSP (P

Summary objective Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. methods We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT–PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. results No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P

OBJECTIVE To audit our practice of performing ovarian and adrenal venous catheterization and sampling in hyperandrogenic women who fail to suppress their elevated androgen levels following a 48-h low-dose dexamethasone suppression test (LDDST). We considered the technical success rate of catheterization, the extra information obtained in addition to the standard biochemical tests and imaging findings, and the impact of sampling on management decisions. DESIGN A retrospective analysis of the results of all ovarian and adrenal venous catheterizations performed at St Bartholomew's Hospital, London, in the years 1980-1996. PATIENTS AND METHODS Baseline ovarian and adrenal androgens were measured in all women presenting with symptoms and signs of hyperandrogenism. Those patients who failed to suppress their elevated testosterone (T), androstenedione (A4) and/or dehydroepiandrosterone-sulphate (DHEAS) levels following a LDDST to within the normal range or to less than 50% of the baseline value were investigated further with adrenal computed tomography (CT), ovarian ultrasound, and ovarian and adrenal venous catheterization and sampling. RESULTS Results were available in 38 patients. The overall catheterization success rate was: all four veins in 27%, three veins in 65%, two veins in 87%. The success rate for each individual vein was: right adrenal vein (RAV) 50%, right ovarian vein (ROV) 42%, left adrenal vein (LAV) 87% and left ovarian vein (LOV) 73%. Eight patients were found to have tumours by means of imaging (adrenal CT and ovarian ultrasound), three adrenal and five ovarian, seven of which underwent operation. In six of these patients the clinical presentation was suggestive of the presence of a tumour; in addition, the combination of imaging findings allowed the detection of suspicious adrenal and ovarian masses in all eight cases. The five patients with ovarian tumours had serum testosterone levels > 4.5 nmol/l. In a further eight patients, laparotomy was performed based on a combination of diagnostic and therapeutic indications; in two of these patients the catheterization results were suggestive of an ovarian tumour. All these eight patients were shown histologically to have polycystic ovarian syndrome (PCOS), and no occult ovarian tumour was identified. None of the patients with nontumourous hyperandrogenism had a baseline testosterone level in excess of 7 nmol/l (median 4.4 nmol/l, range 2.5-7 nmol/l). CONCLUSIONS Our results suggest that ovarian and adrenal venous catheterization and sampling should not be performed routinely in women presenting with symptoms and signs of hyperandrogenism, even if they fail to suppress their elevated androgen levels to a formal 48-h LDDST. All patients presenting with symptoms and signs of hyperandrogenism and elevated androgen levels, and where the suspicion of an androgen-secreting tumour is high, should have adrenal CT and ovarian ultrasound imaging to detect such a tumour. Venous catheterization and sampling should be reserved for patients in whom uncertainty remains, as the presence of a small ovarian tumour cannot be excluded on biochemical and imaging studies used in this series alone. Its use should be restricted to units with expertise in this area.

OBJECTIVE: Growth hormone replacement therapy in GH-deficient children is associated with enhanced adrenal androgen production, raising the possibility that GH might stimulate adrenocortical hormone secretion. This has not been extensively investigated in adults to date. GH is a potent modulator of the activity of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme and by altering cortisol metabolism can affect the function of the hypothalamo-pituitary-adrenal (HPA) axis and therefore potentially of adrenal androgen secretion. This study examined the effects of GH replacement in GH-deficient adults on adrenal androgen secretion. DESIGN: Prospective study of the effect of GH replacement therapy on adrenal androgen production in patients with adult onset hypopituitarism over a 12-month period. PATIENTS AND METHODS: Thirty adult GH-deficient patients were classified into two groups according to their cortisol responses to an insulin-induced hypoglycaemia or a glucagon stimulation test: 13 patients were adrenocorticotropic hormone (ACTH)-sufficient (nine females, age 45.1 +/- 3 years), whereas 17 patients were ACTH-deficient (11 females, age 45.5 +/- 3 years). Serum samples were collected before patients were initiated on GH replacement therapy using a dose titration regimen, and after 6 and 12 months on GH therapy for measurement of serum IGF-I, dehydroepiand-rosterone sulphate (DHEAS), Delta4-Androstenedione (A4), testosterone, cortisol, sex hormone binding globulin (SHBG) and cortisol binding globulin (CBG). RESULTS: Six months after the initiation of GH replacement therapy, serum IGF-I levels were within the normal age-related reference range in both groups of patients and this was maintained at 12 months [in all patients 0 vs. 6 months: median (interquartile range): 92.5 ng/ml (73-116 ng/ml) vs. 191 ng/ml (159-224 ng/ml), P < 0.01]. In both ACTH-sufficient and -deficient groups of GH-deficient patients, pretreatment serum DHEAS levels were lower than the normal age-related reference range (P < 0.01); the ACTH-deficient patients had significantly lower DHEAS levels than the ACTH-sufficient patients [median (interquartile range): 0.5 micro mol/l (0.4-1.2 micro mol/l) vs. 1.5 micro mol/l (0.6-2.7 micro mol/l), P < 0.05]. Following GH replacement therapy, median levels of serum DHEAS levels rose from 1.5 micro mol/l (0.6-2.7 micro mol/l) to 1.9 micro mol/l (1.9-3.9 micro mol/l) in ACTH-sufficient patients, increasing in 11 of the 13 patients (P < 0.02). In this group, the median percentage increase from baseline was 32% at 6 months (P < 0.05). In contrast, baseline serum DHEAS levels [0.5 micro mol/l (0.4-1.2 micro mol/l)] declined in or from the measurable range in 47% of ACTH-deficient patients [median -16%; range -36-0] and only in one patient a + 0.2 micro mol/l increase was observed. GH dose requirements tended to be lower in ACTH-sufficient patients [1.2 U/day (0.8-1.4 U/day) vs. 1.6 U/day (1.0-2.0 U/day); P = 0.062]. There were no significant changes in serum testosterone, A4, SHBG and/or CBG levels, compared to the pretreatment levels, in either group of patients over the 12 months of GH replacement. CONCLUSIONS: This study shows that median serum DHEAS levels are significantly lower in GH-deficient patients, even those with intact ACTH reserve, than in aged-matched controls. GH replacement therapy is associated with a significant increase in mean serum DHEAS only in ACTH-sufficient patients. These findings are consistent with either (i) GH stimulation of adrenal androgen production in the permissive presence of ACTH or (ii) an inhibitory effect of GH on 11beta-HSD type 1 activity leading to enhanced cortisol clearance, subsequent activation of the HPA axis and ACTH-mediated androgen secretion.

Summary objective Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa. Pituitary GH-secreting tumours are found in approximately 10% of patients with CNC. One of the genes responsible for CNC, the PRKAR1A gene located on human chromosome 17q22-24, has recently been cloned. This represents a putative tumour suppressor gene, coding for the type 1α regulatory subunit of protein kinase A (PKA), which is found to be mutated in approximately half of the patients with CNC. However, it is currently unclear as to whether similar mutations occur in sporadic pituitary tumours. We have therefore investigated a series of GH-secreting and other pituitary tumours for sequence abnormalities in the PRKAR1A gene. The mRNA produced by the PRKAR1A undergoes decay if it codes for a truncated protein; we therefore also determined PRKAR1A mRNA levels in the tumours, and compared them with known mutant PRKAR1A-carrying lymphocyte samples. methods We extracted RNA from a series of pituitary tumours, reverse transcribed it to cDNA, and directly sequenced the PRKAR1A coding sequence in 17 GH-secreting, three prolactin-secreting, three ACTH-secreting, one FSH-secreting and 10 nonfunctioning pituitary tumours. Lymphocyte and tumour tissue RNA from two patients with CNC was used as positive controls. Using duplex polymerase chain reaction (PCR) with the PRKAR1A and the ‘housekeeping’ gene GAPDH, we determined the relative expression of the PRKAR1A gene in the unknown as well as in the positive control samples. results and conclusion No mutations were found in any of the exons sequenced. Relative mRNA expression was not decreased in any of the sporadic pituitary tumour samples. The present data thus do not suggest a major role for the PRKAR1A tumour suppressor gene in sporadic GH-secreting or other pituitary tumours.

OBJECTIVE: Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. PATIENTS: Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). RESULTS: A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. CONCLUSIONS: Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals.

1993). The initial management of NET comprises surgical excision of the primary tumour (aimed at reducing as much as possible of the tumour mass); additionally, in patients who are not cured by surgery alone, medical therapy is used for the control of symptoms and humoral syndromes with agents such as somatostatin analogues and/or a-interferon. Specific therapy with radiopharmaceuticals using radio-labelled substances such as meta-iodobenzylguanidine (MIBG) or somatostatin analogues appears promising for some tumours which show diagnostic uptake, and is the first-line systemic management for sensitive cases. Hepatic artery ligation and/or chemoembolization is also used in patients with excessive hepatic tumour load and uncontrollable symptoms. The control of tumour growth with chemotherapeutic agents is currently mainly reserved for patients with recurrent and/or progressive disease and where other therapeutic modalities have failed. Chemotherapy may be particularly helpful for selected cases of advanced NET, especially pancreatic or poorly differentiated NET. This review deals with the general role of chemotherapy in the management of malignant NET, its integration with other modes of therapy, and the specific protocols which have been used. Histological classification and differentiation of NET

Objective Meta-iodo-benzyl-guanidine labelled with 131-iodine [(131)I-mIBG] has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non-catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of (131)I-mIBG, we have reviewed all patients who had received this form of treatment in our department. Design Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with (131)I-mIBG and were followed-up according to a defined protocol in a given time frame. Patients Thirty-seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with (131)I-mIBG over a 15-year period were included in this analysis. Measurements The symptomatic, hormonal and tumoural responses before and after (131)I-mIBG therapy over a median follow-up duration of 32 months (range 5-180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18-81 years), 15 were treated with (131)I-mIBG alone whereas the other 22 received additional therapy. Results A total of 116 therapeutic (131)I-mIBG doses were administered [mean cumulative dose 592 mCi (21.9 GBq); range 200-1592 mCi (7.4-58.9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with (131)I-mIBG alone and 84% who received additional therapy showed stable disease over the period of follow-up. Overall survival during the period of the study was 71%. The overall 5-year survival rate was 85% (95% confidence interval, 72-99%) for all patients and 78% (95% confidence interval, 55-100%) for the carcinoid group alone, according to Kaplan-Meier analysis. Symptomatic control was achieved in all the patients treated with (131)I-mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. (131)I-mIBG therapy was safe and well tolerated. Serious side-effects necessitating the termination of (131)I-mIBG therapy were seen in only 2 of our patients. Conclusions (131)I-mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.

A 43-year-old female with a 24-years history of hypertension presented for further investigation and management of primary hyperaldosternoism. Postural studies were not conclusive and magnetic resonance (MR) imaging demonstrated a 27 × 18 mm lesion of the right adrenal gland which showed no signal loss during in and out of phase imaging. Although these appearances were considered to be atypical of those seen on MR in patients with aldosterone producing adrenal adenomas the patient underwent an adrenalectomy with removal of a 3 × 3 × 2 cm right adrenal mass. Post-operatively she became hypotensive and a 0900 hours serum cortisol was undetectable (

OBJECTIVE Women with Cushing's syndrome (CS) may present with menstrual irregularity and symptoms/signs of hyperandrogenism, a phenotype similar to that of the polycystic ovarian syndrome (PCOS); however, currently there are no data on the prevalence of either polycystic ovaries (PCO) and/or PCOS in patients with CS. The aim of this study was to investigate their presence among women of reproductive age presenting with CS by analysing clinical, endocrinological and ultrasonographic features. DESIGN Prospective study of all women within the reproductive age (range 18-40 years) who presented with CS between August 1994 and January 2000. SUBJECTS AND METHODS Thirteen women (median age 32 years, range 18-39 years) with CS were evaluated. The diagnosis of CS was based on the presence of appropriate clinical features and an elevated serum midnight cortisol with failure to suppress 0900 hours serum cortisol to less than 50 nmol/l following a formal low-dose dexamethasone suppression test (LDDST). All women had their clinical features relevant to possible hyperandrogenism, menstrual disorder and infertility recorded, and circulating gonadotrophins, oestradiol, androgens and SHBG levels measured; ovarian ultrasonography was performed during their initial assessment. Relevant MR/CT imaging of the pituitary and/or adrenal glands was performed. RESULTS Eleven women had ACTH-dependent CS [nine Cushing's disease (CD), one ectopic ACTH syndrome due to a bronchial carcinoid, one periodic CS of unknown origin); two patients had ACTH-independent CS (adrenal adenomas). All women with CS had at least one symptom/sign of hyperandrogenism (13 hirsutism, seven acne, five male-pattern alopecia). Nine women (70%) had menstrual disturbances (four oligomenorrhoea, four amenorrhoea, one polymenorrhoea) while four women (30%) had a normal menstrual pattern. Serum oestradiol levels for the group as a whole were similar to those observed in the early follicular phase of normally menstruating women; however, seven women had low oestradiol, LH and FSH levels suggestive of hypogonadotrophic hypogonadism. Serum androgen levels (testosterone, androstendione and DHEAS), even in the presence of symptoms/signs of hyperandrogenism, were within the normal reference range but SHBG levels were uniformly decreased even in women with normal menstrual cycles. There was a negative correlation between urinary free cortisol, but not mean serum cortisol, and serum oestradiol, testosterone and SHBG levels (r = - 0.8, r = - 0.86 and r = - 0.66, P 140 pmol/l) had higher serum androstenedione, and lower urinary free cortisol levels, than women who were oestrogen deficient (E2 < 140 pmol/l). Six of the 13 women (46%) had ovarian morphology suggestive of PCO, four of six oestrogen sufficient women and two of seven oestrogen deficient women. The results did not differ according to the underlying cause of CS. CONCLUSIONS PCO and PCOS are common in women with Cushing's syndrome; women with Cushing's syndrome and only moderately elevated cortisol secretion maintain gonadotrophin stimulation to the ovary with normal oestradiol levels, in contrast to women with Cushing's syndrome and higher cortisol secretion who develop hypogonadotrophic hypogonadism. However, even in the latter group, high ovarian volumes were maintained and some had ovarian morphology suggestive of PCO.

OBJECTIVE To study the effects of short (6 months) and longer-term (up to 24 months) growth hormone (GH) replacement therapy using a dose titration regimen, on lipid and glucose metabolism in GH-deficient, hypopituitary adults. DESIGN On-going open study of GH treatment up to 24 months. Measurements were performed at baseline and at 6, 12, 18 months and 2 years during therapy (data shown at 6 months and 2 years only). Using a dose titration regimen the median GH dose used to achieve and maintain IGF-I levels above the median, but below the upper limit of the age-related reference range (median IGF-I 202.5 μg/l, range 76–397 μg/l), was 1.2 IU daily (range 0.4–3 IU) [0.8 IU/day, males; 1.6 IU/day, females]. PATIENTS Ninety GH-deficient hypopituitary adults (54 female, median age 48 years, range 19–79 years) entered the study and 24 (14 female, median age 45 years, range 32–79 years) have concluded the 2 year period of assessment. MEASUREMENTS Body mass index (BMI), waist and hip circumference ratio (WHR), fasting lipids, glucose and glycated haemoglobin (HbA1c) levels were measured at 6 month intervals during GH therapy. RESULTS Using the dose titration regimen, compared to pretreatment values, total and low density lipoprotein (LDL)-cholesterol levels were significantly lower at 6 months (mean ± SEM, 5.61 ± 0.1 vs. 5.25 ± 0.1, and 3.85 ± 0.19 vs. 3.43 ± 0.26, respectively, P 6.4 mmol/l) obtained the greatest cholesterol reduction (mean ± SEM, 7.13 ± 0.14 mmol/l vs. 5.76 ± 0.31 mmol/l, P

BACKGROUND The insulin tolerance test (ITT) is the reference standard for the diagnosis of cortisol and growth hormone (GH) deficiency, but problems have occurred in small children in inexperienced hands and it is contraindicated in patients with cardiac disease and epilepsy. Hexarelin is a growth hormone-releasing peptide with GH-, ACTH/cortisol- and prolactin-releasing effects which involve both hypothalamic and direct pituitary mechanisms. We therefore investigated whether it could be used to test GH and ACTH/cortisol reserve in patients with pituitary disease. METHODS AND SUBJECTS The changes in GH and cortisol in response to insulin-induced hypoglycaemia (intravenous human Actrapid 0.15 IU/kg) and hexarelin (2 μg/kg) in 19 patients with possible pituitary disease (5 males, mean age 39 years, range 21–70) were compared. The patients' responses during the hexarelin test were also compared to normal ranges of GH and cortisol responses established in healthy volunteers following hexarelin administration. RESULTS AND DISCUSSION GH peak levels were significantly higher after hexarelin than after hypoglycaemia (mean ± SEM; 67.1 ± 16 vs. 26.9 ± 6.8 mU/l respectively; P 580 nmol/l is indicative of normal cortisol reserve, as established in patients undergoing surgery; only five of the normal volunteers and one of the thirteen patients with a normal ACTH/cortisol reserve on ITT had a peak cortisol >580 nmol/l in response to hexarelin. CONCLUSION Adult patients who have a subnormal peak GH response to hexarelin are likely to be GH deficient on an insulin tolerance test. However, our data suggest that the hexarelin test is not a useful test of ACTH/cortisol reserve. The hexarelin test could be a useful first/screening test to diagnose adult GH deficiency, particularly in patients in whom an insulin tolerance test is contraindicated or who are already ACTH deficient and in whom the GH reserve alone is of interest.

Secondary tumours of any type in the breast are rare. A review of the literature demonstrated only 23 cases of carcinoid tumours with associated breast metastasis, as distinct from primary carcinoid tumours of the breast. Distant metastases from carcinoid tumours are correlated with poor prognosis and survival. Although both primary and metastatic mammary carcinoid tumours are uncommon, the recognition of the true origin of the tumours may be of importance owing to the different clinical management and prognosis of the two conditions. Recently, radionuclide-labelled imaging techniques have been applied to the localization of such lesions, based on isotope uptake by receptors present in these neuroendocrine tumours. We report two new cases of carcinoid tumours with breast metastases, the primaries being in the ileocaecal valve and the bronchus, respectively. The diagnosis of a carcinoid tumour was based on the clinical, biochemical, histopathological and immunostaining features. Furthermore, these patients had both 123I-MIBG and 111In pentetreotide scintigraphy performed. These radionuclides play a useful role in the localization and potentially in the management of carcinoid tumours and their distant metastases.

Objective The insulin tolerance test (ITT) is the established reference test for assessing the hypothalamo-pituitary-adrenal (HPA) axis. Various authorities, however, have suggested that the 250 microgram short ACTH stimulation test may be used to assess the HPA axis in place of the ITT in suspected hypopituitarism, although a number of other studies have suggested that the test may be unreliable in this setting. In this study, the ITT (or glucagon test) has been compared with the 250 microgram short ACTH stimulation test in patients with pituitary tumours pre-operatively and within 2 weeks of trans-sphenoidal hypophysectomy. Design An ITT, or a glucagon test when the ITT was contraindicated, and the 250 micrograms short ACTH stimulation test, were performed in all the patients before (an ITT in 18 and a glucagon test in three patients) and within 2 weeks after trans-sphenoidal hypophysectomy (an ITT in 16 and a glucagon test in five patients). Patients Twenty-one patients with pituitary disorders (15 with acromegaly, one with a prolactinoma and five with non-functioning tumours) were studied; four had a microadenoma, two a mesoadenoma and 15 a macroadenoma. Measurements Serum cortisol was measured by radioimmunoassay. A normal response was defined as a rise in serum cortisol to 580 nmol/l or above for all the tests. Results Before surgery, three of 18 patients (17%) had a discrepancy between the ITT and the 30 minute short ACTH stimulation test and one of three between the glucagon test and the 30 minute short ACTH stimulation test. Combined together, pre-operatively, four of 21 patients (19%) had discrepant results. In the early post-operative period, the discrepancy between ITT and the 30 minute short ACTH stimulation test was higher with four of 16 patients (25%) showing discordant results; one of the five patients tested had a discrepancy between the glucagon test and the 30 minute short ACTH stimulation test. On combining the tests, the post-operative discrepancy was five of 21 patients (24%). Conclusions The 250 microgram short ACTH stimulation test produces discordant results from the ITT in a clinically significant proportion of affected patients when assessing the HPA axis, although the rate of discordance varies according to the criteria used for normality for both the tests. We suggest that the ITT should remain the preferred test for assessing ACTH secretory capacity compared with the standard 250 microgram short ACTH stimulation test, both in the preoperative and in the early post-trans-sphenoidal hypophysectomy period.