3 Tesla intra-operative MRI as an adjunct to endoscopic pituitary surgery: an early assessment of clinical utility.

BACKGROUND: Extent of resection is a major determinant of outcomes following pituitary surgery. Intra-operative magnetic resonance imaging (iMRI), provides an immediate assessment of the extent of resection, allowing further tumour resection during the same procedure. However, such systems are expensive and significantly increase operative time, prompting some authors to question the additional benefit conferred by iMRI when combined with endoscopy. Our aim was to assess the impact of combining 3 T iMRI with endoscopy in patients with pituitary tumours. METHODS: We retrospectively reviewed a prospectively maintained database to identify patients who underwent iMRI guided endoscopic resection of pituitary tumours between May 2017 and November 2018 (iMRI cohort). This cohort was compared with a pre-iMRI cohort of patients who underwent endoscopic resection of pituitary adenomas. Operative time, extent of resection, control of endocrine disease and post-operative complications were recorded and analysed. RESULTS: Thirty-seven patients were included in each cohort. iMRI facilitated additional tumour resection in 6/37 (16%) of cases. In 4/37 cases (11%), iMRI prompted a return to theatre but no further tumour could be identified. The overall GTR rate, following iMRI was 24/37 (65%) as compared to 21/37 (57%) in the pre-iMRI cohort. Cure of endocrine disease associated with hormonally active tumours was achieved in 9/11 (82%) of cases in the iMRI cohort. The mean operative time in the iMRI cohort was 327 minutes (five hours 27 minutes). CONCLUSIONS: 3 T iMRI provides immediate identification of residual tumour following endoscopic pituitary surgery. This allows for resection of surgically accessible residual disease during the same procedure and is likely to reduce the requirement for later re-intervention. However, the use of iMRI in this setting is associated with significant resource allocation issues which must be considered prior to the widespread adoption of this technique.

Obesity is common at diagnosis of childhood pituitary adenoma and may persist following successful treatment.

OBJECTIVE: There is a paucity of data describing long-term outcomes of paediatric patients with pituitary adenoma. In this report, we describe clinical features, treatment and outcomes of a paediatric cohort. DESIGN: Retrospective cohort study. PATIENTS: Twenty-four white Caucasian patients aged <16 years from a single tertiary care centre in the United Kingdom at diagnosis followed for (median, range) 3.3, 0.7-8.4 years. MEASUREMENTS: Clinical and radiological data at diagnosis and follow-up. RESULTS: Thirteen patients had prolactinomas (54.1%, age: 15.2 years, 13.2-15.8 years; all females), including ten macroadenomas (11.0-35.0 mm). Patients presented with menstrual disorders (91%), headache (46%), galactorrhoea (46%) and obesity (body mass index [BMI] SDS > 2): (38%). Ten patients with prolactinoma were treated with dopamine agonist alone, 3 also required surgery and 2 patients, cabergoline, surgery plus radiotherapy. Five patients had Cushing's disease (20.8%, age: 14.0, 4.0-15.7 years; 2 female), including one macroadenoma (24 mm). Patients presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure (09.00 cortisol < 50 nmol/L). Two patients relapsed 3- and 6 years following surgery, requiring radiotherapy. One patient also required bilateral adrenalectomy. Six patients had nonfunctioning pituitary adenoma (25.0%, age: 15.8, 12.5-16.0 years; 2 female), including two macroadenomas (20.0-53.0 mm). Patients presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections; two recurred following surgery and required radiotherapy. On latest follow-up; 13 (54.1%) patients were obese (BMI 3.09 SDS; range: 2.05-3.73 SDS). CONCLUSION: Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment. Adenomas were larger, more resistant to treatment, and more likely to recur than in adult populations.

Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response.

Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean (n = 6), normoglycemic obese (n = 6), obese with impaired glucose regulation (IGR; n = 6), and obese T2DM (n = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol·kg-1·min-1) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC0-4 h ± SE, 41,992 ± 9,843 µmol·l-1·min-1 vs. 71,468 ± 13,605 with placebo, P = 0.039, 95% CI: 0.31-0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 ± 0.4 vs 0.86 ± 0.1-fold with placebo, P = 0.043, 95% CI: 0.1-1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, r = 0.56, P = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM.

Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition.

PCOS (polycystic ovary syndrome) is associated with IR (insulin resistance), increased visceral fat and NAFLD (non-alcoholic fatty liver disease) all of which may contribute to endothelial dysfunction, an early marker of CVD (cardiovascular disease) risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of AT (adipose tissue) compartments and the size of intracellular TAG (triacylglycerol) pools in liver and skeletal muscle. A total of 19 women with PCOS (means±S.D.; 26±6 years, 36±5 kg/m2) and 16 control women (31±8 years, 30±6 kg/m2) were recruited. Endothelial function was assessed in the brachial artery using FMD (flow-mediated dilation). VAT (visceral AT) and abdominal SAT (subcutaneous AT) volume were determined by whole body MRI, and liver and skeletal muscle TAG by 1H-MRS (proton magnetic resonance spectroscopy). Cardiorespiratory fitness and HOMA-IR (homoeostasis model assessment of IR) were also determined. Differences between groups were analysed using independent Student's t tests and ANCOVA (analysis of co-variance). FMD was impaired in PCOS by 4.6% [95% CI (confidence interval), 3.0-7.7; P<0.001], and this difference decreased only slightly to 4.2% (95% CI, 2.4-6.1; P<0.001) when FMD was adjusted for individual differences in visceral and SAT and HOMA-IR. This magnitude of impairment was also similar in lean and obese PCOS women. The results suggest that endothelial dysfunction in PCOS is not explained by body fat distribution or volume. FMD might be a useful independent prognostic tool to assess CVD risk in this population.

Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle.

Non-alcoholic fatty liver disease (NAFLD), characterized by lipid deposition within the liver [intrahepatocellular lipid (IHCL)], is associated with insulin resistance and the metabolic syndrome (MS). It has been suggested that impaired skeletal muscle mitochondrial function may contribute to ectopic lipid deposition, and the associated MS, by altering post-prandial energy storage. To test this hypothesis, we performed a cross-sectional study of 17 patients with NAFLD [mean±S.D.; age, 45±11 years; body mass index (BMI), 31.6±3.4 kg/m2] and 18 age- and BMI-matched healthy controls (age, 44±11 years; BMI, 30.5±5.2 kg/m2). We determined body composition by MRI, IHCL and intramyocellular (soleus and tibialis anterior) lipids (IMCLs) by proton magnetic resonance spectroscopy (1H-MRS) and skeletal muscle mitochondrial function by dynamic phosphorus magnetic resonance spectroscopy (31P-MRS) of quadriceps muscle. Although matched for BMI and total adiposity, after statistical adjustment for gender, patients with NAFLD (defined by IHCL ≥ 5.5%) had higher IHCLs (25±16% compared with 2±2%; P<0.0005) and a higher prevalence of the MS (76% compared with 28%) compared with healthy controls. Despite this, the visceral fat/subcutaneous fat ratio, IMCLs and muscle mitochondrial function were similar between the NAFLD and control groups, with no significant difference in the rate constants of post-exercise phosphocreatine (PCr) recovery (1.55±0.4 compared with 1.51±0.4 min-1), a measure of muscle mitochondrial function. In conclusion, impaired muscle mitochondrial function does not seem to underlie ectopic lipid deposition, or the accompanying features of the MS, in patients with NAFLD.

Evolution in functionality of a metastatic pancreatic neuroendocrine tumour (pNET) causing Cushing's syndrome: treatment response with chemotherapy.

BACKGROUND: We report the case of a patient who had a non-functional metastatic pancreatic neuroendocrine tumour (pNET), which changed in functionality during the course of the disease. This case demonstrates the effectiveness of conventional cytotoxic chemotherapy in the management of select group of patients with this rare, challenging condition. CASE PRESENTATION: Our patient was a 34 year old man under oncology follow up, diagnosed with a non-functional metastatic pancreatic neuroendocrine tumour treated with a Whipple's procedure two years ago. Despite treatment with somatostatin analogues and sunitinib, a tyrosine kinase inhibitor, he had demonstrated radiological progression of his metastatic disease. He now presented with a short history of Cushing's syndrome. A presumptive diagnosis of a rapidly progressive, metastatic, functional pNET with ectopic ACTH production was made, confirmed biochemically and with liver biopsy. The proliferative index, Ki-67 of 20% of the liver biopsy prompted us to treat him with conventional cytotoxic chemotherapy using streptozocin, 5-fluorouracil and doxorubicin. Prior to its administration clinical and biochemical control of the hypercortisolemic state was achieved with metyrapone. However the clinical, biochemical and radiological response to chemotherapy was so dramatic obviating the need for metyrapone therapy. CONCLUSIONS: Non-functional pNETs may evolve in their clinical and biologic behaviour producing functional hormonal syndromes. Chemotherapy may be an effective therapeutic modality in such circumstances.

Low libido despite high normal testosterone levels in a male with an FSH-secreting pituitary macroadenoma.

Summary: Functioning gonadotroph adenomas with clinical manifestations are extremely rare and the majority of these are FSH-secreting macroadenomas. Clinical symptoms are due to excess gonadotrophins and sex hormones, and these may be present for a long time before the diagnosis of pituitary adenoma is made. We present the case of a 37-year-old Caucasian male with clinical manifestations of an FSH-secreting pituitary macroadenoma. He had sexual dysfunction for a year followed by bilateral testicular pain and enlargement which was initially treated as suspected recurrent epididymitis, but his symptoms did not resolve. He presented a year later with headaches and bilateral superior temporal visual field defects. Brain imaging confirmed a pituitary macroadenoma with optic chiasm compression. Pituitary profile demonstrated an unusually high FSH with high normal LH and normal testosterone level. The patient successfully underwent transsphenoidal hypophysectomy and histology confirmed gonadotroph differentiation and immunoreactivity predominantly with FSH. Gonadotrophin levels and testosterone dropped significantly after surgery, and he was started on testosterone replacement. MR imaging, 2 years post surgery, showed no recurrence of pituitary adenoma. In conclusion, testicular enlargement and hypogonadal symptoms associated with low testosterone levels are recognised features in FSH-secreting pituitary adenomas. Our patient had hypogonadal symptoms but consistently high normal testosterone levels prior to surgery. The reason for low libido despite high testosterone is unclear. Our case highlights the need to suspect such rare underlying pituitary pathology when dealing with unusual combinations of hypogonadal symptoms, testicular enlargement with low or normal testosterone levels. Learning points: Functioning pituitary adenomas that secrete excess follicle-stimulating hormone (FSH) are very rare and often present with symptoms related to pituitary mass effect. Testicular enlargement alongside sexual dysfunction are commonly reported symptoms amongst male patients. Pituitary profile results demonstrate a raised FSH level with either a low, normal, or even high testosterone level which may not always correlate to clinical symptoms. Pituitary pathology should be considered in males presenting with unusual combinations of testicular enlargement and hypogonadal symptoms even with normal testosterone levels.

Management of pituitary incidentalomas.

Pituitary incidentalomas are common findings with increasing use of modern neuroradiological imaging undertaken for symptoms unrelated to pituitary disease. The prevalence of these lesions is ∼10% in autopsy studies and the incidence varies from 10% to 38% on magnetic resonance imaging in the published literature. They are almost always benign in nature and most are non-functioning (non-secreting) adenomas. Although many individuals are asymptomatic at diagnosis, some with functioning (secreting) pituitary adenomas or larger non-functioning adenomas have symptoms. All identified cases should have a thorough clinical and endocrinological evaluation to help with precise management, which depends on the size of the lesion, hormonal status (functioning versus non-functioning adenoma) and the presence of visual deficits resulting from optic nerve compression by the pituitary adenoma. Here, we provide an overview of the initial assessment and management of pituitary incidentalomas for clinicians not routinely involved in the management of pituitary disease.

Inferior petrosal sinus ACTH and prolactin responses to CRH in ACTH-dependent Cushing's syndrome: a single centre experience from the United Kingdom.

Inferior petrosal sinus sampling (IPSS) of ACTH with CRH stimulation helps distinguish pituitary ACTH-dependent Cushing's syndrome from the ectopic ACTH syndrome (EAS). The usefulness of the paradoxical response of other pituitary hormones including prolactin to CRH remains controversial. Data from 33 IPSS procedures carried out at the Walton Centre for Neurology and Neurosurgery in Liverpool were analyzed. Patients were selected for this procedure if they had been diagnosed with ACTH dependent Cushing's syndrome and the majority had no obvious pituitary adenoma on Magnetic Resonance Imaging. Satisfactory simultaneous bilateral catheterization was accomplished in 23/33 (success rate 70%). The diagnostic sensitivity of a basal central/peripheral ACTH ratio >2.0 and >3 post-CRH was 94%. In two patients with subsequently confirmed EAS the maximal central/peripheral ACTH ratio was <2.0 on basal samples and did not change following CRH. The maximal central/peripheral prolactin ratio was noted at 5 min post-CRH, coinciding with the maximal central/peripheral ACTH ratio. The intersinus gradient (ISG) of ACTH was paralleled by a consistent ISG of prolactin and in 7 out of 9 patients (with successful bilateral IPSS and unilateral adenomas) the ISG of prolactin correctly lateralized the microadenoma whereas the ISG of ACTH correctly lateralized in 8 out of 9 patients. Neither of the patients with EAS achieved a central/peripheral prolactin ratio >2 in the basal state and >3 post-CRH. Bilateral catheterization of inferior petrosal sinuses can be successful in up to 70% of cases. Prolactin measurements do not have superior lateralizing capability compared with ACTH but may be useful in the differential diagnosis of pituitary-driven from EAS.

Etomidate in the management of severe Cushing's disease and MRSA bacteraemia in a district general hospital in the United Kingdom.

SUMMARY: We report our experience on managing a case of florid Cushing's disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital. LEARNING POINTS: Severe Cushing's syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11ß-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.

Is there a role for ghrelin and peptide-YY in the pathogenesis of obesity in adults with acquired structural hypothalamic damage?

CONTEXT: Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established. OBJECTIVE: Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity. SETTING: The study took place at a University Medical Center. PARTICIPANTS: Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat. INTERVENTIONS: Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal. MAIN OUTCOME MEASURES: We assessed ghrelin, PYY, and appetite ratings. RESULTS: The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group. CONCLUSIONS: Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage.

PURPOSE: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity. METHODS: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index > or =30 kg/m(2) at the latest follow-up, which had increased by at least 2 kg/m(2) since diagnosis of the tumor). RESULTS: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n = 22] vs. 24% [n = 10] at the time of diagnosis, P < 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] = 13; 95% confidence interval [CI]: 2.0 to 86; P = 0.007) and growth hormone replacement (OR = 7.6; 95% CI: 1.1 to 51; P = 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain. CONCLUSION: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered.

GH deficiency after traumatic brain injury: improvement in quality of life with GH therapy: analysis of the KIMS database.

OBJECTIVE: Prevalence of GH deficiency (GHD) caused by traumatic brain injury (TBI) is highly variable. Short-term studies show improvement in quality of life (QoL) during GH replacement (GHR), but long-term data are lacking. The aim of this study was to analyse the clinical characteristics of post-traumatic hypopituitarism and the QoL effects of long-term GHR. DESIGN/METHODS: Pfizer International Metabolic Database patients with GHD caused by TBI and by non-functioning pituitary adenoma (NFPA) were compared regarding: clinical characteristics at baseline and 1-year of GHR, and QoL response up to 8-years of GHR (QoL-AGHDA total scores and dimensions) in relationship with country-specific norms. RESULTS: TBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (P<0.0001), had a higher incidence of isolated GHD, higher GH peak, a more favourable metabolic profile and worse QoL, were shorter by 0.9 cm (1.8 cm when corrected for age and gender; P=0.004) and received higher GH dose (mean difference: 0.04 mg/day P=0.006). In TBI patients, 1-year improvement in QoL was greater than in NFPA (change in QoL-AGHDA score 5.0 vs 3.5, respectively, P=0.04) and was sustained over 8 years. In TBI patients, socialisation normalised after 1 year of GHR, self-confidence and tenseness after 6 years and no normalisation of tiredness and memory was observed. CONCLUSION: Compared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL.

Intracranial desmoplastic small round cell tumor presenting as a suprasellar mass.

Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive neoplasms that typically arise from abdominal and pelvic peritoneum in young adults. Other primary sites are uncommon, and an intracranial origin is exceptionally rare. Here the authors report the first case of a DSRCT presenting as a primary suprasellar tumor causing panhypopituitarism and severe bitemporal hemianopia in a young man. Macroscopic debulking of the tumor was undertaken, and histology revealed features of DSRCT. Reverse transcription polymerase chain reaction confirmed the presence of Ewing's sarcoma-Wilms tumor 1 (EWS-WT1) gene rearrangement specific to DSRCT. Postoperative whole-body imaging showed no primary malignancy elsewhere. The tumor recurred 4 months after surgery, and this was followed by cervical and mediastinal lymph node metastases. The patient died 20 months after initial presentation of rapidly progressive disease. DSRCTs should be included in the differential diagnosis of an unusual suprasellar mass in young adults. Early diagnosis is essential, and once the tumor is identified histologically, gross-total resection and radical postoperative treatment involving radiotherapy, chemotherapy, and close surveillance are required because of the lesion's potential for rapidly progressive malignancy.

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients.

BACKGROUND: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. OBJECTIVE: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. DESIGN: This was designed as a retrospective, multicenter study. SETTING: Thirteen University hospitals were studied. PATIENTS: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). MEASUREMENTS: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). RESULTS: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 µg/dL] vs 348.6 nmol/L [12.6 µg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 µg/dL] vs 491.1 nmol/L [17.8 µg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 µg/24 h] vs 452.6 nmol/24 h [164 µg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 µg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 µg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. CONCLUSIONS: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Acute peripheral administration of synthetic human GLP-1 (7-36 amide) decreases circulating IL-6 in obese patients with type 2 diabetes mellitus: a potential role for GLP-1 in modulation of the diabetic pro-inflammatory state?

BACKGROUND: To explore the effects of acute administration of GLP-1 and GIP on circulating levels of key adipocyte-derived hormones and gut-brain peptides with established roles in energy and appetite regulation, modulation of insulin sensitivity and inflammation. METHODS: Six obese male patients with diet-treated type 2 diabetes (T2DM) and 6 healthy lean subjects were studied. The protocol included 4 experiments for each participant that were carried out in randomised order and comprised: GLP-1 infusion at a rate of 1 pmol/kg/min for 4h, GIP at a rate of 2 pmol/kg/min, GLP-1+GIP and placebo infusion. Plasma leptin, adiponectin, IL-6, insulin, ghrelin and obestatin were measured at baseline, 15, 60, 120, 180 and 240 min following the start of infusion. RESULTS: Patients with T2DM had higher baseline IL-6 compared with healthy [day of placebo infusion: T2DM IL-6 mean (SEM) 1.3 (0.3) pg/ml vs 0.3 (0.1)pg/ml, p=0.003]. GLP-1 infusion in T2DM was associated with a significant reduction in circulating IL-6 [baseline IL-6 1.2 pg/ml vs IL-6=0.7 at 120 min, p=0.0001; vs IL-6=0.8 at 180 min, p=0.001]. There was no significant change in leptin, adiponectin, ghrelin or obestatin compared to baseline on all 4 experimental days in both groups. CONCLUSION: Short-term infusion of supraphysiological concentrations of GLP-1 in T2DM results in suppression of IL-6, a key inflammatory mediator strongly linked to development of obesity and T2DM-related insulin resistance. It remains to be confirmed whether GLP-1-based diabetes therapies can impact favourably on cardiovascular outcomes.

Low prevalence of hypopituitarism after subarachnoid haemorrhage using confirmatory testing and with BMI-specific GH cut-off levels.

OBJECTIVE: Hypopituitarism following subarachnoid haemorrhage (SAH) has been reported to be a frequent occurrence. However, there is considerable heterogeneity between studies with differing patient populations and treatment modalities and most importantly employing differing endocrine protocols and (normal) reference ranges of GH. We aimed to examine prospectively a cohort of SAH survivors for development of hypopituitarism post-SAH using rigorous endocrine testing and compare GH response to glucagon stimulation with a cohort of healthy controls of a similar BMI. DESIGN AND METHODS: Sixty-four patients were investigated for evidence of hypopituitarism 3 months post-SAH with 50 patients tested again at 12 months. Glucagon stimulation testing (GST), with confirmation of deficiencies by GHRH/arginine testing for GH deficiency (GHD) and short synacthen testing for ACTH deficiency, was used. Basal testing of other hormonal axes was undertaken. RESULTS: Mean age of patients was 53±11.7 years and mean BMI was 27.5±5.7 kg/m(2). After confirmatory testing, the prevalence of hypopituitarism was 12% (GHD 10%, asymptomatic hypocortisolaemia 2%). There was no association between hypopituitarism and post-SAH vasospasm, presence of cerebral infarction, Fisher grade, or clinical grading at presentation. There was a significant correlation between BMI and peak GH to glucagon stimulation in both patients and controls. CONCLUSIONS: Identification of 'true' GHD after SAH requires confirmatory testing with an alternative stimulation test and application of BMI-specific cut-offs. Using such stringent criteria, we found a prevalence of hypopituitarism of 12% in our population.

Hypothalamic obesity: prevalence, associations and longitudinal trends in weight in a specialist adult neuroendocrine clinic.

OBJECTIVE: Obesity is highly prevalent among adults with acquired, structural hypothalamic damage. We aimed to determine hormonal and neuroanatomical variables associated with weight gain and obesity in patients following hypothalamic damage and to evaluate the impact of early instigation of weight loss measures to prevent or limit the severity of obesity in these patients. DESIGN: Retrospective study of 110 adults with hypothalamic tumours attending a specialist neuroendocrine clinic. BMI was calculated at diagnosis and at last follow-up clinic visit. Endocrine data, procedures, treatments and weight loss measures were recorded and all available brain imaging reviewed. RESULTS: At last follow-up, 82.7% of patients were overweight or heavier (BMI≥25 kg/m(2)), 57.2% were obese (BMI≥30 kg/m(2)) and 14.5% were morbidly obese (BMI≥40 kg/m(2)). Multivariate analysis revealed that use of desmopressin (odds ratio (OR)=3.5; P=0.026), GH (OR=2.7; P=0.031) and thyroxine (OR=3.0; P=0.03) was associated with development of new or worsened obesity. Neuroimaging features were not associated with weight gain. Despite proactive treatments offered in clinic in recent years (counselling, dietetic and physical activity advice, and anti-obesity medications), patients have continued to gain weight. CONCLUSIONS: Despite increased awareness, hypothalamic obesity is difficult to prevent and to treat. Improved understanding of the underlying pathophysiologies and multicentre collaboration to examine efficacy of novel obesity interventions are warranted.

Impulse control disorder in a patient on long-term treatment with bromocriptine for a macroprolactinoma.

Impulse control disorders (ICDs) constitute socially disruptive behaviors such as pathological gambling, impulsive eating, compulsive shopping, and hypersexuality. These conditions are well recognized in patients on dopamine agonist (DA) therapy for Parkinson disease. Dopamine agonists are widely used as first-line agents in the treatment of prolactinomas, but ICDs in this group of patients are relatively rare, perhaps because of lower therapeutic doses used. A review of the literature yielded only a few cases of ICDs in patients on DA treatment for prolactinomas. These symptoms are perhaps underreported because of lack of awareness among patients and health care professionals. Impulse control disorders are recognized psychiatric disorders that have significant psychological and social implications, and patients need to be counselled about this rare possibility when embarking on prolonged DA therapy. We describe a young patient with severe, socially disruptive impulsivity manifesting with pathological gambling who had been on long-term bromocriptine therapy for a macroprolactinoma.

Exercise training in polycystic ovarian syndrome enhances flow-mediated dilation in the absence of changes in fatness.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) is associated with an adverse cardiovascular disease (CVD) profile. A surrogate marker for CVD risk is endothelial dysfunction. Limited studies exist examining the cardiovascular and metabolic effects of exercise in PCOS and specifically its impact on endothelial function. Therefore, the aim of the current study was to investigate the impact of exercise on endothelial function, in parallel with body composition, insulin resistance, and cardiopulmonary fitness in PCOS. METHODS: Ten women with PCOS (27 yr, 95% confidence interval [CI] = 23-32; 31 kg·m⁻², 95% CI = 28-34) completed a 16-wk exercise (EX) program, and seven women with PCOS (29 yr, 95% CI = 24-35; 35 kg·m⁻², 95% CI = 31-40) undertook conventional care (CC) following lifestyle advice. Brachial artery endothelial function was assessed pre- and postintervention using flow-mediated dilation adjusted for variability in baseline diameter. Visceral and abdominal subcutaneous adipose tissue was assessed using whole-body magnetic resonance imaging and ¹H magnetic resonance spectroscopy quantified liver fat. Cardiorespiratory fitness, glycemic control, hormone, and lipid profiles were also assessed. Data were analyzed using covariate-controlled generalized estimating equations. RESULTS: At follow-up, EX improved flow-mediated dilation by 3.6% (95% CI = 0.5-6.7, P = 0.03) more than CC. There was a parallel improvement in cardiorespiratory fitness of 4.7 mL·kg⁻¹·min⁻¹ (95% CI = 1.4-7.9, P < 0.001) with EX versus CC. These changes were not explained by changes in visceral adipose tissue, subcutaneous adipose tissue, liver fat or insulin resistance. CONCLUSIONS: Supervised exercise in women with PCOS improves endothelial function, an adaptation associated with reduced CVD risk. This change occurs independent of changes in body weight or composition. The success of public health interventions in this patient group should not be solely judged by weight loss.