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Background\ud \ud Xanthogranulomas are inflammatory masses most commonly found at peripheral sites such as the skin. Sellar and parasellar xanthogranulomas are rare and present a diagnostic challenge as they are difficult to differentiate from other sellar lesions such as craniopharyngiomas and Rathke’s cleft cysts pre-operatively. Their radiological imaging features are yet to be clearly defined, and clinical outcomes after surgery are also uncertain. This study reviews clinical presentation, radiological appearances, and clinical outcomes in a cohort of patients with pituitary xanthogranulomas.\ud \ud \ud Methods\ud \ud A prospectively maintained pituitary surgery database was screened for histologically confirmed pituitary xanthogranulomas between May 2011–December 2016. Retrospective case note assessments were then performed by three independent reviewers. Patient demographics, clinical presentations, imaging, and clinical outcomes were analysed.\ud \ud \ud Results\ud \ud During the study period 295 endoscopic endonasal pituitary surgeries were performed. Six patients had confirmed pituitary xanthogranulomas (2%). Patients most commonly presented with visual field deficits and/or endocrine dysfunction. Common imaging features included: a cystic consistency, hyperintensity on T1-weighted MR images, and contrast enhancement either peripherally (n = 3) or homogenously (n = 3). The most common pre-operative endocrine deficits were hyperprolactinaemia and hypoadrenalism (at least one of which was identified in 4/6 patients; 66%). Thirty-three percent (2/6) of patients presented with diabetes insipidus. The most common post-operative endocrinological deficits were adrenocortical dysfunction (66%) and gonadotropin deficiency (66%). Visual assessments normalised in all six patients post-operatively. Gross total resection was achieved in all patients, and at median follow up of 33.5 months there were no cases of tumour recurrence.\ud \ud \ud Conclusions\ud \ud The prevalence of pituitary xanthogranulomas in our series is higher than that suggested in the literature. Surgery restored normal vision to all cases, however four patients (67%) required long-term hormonal replacement post-operatively. Imaging features such peripheral rim enhancement, a suprasellar tumour epicentre, and the absence of both calcification or cavernous sinus invasion were identified as potential indicators that together should alert clinicians to the possibility of pituitary xanthogranuloma when assessing patients with cystic sellar and parasellar tumours.

Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognized. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico-legal responsibilities of the prescriber and dispenser.

Key Clinical Message Pituitary apoplexy may cause xanthochromia and mimic the clinical presentation of subarachnoid hemorrhage.

In his first press conference as president on February 9, 2009, Mr. Obama attempted to justify continuing attacks by American Predator and Reaper unmanned aerial drones in Pakistan. These unprecede...

The United States government has a well‐documented history of launching and supporting dirty wars in countries that are under its influence. From the Philippines, Indonesia, and Vietnam to Uruguay,...

Hyponatraemia is defined as a serum sodium concentration below 135 mmol/l. It causes major diagnostic and management problems in practice. Hyponatraemic disorders are divided into euvolaemic, hypervolaemic and hypovolaemic. In the evaluation of the hyponatraemic patient, history taking should focus on identifying the potential cause, duration and symptomatology. Clinical examination should include assessment of volume status. Acute hyponatraemia of less than 48 h duration requires prompt correction. Treatment may involve hypertonic saline, isotonic saline and appropriate hormone replacement therapy depending on the aetiology. Chronic hyponatraemia should be treated with caution because of the risk of central pontine myelinolysis.

Background Alstrom syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well-recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. Materials and methods Fifteen subjects with AS (mean age 21 years, range 10–35) were studied and compared with age-, sex-, and blood pressure-matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid-femoral and carotid-radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. Results Comparing AS subjects vs. controls (mean ± SD), AIX was elevated in AS subjects (18 ± 9% vs. 3 ± 11%, P

Previously in Peace Review, I described in “From Nuremberg to Fallujah” how the war in Iraq constitutes aggression as it is defined under international law. At the time I was writing that report, d...

A version of this essay previously appeared in Online Journal 14(27) (www.onlinejournal.com) and in Z Magazine 18:2 (Feb. 2004).

In patients with cancer, adrenal enlargement due to either metastatic disease or diffuse non-metastatic hyperplasia is increasingly recognized with modern imaging techniques. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by non-suppressible hypercortisolism, has also been described in neoplasia in the absence of ectopic adrenocorticotrophic hormone (ACTH) production. In the majority of cases of malignancy-associated hypercortisolism, it might be expected that the presence of malignant disease would be clinically apparent, thus rendering a detailed endocrinological evaluation of the HPA axis unnecessary. However, in the present case we describe a patient with occult malignancy presenting with bilateral adrenocortical enlargement and non-suppressible hypercortisolism that was not due to the ectopic ACTH syndrome. There were no clinical Cushingoid features other than hypertension and new-onset diabetes mellitus. Detailed diagnostic investigations for the possibility of Cushing's syndrome were performed before the underlying diagnosis of gastric adenocarcinoma eventually became apparent. Characteristics and potential mechanisms of non-suppressible hypercortisolism in cancer are discussed. We believe that this scenario will occur with greater frequency in the future, given the increasing early use of sophisticated high-resolution imaging for the evaluation of suspected intra-abdominal pathology.

Summary objectives Untreated growth hormone deficiency (GHD) is implicated in the increased cardiovascular risk associated with adult hypopituitarism. Oxidative stress, predisposing to lipid peroxidation, may be an important mediator of endothelial dysfunction, a pro-atherogenic state associated with adult GHD. design and patients In a randomized, double-blind, placebo-controlled study we investigated the effects of GH replacement on low-density lipoprotein (LDL) oxidation and neutrophil superoxide (O2−) generating capacity in 32 GHD adults (19 males, 13 females; age range 19–64 years) over 3 months. Thirty age- and sex-matched healthy controls were also studied. measurements Lipid hydroperoxides (HPOs) in plasma were measured using the ferrous oxidation with xylenol orange (FOX) assay. The susceptibility of LDL to oxidation was assessed by the copper-catalysed lag phase of LDL oxidation. Neutrophil O2−generating capacity was assessed by a lucigenin-based chemiluminescent assay of NADPH oxidase activity. Body composition was assessed using bioelectrical impedance analysis. results Compared to controls, GHD subjects had higher LDL cholesterol (4·0 ± 0·8 vs. 3·5 ± 0·9 mmol/l, P

OBJECTIVE Cabergoline therapy normalizes prolactin levels and reduces the size of macroprolactinomas. However there are no data indicating whether cabergoline can normalize growth hormone secretion in patients who were growth hormone deficient at the time of diagnosis of a macroprolactinoma. SUBJECTS AND METHODS We studied nine patients with biochemical and radiological evidence of a macroprolactinoma who were also growth hormone deficient (peak growth hormone response to insulin-induced hypoglycaemia 10 mU/l) after cabergoline therapy. Those that remained growth hormone deficient after treatment were all panhypopituitary at baseline while those that recovered showed only partial anterior hypopituitarism. CONCLUSION These data indicate that growth hormone secretion may recover following successful reduction of prolactin levels after cabergoline therapy for a mean of 22 months (range 6–28 months) in most but not all subjects with a macroprolactinoma. It is therefore advisable that individuals with a macroprolactinoma in whom growth hormone replacement therapy is being considered undergo repeat assessment of growth hormone secretion following medical treatment.

OBJECTIVES Adult GH deficiency (GHD) is associated with profound alterations in body composition, lipid profiles and quality of life which frequently improve after GH therapy. However, the beneficial effects of treatment are not derived by all and consequently some scepticism persists with regard to the use of GH therapy in adults. We assessed whether a 3-month therapeutic assessment with GH therapy could be used to determine which GHD adults should be treated over the longer term. We also assessed the continued prescription of GH by general practitioners (GPs) following the initial therapeutic assessment. DESIGN A three month open therapeutic trial of GH in GHD adults. Patients were treated with GH at an initial dose of 0.01 iU/kg/d, increased after 1 month to 0.015 iU/kg/d for males and 0.02 iU/kg/d for females. After completion of the three months the continued prescription of GH by the GPs was assessed. PATIENTS All adult GHD patients were considered for GH therapy. Thirty-nine GHD adults wanted GH therapy (group 1) and their baseline characteristics such as age, duration of GHD, and IGF-1 concentration were compared with 24 subjects who declined to receive GH (group 2). MEASUREMENTS Measurements of body composition using bioelectrical impedance analysis, lipids and quality of life measured using a dedicated questionnaire were made before and after GH therapy. The response of the general practitioners to continued GH therapy after the initial therapeutic assessment was also noted. RESULTS Compared with subjects who declined GH therapy (group 2), subjects of group 1 were younger (46.4 ± 14.4 vs. 54.2 ± 15.7 years, P

A 42-year-old house wife presented with worsening headaches over 6 months in the absence of visual symptoms or symptoms suggestive of focal neurology. She was a life-long smoker. Systems review was unremarkable apart from secondary amenorrhoea and galactorrhoea of 6 months duration. Her serum prolactin was found to be 620 mU/l (60-400), FT4 12.6 nmol/l (9.8-23.1), TSH 1.38 mU/l (0.35-5.5), oestradiol < 73 pmol/l, LH and FSH of 4.4 and 12.6 mIU/l, respectively. She was on bromocriptine. A presumptive diagnosis of pneumonia, based on pyrexia and CXR findings, was made and she was started on IV antibiotics. Two days later she developed meningism and deterioration of conscious level. (Lumbar puncture results: no organisms, 312 neutrophils and 164 lymphocytes). CT scan revealed a 2.5-cm pituitary adenoma, with suprasellar extension. A repeat hormonal profile revealed FSH 1.4, LH < 0.3 mU/l, oestradiol < 73 pmol/l, prolactin 488 mU/l (60-400), and low random cortisol at 29 nmol/l. T1-weighted MRI revealed a large pituitary mass with evidence of haemorrhage. The patient subsequently underwent a transsphenoidal exploration with resection of the pituitary lesion. Whilst awaiting the histopathology results, CT of chest revealed a 1. 5-cm diameter rounded well defined density in the right lower lobe associated with hilar, pre- and right para-tracheal lymphadenopathy. The histopathology of the pituitary lesion, obtained piecemeal, revealed fragments of fibrous tissue infiltrated by sheets of acidophilic prolactin-positive cells, in keeping with a prolactinoma. In addition, other fragments with blood clot included highly atypical epithelial cells with mitotic figures. These were negative for prolactin but showed HMFG-and CEA-positivity, excluding them from a pituitary lineage. Transbronchial biopsy revealed moderately differentiated adenocarcinoma, with evidence of lymphatic spread. The overall conclusion was of bronchogenic adenocarcinoma, metastasizing to a prolactinoma and complicated by apoplexy.

OBJECTIVES Adult hypopituitarism with growth hormone deficiency (GHD) results in reduced exercise capacity, detrimental changes in body composition and lipid profiles and may be associated with an excess cardiovascular mortality. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes to the deposition of unstable atherosclerotic plaques. We have used a noninvasive method to assess endothelial function in the brachial arteries of a group of treated hypopituitary adults with GHD, and a group of healthy age-and sex-matched controls. PATIENTS Seventeen hypopituitary adults with GHD (13 male, 4 female) aged 26–54 years were studied. Each patient was receiving standard replacement therapy for all other hormonal deficiencies such that all target hormones were maintained in the normal reference range. All observations obtained were compared with those made in age- and sex-matched control subjects. All study subjects had no identifiable risk factors for endothelial dysfunction. MEASUREMENTS Using an ultrasound vessel wall tracking system, the diameter of the left brachial artery was measured at rest, in response to reactive hyperaemia (endothelium-dependent dilation) and following sublingual glyceryl trinitrate (GTN) (endothelium-independent vasodilatation). We also measured fasting lipids, insulin, plasma glucose, glycated haemoglobin (HbA1c) and IGF-1, and studied the relationship of these parameters to endothelial function. RESULTS Flow mediated endothelium-dependent dilatation (FMD), expressed as a percentage change from resting base-line diameter, was significantly impaired in the GHD group (3.70 ± 2.36% vs. 7.30 ± 2.42%, P

OBJECTIVE We have investigated plasma potassium changes during insulin-induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis. DESIGN Hypoglycaemia was induced through the administration of intravenous soluble insulin (0.1 U/Kg, IV). SUBJECTS 23 consecutive adult patients undergoing routine biochemical evaluation for hypopituitarism. MEASUREMENTS GH, cortisol glucose, sodium and potassium levels were measured at 0, 30, 60, 90 and 120 min after insulin administration. Pituitary function was also assessed through measurement of TSH, thyroid hormones, LH/FSH, testosterone and 17-oestradiol. IGF-I concentrations were also analysed. RESULTS All patients achieved adequate hypoglycaemia (nadir glucose

Although two thirds or more of patients with microprolactinoma achieve normal serum prolactin levels over the long term after withdrawal of dopamine agonist therapy, there is no agreement on the appropriate duration of treatment, and treatment is not always interrupted. In this retrospective analysis of 89 patients, 84 women and 5 men with a mean age of 33 years, remissions were analyzed in 67 patients treated with 0.5 to 3 mg cabergoline weekly and 22 others given 2.5 to 10 mg bromocriptine daily. The mean duration of therapy was 3.1 years, and patients were followed for at least 1 year after treatment ended. None of the patients received medication other than a dopamine agonist. Seven women discontinued treatment when they became pregnant. All patients were symptomatic and hyperprolactinemic when first seen. Among 57 patients (64%) who had a recurrence after treatment stopped were 46 (81%) who had recurrent symptomatic hyperprolactinemia within 12 months after stopping treatment. The average interval was 9.6 months. Thirty-two patients, 36% of the total, achieved remission after at least 1 year of follow up; the mean duration of remission was 3.6 years. Nearly 85% of these patients remained in remission for longer than 2 years. Four of them were asymptomatic despite being hyperprolactinemic. The 2 dopamine agonists were equally effective. The overall median duration before relapse after discontinuance of treatment was 12 months. Logistic regression analysis failed to demonstrate an association between the risk of recurrence and age at presentation, imaging of an adenoma, or the duration of treatment. When dopamine agonist therapy is abruptly withdrawn after 2 years or longer in patients with microprolactinoma, 30% to 40% achieve long-term remission without side effects. Because symptomatic hyperprolactinemia may develop more than 1 year after treatment stops, long-term follow up is essential.

Covalent linkage of the A chain of ricin to the LICR-LOND-Fib75 monoclonal antibody produced an immunotoxin, Fib75-SS-ricin A, which demonstrated immunospecific toxicity to human bladder carcinoma cells in tissue culture (Forrester et al., 1984). The present studies have shown that ricin B chain potentiates the toxicity of the immunotoxin by two orders of magnitude and also significantly increases the rate of protein synthesis inhibition. Using immunoelectron microscopy, the receptor-mediated endocytosis and intracellular routing of the immunotoxin was studied with and without ricin B chain treatment after immunolocalisation of the conjugate. Fib75-SS-ricin A was internalised by the EJ cells predominantly in uncoated pits and vesicles and directed to the endosomes. Some degradation of the complex appeared to take place in multivesicular endosomes at early timepoints and 24 h after internalisation, most of the immunotoxin was found in lysosomes. Some ricin A chain epitopes were detected in Golgi vesicles. Cells treated with immunotoxin and ricin B chain endocytosed the complex predominantly in coated pits and coated vesicles. Using pre-embedding immunoperoxidase techniques, ricin chains were found in the whole Golgi complex and most of the conjugate escaped lysosomal degradation. Internalised immunotoxin was recycled back to the plasma membrane in an active form associated with vesicles which appeared to be derived predominantly from multivesicular endosomes. A similar mode of recycling has recently been reported (McIntosh et al., 1990) for ricin holotoxin in the same cell line. These observations may explain the potentiating effect of toxin B chains in the antibody-directed targeting of toxin A chains. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 8 Figure 9

Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well-recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS.Fifteen subjects with AS (mean age 21 years, range 10-35) were studied and compared with age-, sex-, and blood pressure-matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid-femoral and carotid-radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured.Comparing AS subjects vs. controls (mean +/- SD), AIX was elevated in AS subjects (18 +/- 9% vs. 3 +/- 11%, P0.0001). No significant changes in brachial PWV (8.1 +/- 1.3 m s(-1) vs. 7.3 +/- 1.1 m s(-1), P = 0.14) or aortic PWV (6.5 +/- 1.1 m s(-1) vs. 6.0 +/- 1.0 m s(-1), P = 0.26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters.In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.

We describe the case of a 30-year-old female patient with a 7-year history of multiple sclerosis, who presented with an 18-month history of secondary amenorrhoea and vague symptoms which included poor sleep and impaired concentration. Endocrine investigations revealed hypogonadotrophic hypogonadism and GH deficiency, a probable consequence of a hypothalamic plaque. This is the first report of hypogonadotrophic hypogonadism and GH deficiency occurring in conjunction with multiple sclerosis. As such, it should raise suspicion of endocrine dysfunction occurring in a condition with such a vast spectrum of disability as multiple sclerosis.

The purpose of the present study was to identify the effect of treatment with recombinant human growth hormone (rhGH) on seven somatic characteristics and eight clinical cardiovascular risk factors. Twenty-seven male and 24 female patients between the ages of 21 and 60 years were examined. The investigation was a double-blind, placebo-controlled study of 12 months duration. Patients were assigned randomly to treatment (T) and placebo (P) groups. In the first 6 months group T received rhGH and group P placebo. In the second 6 months both groups received rhGH. Complete data were available for 23 males and 20 females. Increments were calculated between 6 months -BL (increment 1) and 12-6 months (increment 2) in both T and P groups. Apart from the somatotype, data were analysed with a 2 x 2 mixed analysis of variance (ANOVA) using treatment (rhGH and placebo) and time (increments 1 and 2). Somatotype data were analysed using a 2 x 3 multivariate ANOVA. Three significant interactions were identified in males: waist circumference (P = 0.006), trunk fat (P = 0.0001), and conicity index (P = 0.001). The only significant interaction in females was trunk fat (P = 0.006). In general, treatment and placebo groups responded differently by time and treatment. Responses were similar in males and females. In the first 6 months when group P was on placebo, waist circumference, trunk fat, and conicity index increased slightly; with group T on rhGH somatic variables declined markedly. In the second 6 months when both groups received rhGH there was a marked decline in group P and a continued decline (but less steeply) in group T. In males there were significant decreases in endomorphy in group T and increases in mesomorphy in group P. In females the somatotype remained stable. There were no significant interactions in clinical cardiovascular risk factors in either males or females. Favourable responses occurred in male and female lipid profiles, although these were not significant. It was concluded that in males waist circumference, trunk fat, conicity index, and somatotype responded significantly to treatment with rhGH; in females the only significant response was trunk fat.

Insulin therapy may influence cardiovascular disease (CVD) and lipid metabolism in type 2 diabetes (T2D). Exaggerated postprandial lipaemia (PPL) is a feature of diabetic dyslipidaemia affecting CVD via enhanced oxidative stress (OS) and endothelial dysfunction. We assessed endothelial function and OS during PPL following insulin and vitamin C. Twenty (17 M) T2D patients were studied (mean Hba1c 8.4%) at baseline, following 6 weeks of insulin lispro (0.2 Iu kg-1) and vitamin C 1-g daily. Eight-h lipid and glucose profiles were measured following a fatty meal. Endothelial function (flow-mediated vasodilatation: FMD) and OS were measured at fasting, 4 h and 8 h.Glucose, body mass index, and total and LDL cholesterol remained unchanged. FMD improved. Placebo group: fasting, 1.1 +/- 1.2 to 4.2 +/- 1.1% (P0.001); 4-h, 0.3 +/- 1.2 to 3.1 +/- 0.9% (P0.01); 8-h, 0.7 +/- 1.1 to 3.76 +/- 1.1% (P0.001). Vitamin C group: fasting, 0.9 +/- 1.1 to 6.1 +/- 1.3% (P0.001); 4-h, 0.7 +/- 1.5 to 4.9 +/- 2.1% (P0.001); 8-h, 0.8 +/- 0.9 to 5.8 +/- 0.6% (P0.01). Post-prandial lipaemia was attenuated: TG area-under-curve (mmol L-1 8 h-1), 52.6 +/- 11 to 39.1 +/- 12.5 (placebo group), P0.02; and 56.9 +/- 8 to 40.1 +/- 10.3 (vitamin C group), P0.02. Oxidative stress was reduced, with greater changes in the vitamin C group.Insulin may thus exert vascular benefits in T2D, by modifying fasting and postprandial lipid metabolism resulting in reduced OS and improved EF. Vitamin C therapy may augment the vascular benefits of insulin in T2D through additional effects on OS and EF.

Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening.In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied.Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured.At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P0.05) and between FMD and the augmentation index (r = - 0.58, P0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P0.01). There were no significant changes in the placebo group.Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.

Cabergoline therapy normalizes prolactin levels and reduces the size of macroprolactinomas. However there are no data indicating whether cabergoline can normalize growth hormone secretion in patients who were growth hormone deficient at the time of diagnosis of a macroprolactinoma.We studied nine patients with biochemical and radiological evidence of a macroprolactinoma who were also growth hormone deficient (peak growth hormone response to insulin-induced hypoglycaemia10 mU/l). Patients were assessed before and after cabergoline therapy to assess their growth hormone secretory status, IGF-I levels, cortisol response and change in tumour size.Treatment with cabergoline was associated with a significant reduction in prolactin concentration (74341 +/- 31939 mU/l vs. 265.9 +/- 86.3, P = 0.009). The mean change in peak growth hormone response to insulin-induced hypoglycaemia was significantly greater following cabergoline therapy compared with pretreatment levels (33.5 +/- 11.8 mU/l vs. 4. 34 +/- 1.21 mU/l, P = 0.022). However IGF-I levels were not different after treatment when compared with baseline although a nonsignificant trend towards improvement was noted (24.2 +/- 3.97 nmol/l vs. 18.4 +/- 4.94 nmol/l, P = 0.058). The mean peak cortisol concentration was 407.7 +/- 64.1 nmol/l before treatment with a nonsignificant rise to 477.4 +/- 84.8 nmol/l, P = 0.813 after treatment. These changes were associated with a significant reduction in mean maximal tumour diameter (21.2 +/- 2.9 mm vs. 29.1 +/- 2.8 mm, P = 0.009). There was no significant difference in either prolactin concentration or tumour size pre- or post-treatment between those who recovered growth hormone secretion and those that did not. Six of the nine (67%) patients recovered a normal growth hormone response (10 mU/l) after cabergoline therapy. Those that remained growth hormone deficient after treatment were all panhypopituitary at baseline while those that recovered showed only partial anterior hypopituitarism.These data indicate that growth hormone secretion may recover following successful reduction of prolactin levels after cabergoline therapy for a mean of 22 months (range 6-28 months) in most but not all subjects with a macroprolactinoma. It is therefore advisable that individuals with a macroprolactinoma in whom growth hormone replacement therapy is being considered undergo repeat assessment of growth hormone secretion following medical treatment.

Adult GH deficiency (GHD) is associated with profound alterations in body composition, lipid profiles and quality of life which frequently improve after GH therapy. However, the beneficial effects of treatment are not derived by all and consequently some scepticism persists with regard to the use of GH therapy in adults. We assessed whether a 3-month therapeutic assessment with GH therapy could be used to determine which GHD adults should be treated over the longer term. We also assessed the continued prescription of GH by general practitioners (GPs) following the initial therapeutic assessment.A three month open therapeutic trial of GH in GHD adults. Patients were treated with GH at an initial dose of 0.01 iU/kg/d, increased after 1 month to 0.015 iU/kg/d for males and 0.02 iU/kg/d for females. After completion of the three months the continued prescription of GH by the GPs was assessed.All adult GHD patients were considered for GH therapy. Thirty-nine GHD adults wanted GH therapy (group 1) and their baseline characteristics such as age, duration of GHD, and IGF-1 concentration were compared with 24 subjects who declined to receive GH (group 2).Measurements of body composition using bioelectrical impedance analysis, lipids and quality of life measured using a dedicated questionnaire were made before and after GH therapy. The response of the general practitioners to continued GH therapy after the initial therapeutic assessment was also noted.Compared with subjects who declined GH therapy (group 2), subjects of group 1 were younger (46.4 +/- 14.4 vs. 54.2 +/- 15.7 years, P0.05) and had lower peak GH responses to provocative testing (1.4 +/- 2.1 vs. 2.9 +/- 2.7 mU/l, P0.001), though there were no differences between IGF-1 concentration (11.7 +/- 6.2 vs. 14. 2 +/- 7.9 nmol/l). Following three months of GH therapy, there were significant improvements in all measured parameters including increased free fat mass (50.2 vs. 52.4 kg, P0.005) and total body water (37 vs. 38.7 l, P0.005), reduced fat mass (31.6 vs. 29.8 kg, P0.005), reduced AGHDA score (7 vs. 4, P0.001) and reduced cholesterol (6.3 vs. 5.8 mmol/l, P0.001), LDL (4 vs. 3.33 mmol/l, P0.001) and cholesterol/HDL ratio (5.57 vs. 4.67, P0.001). IGF-1 concentrations were significantly increased following treatment (12 vs. 32.4 nmol/l). Six subjects decided to discontinue GH therapy, 2 before the end of the study due to potential drug-related side-effects and 4 subjects derived no benefit from treatment. Despite the demonstrable benefits of treatment for the remaining 33 GHD adults, 6 GPs refused to continue to prescribe GH therapy for reasons of lack of familiarity with the drug or advice from their health authority.Patients who wanted GH therapy were usually younger and more severely GHD than counterparts who elect not to be treated. However, a therapeutic trial of GH therapy is required to distinguish those subjects who derive benefit from treatment. We have shown that three months of low dose GH therapy is a sufficient period to elicit significant beneficial responses in quality of life, body composition parameters and lipids for the majority of patients and appears to be a sufficient period for patients to decide whether they want longer term therapy. The initial therapeutic trial also provides the objective evidence for the general practitioners to decide upon the continued prescription of therapy. Despite the positive evidence provided by this study, a small minority of general practitioners still refuse to prescribe GH therapy.

Adult hypopituitarism with growth hormone deficiency (GHD) results in reduced exercise capacity, detrimental changes in body composition and lipid profiles and may be associated with an excess cardiovascular mortality. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes to the deposition of unstable atherosclerotic plaques. We have used a noninvasive method to assess endothelial function in the brachial arteries of a group of treated hypopituitary adults with GHD, and a group of healthy age- and sex-matched controls.Seventeen hypopituitary adults with GHD (13 male, 4 female) aged 26-54 years were studied. Each patient was receiving standard replacement therapy for all other hormonal deficiencies such that all target hormones were maintained in the normal reference range. All observations obtained were compared with those made in age- and sex-matched control subjects. All study subjects had no identifiable risk factors for endothelial dysfunction.Using an ultrasound vessel wall tracking system, the diameter of the left brachial artery was measured at rest, in response to reactive hyperaemia (endothelium-dependent dilation) and following sublingual glyceryl trinitrate (GTN) (endothelium-independent vasodilatation). We also measured fasting lipids, insulin, plasma glucose, glycated haemoglobin (HbA1c) and IGF-1, and studied the relationship of these parameters to endothelial function.Flow mediated endothelium-dependent dilatation (FMD), expressed as a percentage change from resting base-line diameter, was significantly impaired in the GHD group (3.70 +/- 2.36% vs. 7.30 +/- 2.42%, P0.001). In contrast, GTN-mediated dilatation was similar in both groups. There were no differences in total cholesterol, HDL cholesterol, LDL cholesterol or plasma triglyceride between the groups. Both fasting insulin (27.1 +/- 18.1 vs. 15.89 +/- 6.65 mU/l, P0.05) and glycated haemoglobin (HbA1c) levels (5.29 +/- 0.43 vs. 4.91 +/- 0.43%, P0.05) were significantly higher in the GHD group. FMD in both groups showed an inverse relationship with total cholesterol (r = -0.58, P0.05, GHD and r = -0.55, P0.05 controls). However, in the GHD subjects, there was a strong inverse relationship between FMD and LDL-cholesterol (r = -0.81, P0.0001). No other relationships were noted between FMD and any other metabolic parameters, or characteristics of GHD.Endothelial dysfunction is present in GH deficient adults prior to the onset of overt atherosclerotic disease. The similar glucose yet elevated fasting insulin levels imply a state of relative insulin insensitivity. The strong inverse correlation between endothelial dysfunction and LDL-cholesterol suggests a possible aetiological role for LDL-cholesterol in the pathogenesis of any excess cardiovascular risk associated with adult hypopituitarism.

In diseases characterised by abundant T-cell mitotic activity, large-scale release of paracrine hormones from activated T cells may have adverse consequences including malignant change in bystander cells and gross physiological disturbances.

The present investigation examined changes in strength in growth hormone deficient (GHD) adults following treatment with recombinant human growth hormone (rhGH), and assessed their relationship to changes in fat-free mass (FFM), total body potassium (TBK), total body water (TBW), the concentration of TBK and TBW per kg FFM, and insulin like growth factor-1 (IGF-1). The investigation was double-blind and placebo-controlled for a period of 6 months; this was followed by a period of open treatment for a further 6 months. Patients were assigned randomly to experimental (E) and control (C) groups. In the first 6 months group E received rhGH and group C placebo; in the second 6 months both groups received rhGH. Serial data were analysed for 23 males (11 group E, 12 group C) and 20 females (10 group E, 10 group C). Body composition was assessed by dual energy X-ray absorptiometry, TBK and TBW. Muscle strength was recorded for arm flexion, leg extension and hand grip. Significant increases in FFM occurred in the first 6 months in group E (2.3 kg males, 1.4 kg females) and in the second 6 months in group C (2.4 kg males, 1.4 kg females). There was a modest increase in absolute strength with time, although only three increments were significant (knee extension in group E males and arm flexion in groups E and C females), all of which occurred during the 6-12 month period. Allometric scaling did not improve the identification of significant increments of strength. The mean concentrations of TBK (males 57.0-58.6, females 51.4-53.9 mmol) and TBW (males 0.65-0.69, females 0.65-0.68 l) per kg FFM, were significantly smaller at all stages of the trial than the reference values, suggesting that treatment had not fully normalized these variables. Likewise, the relationship between most of the increments of regional and total strength, and the corresponding increments of FFM, were generally poor and not significant. It was concluded that the reduced concentrations of TBK and TBW per kg FFM, which may be the effect of an inappropriate dose regime or mode of delivery, may, in part, contribute to the anomaly between increases in strength and FFM.

We have investigated plasma potassium changes during insulin-induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis.Hypoglycaemia was induced through the administration of intravenous soluble insulin (0.1 U/Kg, i.v.).23 consecutive adult patients undergoing routine biochemical evaluation for hypopituitarism.GH, cortisol glucose, sodium and potassium levels were measured at 0, 30, 60, 90 and 120 min after insulin administration. Pituitary function was also assessed through measurement of TSH, thyroid hormones, LH/FSH, testosterone and 17-oestradiol. IGF-I concentrations were also analysed.All patients achieved adequate hypoglycaemia (nadir glucose2 mmol/l). 15 patients had GHD (peak GH10 mU/l) either in isolation or as part of a spectrum of pituitary hormone deficiencies. The remaining 8 patients had normal pituitary function. Plasma potassium concentrations (mean +/- SEM) fell from 3.8 +/- 0.3 mmol/l (normals) and 3.8 +/- 0.2 mmol/l (GHDs) to nadir concentrations of 3.0 +/- 0.2 mmol/l and 3.1 +/- 0.3 mmol/l, respectively (P0.005). Overt hypokalaemia (3.5 mmol/l) occurred in 13/15 GHDs and all normals. There were no significant differences between the groups.Insulin-induced hypoglycaemia causes similar degrees of significant hypokalaemia in patients with normal pituitary function and in those with GH deficiency, either alone or in combination with other pituitary hormone deficiencies. Therefore, insulin-induced hypoglycaemia does not appear to be associated with any greater risk of hypokalaemia in hypopituitary adults with GHD compared to those with normal anterior pituitary function.

Lesson of the week: Hypopituitarism after coronary artery bypass grafting▲ {#article-title-2} Hypopituitarism may develop secondary to pituitary infarction after coronary artery bypass grafting Pituitary infarction may present in many different ways ranging from the entirely silent to the florid neuro-ophthalmological features of apoplexy.1 It may occur in a normal or an adenomatous pituitary and may be precipitated by haemodynamic changes.1 We present two cases of panhypopituitarism which developed insidiously as a result of pituitary infarction which occurred during coronary artery bypass grafting. A 57 year old man was referred to our endocrine unit because of impotence and reduced libido. Twenty months earlier he had undergone coronary artery bypass grafting. Before surgery he had had normal potency, but erectile dysfunction and reduced libido occurred immediately after. Three months before surgery he had complained of tiredness; his concentration of free thyroxine was 3 pmol/l and thyroid stimulating hormone was 50 mU/l. Primary hypothyroidism was diagnosed. He was treated with thyroxine, which led to clinical improvement and normalisation of thyroid function before surgery. Coronary artery bypass grafting was performed after investigation of exertional chest pain which occurred after myocardial infarction. It was an uncomplicated procedure; the left internal mammary artery was grafted to the left anterior descending artery and the saphenous vein was grafted to the obtuse marginal artery. Recovery immediately after surgery was uneventful and the patient was discharged on the ninth day after surgery despite plasma concentrations of sodium having fallen from a normal preoperative value to 125 mmol/l (normal range 133 to 144 mmol/l). He was readmitted 1 week later with nausea, weakness, a mild fever of 37.5°C, and severe hyponatraemia (plasma sodium concentration 114 mmol/l) (table 1). Urea and potassium concentrations were normal. The results of a full blood count were normal and blood cultures were negative. View this table: Table 1 Results of endocrine tests on two patients who developed hyponatraemia after …

Ethane oxidation was studied in ethane-grown resting cells (mycelia) of an Acremonium sp. and in cell-free preparations of such mycelia. From resting cell experiments evidence was found for a pathway of ethane oxidation via ethanol, acetaldehyde, and acetic acid. In vitro studies indicated that ethane-oxidizing activity in such mycelia occurred predominantly in the microsomal fraction of crude homogenates. Microsomal preparations were inactive in the absence of added coenzyme. Marked stimulation of activity was obtained in such preparations with reduced nicotinamide adenine dinucleotide phosphate and to a much lesser degree with nicotinamide adenine dinucleotide phosphate. Ethane oxidation was inhibited by sodium azide and carbon monoxide.

CBA/H and CBA/HT6T6 radiation chimeras were prepared by lethal irradiation and subsequent reconstitution with bone marrow of the host karyotype and thymocytes of the opposite karyotype. After T- and B-cell chimerism had been established, the animals were inoculated with SEW A or TA3Ha ascites tumor. Tumor-donor cell hybrids were isolated following the explantation of TA3Ha tumor in selective HAT medium and by selecting for adherent cells from SEWA. The T6T6 chromosomal marker served to distinguish between the type of cell involved in the fusion. In all hybrids the donor component was a nonthymus-derived cell.

The repopulation of the thymus was studied in mice after a potentially lethal dose of irradiation and injection of different numbers of syngeneic but chromosomally distinguishable bone marrow cells. The more bone marrow cells were injected, the earlier was the changeover from dividing host cells to dividing donor cells observed. At both 30 and 60 days after irradiation, the number of donor-derived T cells in the peripheral blood responding to phytohemagglutinin was directly proportional to the number of donor bone marrow cells injected, but the number of host-derived T cells was inversely proportional. Experiments in which mistures of two syngeneic chromosomally distinguishable haematopoietic cell populations were injected after irradiation suggested that relatively small numbers of haematopoietic cells can be responsible for repopulating a single femur. Analysis of the thymus showed that the dividing cell populations within the thymus can also derive from very few precursor cells, possibly as few as one or two.

An account is presented of unsuccessful attempts to cure the NK/Ly ascites tumor in mice by doses of Degranol or irradiation which, had they not been followed by syngeneic marrow therapy, would have proved lethal as a consequence of hematopoietic failure. Reasons for the lack of success are discussed and it is concluded that even the high doses of anti-tumor agents given were insufficient to eradicate the tumor and that the treated animals died before the controls because a virus or viruslike entity associated with the tumor seriously impeded hematopoietic recovery. (auth)

The capacities of cells of thymus and bone marrow origin taken from radiation chimaeras to produce antibody during a secondary immune response have been tested in an in vivo transfer system. Although it could be shown that thymus-derived cells respond vigorously by mitosis to antigenic stimulation they were not capable of antibody production. By contrast bone marrow-derived cells did not in the first 3 days respond mitotically to antigenic stimulation but they were capable of limited antibody production. Most antibody was found when both cell populations were allowed to react to antigenic stimulation.

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Thymus-deprived mice are unable to react with eosinophilia to an appropriate stimulus, but their ability to mount a neutrophil leucocytosis in response to pyogenic infection is unimpaired. It appears that thymus-processed lymphocytes are required for induction of eosinophil but not of neutrophil leucocytosis.

Thymus-deprived and normal DBA/2 mice show no difference in the immune response to bacteriophage fd, an antigen for which these mice are low responders. Thymectomy in high responders reduces the response 100–1000-fold. The immune response to SRBC in the deprived and normal DBA/2 has also been tested. The drastically reduced response in deprived mice shows that these animals indeed lack thymic influence. Low responder DBA/2 mice have a weak primary and secondary response to the phage fd. They largely produce IgM, but in spite of that, they are able to build up an immunological memory. The data suggest that the inability of DBA/2 mice to respond well to fd is a thymus deficiency. This observation is supported by the finding that polyacrylic acid converts low responder DBA/2 mice to high responders. Genetically thymusless (nude) C57BL/6-nu/nu mice are low responders, but, in contrast to DBA/2, are unable to form an immunological memory. The secondary response is identical in height and rate with a primary response.