Sami Medbak

Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure

OBJECTIVE Previous studies of surgical treatment for acromegaly have used varied criteria for ‘cure’, but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer‐term outcome for patients not offered further treatment when post‐operative levels of GH < 5 mU/l were achieved.

Blunted adrenocorticotropin and Cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome

Hyperfunctioning of the pituitary‐adrenal axis has been suggested as the pathophysiological basis for chronic fatigue syndrome (CFS). Blunted adrenocorticotropin (ACTH) responses but normal Cortisol responses to exogenous corticotropin‐releasing hormone (CRH), the main regulator of this axis, have been previously demonstrated in CFS patients, some of whom had a comorbid psychiatric disorder. We wished to re‐examine CRH activation of this axis in CFS patients free from concurrent psychiatric illness. A sample of 14 patients with CDC‐diagnosed CFS were compared with 14 healthy volunteers. ACTH and Cortisol responses were measured following the administration of 100 μg ovine CRH. Basal ACTH and Cortisol values did not differ between the two groups. The release of ACTH was significantly attenuated in the CFS group (P<0.005), as was the release of Cortisol (P<0.05). The blunted response of ACTH to exogenous CRH stimulation may be due to an abnormality in CRH levels with a resultant alteration in pituitary CRH receptor sensitivity, or it may reflect a dysregulation of vasopressin or other factors involved in HPA regulation. A diminished output of neurotrophic ACTH, causing a reduced adrenocortical secretory reserve, inadequately compensated for by adrenoceptor upregulation, may explain the reduced Cortisol production demonstrated in this study.

Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome

OBJECTIVE Cushings syndrome In childhood and adolescence Is rare. We analysed the clinical presentation, Investigation, management and therapeutic outcome In 12 paediatric patients with Cushings syndrome.

The low dose ACTH test in chronic fatigue syndrome and in health

A number of dynamic tests of the hypothalamic–pituitary–adrenal axis provide evidence for a mild cen_tral adrenal insufficiency in chronic fatigue syndrome (CFS). The 1 μg adrenocorticotropin (ACTH) test has been proposed to be more sensitive than the standard 250 μg ACTH test in the detection of subtle pituitary–adrenal hypofunctioning. We aimed to establish whether the 1 μg ACTH test would support such a dysregulation in CFS, and also, given the relative novelty of this test in clinical practice and the uncertainty with regard to appropriate cut‐off values for normality, to compare our healthy volunteer data with those of previous studies.

Administration of human recombinant insulin-like growth factor-I in critically ill patients

OBJECTIVES To study the pharmacokinetics of a single subcutaneous dose of recombinant human insulin-like growth factor-I (IGF-I) in patients with systemic inflammatory response syndrome in the intensive care unit (ICU). To evaluate the effects of exogenous recombinant human IGF-I on circulating concentrations of IGF-I binding protein-1 (IGFBP-1), IGF-I binding protein-3 (IGFBP-3), and growth hormone in the critically ill patient; to assess the safety of the subcutaneous administration of 40 microg/kg of recombinant human IGF-I in these patients; and to investigate any effect this dose might have on nitrogen balance, creatinine clearance, and serum electrolyte and lipid concentrations. DESIGN Open-labeled, noncontrolled, prospective, single-dose study of eight fully evaluable ICU patients with systemic inflammatory response syndrome. SETTING ICUs in a teaching hospital and a linked district general hospital in England. PATIENTS Nine patients were examined, eight of whom were fully evaluable. INTERVENTIONS Subcutaneous administration of 40 microg/kg of recombinant human IGF-I. MEASUREMENTS AND MAIN RESULTS Blood samples were taken 24 hrs before the subcutaneous injection of 40 microg/kg of recombinant human IGF-I, and for 48 hrs thereafter. Urine was collected throughout this period. Serum concentrations of IGF-I, IGFBP-1, IGFBP-3, growth hormone, and insulin were measured by radioimmunoassay. IGF-I concentrations (median and range) increased significantly above baseline values (35 ng/mL [20 to 144]) from 15 mins (p < .02) until 10 hrs (p < .02) after injection of recombinant human IGF-I. Peak IGF-I concentrations were sustained from 2 hrs (90.5 ng/mL [23 to 228]) to 5 hrs (88.5 ng/mL [29 to 300]). By 24 hrs, circulating IGF-I concentrations had returned to baseline values. Baseline IGF-I concentrations were extremely low, and although peak values were three times greater, these values only approached the fifth percentile of defined reference ranges for normal values. Compared with values in less seriously ill patients, maximum IGF-I concentrations were reached earlier, the elimination half-life was shorter, clearance was more rapid, and the apparent volume of distribution was similar. IGFBP-3 concentrations also increased after recombinant human IGF-I injection, and at 3 to 4 hrs were significantly elevated, from 30 mins (p = .04) to 8 hrs (p = .04). There was marked between-patient variability in changes in circulating IGF-I, and IGFBP-1, and IGFBP-3 concentrations. More severely ill patients had the lowest circulating IGF-I concentrations and the least response to exogenous recombinant human IGF-I. Elevated baseline circulating growth hormone concentrations (2.3 ng/mL, range 0.8 to 4 [5.1 mU/L, 1.5 to 8]) were significantly depressed from 4 hrs (0.5 ng/mL, 0.5 to 1.5 [1 mU/L, 1 to 3], p = .01) to 6 hrs (0.8 ng/mL, 0.5 to 4 [1.5 mU/L, 1 to 8], p = .02) after recombinant human IGF-I administration. CONCLUSION We observed no adverse effects (e.g., hypoglycemia) that could be attributed to recombinant human IGF-I therapy.

The effect of naloxone on adrenocorticotropin and cortisol release: evidence for a reduced response in depression

BACKGROUND Endogenous opioid peptides inhibit the hypothalamic-pituitary-adrenal (HPA) axis by influencing the release of hypothalamic corticotropin releasing factors. This study examines whether increased activity of the HPA axis in major depression is associated with reduced opioid tone. METHODS We measured the adrenocorticotropin (ACTH) and cortisol responses to an intravenous bolus of naloxone 0.125 microg/kg in 13 depressed outpatients and 13 healthy volunteers. RESULTS The mean cortisol response was significantly reduced (P<0.05), and the ACTH response was also non-significantly reduced in the depressed subjects. CONCLUSIONS These findings imply that the degree of inhibitory endogenous opioid tone is reduced in depression. Various mechanisms for the finding are discussed, including possible alteration in the function of alpha-adrenergic pathways. CLINICAL IMPLICATIONS Reduced endogenous opioid tone may explain why some depressed individuals self-medicate with opiates, and depression is associated with opiate withdrawal. Opioid pathways may have a role in the mechanism of action of antidepressant drugs, and may be of relevance in the development of novel antidepressants. LIMITATIONS OF THE STUDY The sample size was small, leading to a failure of the difference of the basal cortisol levels and also the delta ACTH between the groups to reach statistical significance.

ACTH and cortisol release following intravenous desmopressin: a dose–response study

Desmopressin (DDAVP) is a synthetic analogue of AVP, the companion regulator of corticotrophin‐releasing hormone (CRH) in the control of ACTH synthesis and release from the pituitary corticotrophs. The body of evidence from human studies suggests that DDAVP alone, unlike AVP, does not bring about ACTH release, although recent evidence suggests idiosyncracies of response in healthy subjects. We examined whether DDAVP exerted any consistent effect on ACTH and cortisol release, and also if this occurred in a dose‐dependant manner.

Naloxone-mediated activation of the hypothalamic–pituitary–adrenal axis in chronic fatigue syndrome

BACKGROUND Opioidergic pathways have an inhibitory regulatory influence on the hypothalamic-pituitary-adrenal axis (HPA) in man. Previous studies have suggested impairment of pituitary-adrenal activation in chronic fatigue syndrome (CFS). We, therefore, decided to investigate the extent of opioid inhibition of HPA activity in CFS as a possible explanation for the reputed HPA hypofunctioning in patients with CFS. METHOD Thirteen patients with CFS, diagnosed according to CDC criteria, were compared with thirteen healthy subjects. Adrenocorticotropin (ACTH) and cortisol (CORT) responses were measured following the administration of the opiate antagonist naloxone. RESULTS Baseline ACTH and cortisol levels did not differ between the two groups. The release of ACTH (but not cortisol) was significantly blunted in the CFS subjects compared with controls. CONCLUSIONS Naloxone mediated activation of the HPA is attenuated in CFS. Excessive opioid inhibition of the HPA is thus an unlikely explanation for the HPA dysregulation in this disorder.

RESPONSE OF CIRCULATING SOMATOSTATIN, INSULIN, GASTRIN AND GIP, TO INTRADUODENAL INFUSION OF NUTRIENTS IN NORMAL MAN

We have studied the effect of direct infusion of nutrients into the duodenum of normal subjects on circulating plasma somatostatin, insulin, gastrin and gastric inhibitory polypeptide (GIP) levels. Six normal subjects were given on four separate occasions 150 ml of isotonic solutions containing 100 calories of carbohydrate, protein, or fat, and a control solution of saline, by infusion into the second part of the duodenum. Plasma somatostatin rose slightly after carbohydrate, mean basal 30 ± 3 pg/ml, peak 46±16 pg/ml at 15 min; and more markedly after protein, peak 57 ± 9 pg/ml at 30 min. However, fat was the most potent intraduodenal stimulus to plasma somatostatin release into circulation, peak 101 ± 11 pg/ml at 30 min. The plasma insulin rise was greatest after carbohydrate, peak 68 ± 10 i.u., but there was a significant rise after protein also, peak 34 ±6 i.u. Plasma gastrin rose significantly after protein only, peak 70 ± 22 pg/ml. Plasma GIP rose markedly after carbohydrate, basal 506 ± 50 pg/ml, peak 1480 ± 120 pg/ml. Protein was also a potent stimulus of circulating plasma GIP release, peak 1200 ± 190 pg/ml, while fat was the least potent, peak 730±190 pg/ml. Thus, calorie for calorie, fat is the most potent intraduodenal nutrient stimulus of circulating somatostatin. We postulate therefore that somatostatin may be an enterogastrone–a circulating hormone released by intraduodenal fat which inhibits gastric acid secretion. Fat is the least potent intraduodenal nutrient stimulus of circulating GIP release. This is evidence against the hypothesis that circulating GIP acts as an enterogastrone.

IMMUNOREACTIVE SOMATOSTATIN CHANGES DURING INSULIN‐INDUCED HYPOGLYCAEMIA AND OPERATIVE STRESS IN MAN

Little is currently known about the factors controlling somatostatin secretion. A radioimmunoassay has been developed that is sufficiently specific and sensitive to be used for physiological studies of circulating levels in man. During insulin‐induced hypoglycaemia a rise in plasma somatostatin was seen in each of ten subjects studied. Although this paralleled the rise in circulating glucagon and growth hormone, no individual relationships were found either between these variables or to any change in cortisol or insulin C‐peptide. In contrast no rise in somatostatin was seen during surgical stress. Thus, contrary to expectation, circulating somatostatin levels can be altered by metabolic stimuli. It seems likely that this peptide may serve an endocrine as well as a paracrine role since its modulating effects may occur not only near to but also at a distance from the site of secretion. It is not yet clear whether the somatostatin measured comes from the hypothalamus, any other part of the central nervous system or the gastrointestinal tract.