Insulin Stress Test Research Articles

Somatostatin and Thyrotrophin‐Releasing Hormone Response and Receptor Status of a Thyrotrophin‐Secreting Pituitary Adenoma: Clinical and in vitro Studies

Abstract We have described a patient with a thyrotrophin-secreting pituitary adenoma and correlated a detailed physiological and anatomical investigation of the surgically resected tumour with its in vivo regulation. Thyrotrophin secretion was inhibited by circulating thyroid hormones, dopaminergic agonists and the somatostatin analogue SMS 201-995 but could not be stimulated by thyrotrophin-releasing hormone or further inhibited by exogenous triiodothyronine. Prolonged treatment with SMS 201-995 caused tumour shrinkage as shown by successive computed tomography scans but was accompanied by tumour desensitization and the development of diabetes mellitus. This is the first thyrotroph adenoma in which somatostatin receptors have been directly demonstrated and shown to completely block thyrotrophin-releasing hormone-induced inositol phospholipid accumulation when occupied. In addition, preincubation with triiodothyronine significantly inhibited thyrotrophin-releasing hormone-induced inositol phospholipid turnover in dispersed pituitary cells indicating that in this tumour, circulating thyroid hormones were exerting feedback inhibition at the level of the pituitary either by reducing the number of thyrotrophin-releasing hormone receptors and/or their coupling to second messenger pathways. In keeping with this hypothesis, the acute reduction in intrapituitary triiodothyronine by sodium ipodate in vivo had no effect on peripheral thyrotrophin over 6 h suggesting that the onset of the effect of triiodothyronine withdrawal on thyrotrophin secretion was suitably delayed. The importance of the inositol phospholipid second messenger pathway in transducing the secretory response in this tumour was further corroborated by electrophysiological studies which demonstrated thyrotrophin-releasing hormone-induced changes in K(+) currents which are dependent on intracellular Ca(2+) ions, presumably mobilized via the inositol phospholipids. In addition to thyrotrophin and alpha subunit, growth hormone mRNA and growth hormone were found throughout the tumour as were two populations of cells distinguished electron microscopically by the size of their secretory granules. Although acromegalic features are not unusual in thyrotroph adenomas, our patient showed no evidence of inappropriate growth hormone secretion during surgery or in response to pre- or post-operative insulin stress tests.

Hypotensive and sedative effects of insulin in autonomic failure.

The haemodynamic responses to intravenous insulin (0.15 units/kg) were measured in five patients with chronic autonomic failure who were not receiving drug treatment. After the administration of insulin supine blood pressure fell steadily, with a substantial reduction even before the onset of hypoglycaemia. None of the patients showed the usual range of neuroglycopenic symptoms, but they all became drowsy, with increasing sedation as the blood glucose concentration fell. In four other patients with autonomic dysfunction intravenous injection of 25-50 ml of 50% glucose alone caused a striking, although transient, fall in blood pressure. Hypoglycaemia was reversed by a 10 minute intravenous infusion of 100 ml of 25% glucose; this did not lower blood pressure further and rapidly restored previous levels of alertness. Consideration must be given to the hypotensive potential of insulin in patients with autonomic failure during an insulin stress test. The inability of these patients to show the usual manifestations of hypoglycaemia, plus the short lived, though pronounced, reduction in blood pressure after intravenous administration of 50% glucose, may further increase the risks of this procedure.

PITUITARY FUNCTION TESTS IN THE ELDERLY: ARE HYPOTHALAMIC RELEASING FACTORS THE INVESTIGATION OF CHOICE?

The use of the new hypothalamic releasing factors corticotrophin releasing factor (CRF) and growth hormone releasing factor (GHRH) has been proposed as a potential replacement for the insulin stress test in the investigation of pituitary function. The response to the injection of 100 micrograms of each compound was studied in nine elderly in-patient subjects. In response to GHRH, only four subjects demonstrated a rise in growth hormone; in response to CRF, only one subject showed a rise in cortisol. In the patients studied the combined GHRH and CRF test did not cause any cortisol or GH response in the majority.

Abnormalities of growth hormone release in response to human pancreatic growth hormone releasing factor (GRF (1-44) ) in acromegaly and hypopituitarism.

Human pancreatic growth hormone releasing factor (GRF (1-44)) is the parent molecule of several peptides recently extracted from pancreatic tumours associated with acromegaly. A study was conducted to examine its effects on the release of growth hormone in normal volunteers and in patients with hypopituitarism and acromegaly. GRF (1-44) dose dependently stimulated the release of growth hormone in normal people and produced no appreciable side effect. This response was grossly impaired in patients with hypopituitarism and, although similar to the growth hormone response to hypoglycaemia, was of quicker onset and a more sensitive test of residual growth hormone function. Patients with acromegaly appeared to fall into (a) those with a normal response to GRF, whose growth hormone suppressed significantly with oral glucose, and (b) those who had an exaggerated response to GRF (1-44), whose growth hormone had not suppressed previously after oral glucose. Present methods for testing growth hormone deficiency entail using the insulin stress test, which is time consuming, unpleasant, and sometimes dangerous. A single intravenous injection of GRF now offers the possibility of an easier, safer, and more reliable routine test for growth hormone deficiency. It has the further advantage of being free of side effects and readily performed in outpatients. Hence it seems likely to become the standard test and take the place of the insulin stress test.

Negative rate-sensitive feedback effects on adrenocorticotrophin secretion by cortisol in normal subjects.

Plasma ACTH and corticosteroid levels were measured in normal subjects during constant infusion of either 0.9% (W/V) NaCl solution or cortisol, and during insulin-induced hypoglycaemia. During infusions of 0.9% NACl solution the secretion of ACTH and corticosteroids was episodic. Fast, rate-sensitive, negative feedback inhibition of ACTH secretin was observed during cortisol infusions, when the corticosteroid levels were within the physiological range (200-750 nmol/l) and were rising at a rate of between 5 and 10 nmol/l per min for 30 min or longer. When plasma corticosteroid levels were in a steady state, the initial fast feedback effects were abolished and ACTH secretion resumed. However, this recovery of ACTH secretion was not seen when the corticosteroid levels were persistently above 800 nmol/l. It appears that corticosteroid-induced negative feedback in man may be both rate- and level-sensitive. During insulin stress test ACTH secretion fell at time when the plasma corticosteroid level was rising rapidly (greater than 5 nmol/1 per min) despite persistent hypoglycaemia.

Platelet aggregation studies during transient hypoglycaemia: a potential method for evaluating platelet function.

The effect of acute hypoglycaemia on platelet function was examined in patients undergoing an insulin stress test. Enhanced platelet aggregation was observed in all cases but platelet count, platelet adenine nucleotides, and the plasma level of von Willebrand factor were unchanged overall. The onset of the hypoglycaemia-induced increase in platelet aggregation coincided with the lowest blood glucose levels recorded and with the clinical signs of adrenaline release. Increased platelet aggregation was maintained thereafter for the two-hour test period. There was no apparent correlation with changes in cortisol, growth hormone, and prolactin. No change in platelet function was observed after the administration of L-dopa. We suggest that the measurement of platelet aggregation during a standard insulin stress test may provide a means of evaluating platelet function in vivo and the influence of drugs thereon.

Hypothalamo-pituitary-adrenal function in intrinsic non-atopic asthma.

Sixteen patients with intrinsic non-atopic asthma with persistent wheezing who had never been treated with corticosteroids showed normal adrenocortical responses to prolonged stimulation with Tetracosactin Depot. In a subgroup of six patients the hypothalamo-pituitary-adrenal (HPA) response to a standard insulin stress test was normal. It is concluded that impaired responsiveness of the HPA axis is unlikely to be a common factor in initiating or maintaining airways obstruction in patients with intrinsic asthma.

Betamethasone valerate in corticosteroid-dependent asthmatics: The integrity of the hypothalamic pituitary adrenal axis

In a single-blind trial 29 patients with corticosteroid-dependent asthma reduced their daily dose of oral prednisolone by i mg/week while using a placebo inhaler until an unacceptable degree of asthma occurred. Betamethasone-17-valerate in a dose of 800 μg/day and if necessary 16oo μg/day was then substituted for the placebo inhaler and the reduction of oral prednisolone continued until the prednisolone was withdrawn completley or an unacceptable degree of asthma recurred. In 22 patients (76%) prednisolone was withdrawn completely, i i on 800 μg and ii on 16oo μg betamethasone-17-valerate. The mean reduction of prednisolone was 3·8 mg on placebo, 5·4 mg on 800 μg and a further 1·8 mg in patients requiring i 600 μg of betamethasone-17-valerate. The hypothalamic pituitary adrenal (HPA) axis was assessed by tetracosactrin and insulin stress tests at the start of the study and after withdrawal of oral prednisolone. The results indicate that an HPA axis which is completely suppressed by systemic corticosteroids can regain normal integrity when the systemic steroid is replaced by betamethasone-17-valerate in a dose of either 8oo μg/day or i6oo μg/day. Candidiasis was observed, but will be reported later.

Studies on the plasma amino acid changes during the insulin-stress test in man

An vier Personen in unterschiedlichem Ernahrungs- und hormonellem Status wurde ein Insulin-Stress-Test durchgefuhrt. Bis zu 180 min nach der Insulininjektion wurde im Abstand von 30 bzw. 60 min der Gehalt an Blutzucker, 11-OHCS und das Aminosaurespektrum im Plasma bestimmt. Die Grose des Abfalls der Aminosauren nach Insulin ist abhangig von der Hohe des Ausgangsniveaus der Aminosauren und steht nicht in Beziehung zu der Starke der Hypoglykamie. Dem reaktiven Anstieg der endogenen Glucocorticoide im Blut folgt ein Anstieg der meisten Aminosauren besonders von Taurin, Lysin und Glutaminsaure. Sind bestimmte Schwellenwerte fur die einzelnen Aminosauren erreicht, tritt wieder eine Abnahme fast aller Aminosauren im Plasma auf. Die Befunde konnten durch entsprechende Ergebnisse bei einem ACTH-Infusionsversuch gestutzt werden. Gleichzeitige Erniedrigung des Spiegels an endogenem aktivem Insulin scheint die Wirkung eines erhohten endogenen Glucocorticoidgehaltes auf die Aminosauren im Plasma zu verstarken.

The thermal conductivities of metal crystals—I. Bismuth

In a single-blind trial 29 patients with corticosteroid-dependent asthma reduced their daily dose of oral prednisolone by i mg/week while using a placebo inhaler until an unacceptable degree of asthma occurred. Betamethasone-17-valerate in a dose of 800 μg/day and if necessary 16oo μg/day was then substituted for the placebo inhaler and the reduction of oral prednisolone continued until the prednisolone was withdrawn completley or an unacceptable degree of asthma recurred.In 22 patients (76%) prednisolone was withdrawn completely, i i on 800 μg and ii on 16oo μg betamethasone-17-valerate. The mean reduction of prednisolone was 3·8 mg on placebo, 5·4 mg on 800 μg and a further 1·8 mg in patients requiring i 600 μg of betamethasone-17-valerate.The hypothalamic pituitary adrenal (HPA) axis was assessed by tetracosactrin and insulin stress tests at the start of the study and after withdrawal of oral prednisolone. The results indicate that an HPA axis which is completely suppressed by systemic corticosteroids can regain normal integrity when the systemic steroid is replaced by betamethasone-17-valerate in a dose of either 8oo μg/day or i6oo μg/day. Candidiasis was observed, but will be reported later.