ACTH and vasopressin responses to insulin-induced hypoglycemia in intact and neurohypophysectomized conscious dogs.

Factors from the neurohypophysis are important in the control of anterior pituitary function. This study evaluated the hypothesis that the neurophypophysis is an integral component of the adrenocorticotropin (ACTH) response to certain stimuli. Furthermore, we investigated the possibility that the importance of the neurohypophysis during corticotropic stimuli can be classified by the magnitude of the systemic vasopressin response induced. The ACTH response to insulin-induced hypoglycemia (INS), nitroprusside hypotension (NP), or ovine corticotropin-releasing factor (CRF) infusion (20 ng/kg/min) was measured in dogs before (intact) and greater than 2 weeks after selective transbuccal neurohypophysectomy (NHX). INS (0.2 U/kg) resulted in a significant decrease in plasma glucose from 93 +/- 1 to 33 +/- 2 mg/dl at 30 min and a significant increase in plasma ACTH from 53 +/- 10 to 306 +/- 33 pg/ml in intact dogs whereas the vasopressin (AVP) response was small (2.8 +/- 0.3 to 5.5 +/- 0.7 pg/ml). NHX had no effect on the blood glucose or ACTH response to INS. NP resulted in large increases in ACTH from 54 +/- 8 to 351 +/- 89 pg/ml and in AVP from 2.7 +/- 0.2 to 272 +/- 98 pg/ml. In contrast to INS, NHX significantly attenuated the ACTH and AVP responses to NP. The ACTH response to CRF was not attenuated by NHX, indicating normal pituitary corticotropic function. In summary, NHX attenuated the ACTH response to hypotension (large peripheral AVP response) but not to INS or CRF (small peripheral AVP response).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma beta-endorphin responses to somatostatin, thyrotropin-releasing hormone, or vasopressin in Nelson's syndrome

To elucidate the regulation of secretion of beta-endorphin in Nelson's syndrome, both ACTH and beta-endorphin were measured using RIA. We found that beta-endorphin and ACTH were secreted concomitantly in responses to the administration of lysine-8-vasopressin and TRH. Conversely, the administration of somatostatin to this patient reduced the secretion of both beta-endorphin and ACTH. Thus, beta-endorphin is probably secreted cooredinately with ACTH in patients with Nelson's syndrome.     

Plasma corticotrophin releasing hormone, vasopressin, ACTH and Cortisol responses to acute myocardial infarction

OBJECTIVES We assessed the magnitude and duration of the response of hypothalamic-pituitary-adrenal hormones to the stress of myocardial infarction, in the presence and absence of angiotensin converting enzyme inhibitors. In particular, we wished to analyse the interrelationships between peripheral plasma levels of corticotrophin releasing hormone (CRH), vasopressin (AVP) and adrenocorticotrophin (ACTH), and also between ACTH and Cortisol, during a prolonged medical stress. DESIGN All hormones were measured within 6 hours of the onset of an acute myocardial infarction. Patients were randomly allocated to three different study groups according to a double blind procedure. PATIENTS Group 1 (10 patients) received placebo treatment, Group 2 (13 patients) received a maintenance dose of captopril 25 mg three times daily, Group 3 (11 patients) received enalapril 5 mg three times daily. MEASUREMENTS Peptide hormones were measured by radioimmunoassay, and Cortisol by ELISA. Reference ranges for all hormones were obtained from 40 or more volunteers from the electoral roll. RESULTS At the start of the study, mean±SEM plasma AVP (27.9 ± 4.6 pmol/l) was significantly (P<0 001) raised above the mean for the reference range (1.82 ± 0.09 pmol/ I), and 12 patients had values >50 pmol/l. Mean plasma Cortisol (960 ± 89.6 nmol/l) was also raised above the reference range mean (554±28 nmol/l, P<0.001), as was mean plasma CRH (4.97 ± 0.5 pmol/l, reference mean 1.52± 0.09 pmol/l, P<0001). By contrast, mean ACTH (3.88 ± 0.66 pmol/l) was significantly less than the reference mean (10.7 ± 0.7 pmol/l, P<0.001). During the 72-hour observation period there was a highly significant fall (P<0.001) in plasma CRH, AVP and Cortisol. By contrast, plasma ACTH rose, and the change with time of ACTH was significantly different from the fall in plasma CRH, AVP or Cortisol (P<0.001 for each comparison). No significant differences in plasma CRH, AVP, ACTH or Cortisol responses to placebo, captopril or enalapril were observed. CONCLUSIONS Within 6 hours of a myocardial infarction, mean plasma CRH, AVP and Cortisol values were very significantly raised above mean control values, while ACTH was very significantly reduced. During the 3 days following an acute myocardial infarction, plasma CRH, AVP and Cortisol fell substantially, and this pattern was not influenced by angiotensin converting enzyme inhibitors. By contrast, plasma ACTH showed a significant increase with time. This suggests that the usual relationships between CRH, AVP and ACTH, and between ACTH and Cortisol are disturbed in patients admitted to hospital with myocardial infarction. Maximum levels of AVP observed in 12 patients exceeded 50 pmol/l, which may be sufficiently high to interfere with tissue perfusion. It is postulated that V₁, AVP receptor antagonists may have a therapeutic application in limiting infarct size.     

Plasma adrenocorticotrophin, cortisol and aldosterone responses to ovine corticotrophin-releasing factor and vasopressin in sheep

Ovine corticotrophin-releasing factor (oCRF) (1 microgram/kg) and arginine vasopressin (AVP) (1 microgram/kg) were injected iv in sheep, both separately and in combination. Plasma levels of immunoreactive ACTH (IR-ACTH), cortisol, and aldosterone were measured for 3 h after the injections. Mean levels before injections were 8 +/- 4 pmol/l for ACTH, 7 +/- 3 nmol/l for cortisol, and 28 +/- 9 pmol/l for aldosterone. CRF caused a rapid rise in IR-ACTH and a peak level of 125 +/- 52 pmol/l was obtained 15 min after injection. Highest values for cortisol and aldosterone levels were 40 +/- 9 nmol/l and 64 +/- 13 pmol/l, respectively, 30 min after injection. AVP also increased IR-ACTH (maximum level: 202 +/- 77 pmol/l at 5 min) and aldosterone (128 +/- 36 pmol/l at 15 min), whereas the cortisol increase was lower than after CRF. Simultaneous injection of CRF and AVP produced an addition of the IR-ACTH response (295 +/- 82 pmol/l at 15 min), but the changes in cortisol levels were similar to those obtained after CRF alone and those in aldosterone levels resembled those induced by AVP alone. Plasma Na and K, osmolality, and plasma renin activity (PRA) were not modified by either CRF or AVP. It is suggested that the increase in aldosterone levels after CRF could be mediated by ACTH and that after AVP by an IR-ACTH peptide with less effect on cortisol secretion.     

ACTH and cortisol responses to glucagon stimulation.

The effect of the intramuscular injection of various doses of glucagon in 15 healthy subjects was studied. Significant elevations of plasma ACTH, and cortisol were found to occur 3 h after the administration of 4 mg of crystalline glucagon. Mean levels in 7 subjects were for ACTH 44 +/- 30 (SD) pg/ml, and for cortisol 14 +/- 6 (SD) mug/100 ml at the beginning of the test, and rose to 109 +/- 48 (SD) pg/ml and to 23 +/- 5 (SD) mug/100 ml respectively following glucagon. The peak response of ACTH and cortisol was preceded by a significant rise of plasma insulin, by a fall of the blood glucose, which was initially increased by the administration of glucagon, and by the symptoms of nausea and sweating. This study demonstrates that the intramuscluar administration of glucagon (4 mg) provids a potent stimulus to ACTH and cortisol secretion in healthy subjects.     

Adrenocorticotropin and cortisol responses to vasopressin during pregnancy.

CRH is secreted by the placenta into the maternal and fetal circulation during pregnancy in humans and non-human primates. ACTH and cortisol responses to exogenous CRH are blunted during pregnancy. In the present study we examined the pituitary-adrenal response to another corticotropin releasing factor, vasopressin. Studies were performed in chronically catheterized female baboons moving freely in their home cages; 13 studies were performed in 4 pregnant animals, and 8 studies were performed in 6 nonpregnant animals. Vasopressin was administered iv in 2 doses (0.3 and 3.0 U), and plasma samples were obtained for CRH, ACTH, and cortisol measurements. Results are expressed as the mean +/- SEM. Baseline plasma CRH was 240 +/- 20 pmol/L in the pregnant animals and unmeasurable (less than 20) in the nonpregnant animals. In the pregnant animals, ACTH concentrations rose from a baseline of 6.4 +/- 1.3 pmol/L to 10.1 +/- 0.4 after 0.3 U vasopressin and to 24.9 +/- 5.2 after 3.0 U vasopressin. In the nonpregnant animals, ACTH levels were 5.8 +/- 1.3 at baseline, 6.7 +/- 1.3 after the 0.3-U dose, and 14.6 +/- 2.4 after the 3.0-U dose. The peak ACTH response after each dose of vasopressin was higher in the pregnant animals than in the nonpregnant animals (P less than 0.05). The baseline cortisol level in the pregnant animals was 960 +/- 80 nmol/L and rose to 1370 +/- 110 and 1535 +/- 165 after the 2 doses of vasopressin, respectively. The baseline cortisol concentration in the nonpregnant animals was 910 +/- 86 nmol/L. The cortisol level was 990 +/- 75 after the 0.3-U vasopressin dose and 1380 +/- 140 after the 3.0-U dose. The peak cortisol response after the 0.3-U dose was significantly higher in the pregnant animals (P less than 0.02), while the peak cortisol responses after the 3.0-U dose were similar in the 2 groups of animals. In a single animal, vasopressin was administered sequentially at 4 gestational ages during pregnancy and then 2 times in the postpartum period. The ACTH response to vasopressin increased as pregnancy progressed and then decreased in the postpartum period. In summary, the ACTH and cortisol responses to 0.3 and 3.0 U vasopressin, iv, are enhanced during pregnancy in the baboon, although the responses to exogenous CRH are blunted during gestation. We conclude that the chronic placental CRH stimulation of the pituitary-adrenal axis during pregnancy leads to an enhanced response to vasopressin and a down-regulation of the response to exogenous CRH.     

Inhibition by dexamethasone of arginine vasopressin and ACTH responses to insulin-induced hypoglycemia and cigarette smoking in normal men

Glucocorticoids are known to inhibit the AVP response to osmotic and hemodynamic stimuli in humans. In the present study, we examined whether the AVP response to other primary stimuli, such as insulin-induced hypoglycemia and cigarette smoking was sensitive to inhibition by dexamethasone. The plasma ACTH responses were also measured. Twenty-four normal men were randomly divided into 3 groups of 8 subjects. One group was tested with insulin (0.15 IU/kg in an iv bolus) and another group with cigarette smoking (2 non-filter cigarettes smoked in succession within 10 min) with and without pretreatment with dexamethasone (2 or 4 mg in an iv bolus 10 min before insulin or smoking). The third group was tested with dexamethasone alone (2 or 4 mg in an iv bolus). The administration of dexamethasone (2 or 4 mg) alone did not modify the circulating levels of AVP and ACTH at any time during the next hour. The hypoglycemic response to insulin was similar regardless of dexamethasone treatment. AVP rose sharply in response to both hypoglycemia and smoking, reaching mean peak levels at 45 and 30 min, respectively. After both stimuli, the mean peak levels of AVP were 2.25 times higher than baseline. Pretreatment with dexamethasone (2 or 4 mg) significantly decreased the AVP responses to both hypoglycemia and cigarette smoking. Following pretreatment with dexamethasone (2 or 4 mg) the AVP increments in response to hypoglycemia or cigarette smoking were only 1.7 times higher than baseline. The plasma concentrations of ACTH were strikingly increased by hypoglycemia. The mean peak level was 3.5 times higher than baseline and was reached at 45 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma cortisol, PRL, ACTH, AVP and corticotrophin releasing hormone responses to direct current cardioversion and electroconvulsive therapy

OBJECTIVE We aimed to evaluate and contrast the hypothalamo–pituitary–adrenal (HPA) response to direct current (DC) cardioversion and electroconvulsive therapy (ECT). SUBJECTS Six male subjects (mean age 61.2 years, range 46–74) with chronic atrial fibrillation were selected for cardioversion. Six subjects with depression (one male, five female; mean age 43.2 years, range 31–59) were selected for ECT. Those taking glucocorticoid drugs, opiates or β-adrenoceptor antagonists were excluded. MEASUREMENTS Patients attended for serial blood sampling on the day of cardioversion or ECT, and for an equivalent time period on a control day at least one week before. Intravenous propofol was given to each subject for anaesthesia on the day of cardioversion or ECT. On both study and control days, blood samples were taken at ?30, ?15, 0 (just prior to cardioversion or ECT), +5, +10, +15, +30, +60, +90 and +120 minutes for assay of cortisol, PRL, ACTH, AVP and CRH. RESULTS For cardioversion: plasma cortisol increased from 252.5 ± 39.8 to a maximum of 721.3 ± 50 nmol/l at 30 minutes (P < 0.0001 compared with control day). ACTH increased from 12.8 ± 2.8 to a maximum of 64 ± 14 pmol/l at 5 minutes (P < 0.0001 compared with control day). AVP increased from 6.6 ± 3.3 to a maximum of 42.9 ± 16 pmol/l at 5 minutes post-cardioversion (P < 0.005 compared with control day). PRL increased from 141 ± 28 mIU/l to a maximum of 873 ± 219 mIU/l at 10 minutes (P < 0.001 compared with control day). There was no significant difference in CRH responses between cardioversion and control days. There was no significant correlation between total electrical energy delivered and maximum ACTH and AVP responses (R = 0.54 and ?0.13, respectively). For ECT: on the day of ECT plasma cortisol increased from 419.5 ± 25.9 to a maximum of 614.7 ± 26.9 nmol/l (P < 0.002 compared with control day). ACTH increased from 22.7 ± 6.2 to a maximum of 77.8 ± 19.1 pmol/l (P < 0.0003 compared with control day). PRL increased from 771 ± 317 to a maximum of 3152 ± 703 mIU/l (P < 0.001 compared with control day, and significantly greater than the peak response to cardioversion, P < 0.03). AVP increased from 13.0 ± 10.8 to a maximum of 35.1 ± 5.6 pmol/l (P < 0.02 compared with control day). There was no significant difference in CRH responses between ECT and control days. Peak cortisol and ACTH responses did not differ significantly between ECT and cardioversion. Baseline cortisol levels, however, were significantly higher in the depressed group compared with the cardioversion group, P < 0.02, but not ACTH or AVP. CONCLUSION Significant hypothalamic–pituitary–adrenal activation and PRL release occur in response to both cardioversion and ECT. AVP may have an important role in mediating the acute ACTH response to electrical stimulation.     

The plasma cortisol and corticotropin response to hypoglycemia following adrenal steroid and ACTH administration.

The plasma cortisol response to hypoglycemia is widely used as a test of hypothalamic-pituitary-adrenal function. It was the aim of this study to determine whether this test gives a reliable indication of pituitary corticotropin (ACTH) release in patients recovering from adrenocortical suppression due to corticosteroid or ACTH therapy. The 16 patients who were studied (6 on more than one occasion) had received in excess of 5 mg predinisone or equivalent daily for over 12 months. The insulin tolerance tests were carried out 18 h after stopping steroid therapy. The tests were then repeated three to four days after adrenal function had been restored (as indicated by urinary oxogenic steroid excretion of greater than 35 mg/24 h) by zinc tetracosactrin administration. The ACTH response to hypoglycemia was significantly impaired in the steroid-treated group. However with the exception of one patient who had persistently elevated resting ACTH levels there was a significant correlation (P less than 0.01) between the maximum increments in plasma cortisol and ACTH during hypoglycemia. No significant difference in sensitivity to endogenous ACTH could be demonstrated between the steroid-treated group and 12 normal control subjects. Following ACTH administration the plasma ACTH and growth hormone responses to hypoglycemia were significantly reduced, but the response in plasma cortisol was not significantly affected. It is concluded that the plasma cortisol response to hypoglycemia gives a useful indication of ACTH release in steroid-treated patients provided that they have not recently received exogenous ACTH.     

Pulsatile ACTH and cortisol in goats: effects of insulin-induced hypoglycemia and dexamethasone.

Insulin-induced hypoglycemia is a metabolic stress that stimulates secretion of adrenocorticotropic hormone (ACTH) and cortisol in a number of animal species. Dexamethasone is a potent synthetic glucocorticoid that suppresses the secretion of ACTH and cortisol. Both ACTH and cortisol exhibit complex secretory patterns demonstrating ultradian and circadian rhythms. This work investigated the pattern of ACTH and cortisol response to hypoglycemia in goats and the effect of dexamethasone on this response. Five goats were pretreated with dexamethasone (0.1 mg/kg) and 5 with saline. Blood samples were taken every 2 min for 60 min before and 60 min after administration of insulin (2.5 IU/kg, i.v.). Immunoreactive ACTH and cortisol were measured in all samples and glucose in selected samples. Data sets were analyzed for significant pulses with the Cluster Analysis program. Complete data sets were compared as well as those for each 30-min interval. Plasma glucose was lower than preinsulin levels at 10 min, declined rapidly between 10 and 30 min, and remained low 30-60 min after insulin injection in both treatment groups. Controls showed a rapid rise in ACTH and cortisol beginning 30 +/- 10 min postinsulin. The increase in mean plasma hormone levels during hypoglycemia was predominantly due to an increase in amplitude of secretory pulses for ACTH and cortisol compared with the 30 min before insulin. Dexamethasone significantly lowered mean ACTH and cortisol levels and prevented alteration in plasma ACTH and cortisol secretion during hypoglycemia but did not totally ablate pulsatile activity of either hormone. The amplitude of ACTH and cortisol pulses was significantly decreased by dexamethasone treatment. The frequency of cortisol but not ACTH pulses was also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma catecholamines and the counterregulatory responses to hypoglycemia in infants: a critical role for epinephrine and cortisol

The purpose of this study was to define plasma catecholamine responses as part of the counterregulatory hormonal reaction to hypoglycemia in infants after a regular 3- to 4-h feed was omitted. Hormone levels were assessed once, at the end of the fast or at hypoglycemia. The 121 infants were subdivided into three groups for analysis: normoglycemia (n = 94, 78%); transient hypoglycemia (n = 11, 9%); or severe and persistent hypoglycemia (n = 16, 13%). The severe and persistent hypoglycemic group had significantly higher levels of cortisol and epinephrine than the normoglycemic group. Norepinephrine and glucagon levels did not differ between the groups. Human GH levels were higher in the transiently hypoglycemic group but not in the severe and persistent hypoglycemic group. Prefeed blood lactate levels differed significantly among the groups and were highest in the severe and persistent groups. Multiple regression analysis showed that cortisol levels were significantly higher in infants who had severe and persistent hypoglycemia. The counterregulatory hormonal response in infants to severe and persistent hypoglycemia was limited to elevations in only cortisol and epinephrine levels but did not involve glucagon or human GH. This limited hormonal response may also contribute to the frequent occurrence of hypoglycemia in these infants.     

Effect of an antiserotoninergic drug, metergoline, on the ACTH and cortisol response to insulin hypoglycemia and lysine-vasopressin in man.

The effect of metergoline, a specific antiserotoninergic drug, on ACTH secretion was investigated in 29 normal volunteers and in 4 patients with increased ACTH production (3 with Addison's disease, 1 with Cushing's disease). In 15 normal subjects, a 4-day treatment with 10 mg daily of metergoline significantly blunted the ACTH response to insulin hypoglycemia. Mean peak ACTH values before and after treatment were, respectively, 333 +/- 39.2 (SE) and 235 +/- 38.8 pg/ml (P less than 0.05). The corresponding values of plasma cortisol were 29.6 +/- 2.96 and 20.5 +/- 2.67 mug/100 ml (P less than 0.05). In contrast, metergoline failed to affect the ACTH response to lysine-vasopressin (LVP) administered iv (8 subjects studied) and im (6 subjects studied). In 3 patients suffering from Addison's disease, an appreciable although not statistically significant lowering of the plasma ACTH levels was noted during metergoline administration. The mean pre- and post-treatment values of plasma ACTH in these patients were, respectively, 1116 +/- 192.2 and 666 +/- 100.8 pg/ml, 4240 +/- 50.0 and 3398 +/- 368.0 pg/ml, and 431 +/- 44.0 and 352 +/- 23.9 pg/ml. In one patient with Cushing's disease caused by a pituitary adenoma, metergoline did not appreciably modify plasma ACTH levels. Taken together, these results lend support to the concept of a physiological stimulating effect of serotonin on ACTH secretion. Moreover, they are compatible with the view that serotonin exerts its action chiefly at the hypothalamic level while LVP promotes ACTH release by a primary action on the pituitary.     

Plasma cortisol profiles in Cushing's syndrome.

Plasma cortisol profiles were studied by the frequent sampling method in 5 patients with Cushing's disease (CD), 7 patients with Cushing's syndrome due to adrenocortical adenoma (AA), and one patient with bronchogenic carcinoma. Plasma ACTH was measured by radioimmunoassay at 10 min intervals in 2 of the subjects. In CD, there was distinct episodic secretion of cortisol and ACTH; the coefficients of variation about the mean plasma cortisol concentration ranged from 24 to 27%; plasma ACTH ranged from zero to 455 pg/ml with a mean of 94 pg/ml. In AA, the tumour secreted cortisol at a constant rate with little fluctuation; the coefficients of variation of plasma cortisol concentration ranged from 8 to 14%; plasma concentrations of ACTH were always near zero. In the patient with bronchogenic carcinoma, the coefficient of variation of cortisol was 14%. These results were apparent even in profiles of plasma cortisol concentrations measured over only a 6 h period. It is concluded that characteristics of plasma cortisol and ACTH secretory patterns are helpful in differentiating Cushing's syndrome of differing aetiology.     

ACTH and cortisol response to bromocriptine, and results of long-term therapy, in Cushing's disease.

Plasma corticotrophin (ACTH) was lowered in 4 out of 5 patients with pituitary dependent Cushing's syndrome (one of whom was studied only after bilateral adrenalectomy) after a single oral dose of 2.5 mg bromocriptine, but plasma cortisols were unaltered in the 3 patients in whom it was measured. Three patients were observed during treatment with bromocriptine for 16 to 87 weeks. One improved symptomatically while maintained on a combination of metyrapone and bromocriptine, but plasma ACTH levels remained high even when the dose of bromocriptine was increased to 20 mg daily. Bromocriptine therapy was discontinued after 16 weeks in the second patient due to the development of mental depression. Her clinical features had not improved during this time. The third patient, who also underwent a course of pituitary irradiation, became, and remains, symptom free, with satisfactory plasma ACTH and cortisol levels for the 87 weeks he has received bromocriptine. The role of bromocriptine in the management of Cushing's disease seems limited despite the fact that plasma ACTH may fall after a test dose of the drug.     

Plasma GH responses to GHRH and insulin-induced hypoglycemia in man

Changes in plasma GH levels in response to an intravenous bolus injection of 200 micrograms GHRH-44 or 0.1 U/kg body weight regular insulin were examined in normal men who were pre-treated with 200 micrograms GHRH-44 or 0.1 U/kg body weight regular insulin 120 min in advance. The prior bolus injection of GHRH-44 inhibited the plasma GH response to the subsequent administration of GHRH-44 whereas the plasma GH response to the subsequent injection of insulin was not influenced by the prior administration of GHRH-44. The prior administration of insulin attenuated the plasma GH response to the subsequently given GHRH-44. These results suggest that desensitization of GHRH receptors in somatotrophs and/or somatostatin hypersecretion induced by increase in plasma GH levels following the prior GHRH-44 administration may be involved in the mechanism by which the prior GHRH-44 administration or insulin-induced hypoglycemia suppressed plasma GH responses to the following GHRH-44 administration. Sudden suppression of somatostatin secretion, which causes rebound of GH secretion, may occur in insulin-induced hypoglycemia.