Free fatty acids inhibit adrenocorticotropin and cortisol secretion stimulated by physical exercise in normal men

BACKGROUND: The basal circulating levels of ACTH and cortisol, but not the ACTH/cortisol response to hCRH, are significantly reduced by free fatty acid (FFA) infusion. OBJECTIVE: To verify whether FFA infusion modifies the ACTH/cortisol response to physical exercise, a well-known activator of the HPA axis at suprapituitary level. DESIGN: Exercise tests on a bicycle ergometer during infusion of a lipid-heparin emulsion (LHE) (experimental test) or normal saline (NaCl 0.9%) (control test). SETTING: Department of Cardiology at the University-Hospital. SUBJECTS: Seven healthy male subjects aged 25-33 years. INTERVENTIONS: On two mornings, at weekly intervals, LHE or saline were infused for 60 min; infusion started 10 min before exercise test on a bicycle ergometer, which lasted about 15 min. MAIN OUTCOME MEASURES: Circulating ACTH/cortisol levels and physiological variables during physical exercise. RESULTS: FFA levels (0.4 +/- 0.1 mEq/l) remained constant during control test, whereas they progressively rose (peak at 60 min, 2.7 +/- 1.0 mEq/l) during LHE infusion. Neither basal nor exercise-induced changes in physiological variables were modified by LHE infusion. Both ACTH and cortisol increased during exercise, with peak levels at 20 min and 30 min (control test: 103% and 42%, P < 0.001; experimental test: 28.5% and 18.6%, P < 0.05 higher than baseline, respectively). Both ACTH and cortisol responses were significantly lower in the experimental than in the control test (at 20 min P < 0.002 and at 30 min P < 0.05 for ACTH; at 20 min P < 0.05 and at 30 min, 40 min and 50 min P < 0.001 for cortisol). CONCLUSIONS: These data represent the first demonstration of an inhibitory action of increased circulating FFA levels on the HPA axis under stimulatory conditions (i.e. physical exercise, a challenge acting at suprapituitary level). In contrast, previous studies did not show FFA effects on the CRH-induced ACTH/cortisol response. Therefore, our data suggest negative effects of FFAs on the HPA axis at hypothalamic or higher centres in the central nervous system.     

Effects of free fatty acids on ACTH and cortisol secretion in anorexia nervosa

OBJECTIVE: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects. DESIGN: Eight women with anorexia nervosa (ANW; means +/- s.e.m.: 23.9 +/- 2.3 years of age; body mass index (BMI): 14.9 +/- 0.6 kg/m2) and seven normal women (NW; 25.6 +/- 2.3 years of age; BMI: 22.8 +/- 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion. RESULTS: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P < 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P < 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P < 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P < 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P < 0.05). CONCLUSIONS: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity.     

Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats.

Intravenous administration of Intralipid 10% increases blood levels of essential free fatty acids. In rats and man, this is associated with an inhibition of GH secretion from the anterior pituitary. Because GH is lipolytic, the inhibition of its secretion may represent a negative feedback action of the fats on pituitary sensitivity to GH-releasing hormone. Since corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would inhibit the HPA axis. Rats were cannulated via the jugular vein and infused with different doses of heparin-Intralipid 10% or heparin-saline; sequential blood samples were obtained and analyzed for ACTH, corticosterone, FFA, and glucose. Intralipid at 2.85 ml/kg increased plasma FFA to over 3 meq/liter by 15 min, with a return to baseline by 60-90 min. There was no effect of the infusion on plasma osmolarity or pH. At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in Intralipid-infused rats, but were unchanged in saline controls. This dose of Intralipid increased corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still significantly greater than those in saline controls. Lower doses of Intralipid also significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to those in controls. The effects of Intralipid on corticosterone secretion could not be attributed to the presence of glycerol in the suspension, since glycerol infusions had no significant effect on steroid levels compared to those in saline controls. In dexamethasone-pretreated rats, there was no significant rise in plasma corticosterone after either of two Intralipid doses, suggesting that the action of Intralipid was at a site within the HPA axis above the adrenal gland. This finding also suggested that the high steroid levels after Intralipid treatment were not due to interference with the corticosterone RIA. This was verified by the finding that there was no increase in plasma immunoreactive corticosterone after Intralipid infusion into adrenalectomized rats. Intralipid also caused an increase in plasma glucose levels that was first significant at 60 min and declined to baseline by 180 min, possibly reflecting increased autonomic activity or peripheral insensitivity to insulin. The results suggest that high circulating FFA levels activate, rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid production and increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously unrecognized positive feedback loop.(ABSTRACT TRUNCATED AT 400 WORDS)     

Alprazolam,a benzodiazepine,does not modify the ACTH and cortisol response to hCRH and AVP,but blunts the cortisol response to ACTH in humans

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GABA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pituitary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodiazepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodiazepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22 kg/m2) on: 1) the ACTH and cortisol responses to hCRH (2.0 microg/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1-24 (0.06 and 250 microg iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean+/-SE: 29.8+/-4.4 pg/ml and 199.3+/-19.6 microg/l) were similar to those recorded after AVP (31.7+/-6.5 pg/ml and 164.8+/-18.0 microg/l); the cortisol response to 0.06 microg ACTH (190.4+/-11.8 microg/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 microg ACTH (260.6+/-17.4 microg/l). AL did not modify the ACTH response to both hCRH (42.5+/-7.1 pg/ml) and AVP (33.3+/-2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3+/-12.7 microg/l) and AVP (119.4+/-14.5 microg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 microg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0+/-7.7 microg/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7+/-16.6 microg/l). The DHEA and aldosterone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.     

Thyroid hormone therapy modulates hypothalamo-pituitary-adrenal axis

To observe the influence of thyroid hormone therapy on hypothalamo-pituitary-adrenal (HPA) axis, a group of 14 athyreotic women due to thyroid cancer treatment were studied before and after thyroid suppression therapy with thyroxine (T4). Changes in plasma adrenocorticotropin (ACTH) and cortisol levels in response to human corticotropin-releasing hormone (hCRH; 100μg, i.v.) were estimated under hypothyroid conditions and after T4 suppression therapy with 2.5μg/kg/day for two months (n=14). A group of seven healthy women was evaluated as a control group. A greater increase in ACTH levels by hCRH was observed in patient group both before and after suppression therapy compared than that of control group. Plasma cortisol levels after hCRH stimulation were also greater in patient group both before and after suppression therapy than that of control group. In conclusion, both hypothyroidism and subclinical hyperthyroidism with suppressive doses of thyroid hormone induced a hypersensitivity of ACTH to hCRH. Considering the role of thyroid hormone on HPA axis, the mechanisms of ACTH hypersensitivity may be different between these two conditions.     

Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans

An inhibitory influence of insulin-like growth factor-I (IGF-I) on hypothalamus-pituitary-adrenal (HPA) axis has been hypothesized. In fact, it has been reported that the rhGH (recombinant human GH)-induced IGF-I increase inhibits both cortisol and GH response to MK-0677, a non-peptidyl GH secretagogue in animals. The aim of this study was to further clarify the inhibitory role, if any, of IGF-I on corticotroph function. We studied the effect of rhIGF-I (recombinant human IGF-I; 20 microg/kg s.c. at -180 min) or placebo on the ACTH and cortisol responses to hCRH (human CRH; 2.0 microg/kg i.v. at 0 min) or hexarelin (HEX; 2.0 microg/kg i.v. at 0 min), a peptidyl GHS, in normal young women. The effect of rhIGF-I on the GH response to HEX was also studied. The subjects were six normal young women [age: 26-35 yr; body mass index (BMI): 19-23 kg/m2] in their early follicular phase. The results showed that after s.c. rhIGF-I administration, circulating IGF-I levels increased approximately 77%, peaking at -60 min and persisting similar up to +120 min. The mean ACTH, cortisol and GH concentrations did not change from -180 to 0 min when evaluated after both placebo or rhIGF-I. CRH and HEX induced similar ACTH (peak vs baseline, mean+/-SE: 47.5+/-10.9 vs 21.3+/-3.0 pg/ml and 30.3+/-6.9 vs 19.2+/-3.8 pg/ml, respectively; p<0.04) and cortisol responses (177.5+/-5.4 vs 109.3+/-10.3 microg/l and 149.4+/-12.3 vs 119.8+/-16.4 microg/l, respectively, p<0.04). RhIGF-I pretreatment did not modify the ACTH and cortisol responses to hCRH (46.0+/-13.8 pg/ml and 181.1+/-16.9 microg/l, respectively) as well as those to HEX (28.8+/-5.0 pg/ml and 144.1+/-16.2 microg/l, respectively). On the other hand, the GH response to HEX was clearly reduced by rhIGF-I (23.9+/-4.7 vs 64.7+/-14.8 microg/l, p<0.05). Our findings show that rhIGF-I-induced increase of circulating IGF-I levels exerts negative feedback action on somatotroph secretion, while it does not modify the corticotroph and the adrenal responsiveness to CRH or hexarelin.     

Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans.

Animal studies indicate that mineralocorticoid receptors (MR) in the hippocampus play a major role in the glucocorticoid feedback control of the hypothalamo-pituitary-adrenal (HPA) axis. Specifically, MR mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity. The stimulatory effect of intracerebroventricular and intrahippocampal MR blockade on the HPA axis in animals has been clearly shown, whereas the effect of systemic administration of mineralocorticoid antagonists in humans is still contradictory. To clarify this point, in seven normal young women (aged 25-32 yr; body mass index, 19.0-23.0 kg/m(2)) we studied the effects of canrenoate (CAN; 200 mg as iv bolus at 2000 h, followed by 200 mg infused in 500 mL saline over 4 h up to 2400 h) or placebo (saline, 1.0 mL as iv bolus at 2000 h, followed by 500 mL over 4 h up to 2400 h) on the spontaneous ACTH, cortisol, dehydroepiandrosterone (DHEA) and aldosterone secretion as well as on the ACTH, cortisol, and DHEA responses to human CRH (2.0 microg/kg as iv bolus at 2200 h) or arginine vasopressin (AVP; 0.17 U/kg as im bolus at 2200 h). Blood samples were taken every 15 min from 2000-2400 h. During placebo, spontaneous ACTH and cortisol levels showed progressive decreases (P < 0.05) from 2000-2400 h (baseline vs. nadir, mean +/- SEM, 2.0 +/- 0.3 vs. 1.4 +/- 0.2 pmol/L and 115.1 +/- 23.7 vs. 63.5 +/- 24.3 nmol/L), whereas DHEA and aldosterone levels did not change. CRH induced clear increases in ACTH, cortisol, and DHEA levels (peaks, mean +/- SEM, 7.1 +/- 1.1 vs. 1.6 +/- 0.2 pmol/L, 322.9 +/- 19.5 vs. 92.8 +/- 24.5 nmol/L, and 44.2 +/- 2.7 vs. 20.0 +/- 3.0 nmol/L; P < 0.05). Similarly, AVP elicited significant increases in ACTH, cortisol, and DHEA levels (3.8 +/- 0.3 vs. 1.5 +/- 0.1 pmol/L, 211.9 +/- 27.2 vs. 67.7 +/- 9.7 nmol/L, and 51.6 +/- 4.0 vs. 16.3 +/- 2.0 nmol/L; P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA levels showed progressive rises, which begun at approximately 60 min and peaked between 2300 and 2400 h (ACTH, 3.4 +/- 0.4 vs. 1.1 +/- 0.3 pmol/L; cortisol, 314.5 +/- 49.6 vs. 123.3 +/- 13.2 nmol/L; DHEA, 52.0 +/- 8.8 vs. 21.0 +/- 2.3 nmol/L; P < 0.05 vs. baseline as well as vs. the same time points during placebo). Aldosterone secretion was not modified by CAN. The ACTH, cortisol, and DHEA responses to human CRH were enhanced by CAN (10.0 +/- 1.7 pmol/L, 462.2 +/- 36.9 nmol/L, and 66.3 +/- 8.8 nmol/L), although statistical significance (P < 0.05) was obtained for cortisol and DHEA only. Also the ACTH, cortisol and DHEA responses to AVP were amplified by CAN (8.0 +/- 2.6 pmol/L, 324.0 +/- 34.8 nmol/L, and 77.8 +/- 4.0 nmol/L); again, statistical significance (P < 0.05) was obtained for cortisol and DHEA only. In conclusion, our study shows that the blockade of MR by CAN significantly enhances the activity of the HPA axis in humans, indicating a physiological role for MR in its control. These results also suggest that the stimulatory effect of CAN on HPA axis is mediated by concomitant modulation of CRH and AVP release.     

The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic–pituitary–adrenal (HPA) axis in humans

Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic–pituitary–adrenal (HPA)-axis, mediating the “proactive”-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15′, from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 μg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.     

Effects of hyperlipidaemia on glucocorticoid metabolism: results of a randomized controlled trial in healthy young women

Objective It is well established that the hypothalamic–pituitary–adrenal (HPA) axis is altered in obese individuals. Hyperlipidaemia with elevated levels of free fatty acids (FFAs) is also frequently seen in obesity and in the metabolic syndrome. We hypothesized, therefore, that hyperlipidaemia may alter the activity of the HPA axis. Patients and methods The effects of hyperlipidaemia, including increased circulating FFAs, on ACTH secretion and cortisol metabolism were analysed in 13 healthy young women during the early follicular phase of two subsequent cycles. We administered a 20% lipid/heparin (LHI) or a saline/heparin infusion (SHI) using a crossover design in random order for 330 min. A detailed characterization of glucocorticoid metabolism was performed by measurement of plasma ACTH, cortisol and urinary excretion rates of adrenal glucocorticoids and the glucocorticoid metabolites. Results We observed that LHI‐induced hyperlipidaemia elevated serum cortisol levels compared to SHI. No changes in plasma ACTH levels, daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid precursors/metabolites and the calculated activities of the 5α‐reductase, 3β‐hydroxysteroid dehydrogenase (HSD), 11‐, 17‐, 21‐hydroxylase and 11β‐HSD 1 or 2 were found. Conclusion Our randomized controlled trial suggests that the adrenal sensitivity to ACTH may be enhanced by LHI‐induced hyperlipidaemia in normal‐weight healthy young women. This effect might contribute to the disturbances of the HPA axis described in women with abdominal obesity and impaired lipid metabolism.     

Effects of the combined administration of hexarelin, a synthetic peptidyl GH secretagogue, and hCRH on ACTH, cortisol and GH secretion in patients with Cushing's disease

Hexarelin (HEX) is a peptidyl GH secretagogue (GHS) which markedly stimulates GH release but, like other GHS, possesses also CNS-mediated ACTH- and cortisol-releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in patients with Cushing's disease (CD). To further clarify the mechanisms by which HEX stimulates the activity of hypothalamo-pituitary-adrenal (HPA) axis in man, in 6 patients with CD (6 women, 38-68 yr old) and in 7 control subjects (CS, 7 women, 22-29 yr old) we studied the effects of HEX (2.0 microg/kg i.v.) and/or hCRH (2.0 microg/kg i.v.) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all subjects. Basal ACTH and F levels in CD were higher than in CS (66.3+/-5.1 vs 16.5+/-0.6 pg/ml and 217.8+/-18.5 vs 134.4+/-4.6 microg/l, respectively; p<0.02). In CS, the ACTH and F responses to HEX, evaluated as deltaAUC (mean+/-SE: 128.7+/-39.2 pg x min/ml and 328.5+/-93.2 microg x min/l, respectively) were lower, though not significantly, than those after hCRH (375.8+/-128.4 pg x min/ml and 1714.2+/-598.0 microg x min/l, respectively), though the peak ACTH and F responses to both stimuli were similar. The co-administration of HEX and hCRH had an additive effect on both ACTH (1189.6+/-237.2 pg x min/ml) and F secretion (3452.9+/-648.6 microg x min/l). In fact, the ACTH and F responses to HEX+/-hCRH were significantly higher (p<0.01) than those elicited by single stimuli. In CD, HEX induced ACTH and F responses (3603.8+/-970.7 pg x min/ml and 10955.9+/-6184.6 microg x min/l, respectively) clearly higher (p<0.002) than those in CS. The HEX-induced ACTH and F responses in CD were higher, though not significantly, than those recorded after hCRH (1432.7+/-793.5 pg x min/ml and 4832.7+/-2146.5 microg x min/l, respectively). On the other hand, the hCRH-induced ACTH and F responses in CD were similar to those in CS. In CD, the coadministration of HEX and hCRH had an additive effect on ACTH (8035.7+/-1191.1 pg x min/ml) but not on F (10985.4+/-3900.8 microg x min/l) secretion. In fact, the ACTH, but not the F response to HEX+hCRH was significantly higher (p<0.02) than that elicited by single stimuli. In conclusion, the present study demonstrates that in patients with Cushing's disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH secretion. Considering that, at least in humans, differently from hCRH, GHS have no interaction with AVP, our present findings further agree with the hypothesis that the ACTH-releasing activity of GHS is, at least partially, independent of CRH-mediated mechanisms.     

Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralocorticoid receptor blockade

CONTEXT: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level. DESIGN: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 +/- 3.2 yr) and eight young (25.0 +/- 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg i.v. bolus followed by 200 mg infused over 4 h). RESULTS: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P < or = 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P < or = 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P < or = 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo. CONCLUSIONS: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.     

Pulsatile administration of human corticotropin-releasing hormone in patients with secondary adrenal insufficiency: restoration of the normal cortisol secretory pattern

Human corticotropin-releasing hormone (hCRH) was administered in a pulsatile fashion to eight patients with secondary adrenal insufficiency. These patients were selected on the basis of a normal or exaggerated plasma ACTH response to exogenous ovine CRH, suggesting sparing of the corticotrophs. A continuous 48-h iv infusion of ACTH to restore the adrenal glands to an ACTH-responsive state preceded hCRH administration. Eight 1 microgram/kg bolus injections of hCRH were administered in a 24-h period. The time intervals between hCRH injections were selected to resemble the frequency of spontaneously occurring secretory episodes of plasma ACTH and cortisol. Four of the patients underwent a second study, of identical design, in which normal saline injections were administered instead of hCRH. Pulsatile hCRH treatment resulted in a secretory pattern of ACTH and cortisol similar to that in normal subjects. ACTH and cortisol levels during saline administration were low and had no circadian variation. These findings indicate that exogenous CRH is able to restore normal basal ACTH and cortisol secretory patterns when given in an appropriate manner. It is possible that the pulsatile administration of hCRH may prove to be a more physiological technique for restoring adrenal function of patients with corticotroph-sparing secondary adrenal insufficiency and may avoid some of the complications of glucocorticoid administration.     

RECOVERY FROM GLUCOCORTICOID INHIBITION OF THE RESPONSES TO CORTICOTROPHIN-RELEASING HORMONE

We have characterized the recovery of the hypothalamic-pituitary-adrenal (HPA) axis from inhibition by short-term prednisolone administration. Prednisolone was given in a dosage averaging 25 mg at 12 h intervals orally for up to 2 weeks to adult volunteers. Human corticotrophin releasing hormone (hCRH) tests were performed at 0901 h using a bolus injection of 1 microgram/kg before and 24-48 h after discontinuing the prednisolone. In the initial control study, hCRH stimulated a two-fold rise in plasma ACTH and a 30% rise in plasma cortisol within 30 min (ACTH rose from 18.5 +/- 4.5, SEM, pg/ml to 36.5 +/- 12.6 pg/ml and cortisol from 415 +/- 58 to 531 +/- 69 nmol/l in response to hCRH. One dose of prednisolone had no effect on the ACTH or cortisol response to hCRH administered 24 h later. Twenty-four hours after discontinuing a 1 week course of prednisolone, baseline plasma ACTH (3.9 +/- 0.6 pg/ml) and cortisol (146 +/- 17 nmol/l) were markedly suppressed, as was the cortisol response to hCRH (peak 198 +/- 22). However, the plasma ACTH response to hCRH was not significantly suppressed. Forty-eight hours after discontinuing prednisolone, the recovery of ACTH secretion was complete (baseline 10.9 +/- 4.2, peak 36.4 +/- 14.8 pg/ml), but the cortisol response to hCRH was still depressed (peak 294 +/- 66 nmol/l). Recovery from a 2 week course of prednisolone had similar characteristics except plasma cortisol was depressed more profoundly. Plasma dehydroepiandrosterone (DHA) during hCRH tests and dehydroepiandrosterone sulphate (DHAS) paralleled plasma cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The corticotropin-releasing hormone test in normal short children: comparison of plasma adrenocorticotropin and cortisol responses to human corticotropin-releasing hormone and insulin-induced hypoglycemia

The human corticotropin-releasing hormone (hCRH) tests were performed in twelve normal short children, and the responses of plasma ACTH and cortisol to iv administration of 1 micrograms/kg hCRH were compared with those to insulin-induced hypoglycemia. After administration of hCRH, the mean plasma ACTH level rose from a basal value of 3.3 +/- 0.4 pmol/l (mean +/- SEM) to a peak value of 9.2 +/- 0.8 pmol/l at 30 min, and the mean plasma cortisol level rose from a basal value of 231 +/- 25 nmol/l to a peak value of 546 +/- 30 nmol/l at 30 min. The ACTH response after insulin-induced hypoglycemia was greater than that after hCRH administration; the mean peak level (P less than 0.01), the percent maximum increment (P less than 0.01), and the area under the ACTH response curve (P less than 0.01) were all significantly greater after insulin-induced hypoglycemia than those after hCRH administration. Although the mean peak cortisol level after insulin-induced hypoglycemia was about 1.3-fold higher than that after hCRH administration (P less than 0.01), neither the percent maximum increment in plasma cortisol nor the area under the cortisol response curve after insulin-induced hypoglycemia was significantly different from that after hCRH administration. Consequently, the acute increases in plasma ACTH after the administration of 1 microgram/kg hCRH stimulated the adrenal gland to almost the same cortisol response as that obtained with a much greater increase in plasma ACTH after insulin-induced hypoglycemia. These results suggest that a plasma ACTH peak of 9-11 pmol/l produces near maximum acute stimulation of adrenal steroidogenesis.     

Glucagon Is an ACTH Secretagogue as Effective as hCRH after Intramuscolar Administration while It Is Ineffective When Given Intravenously in Normal Subjects

It is widely accepted that glucagon stimulates GH, ACTH and cortisol release in humans, though the mechanisms underlying these effects are unclear. Aim of the present study was to evaluate the stimulatory effect of intramuscolar (im) and intravenous (iv) glucagon (GLU) administration on ACTH, cortisol (F) and GH release in normal adult subjects and to compare its effect on hypothalamo-pituitary adrenal (HPA) axis with that of hCRH. To this goal, in 6 normal young women (26–32 yrs, 50–58 kg) we studied the ACTH and F responses to either im or iv GLU (1 mg, approximately 0.017 mg/kg in subjects of 54.1 ± 1.6 kg) administration as well as to iv hCRH (2.0 g/kg) or placebo administration. The GH and glucose variations after GLU administration were also studied. Iv GLU did not modify the spontaneous decrease of ACTH and cortisol levels observed after placebo. Conversely, im GLU elicited clear-cut ACTH and F responses (peak vs baseline, mean ± SEM: 53.0 ± 15.2 vs 19.0 ± 1.5 pg/ml, p < 0.05 and 222.3 ± 23.8 vs 158.3 ± 7.0 g/l, p < 0.05) which were higher than those recorded after hCRH (28.1 ± 4.6 vs 17.4 ± 3.1 pg/ml, p < 0.02 and 182.7 ± 22.8 vs 114.8 ± 12.3 g/l p < 0.02), though this difference did not attain statistical significance. Also GH rise was recorded after im but not after iv GLU administration (11.6 ± 3.4 vs 3.3 ± 0.7 g/l, p < 0.05). Thirty min after both iv and im GLU administration glucose levels showed a similar increase followed by similar decrease. The intramuscular administration of GLU induced negligible side-effects in some subject (mild and transient nausea) which, on the contrary, were clear in all subjects after its intravenous administration (nausea, vomiting, tachicardia). In conclusion, glucagon per se is not an ACTH, cortisol and GH secretagogue. After intramuscular administration glucagon is a stimulus of HPA axis at least as effective as hCRH. The mechanisms underlying the ACTH, cortisol and GH responses to im glucagon unlikely include glucose variations or stress.     

No effect of free fatty acids on adrenocorticotropin and cortisol secretion in healthy young men

Free fatty acids (FFAs) affect anterior pituitary function. However, the effect of FFAs on corticotropin (ACTH) and cortisol in humans is controversial. Thus, we assessed the effect of a pronounced increase in circulating FFA levels induced by infusion of lipid/heparin on ACTH and cortisol secretion in young men. Eight healthy male volunteers who underwent a 10-hour overnight fast were investigated. A 20% lipid/heparin or saline/heparin infusion was given at a rate of 1.5 mL/min for 6 hours. A euglycemic hyperinsulinemic clamp was performed in 6 subjects 4 hours after the start of infusion. To assess steroid metabolism, we measured ACTH, cortisol, FFAs, and urinary steroids. Lipid infusion increased FFAs (6.06 +/- 0.52 vs 0.70 +/- 0.23 mmol/L; P < .005) and induced insulin resistance (glucose infusion rate, 4.08 +/- 2.15 vs 6.02 +/- 2.60 mg/kg per minute; P < .005). Serum cortisol and plasma ACTH decreased independent of lipid/heparin or saline/heparin infusion. In addition, we found no effect of hyperinsulinemia on ACTH and cortisol levels. There were no differences in urinary free cortisol, urinary free cortisone, 5beta-tetrahydrocortisol, 5alpha-tetrahydrocortisol, and tetrahydrocortisone. In conclusion, FFAs had no effect on basal ACTH and cortisol secretion in normal-weight young men. In addition, no alterations in urinary glucocorticoid metabolites were detected, suggesting unchanged cortisol metabolism during lipid infusion.     

Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate

alpha-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that alpha-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an alpha-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of alpha-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1 beta in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (i.c.v) infusion of 20 microg (n = 6) and 50 micro g (n = 4) of human AGRP (83-132)-NH(2) were compared with icv saline infusion. There was a significant stimulatory effect of 20 microg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 microg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 microg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 microg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by alpha-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1 beta or 20 microg of AGRP followed by 50 ng IL-1 beta. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1 beta. The peak ACTH response to IL-1 beta alone was 124 +/- 55 pg/ml vs. 430 +/- 198 pg/ml after IL-1 beta plus AGRP; the peak cortisol response was 70 +/- 8.2 microg/dl vs. 77 +/- 6.2 microg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1 beta. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with alpha-MSH to modulate neuroendocrine responses to inflammation.     

Comparison of the effects of endothelin-1 and -3 on secretion of pituitary hormones in healthy male volunteers.

The investigation was conducted to study the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on adrenocorticotropin (ACTH), cortisol and prolactin release in man. The design was a prospective placebo controlled double-blind study, including 7 healthy males studied on three occasions. After infusion of either 20 ng/min x kg ET-1, ET-3 or normal saline, venous blood samples were drawn 12 times for determination of ACTH, cortisol and prolactin during the pre- within- and postinfusion period. ET-1 infusion induced a significant increase of plasma ACTH (p< 0.009) and prolactin (p<0.0001) whereas cortisol levels increased without reaching significance (p<0.074). Infusion of ET-3 induced no changes in plasma levels of ACTH, cortisol or prolactin. The parallel increase of ACTH and prolactin induced by infusion of ET-1 could indicate an involvement of corticotropin-releasing hormone (CRH) in mediating the ET-1 effect on the HPA-axis in man. Whether this supports a possible role of ET-1 as a modulator of the hypothalamo-pituitary-adrenal (HPA) axis remains to be clarified.     

The combined dexamethasone-suppression/CRH-stimulation test in alcoholics during and after acute withdrawal

BACKGROUND: Chronic alcoholism is often accompanied by disturbances of the hypothalamic-pituitary-adrenal (HPA) system. Patients with alcoholism frequently show nonsuppression in the dexamethasone (Dex) suppression test and also a blunted increase of adrenocorticotropin (ACTH) after injection of corticotropin-releasing hormone (hCRH). However, the underlying mechanisms have not been fully elucidated. The combined Dex/CRH test (pretreatment with 1.5 mg dexamethasone at 2300 hr, injection of 100 microg hCRH at 1500 hr the next day) has been established as a more sensitive tool to investigate HPA system regulation in depressed patients. METHODS: We studied the effect of the combined Dex/CRH test in 19 alcoholic inpatients (9 male, 10 female) during and after withdrawal along with 19 healthy controls. RESULTS: Compared to normal controls, patients showed a severely dysregulated HPA system during withdrawal, with significantly elevated cortisol and ACTH response to hCRH after pretreatment with dexamethasone. After completed withdrawal, cortisol levels after injection of hCRH were almost normalized while ACTH values were partially lower in patients, compared to controls. CONCLUSIONS: We conclude that the HPA system is severely disturbed during alcohol withdrawal, possibly reflecting an exaggerated release of hypothalamic corticotropin and vasopressin.     

Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone

To further investigate the role of opioids in the regulation of the pituitary-adrenal axis we studied the effect of morphine and naloxone on human corticotropin-releasing hormone (hCRH)-induced ACTH, immunoreactive (ir) beta-endorphin, and cortisol release in normal subjects. Protocols: 1. 30 mg of a slow-release preparation of morphine or placebo was given orally 3 h prior to administration of hCRH (0.1 mg iv) (N = 7). 2. Naloxone (4 mg as bolus iv) or placebo was given 5 min prior to hCRH (N = 7). 3. Naloxone (4 mg iv as bolus followed by a continuous infusion of 6 mg over 75 min) or placebo was started 15 min prior to hCRH (N = 6). hCRH was injected at 11.00 h (protocol 1, 2) or at 17.00 h (protocol 3). Oral morphine not only suppressed basal hormone levels (P less than 0.02), but also the peak response to hCRH compared with placebo (cortisol: 270 +/- 50 vs 559 +/- 80 nmol/l; ACTH: 5.1 +/- 1.5 vs 13.1 +/- 2.7 pmol/l; ir beta-endorphin: 48.5 +/- 8.7 vs 88 +/- 14 pmol/l; mean +/- SEM, P less than 0.02). Similarly, the maximum incremental changes and the area under the curve were significantly reduced for all three hormones compared with placebo (P less than 0.05). After 4 mg of naloxone in the morning, no significant hormonal changes in response to hCRH were observed.(ABSTRACT TRUNCATED AT 250 WORDS)