scholarly journals Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback

2001 ◽  
Vol 86 (11) ◽  
pp. 5554-5563 ◽  
Author(s):  
J. D. Veldhuis ◽  
A. Iranmanesh ◽  
D. Naftolowitz ◽  
N. Tatham ◽  
F. Cassidy ◽  
...  
Keyword(s):  
Negative Feedback ◽  
High Dose ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Burst Frequency ◽  
Feedback Controls ◽  
Release Process ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis ◽  
Acth Release

To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low-feedback condition, we quantitated pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally every 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortisol concentrations were sampled concurrently every 10 min for 24 h in nine adults. The metyrapone regimen reduced the amplitude of nyctohemeral cortisol rhythm by 45% (P = 0.0013) and delayed the time of the cortisol maximum (acrophase) by 7.1 h (P = 0.0002). Attenuated cortisol negative feedback stimulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, which rose from 24 ± 1.6 to 169± 31 pg/ml (ng/liter) (P < 0.0001). Augmented ACTH output was driven by a 12-fold amplification of ACTH secretory burst mass (integral of the underlying secretory pulse) (21 ± 3.1 to 255 ± 64 pg/ml; P < 0.0001), yielding a higher percentage of ACTH secreted in pulses (53 ± 3.5 vs. 92 ± 1.3%; P < 0.0001). There were minimal elevations in basal (nonpulsatile) ACTH secretion (by 50%; P = 0.0049) and ACTH secretory burst frequency (by 36%; P = 0.031). The estimated half-life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pulse event duration at half-maximal amplitude) (median, 23 min) did not change. Hypocortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approximate entropy statistic (P= 0.003). This finding was explained by enhanced regularity of successive ACTH secretory pulse mass values (P = 0.032). In contrast, there was no alteration in serial ACTH interpulse-interval (waiting-time) regularity. At the level of 24-h ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold, and delayed the acrophase by 3.4 h from 0831 h to 1154 h (each P < 10−3). In summary, short-term glucocorticoid feedback deprivation primarily (>97% of effect) amplifies pulsatile ACTH secretory burst mass, while minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse frequency. Reduced cortisol feedback paradoxically elicits more orderly (less entropic) patterns of ACTH release due to emergence of more regular ACTH pulse mass sequences. Cortisol withdrawal concurrently heightens the amplitude and mesor of 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. In contrast, the duration of underlying ACTH secretory episodes is not affected, which indicates that normal pulse termination may be programmed centrally rather than imposed by rapid negative feedback. Accordingly, we hypothesize that adrenal glucocorticoid negative feedback controls hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct mechanisms of repressing the mass of ACTH secretory bursts, reducing the orderliness of the corticotrope release process, and modulating the intrinsic diurnal rhythmicity of the hypothalamo-corticotrope unit.

Cortisol feedback in adrenalectomized adult sheep

1995 ◽  
Vol 269 (1) ◽  
pp. E10-E17
Author(s):  
A. McFarlane ◽  
J. Coghlan ◽  
J. Tresham ◽  
E. M. Wintour
Keyword(s):  
Adrenocorticotropic Hormone ◽  
High Dose ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Response Curves ◽  
Adult Sheep ◽  
Severe Hemorrhage ◽  
In Series ◽  
Combined Action ◽  
Acth Release

These experiments tested the sensitivity of cortisol feedback on adrenocorticotropic hormone (ACTH) secretion in adult sheep. In series I, five bilaterally adrenalectomized (ADX) adult sheep were maintained on "low" (125 micrograms/h) or "high" (500 micrograms/h) intravenous cortisol replacement, and dose-response curves were obtained with corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). CRF caused incremental increases in plasma ACTH at the low but not the high dose of cortisol. AVP was similarly ineffective in stimulating ACTH at the high dose of cortisol. However, in series II, where ADX animals were again maintained on low or high cortisol infusions, a combined infusion of CRF and AVP was able to stimulate a robust ACTH response during both steroid replacement regimens. These studies demonstrate that the pituitary represents a major site of steroid feedback in the sheep, with a relatively small increase in the concentration of cortisol, within the normal unstressed physiological range, being able to inhibit ACTH secretion in response to exogenous CRF and AVP. However, under these conditions, inhibition of ACTH release can be overcome by the combined action of CRF and AVP. Further studies in series III, concerned with the nature of glucocorticoid inhibition of AVP release, demonstrate that whereas exposure to maximal cortisol levels (5,000 micrograms/h) completely abolishes the ACTH response to severe hemorrhage (15 ml/kg over 15 min), AVP release is maintained, suggesting that the system controlling AVP release during hemorrhagic stress is less sensitive to the negative influences of glucocorticoids than is the system controlling ACTH release.

Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use

2015 ◽  
Vol 174 (11) ◽  
pp. 1421-1431 ◽  
Author(s):  
Ozlem Cavkaytar ◽  
Dogus Vuralli ◽  
Ebru Arik Yilmaz ◽  
Betul Buyuktiryaki ◽  
Ozge Soyer ◽  
...  
Keyword(s):  
Hypothalamic Pituitary Adrenal Axis ◽  
High Dose ◽  
Inhaled Corticosteroid ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids

1991 ◽  
Vol 85 (6) ◽  
pp. 501-510 ◽  
Author(s):  
P.H. Brown ◽  
G. Blundell ◽  
A.P. Greening ◽  
G.K. Crompton
Keyword(s):  
High Dose ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Glucocorticoid negative feedback in sheep corticotrophs: a comparison with AtT-20 corticotroph tumor cells

1994 ◽  
Vol 267 (2) ◽  
pp. R463-R469
Author(s):  
T. P. Clark ◽  
R. J. Kemppainen
Keyword(s):  
Protein Kinase ◽  
Calcium Channel ◽  
Negative Feedback ◽  
Intracellular Signaling ◽  
Glucocorticoid Receptors ◽  
Mechanistic Model ◽  
Cell Types ◽  
Dependent Manner ◽  
Acth Secretion ◽  
Acth Release

Early glucocorticoid feedback in sheep anterior pituitary (AP) cells was compared and contrasted with that in mouse pituitary tumor AtT-20 cells. Dexamethasone (DEX) inhibited corticotropin-releasing hormone (CRH)-stimulated adrenocorticotropin (ACTH) release in a concentration- and time-dependent manner with similar potency amongst cell types. This inhibition was mediated through type II glucocorticoid receptors and required the synthesis of new protein. However, stimulation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) resulted in greater ACTH release and greater inhibition by DEX in sheep AP cells. In contrast to sheep AP cells, AtT-20 cells were insensitive to glucocorticoids when secretion was stimulated by KCl depolarization or the voltage-dependent calcium channel agonist, maitotoxin (MTX). In both cell types, CRH-, KCl-, and MTX-stimulated ACTH release was inhibited by the calcium channel blocker, nifedipine (NIF). Whereas NIF also inhibited PMA-induced ACTH secretion in AtT-20 cells, it did not in sheep AP cells. These data demonstrate that early glucocorticoid feedback is operative in sheep corticotrophs and that AtT-20 cells appear to serve as an appropriate mechanistic model for aspects of negative feedback when the CRH-protein kinase A pathway is activated but may not be appropriate when ACTH secretion is activated via other intracellular signaling pathways.

Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17beta-estradiol

1997 ◽  
Vol 272 (4) ◽  
pp. R1128-R1134 ◽  
Author(s):  
C. J. Saoud ◽  
C. E. Wood
Keyword(s):  
Negative Feedback ◽  
Sodium Succinate ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Estradiol Treatment ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Basal Plasma ◽  
Acth Concentration ◽  
Ovine Fetal

Parturition in sheep is initiated by increases in activity of the fetal hypothalamic-pituitary-adrenal axis. We have previously reported that cortisol negative feedback efficacy is decreased at the end of gestation. The present study was designed to test the hypothesis that increasing plasma estrogen and/or androgen concentrations in the fetus might increase plasma adrenocorticotropic hormone (ACTH) concentration, either by stimulating ACTH secretion or by altering the negative feedback effect of cortisol on ACTH. Fetal sheep were chronically catheterized and treated with no steroid (control), 17beta-estradiol, or androstenedione (each approximately 0.24 mg/day). After catheterization and implantation of steroid pellet, fetuses were subjected to two short (10 min) periods of sodium nitroprusside-induced hypotension with or without pretreatment with intravenous infusion of hydrocortisone sodium succinate (0.5 microg/min) to test fetal ACTH responsiveness to stress and cortisol negative feedback efficacy. Estradiol treatment significantly increased basal plasma ACTH and cortisol concentrations relative to control fetuses but did not interfere with the inhibition of ACTH secretion by cortisol. Fetal plasma ACTH responses to hypotension were significantly suppressed approximately 60% in both control and estradiol-treated groups. Androstenedione treatment significantly increased basal fetal plasma ACTH and decreased basal fetal plasma cortisol concentration. Androstenedione did not alter stimulated levels of fetal ACTH but did block the inhibition of stimulated ACTH by cortisol. We conclude that increased fetal cortisol and ACTH secretion at the end of gestation may be due to the combined effects of the gonadal steroids in that estradiol increases basal plasma ACTH secretion while androstenedione reduces cortisol negative feedback efficacy.

scholarly journals A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3587-3592 ◽  
Author(s):  
Young Taek Oh ◽  
Ki-Sook Oh ◽  
Insug Kang ◽  
Jang H. Youn
Keyword(s):  
Plasma Glucose ◽  
Plasma Corticosterone ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Plasma Acth ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Adenosine Receptor Agonist ◽  
Plasma Ffa ◽  
The Brain ◽  
Pituitary Adrenal Axis

The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels.

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