NEGATIVE, RATE-SENSITIVE FEEDBACK EFFECTS ON ADRENOCORTICOTROPHIN SECRETION BY CORTISOL IN NORMAL SUBJECTS

1982 ◽  
Vol 92 (3) ◽  
pp. 443-448 ◽  
Author(s):  
S. C. J. READER ◽  
J. ALAGHBAND-ZADEH ◽  
J. R. DALY ◽  
W. R. ROBERTSON
Keyword(s):  
Negative Feedback ◽  
Feedback Inhibition ◽  
Fast Rate ◽  
Normal Subjects ◽  
Constant Infusion ◽  
Stress Tests ◽  
Nacl Solution ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Feedback Effects

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 secretion 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 tests ACTH secretion fell at a time when the plasma corticosteroid level was rising rapidly (> 5 nmol/l per min) despite persistent hypoglycaemia.

Pregnancy alters cortisol feedback inhibition of stimulated ACTH: studies in adrenalectomized ewes

2001 ◽  
Vol 280 (6) ◽  
pp. R1790-R1798 ◽  
Author(s):  
Maureen Keller-Wood ◽  
Charles E. Wood
Keyword(s):  
Plasma Cortisol ◽  
Feedback Inhibition ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Feedback Effects ◽  
Low Concentrations ◽  
Pregnancy And Postpartum ◽  
Cortisol Levels

These studies test the hypothesis that pregnancy alters the feedback effects of cortisol on stimulated ACTH secretion. Ewes were sham-operated (Sham), or adrenalectomized (ADX) at ∼108 days gestation and replaced with aldosterone (3 μg · kg−1· day−1) and with cortisol at either of two doses (ADX + 0.6 and ADX + 1 mg · kg−1· day−1); ewes were studied during pregnancy and postpartum. Mean cortisol levels produced in ADX ewes were similar to normal pregnant ewes (ADX+1) or nonpregnant ewes (ADX+0.6), respectively. Plasma ACTH concentrations in response to infusion of nitroprusside were significantly increased in the pregnant ADX+0.6 ewes (1,159 ± 258 pg/ml) relative to pregnant Sham ewes (461 ± 117 pg/ml) or the ADX+1 ewes (442 ± 215 pg/ml) or the same ewes postpartum (151 ± 69 pg/ml). Plasma ACTH concentrations were not significantly different among the groups postpartum. Increasing plasma cortisol to 20–30 ng/ml for 24 h before hypotension produced similar inhibition of ACTH in all groups. Pregnancy appears to decrease the effectiveness of low concentrations of cortisol to inhibit ACTH responses to hypotension.

ACTH responses to hypotension and feedback inhibition of ACTH increased by chronic progesterone treatment

1998 ◽  
Vol 274 (1) ◽  
pp. R81-R87
Author(s):  
Maureen Keller-Wood
Keyword(s):  
Arterial Pressure ◽  
Acute Treatment ◽  
Adrenocorticotropic Hormone ◽  
Feedback Inhibition ◽  
Acth Secretion ◽  
Baroreceptor Sensitivity ◽  
Feedback Effects ◽  
Plasma Progesterone ◽  
Progesterone Treatment ◽  
Simple Effect

During pregnancy, arterial pressure, baroreceptor sensitivity, and adrenocorticotropic hormone (ACTH) responses to hypotension are decreased. Basal ACTH and cortisol are increased in pregnancy, suggesting a reduction in cortisol feedback inhibition of ACTH. Acute treatment with progesterone decreases arterial pressure, baroreflex-mediated responses, and corticosteroid feedback effects on ACTH. These experiments test the hypothesis that chronic increases in progesterone produce changes in arterial pressure, ACTH responses to stress, and feedback inhibition of ACTH similar to pregnancy. Ewes were treated with progesterone for 60–80 days. This increase in plasma progesterone (to 7.6 ± 0.4 ng/ml) did not alter basal ACTH, cortisol, arterial pressure, or heart rate. However, ACTH and AVP responses to hypotension were augmented in progesterone-treated ewes compared with untreated ewes. Chronic progesterone treatment resulted in greater inhibition of ACTH by cortisol. Because chronic progesterone treatment did not decrease the ACTH response to hypotension or attenuate the feedback control of ACTH secretion, these results suggest that the changes in pituitary-adrenal control during pregnancy do not reflect a simple effect of progesterone alone.

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 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.

Glucocorticoid-mediated responses of plasma ACTH and anterior pituitary pro-opiomelanocortin, growth hormone and prolactin mRNAs during adjuvant-induced arthritis in the rat

1992 ◽  
Vol 9 (3) ◽  
pp. 273-281 ◽  
Author(s):  
A. Stephanou ◽  
N. J. Sarlis ◽  
R. A. Knight ◽  
S. L. Lightman ◽  
H. S. Chowdrey
Keyword(s):  
Mrna Expression ◽  
Hpa Axis ◽  
Negative Feedback ◽  
Anterior Pituitary ◽  
Feedback Inhibition ◽  
Feedback Effect ◽  
High Dose ◽  
Plasma Acth ◽  
Pomc Mrna ◽  
Prolactin Mrna

ABSTRACT Adjuvant arthritis (AA) in the rat leads to chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the loss of its diurnal rhythmicity. We have investigated the effects of adrenalectomy (ADX) and different levels of corticosterone replacement upon plasma ACTH levels and anterior pituitary pro-opiomelanocortin (POMC), GH and prolactin mRNAs during the development of AA. In control ADX animals, we observed the negative feedback effects of exogenous corticosterone on plasma ACTH and anterior pituitary POMC mRNA. In the ADX animal with AA, however, the increased POMC mRNA which was observed was not reduced by exogenous corticosterone on day 7 of AA, although the negative feedback effect of corticosterone on plasma ACTH was intact. On day 14, however, even high dose corticosterone replacement failed to have a significant feedback effect on the raised levels of plasma ACTH. In control ADX animals, corticosterone replacement resulted in increased anterior pituitary GH mRNA and reduced prolactin mRNA. In contrast, in ADX animals with AA, GH mRNA was reduced and there was a further decrease in prolactin mRNA. In these animals, corticosterone replacement did not affect GH or prolactin mRNA expression. These data demonstrate a disruption of the normal mechanisms underlying feedback inhibition of the HPA axis by glucocorticoids during AA. Similarly, the glucocorticoid-dependent regulation of GH and prolactin mRNA expression is altered in AA.

Nycterohemeral difference in inhibition of stress-induced ACTH in adrenalectomized rats

1983 ◽  
Vol 244 (2) ◽  
pp. E186-E189 ◽  
Author(s):  
M. M. Wilson ◽  
S. E. Greer ◽  
M. A. Greer
Keyword(s):  
Feedback Inhibition ◽  
Daily Variation ◽  
Plasma Corticosterone ◽  
Circadian Rhythmicity ◽  
Feedback Signal ◽  
Plasma Acth ◽  
Acth Secretion ◽  
Corticosterone Concentration ◽  
Feedback Suppression ◽  
Adrenalectomized Rats

To determine the interactions among the determinants of ACTH secretion, we examined the influence of circadian rhythmicity on glucocorticoid suppression of ACTH. Adrenalectomized rats were injected with the same amount of corticosterone at 0900 and 1800 h, and plasma ACTH concentrations were determined under basal conditions and after a standard ether stress. At 0900 h, corticosterone suppressed both basal and stress-induced plasma ACTH concentrations. At 1800 h, the same treatment suppressed basal ACTH secretion but not the stress-induced rise. Although the same amount of corticosterone was injected at both times of day, the plasma corticosterone concentration 5 min after injection was higher at 1800 h than at 0900 h. This study indicates that there is a nycterohemeral difference in feedback suppression of stress-induced ACTH secretion by a given dose of corticosterone. The daily variation in feedback inhibition may be due to the additive effect of the evening surge stimulus and the stress stimulus that together override the feedback signal.

Studies with Puromycin on the Mechanism of Negative Feedback Inhibition of ACTH Secretion by Glucocorticoids

Endocrinology ◽  
1967 ◽  
Vol 81 (6) ◽  
pp. 1415-1418 ◽  
Author(s):  
MONTE A. GREER ◽  
PATRICIA BARBER ◽  
CARLA ROCKIE
Keyword(s):  
Negative Feedback ◽  
Feedback Inhibition ◽  
Acth Secretion

IGF-I administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female rhesus monkeys

1995 ◽  
Vol 145 (1) ◽  
pp. 121-130 ◽  
Author(s):  
M E Wilson
Keyword(s):  
Negative Feedback ◽  
Rhesus Monkeys ◽  
Feedback Inhibition ◽  
Control Group ◽  
Feedback Effects ◽  
Adult Females ◽  
Serum Lh ◽  
Female Rhesus ◽  
Igf I ◽  
Intermediate Dose

Abstract Developmental increases in serum LH were assessed in female rhesus monkeys to test the hypotheses that (1) the final stages of puberty are characterized by a decrease in hypersensitivity to oestradiol negative feedback of LH and (2) that increases in IGF-I secretion accelerate this decrease in hypersensitivity. In order to test the first hypothesis, serum LH in the absence of oestradiol and in response to three doses of oestradiol were compared between ovariectomized adult (n=6) and adolescent female monkeys (control group; n=6). The control females were not treated with oestradiol until serum LH had risen to within the 95% confidence interval of serum LH observed in ovariectomized adults. Doses of oestradiol achieved serum levels of approximately 80 ('low'), 160 ('intermediate'), and 250 ('high') pmol/l. For control group females, treatment with the next higher dose of oestradiol was not initiated until serum LH was no longer suppressed by the lower dose. Treatment with oestradiol produced a dose-dependent suppression in serum LH in adults. In contrast, low-dose oestradiol maximally suppressed serum LH throughout the initial treatment period in the control group compared with the adult females. The low oestradiol dose effectively suppressed serum LH throughout the study period in 4/6 of the control group and became ineffective at suppressing LH after 8 months of treatment in 2/6 control group females. Initiation of the intermediate dose of oestradiol to these females again maximally suppressed LH compared with adult females. In order to determine whether IGF-I regulates this change in hypersensitivity to oestradiol negative feedback, a second group of ovariectomized, adolescent monkeys (n=6) were treated chronically with IGF-I to elevate serum IGF-I levels above those of control group females. Using the same protocol described for the control females, developmental changes in serum LH in the absence of oestradiol and in response to oestradiol negative feedback were evaluated. Treatment with IGF-I had no effect on the initial increases in serum LH occurring in the absence of oestradiol. In contrast, the decrease in hypersensitivity to the negative feedback effects of the low oestradiol dose was significantly accelerated in IGF-I-treated females, as the interval from the initiation of treatment to the point at which serum LH was no longer suppressed was shorter in IGF-I-treated (4·4±0·7 months; mean ± s.e.m.) compared with control group females (8·4±1·9 months). Although none of the control group females escaped from the negative feedback effects of the intermediate dose of oestradiol during the course of the study, 2/7 of the IGF-I-treated females did so within 5·5±1·4 months of the initiation of the treatment. The present data indicate that the later stages of puberty in female monkeys are characterized by a decreasing in sensitivity to oestradiol negative feedback inhibition of serum LH and that timing this decrease is regulated by circulating concentrations of IGF-I. These data confirm earlier reports that the developmental increases in the GH axis accelerate the tempo of puberty without affecting its onset. Journal of Endocrinology (1995) 145, 121–130

Fast, rate-sensitive corticosteroid negative feedback during stress

1978 ◽  
Vol 234 (1) ◽  
pp. R39-R45
Author(s):  
M. Kaneko ◽  
T. Hiroshige
Keyword(s):  
Negative Feedback ◽  
Feedback Inhibition ◽  
Fast Rate ◽  
Feedback Regulation ◽  
Plasma Corticosterone ◽  
Absolute Level ◽  
Corticosterone Concentration ◽  
Negative Feedback Regulation ◽  
Control Response ◽  
The Absolute

Characteristics of the fast, rate-sensitive, negative-feedback regulation of adrenocorticotropin secretion during stress was quantitatively analyzed using rats anesthetized with pentobarbital sodium. Various levels of plasma corticosterone were achieved during morning hours by infusing corticosterone solutions of different concentrations. Blood was sampled serially from the carotid artery. An increase in plasma corticosterone concentration 15 min after intravenous, pulsed injection of histamine (230 microgram) during saline intravenous infusion was defined as the “control response”. When plasma corticosterone was rising during corticosterone infusion, the response to histamine stimulus was distinctly inhibited (fast, rate-sensitive feedback inhibition), whereas such an inhibition was not observed when plasma corticosterone levels were not rising, regardless of the absolute level. The critical rate of rise of plasma corticosterone, at or above which the fast rate-sensitive feedback was manifested, was 4-6 microgram/100 ml per min. When three graded doses of histamine were injected while plasma corticosterone levels were increasing at a rate of 6 microgram/100 ml per min, the absolute value of the inhibition observed was indepxendent of the administered dose of the stressor. A hypothetical model for the mechanism of this feedback inhibition, based on the assumption that the hormone effect was proportional to the rate of formation of hormone-receptor complex, satisfied the quantitative characteristics of the inhibition experimentally observed in this study.

Inhibition of stimulated and basal ACTH by cortisol during ovine pregnancy

1996 ◽  
Vol 271 (1) ◽  
pp. R130-R136 ◽  
Author(s):  
M. Keller-Wood
Keyword(s):  
Pregnant Women ◽  
Negative Feedback ◽  
Adrenocorticotropic Hormone ◽  
Feedback Inhibition ◽  
Plasma Acth ◽  
Free Cortisol ◽  
Basal Plasma ◽  
Synthetic Glucocorticoid

In pregnant ewes, as in pregnant women, plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations are increased. Inhibition of free cortisol concentrations by dexamethasone, a synthetic glucocorticoid, is reduced in pregnant women compared with nonpregnant women. These experiments were designed to test the hypothesis that basal and stimulated ACTH concentrations are less sensitive to negative feedback inhibition by cortisol in pregnant ewes than in nonpregnant ewes. Ewes were infused with vehicle and with cortisol at two different rates (1 and 2 micrograms.kg-1.min-1) for 1 h; plasma ACTH concentrations during and after the infusion and after subsequent stimulation by hypotension were measured. Basal plasma ACTH concentrations during a 2-h infusion of cortisol (2 micrograms.kg-1.min-1) were also measured in undisturbed ewes. Cortisol significantly inhibited both stimulated and basal ACTH. The degree of suppression of ACTH was not reduced in the pregnant ewes compared with the nonpregnant ewes. The results indicate that both basal and stimulated ACTH are sensitive to negative feedback inhibition by cortisol during ovine pregnancy.

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