Glucocorticoid feedback control of corticotropin in the hypoxic neonatal rat

The objective of this study was to determine the effects of manipulating glucocorticoid negative feedback on acute ACTH and corticosterone responses to corticotropin-releasing hormone (CRH) injection in 7-day-old rats exposed to normoxia or hypoxia from birth. Chemical adrenalectomy was achieved with aminoglutethimide, and glucocorticoids were replaced with a low dose of dexamethasone. Hypoxia per se increased basal plasma corticosterone and attenuated the plasma ACTH response to CRH. Aminoglutethimide per se decreased plasma corticosterone and strongly increased basal plasma ACTH and anterior pituitary POMC gene expression. Dexamethasone partially attenuated elevations in basal plasma ACTH due to aminoglutethimide in both normoxic and hypoxic pups, but inhibited anterior pituitary POMC expression and CRH-induced plasma ACTH only in hypoxic pups. Despite this inhibition, hypoxic pups treated with both dexamethasone and aminoglutethimide still exhibited a significant CRH-induced increment in plasma ACTH, which was lacking in hypoxic pups not treated with either dexamethasone or aminoglutethimide. We conclude that ACTH responses to acute stimuli in hypoxic neonatal rats are prevented by ACTH-independent increases in corticosterone, rather than by intrinsic hypothalamic-pituitary hypoactivity.     

Ultradian plasma corticotropin and cortisol rhythms: time-series analyses

24-h plasma patterns of ACTH and cortisol were established in 6 subjects who had standard meals and in 4 subjects under continuous enteral nutrition. Temporal relationships between both hormones were analyzed. The individual assay data were subjected to time-series analyses to identify the periods of the oscillations in the plasma levels. The spontaneously occurring cortisol peaks were preceded by increases in ACTH levels, but z-score transformations clearly revealed that ACTH and cortisol were not quantitatively linked throughout the day. Individual subjects' power spectra gave evidence of a predominant periodicity in the oscillations of both hormones. These periodicities varied between individuals. They were 55-140 min for ACTH and 95-180 min for cortisol, indicating that, on occasion, a single cortisol peak may be initiated by two ACTH peaks. Cross spectral analysis of the individual data gave coherence spectra with a large peak which accounted for a substantial concordance of their period length, and cross variance spectra showed a consistent phase relationship between both hormones. These time series analyses applied to the data further support the concept that ACTH is the stimulating factor of cortisol release under basic conditions.     

Plasma corticotropin and cortisol in patients with pituitary adenomas.

Plasma ACTH and cortisol were measured during insulin-induced hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy and in 26 healthy persons. Adrenocortical insufficiency was defined as failure to increase plasma cortisol to at least 500 nmol/liter (18 microgram/dl) during hypoglycemia. No proper distinction was possible between patients with normal and impaired cortisol response to hypoglycemia on the basis of the ACTH results. When all 39 patients were compared to the 26 controls, the cortisol results differed significantly, but those of ACTH did not. These results demonstrate a limited value of ACTH measurements in secondary adrenocortical failure.     

Negative feedback regulation of adrenocorticotropin secretion by cortisol in ovine fetuses

The purpose of this study was to test the hypothesis that physiological increases in the fetal plasma cortisol concentration inhibit fetal ACTH responses to stress. Fetal sheep, between 121 and 131 days gestation, were infused with cortisol (4 micrograms/min) or vehicle for 5 h. One hour after the end of the cortisol or vehicle infusion, fetuses were infused with sodium nitroprusside (100 micrograms/min) to stimulate fetal ACTH and adrenal corticosteroid secretion. Cortisol, but not vehicle, elevated fetal plasma cortisol and suppressed the fetal ACTH and cortisol responses to nitroprusside. Cortisol and 11-deoxycortisol concentrations were significantly correlated in fetal plasma samples drawn during experiments in which cortisol was not infused; however, the cortisol to 11-deoxycortisol ratio was significantly increased during the infusion of nitroprusside. Fetal heart rate increased during vehicle infusion and decreased during cortisol infusion. Fetal blood pressure was not altered by either cortisol or vehicle infusion. Cortisol infusion increased fetal blood hemoglobin concentration, decreased maternal blood hemoglobin concentration, and produced metabolic acidosis in both mother and fetus. Vehicle infusion did not alter either fetal or maternal hemoglobin or pH. The data do not suggest an obvious mechanism for the cortisol-induced changes in fetal and maternal pH and hemoglobin or in fetal heart rate. However, some of the changes might be attributable to changes in fetal sympathetic outflow or to fluid shifts. We conclude that physiological increases in fetal plasma cortisol concentration: 1) inhibit subsequent ACTH responses to stress and 2) alter fetal cardiovascular function.     

Normal cortisol response to corticotropin in patients with secondary adrenal failure

A normal plasma cortisol response to exogenous corticotropin has been advanced as a reliable indication of adequate hypothalamic-pituitary-adrenal function in patients suspected of having secondary adrenal failure. We have examined the validity of this diagnostic strategy in five patients who had undergone hypophysectomy and 27 patients recently treated with glucocorticoids. Eleven of the patients had normal adrenal responses to cosyntropin but had subnormal responses when the entire hypothalamic-pituitary-adrenal axis was examined using metyrapone; no patient who responded normally to metyrapone failed to respond to cosyntropin. Inducing hypoglycemia with insulin yielded results concordant with the results induced by metyrapone in four patients tested. A normal cortisol response to corticotropin alone should not be relied on to exclude secondary adrenal insufficiency. To do this it is necessary to demonstrate normal activity of the entire hypothalamic-pituitary-adrenal axis, which can be conveniently examined using metyrapone.     

Modification of pituitary-adrenal feedback sensitivity in young rats by neonatal treatment with cortisol

Neonatal exposure of rats to cortisol acetate was found to alter pituitary-adrenal feedback regulation at 20-25 days of age. Plasma levels of adrenocorticotrophin (ACTH) after ether stress were reduced in cortisol-treated rats pre-treated with 100 microgram corticosterone/100 g body weight, while rats given vehicle neonatally did not show suppression of the ACTH response below levels in animals given saline only or not injected as pre-treatments. Neonatal cortisol increased sensitivity to dexamethasone in inhibition of the stress response; cortisol-treated animals had a reduced plasma corticosterone response to stress 3 h after pre-treatment with 1.25, 2.5, 25, or 250 microgram dexamethasone/100 g body weight, while the stress response in animals given vehicle neonatally was not inhibited by the lowest dosage of dexamethasone. Neonatal cortisol treatment did not affect corticosteroid-binding globulin (CBG) binding capacity in plasma of 25-day-old animals. Thus, neonatal treatment with cortisol appears to increase feedback sensitivity to circulating corticosteroids at 20-25 days of age.     

Fast glucocorticoid feedback favors 'the munchies'.

In a recent paper, Tasker and colleagues show that glucocorticoids (GCs) act rapidly, probably through membrane receptors, on corticotropin-releasing factor (CRF)-synthesizing cells to release endocannabinoids. These act locally at presynaptic axons via cannabinoid CB-1 receptors to reduce excitatory glutaminergic input, and therefore induce fast feedback inhibition of CRF by GCs. Similar findings in other hypothalamic neurons suggest that this action of GCs might be common in the brain, and could, in part, explain rapid GC effects on food intake.     

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.     

Scaling of morphogen gradients by an expansion-repression integral feedback control

Despite substantial size variations, proportions of the developing body plan are maintained with a remarkable precision. Little is known about the mechanisms that ensure this adaptation (scaling) of pattern with size. Most models of patterning by morphogen gradients do not support scaling. In contrast, we show that scaling arises naturally in a general feedback topology, in which the range of the morphogen gradient increases with the abundance of some diffusible molecule, whose production, in turn, is repressed by morphogen signaling. We term this mechanism “expansion–repression” and show that it can function within a wide range of biological scenarios. The expansion-repression scaling mechanism is analogous to an integral-feedback controller, a key concept in engineering that is likely to be instrumental also in maintaining biological homeostasis.     

Calcium-dependent control of corticotropin release in rat anterior pituitary cell cultures

The role of calcium in the stimulation of ACTH secretion by CRF and other regulators was studied in rat anterior pituitary cells. Incubation of cultured pituitary cells in normal calcium with CRF, vasopressin, angiotensin II, or norepinephrine increased the rate of ACTH release for up to 45 min and then became constant for up to 3 h. In the absence of extracellular calcium, the initial rate of stimulated secretion was unaffected, but after 45 min the secretion rate decreased by 40% for CRF and to a greater extent for the other stimuli. Addition of calcium after 90 min in calcium-free medium restored the CRF-stimulated ACTH release rate to the control value. The absence of extracellular calcium had no effect on CRF-stimulated cAMP accumulation, but intracellular calcium depletion by preincubation of the cells with EGTA completely inhibited CRF-stimulated cAMP production and ACTH release. The voltage-dependent calcium channel antagonist nitrendipine and the calcium channel agonist BK 8644 had little effect on the CRF-stimulated ACTH release rate, while they, respectively, inhibited and enhanced the stimulation by vasopressin and high potassium. In calcium-depleted cells incubated with the calcium ionophore A23187, CRF stimulation of cAMP production and ACTH release were dependent upon extracellular calcium concentrations from 0.1-100 microM. These findings have defined two phases in the stimulation of ACTH release by CRF and cAMP-independent stimuli in cultured pituitary cells: an early phase with a rapid increase in the ACTH release rate which is independent of extracellular calcium, and a late phase of constant secretion rate, with partial extracellular calcium dependence for the stimulation by CRF and complete calcium dependence for the stimulation by non-cAMP-mediated stimuli.     

Evidence for the onset of feedback regulation of cortisol in larval summer flounder

We investigated the functional development of feedback regulation of cortisol levels during early development in a marine teleost, summer flounder, using a novel pharmaceutical approach. Larvae were immersed for 4h in the glucocorticoid agonist dexamethasone (20 microM) and/or the glucocorticoid-receptor antagonist RU486 (0.12 microM) at 1, 7, or 21 days after hatching. The hypothesis was that, if feedback regulation were operational, tissue cortisol concentrations would be suppressed by dexamethasone and stimulated by RU486. Whole-body cortisol content of 1-day-old larvae was significantly decreased from 0.32 ng/g body weight (mean) to 0.08-0.12 ng/g by immersion in dexamethasone, RU486, or both, perhaps due to displacement of cortisol from the yolk sac. There were no changes in cortisol content among treatment groups in 7-day-old larvae. The expectations of our hypothesis were met in 21-day-old larvae. Immersion in RU486 increased cortisol content from 0.29 ng/g (control) to 2.00 ng/g, whereas immersion in dexamethasone (with or without RU486) suppressed cortisol to 0.03-0.04 ng/g. The results indicate that a fully functional hypothalamic-pituitary-interrenal axis is established by 3 weeks after yolk-sac resorption, but before the onset of metamorphosis in summer flounder. This is the earliest detection of feedback regulation in a teleost fish.