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PubMed2002

Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases.

Cushing's syndrome is associated with hypertension in approximately 80% of cases. Hypertension contributes to the marked increased mortality risk of past or current Cushing's syndrome, largely because of increased cardiovascular risk. Observation of the pathophysiological effect of chronically elevated ACTH and cortisol values in patients with ectopic ACTH secretion complements the available data from acute studies of the effects of ACTH and glucocorticoid infusions in normal volunteers. In a retrospective case review, we identified 58 patients with Cushing's syndrome caused by ectopic ACTH secretion, who were treated at the National Institutes of Health between 1983-1997. The diagnosis of an ectopic ACTH cause was confirmed by inferior petrosal sinus sampling and/or pathologic examination of tumor. The commonest causes were bronchial carcinoid (40%) and thymic carcinoid (10%), but 18 of 58 (31%) patients had an unknown source of ectopic ACTH. Hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg in adults) was noted in 45 of 58 (78%) ectopic Cushing's patients, a prevalence similar to that noted in other endogenous Cushing's syndrome etiologies. Hypertension was severe, deemed to require 3 or more drugs by the treating physicians, in 26 of 58 (45%) patients. Hypokalemia was much more prevalent than in patients with other causes of Cushing's syndrome, affecting 33 of 58 (57%) patients. The range of plasma ACTH (17-1557 pg/mL, normal <60) and 24-hour urine cortisol (UC) excretion (192-1600 mcg/24 hr, normal <90) allowed analysis of the influence of these hormones on blood pressure and plasma potassium. There was a significant relationship between 24-hour UC excretion and the presence of hypokalemia (P = 0.003). Eight of nine patients with a UC >6000 mcg/24 hr had hypokalemia. There was no relation between ACTH level and hypokalemia. In addition, we did not find blood pressure severity to be related to UC excretion or ACTH levels. Urine and plasma cortisol and cortisol metabolite measurements suggest that cortisol may act as a mineralocorticoid when in excess, perhaps by saturating the 11beta-hydroxysteroid-dehydrogenase (11beta-HSD2 enzyme) that inactivates cortisol at the renal tubule. The current data suggest that high cortisol levels may be the principal cause of hypokalemic alkalosis in Cushing's syndrome, rather than inhibition of the 11betaHSD2 enzyme by ACTH or the effects of adrenal steroid biosynthetic intermediaries with mineralococorticoid activity.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1986

Ovine fetal adrenal maturation at term and during fetal ACTH administration: evidence that the modulating effect of cortisol may involve cAMP.

Exogenous ACTH1-24 promotes adrenal maturation in fetal sheep, and this effect appears to be modulated in part by cortisol (Challis et al. 1985). We have examined whether similar changes in adrenal metabolism of progesterone occur with ACTH-induced labour as at spontaneous term and whether the site of cortisol modulation is on adrenal steroidogenesis or at the level of cAMP generation. Chronically catheterized fetal sheep were infused in utero for 100 h between days 127 and 131 of pregnancy with P-ACTH, P-ACTH + metopirone, P-ACTH + metopirone + cortisol, or saline. After 100 h the metabolism of [3H]progesterone was measured in adrenal homogenates. Similar incubations were performed with adrenal tissue from fetal sheep at day 130 of pregnancy and at spontaneous labour. In the treatment groups of sheep, cAMP output by dispersed adrenal cells in response to ACTH added in vitro was also determined. Similar qualitative patterns of [3H]progesterone metabolism were found in adrenal homogenates after in vivo ACTH or at term. At both times there was an increase in cortisol and in total 17 alpha-hydroxycorticosteroid accumulation and also evidence for increased activity of 11 beta-hydroxylase enzyme. The formation of total 17 alpha-hydroxycorticosteroids was not affected significantly by concurrent treatment in vivo with metopirone +/- cortisol. The accumulation of cAMP in vitro was increased after in vivo ACTH, attenuated after ACTH + metopirone, but statistical significance over controls was restored after ACTH + metopirone + cortisol treatment. We conclude that ACTH-induced labour and spontaneous parturition in sheep is associated with qualitatively similar changes in progesterone metabolism by the fetal adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxycorticosteroids↗
PubMed2005

Comparative analysis of ACTH and corticosterone sampling methods in rats.

A frequently debated question for studies involving the measurement of stress hormones in rodents is the optimal method for collecting blood with minimal stress to the animal. Some investigators prefer the implantation of indwelling catheters to allow for frequent sampling. Others argue that the implantation of a catheter creates a chronic stress to the animal that confounds stress hormone measures and therefore rely on tail vein sampling. Moreover, some investigators measure hormones in trunk blood samples obtained after anesthesia, a practice that may itself raise hormone levels. To address these controversies, we 1) compared plasma ACTH and corticosterone (Cort) concentrations in pre- and poststress rat blood samples obtained via previously implanted vena cava catheters, tail vein nicks, or clipping the tip off the tail and 2) compared plasma ACTH and Cort in rat blood samples obtained by decapitation with and without anesthesia. Rats sampled via indwelling catheters displayed lower prestress ACTH levels than those sampled by tail vein nick if the time to acquire samples was not limited; however, elevated basal ACTH was not observed in samples obtained by tail clip or tail nick when the samples were obtained within 3 min. Baseline Cort levels were similar in all groups. After restraint stress, the profile of the plasma ACTH and Cort responses was not affected by sampling method. Decapitation with prior administration of CO2 or pentobarbital sodium increased plasma ACTH levels approximately 13- and 2-fold, respectively, when compared with decapitation without anesthesia. These data indicate that tail vein nicking, tail clipping, or indwelling venous catheters can be used for obtaining plasma for ACTH and Cort during acute stress studies without confounding the measurements. However, the elevation in basal ACTH seen in the tail vein nick group at baseline suggests that sampling needs to be completed rapidly (<3 min) to avoid the initiation of the pituitary stress response. Death by CO2 and pentobarbital sodium injection before trunk blood collection cause significant stress to animals, as reflected in the elevated plasma ACTH levels. These results support the use of either chronic vascular cannulas or sampling from a tail vein. However, collection of blood under pentobarbital sodium or CO2 anesthesia is likely to confound the results of stress studies when ACTH is an important endpoint.

Adrenocorticotropic Hormone↗
PubMed1994

Cortisol feedback regulation of pulsatile ACTH secretion in fetal sheep during late gestation.

In fetal sheep, plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations increase during late gestation to surge within 72 h of birth (approximately 146 days gestation). To determine the feedback role of cortisol in control of pulsatile ACTH secretion, six chronically catheterized fetuses were treated with cortisol (1 microgram/h i.v.) for 96 h at 133 days gestation. Before (133 days), during (134 and 137 days), and after (142 days) cortisol treatment (5-min sampling for 2 h), ACTH pulses were evident in each fetus. At 134 days, ACTH pulse peak, nadir, and estimated secretory rate were significantly increased while frequency, amplitude, mean concentrations, and cortisol binding capacity (CBC) were unchanged. At 137 days, most characteristics of pulsatile ACTH secretion remained enhanced compared with pretreatment controls. At 142 days (96 h postinfusion), ACTH secretion parameters returned to pretreatment levels, but cortisol concentrations remained elevated. Cortisol infusion was then reinitiated at 142 days and, 22-24 h later, parameters of ACTH secretion increased except for amplitude, secretory rate, and CBC activity. The data indicate an absence of cortisol negative feedback regulation of pulsatile ACTH secretion. Rather, the ACTH rise that accompanied cortisol infusion suggests that cortisol exerts a positive feedforward influence on ACTH secretion in the ovine fetus near term.

Adrenocorticotropic Hormone↗
PubMed1983

Integral as well as proportional adrenal responses to ACTH.

To characterize adrenal responses to ACTH, conscious dogs were infused for 40 min with normal saline or 20-1,500 ng/min alpha-ACTH. Plasma ACTH and corticosteroid levels were measured during the infusion and for 80 min after the end of the infusion. Half-maximal plateau corticosteroid responses were achieved with ACTH levels of 105 pg/ml (23 pM); a maximal plateau corticosteroid response (10.2 micrograms/100 ml) resulted from ACTH levels greater than 335 pg/ml (74 pM). When levels of ACTH between 335 and 3,000 pg/ml were achieved during the 40-min infusion, the duration of maximal corticosteroid levels was prolonged beyond the duration of the ACTH infusion. Plasma ACTH concentration decreased after the end of the infusion with a half-disappearance time of 3.6 +/- 0.2 min, but plasma corticosteroid concentrations and cortisol and corticosteroid secretory rates remained at or above the plateau secretory rates during the infusion and for about 80 min after the end of an infusion of 1,000 ng ACTH/min. When the total corticosteroid responses to the ACTH infusions were estimated, the relationship between the total corticosteroid response and the logarithm of the ACTH concentration was linear for 80-3,000 pg ACTH/ml.

Adrenal Cortex Hormones↗
PubMed1986

Caudolateral areas of medulla-mediating release of ACTH in cats.

The effect of electrical stimulation of the caudolateral brain stem on plasma adrenocorticotropin (ACTH) was assessed in cats anesthetized with alpha-chloralose-urethan. To examine the influence of stimulus pattern on ACTH release, an equal number of pulses was presented in a continuous pattern and in a burst pattern at each electrode site. Stimulation of the magnocellular portion (layers 4-6) of trigeminal nucleus caudalis evoked a significant (P less than 0.01) and equal peak change in plasma ACTH after continuous pattern (+121 +/- 32 pg/ml) and after burst pattern stimuli (+126 +/- 30 pg/ml, n = 21). In contrast, stimulation of more ventromedial portions (layers 7-8) of nucleus caudalis had no significant effect on plasma ACTH. Stimulation of the trigeminal lateral cervical region the caudal extent of the A1 noradrenergic cell group, or the lateral reticular nucleus evoked significant peak increases in plasma ACTH regardless of stimulus pattern. Transient changes in arterial pressure accompanied brain stem stimulation and were not correlated with the changes in ACTH. The results indicate that stimulation of trigeminal subnucleus caudalis, a brain stem region that processes nociceptor afferent information, evokes a prompt increase in plasma ACTH. Stimulation of brain stem regions that process autonomic and cardiovascular afferent information (A1 region, lateral reticular nucleus) also facilitate ACTH release. No significant influence of stimulus pattern on brain stem-evoked ACTH release was seen. The results support the hypothesis that the influence of the central nervous system on ACTH release may be processed by parallel pathways at the caudal brain stem level.

Adrenocorticotropic Hormone↗
PubMed1994

The effect of intracarotid vasopressin infusion on ACTH release in neurohypophysectomized, conscious dogs.

Neurohypophysectomy (NHX) attenuates the adrenocorticotropic hormone (ACTH) response to arterial hypotension but not corticotropin-releasing hormone (CRH) or insulin-induced hypoglycemia in conscious dogs. The purpose of the present study was to determine if increasing vasopressin (AVP) in the cephalic circulation by carotid infusion normalizes the ACTH response to hypotension attenuated by NHX. Five male, conditioned dogs underwent controlled, acute decreases in arterial pressure (by approximately 25 mmHg) by infusion of sodium nitroprusside (NP) before and > 4 wk after selective NHX. ACTH increased from 40 +/- 3 to 242 +/- 79 pg/ml during NP in the intact state. This response was greatly attenuated after NHX (peak ACTH 81 +/- 15 pg/ml). Simultaneous intravenous infusion of AVP (12.5 ng/min) had a small, augmenting effect on the ACTH response to NP (peak ACTH 120 +/- 27 pg/ml). Intracarotid AVP (12.5 ng/min) greatly augmented the ACTH response to NP (peak ACTH 202 +/- 26 pg/ml) such that it was no longer different from the intact response. Neither intravenous nor intracarotid AVP infusion per se had a great effect on ACTH. A normal ACTH response to hypotension requires an intact neurohypophysis and is mediated by a cephalic action of magnocellular AVP.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Role of nitric oxide and carbon monoxide in modulating the ACTH response to immune and nonimmune signals.

The role played by nitric oxide (NO) and carbon monoxide (CO) was explored in the adult male rat by determining whether antagonizing the activity of the enzymes responsible for the formation of these gases altered the response of the hypothalamic-pituitary-adrenal (HPA) axis to immune (cytokines) or nonimmune (mild electroshocks) signals. The arginine derivative Nomeganitro-L-arginine-methylester (L-NAME), which inhibits all three NO synthase (NOS) isoforms [inducible (i), endothelial (e) and neuronal (n)] significantly augments the ACTH response to blood-borne cytokines, but decreases it in rats exposed to shocks or other physico-emotional stresses. The effect of L-NAME in both models is mimicked by L-nitroarginine (L-NNA) and L-nitromethylarginine (L-NMMA), which block constitutive (e and n) forms of NOS, but not by aminoguanidine (which blocks iNOS) or 7-nitroindazole (which specifically blocks nNOS). Despite the ability of L-NAME to markedly augment the stimulatory effect of vasopressin on ACTH secretion, removal of this peptide does not interfere with the interaction between L-NAME and systemically administered interleukin-1beta (IL-1beta). In contrast, blockade of prostaglandin formation prevents both the stimulatory effect of IL-1beta on ACTH release, and its potentiation by L-NAME. In contrast to the investigation of the importance of endogenous NO, studies focused on the role of CO remain scarce. Our preliminary results suggest that while blockade of the formation of this gas decreases the ACTH response to various stimuli, it also significantly interferes with the effect of L-NAME in rats systemically administered cytokines, and further decreases the ACTH response to shocks in animals also injected with arginine analogs. These results indicate the possible presence of functional interactions between NO and CO in regulating the activity of the HPA axis. Our present working hypothesis is that in the presence of elevated circulating cytokine levels, endogenous NO acts presynaptically to inhibit the release of ACTH secretagogues from nerve terminals in the infundibulum. As the acute ACTH response to these immune proteins is believed to primarily depend on events taking place within the median eminence, blockade of NO formation results in exaggerated ACTH release. During exposure to shocks and other nonimmune stresses, on the other hand, increased ACTH secretion is primarily due to activation of hypothalamic neurons. In this case, because of the stimulatory influence of endogenous NO on hypothalamic perikarya that manufacture corticotropin-releasing factor (CRF) and/or of the afferents to these neurons, blockade of NOS activity blunts CRF production, and consequently ACTH release. What remains undetermined is the net effect of the opposite influences of NO during long-term exposure to immune or nonimmune stress. Finally, it is possible that the conflicting results reported by investigators who study the role of NO and CO in isolated cell preparations may reflect, at least in part, these opposite effects of NO on different elements of the HPA axis.

Adrenocorticotropic Hormone↗
PubMed1998

Effects of dexamethasone and alprazolam, a benzodiazepine, on the stimulatory effect of hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans.

Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26-34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 microg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at -90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean +/- SEM: 28.0 +/- 6.7 vs. 11.7 +/- 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 +/- 15.0 vs. 137.7 +/- 12.6 microg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 +/- 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 +/- 2.5 microg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 +/- 0.9 pg/ml, p < 0.01 and 10.7 +/- 2.0 microg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 +/- 2.0 pg/ml) and cortisol levels (127.6 +/- 14.5 microg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 microg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 +/- 20.5 vs. 2.2 +/- 0.7 microg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 +/- 5.5 microg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 +/- 7.6 microg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.

Adrenocorticotropic Hormone↗
PubMed1976

In vitro release of ACTH from dispersed rat pars intermedia cells. I. Effect of secretagogues.

Studies were made to test the responsiveness of dispersed pars intermedia (PI) cells to a number of secretagogues, that are known to alter ACTH release from the pars distalis (PD) in vitro. In summary, (a) incubation in high (K+), which will increase ACTH release from the PD, did not alter ACTH release from the PI; (b) a crude extract of rat hypothalamus (HE) increased ACTH release from PD and PI; (c) the effect of HE was not due to its vasopression content, since pretreatment of the extract with thioglycolic acid did not modify its ACTH-releasing activity and neither lysine nor arginine vasopressin stimulated ACTH release from the PI; and (d) a partially purified CRF preparation, which will stimulate ACTH release from the PD, did not alter ACTH release from the PI. We conclude that the hypothalamus contains a substance(s) that will stimulate ACTH release from the PI and that the 'secretagogue' is neither vasopressin nor the same CRF that will stimulate ACTH release from the PD.

Adrenocorticotropic Hormone↗
PubMed1987

Intracerebroventricular infusion of a cyclic hexapeptide analogue of somatostatin inhibits hemorrhage-induced ACTH release.

This study examines the effect of intracerebroventricular infusion of the 'superactive' somatostatin (SRIF) analogue cycl--(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) on the plasma adrenocorticotrophic hormone (ACTH) response to hemorrhage in conscious sheep. Hemorrhage (15 ml/kg over 15 min) increased plasma ACTH from 55 +/- 20 to 815 +/- 148 pg/ml at 30 min (p less than 0.001). Infusion of the SRIF analogue intracerebroventricularly at 0.08 microgram/min for 10 min prior to and for 60 min after commencement of hemorrhage resulted in a partial inhibition of the plasma ACTH response. Infusion of the analogue at 0.8 microgram/min blocked the increase in plasma ACTH at 30 min. Plasma ACTH was 21 +/- 3 pg/ml as control and 66 +/- 47 pg/ml at 30 min. The SRIF analogue had no effect on plasma ACTH in the same animals in control experiments with no hemorrhage. These studies suggest that SRIF may act as a central inhibitor of ACTH release. The mechanism by which the SRIF analogue inhibits ACTH secretion is unknown but could involve inhibition of corticotropin-releasing factor release and/or an inhibition of ACTH release from the pituitary gland. The route of administration of the SRIF analogue and the finding that the SRIF analogue did not prevent systemic corticotropin-releasing factor stimulation of ACTH suggest an effect of the SRIF analogue in the hypothalamus.

Adrenocorticotropic Hormone↗
PubMed1987

Site at which angiotensin II acts to stimulate ACTH secretion in vivo.

To investigate the site at which angiotensin II (AII) acts to increase adrenocorticotrophic hormone (ACTH) secretion, the effects of intraventricular (IVT) or intravenous (IV) injection of the AII antagonist saralasin on the ACTH responses to IVT or IV injection of AII were examined in conscious male rats. AII does not cross the blood-brain barrier, but IVT as well as IV saralasin are known to prevent the binding of circulating AII to circumventricular organs. IV AII (0.2-200 ng) induced dose-related increases in ACTH secretion and a transient increase in the corticotrophin-releasing hormone (CRH) content of the median eminence. IVT injection of saralasin (10 micrograms) blocked the ACTH responses to IV AII. The same dose of saralasin given intravenously did not produce a comparable decrease in the ACTH response to IV AII. IVT injection of 1 and 10 ng AII increased plasma ACTH in a dose-related manner. The increase in plasma ACTH induced by IVT administration of angiotensin was not inhibited by IV infusion of saralasin (12 micrograms/kg/min). On the other hand IV infusion of this dose of saralasin abolished or reduced the ACTH response to IV injection of larger doses of AII. These data support the conclusion that circulating AII stimulates ACTH secretion by acting on the circumventricular organs to increase CRH secretion. They also suggest that AII receptors inside the blood-brain barrier as well as AII receptors in the circumventricular organs trigger increases in ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1994

Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1 beta into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1 beta can access the brain to stimulate CRH and, consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 beta to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL beta (100 nl delivered over 60 s) showed that 97% remained within 200 microns of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 microns of the injection site in the sagittal plane. Additional rats received recombinant human IL-1 beta (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-1 beta than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-1 beta. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-1 beta. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-1 beta from hypothalamic explants, as well as the ACTH response to intravenous IL-1 beta. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 beta delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-1 beta (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 micrograms (p < 0.001) = 2.0 micrograms < 4.0 micrograms (p < 0.05). Responses to PGF2 alpha were: CSF < 0.5 micrograms (p < 0.001) < 2.0 micrograms (p < 0.05) = 4.0 micrograms. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1977

Effects of hypothalamic extract and corticosterone on incorporation of 14C-phenylalanine into newly synthesized ACTH-like protein in vitro.

The purpose of the present experiments was firstly, to examine the efficacy of the oxycellulose-Amberlite CG-50 extraction procedure for the isolation of rat pituitary ACTH and secondly, to study the effects of both hypothalamic extract and corticosterone on the synthesis of rat pituitary ACTH. Briefly, 'cold' rat pituitary ACTH was monitored by bioassay in each step of the isolation procedure as a function of corticosterone stimulation in incubated adrenal slices. Labeled ACTH was isolated from rat pituitaries previously incubated in vitro and obtained from adrenalectomized animals and cortisone acetate treated animals to provide further data to substantiate that the labeled isolated protein contained ACTH. Cold ACTH was detected in two purified fractions (oxycellulose and Amberlite CG-50). Adrenalectomy stimulated and cortisone acetate suppressed the incorporation of 14C-phenylalaine into the ACTH-like protein in these two fractions. A continuously increasing uptake of the label into ACTH-like protein in the isolated fractions occurred with time providing evidence that de novo synthesis had taken place. Corticosterone inhibited ACTH synthesis at both 10(-4) and 10(-6) M, whereas, hypothalamic stalk median eminence (HSME) caused a significant, but not dose-related, increase in ACTH synthesis with 3/5, 1, and 2 HSME equivalents added.

Adrenalectomy↗
PubMed1984

Dissociation of plasma cortisol and ACTH responses to dexamethasone in healthy subjects.

We examined the plasma cortisol and ACTH concentrations after graded doses of dexamethasone in a group of young, healthy adults. The decrease in cortisol was uniform in all subjects, and in 8 subjects there was a high degree of correspondence with the plasma ACTH concentration. The remaining 5 subjects had no change in plasma ACTH concentration during dexamethasone administration. All subjects had an expected diurnal change in cortisol on 2 pretreatment days and there was a corresponding diurnal change in ACTH for those subjects who had associated ACTH and cortisol responses after dexamethasone, while those with dissociated ACTH and cortisol after dexamethasone had no diurnal ACTH pattern. These findings were consistent with the 24-hour pattern of ACTH and cortisol before and after 1.0 mg of dexamethasone in 2 of the same subjects. These results are further evidence for ACTH independent regulation of adrenal function and indicate that pituitary-adrenal regulation in man is more complex than the traditional model of ACTH-cortisol feedback would predict.

Adrenocorticotropic Hormone↗
PubMed1985

Inhibition of the ACTH adrenal response to stress by treatment with hydrocortisone, prednisolone and dexamethasone in the rat.

16- and 4-week-old intact and adrenalectomized rats have been treated with different doses of the three glucocorticoids hydrocortisone, prednisolone and dexamethasone by gavage. The delayed feedback effect on plasma ACTH and corticosterone response to an ether stress have been assessed. Almost complete suppression of corticosterone response 20 min after an ether stress and an ACTH suppression to 20% of control values 5 min after an ether stress were observed with 25 micrograms of dexamethasone, 10 mg of prednisolone and 20 mg of hydrocortisone. Although the percent inhibition of corticosterone and ACTH response to stress was comparable, a striking dissociation of the ACTH and corticosterone release was observed in terms of absolute concentrations. A mean ACTH concentration of 462 ng/l after 25 micrograms of dexamethasone was measured together with a barely measurable corticosterone concentration of 3 micrograms%. Similarly, after 10 mg of prednisolone, the mean ACTH concentration was 404 ng/l, whilst the mean corticosterone concentration was 3 micrograms%. This dissociation demonstrates that the corticosterone concentration on its own does not necessarily reflect the ACTH release. At 4 weeks of age, the ACTH response to stress is more difficult to suppress than in adult animals. This is more obvious after adrenalectomy, where the excessive ACTH secretion was less inhibited by all glucocorticoids used. The time between the last steroid gavage and stress must be considered. In 4-week-old animals the ACTH response 16 h after 12.5 micrograms of dexamethasone was inhibited by 22%, whereas 4 h after the same dexamethasone dose the inhibition was 85%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1993

Simultaneous and bilateral inferior petrosal sinus sampling for the diagnosis of Cushing's syndrome: comparison of multihormonal assay, baseline multiple sampling and ACTH-releasing hormone test.

In 29 consecutive patients with adrenocorticotropin (ACTH)-dependent Cushing's syndrome, we compared the usefulness of multiple baseline ACTH evaluations (10/29), multiple hormone evaluation (29/29) and ACTH-releasing hormone (CRH) stimulation (21/29) during simultaneous and bilateral inferior petrosal sinus sampling. The basal inferior petrosal sinus/periphery ratio for ACTH concentrations was greater than 2 in 18 of the 29 patients and CRH challenge caused the appearance of an inferior petrosal sinus/periphery ratio greater than 3 in 6 other patients. The presence of an ACTH-secreting adenoma was surgically proven in all the 24 patients who had an ACTH inferior petrosal sinus/periphery ratio greater than 2 basally or greater than 3 after the CRH test but also in 1 patient who had an inferior petrosal sinus/periphery ratio lower than 2 basally or 3 after the CRH test. In 4 patients, both the very high peripheral ACTH levels, the inferior petrosal sinus/periphery ratio and the complete lack of ACTH increase after CRH indicated the presence of an ectopic ACTH syndrome: a bronchial carcinoid was found in 2 patients, whereas the site of the tumor is still unknown in the remaining 2. An ACTH intersinus gradient greater than 1.4 was found in 23 patients. Among these 23 patients, the side of the adenoma was correctly predicted in 19 patients and wrongly in 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1975

Ectopic production of big ACTH in carcinoma of the lung. Its clinical usefulness as a biologic marker.

This report considers the potential usefulness of adrenocorticotropic hormone (ACTH) determinations in diagnosis and in prognosis for therapy of patients with carcinoma of the lung but without clinical Cushing's syndrome. The report is based on radioimmunoassay data from 129 patients, including 62 with lung cancers and 67 with nonmalignant pulmonary conditions. Elevated plasma ACTH was found in 21 of 24 patients with untreated cancer and the hormone was detected in tumor extracts and/or bronchial washings from the remaining 3. Elevation of plasma ACTH was found in only 10 of 38 treated patients. Absence of clinical Cushing's syndrome in spite of high plasma ACTH concentrations is explained by the observation that the predominant form of ectopic ACTH in plasma is immunoreactive but nonbioactive 'big' ACTH. Prolonged survival, for longer than 19 months, was observed in only 5 patients: all patients with low plasma ACTH after resection of the lung tumor and 2 of 3 patients with low plasma ACTH without therapy. ACTH was found in all available malignant tissue, primary and metastatic, from the lung carcinoma group,but not in normal lung or in 5 tumors metastatic to the lung. Of the 39 patients diagnosed initially to have chronic obstructive pulmonary disease, 14 showed plasma ACTH elevation. However, 3 of these patients with the highest concentrations subsequently manifested carcinoma or carcinoma in situ.

Adrenal Cortex↗