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PubMed1991

Bivalent ACTH antagonists: influence of peptide and spacer components on potency enhancement.

The antagonist potency of a series of bivalent adrenocorticotropic hormone (ACTH) peptides was examined using suspensions of inner zone rat adrenocortical cells. Bivalent antagonists were prepared by bis(maleimide) covalent cross-linking of carboxyl terminal cysteine sulfhydryl groups of synthetic ACTH peptides, Cys25 ACTH(7-25) and Cys39 ACTH(7-39). Antagonist potency enhancement was defined by shifts in ACTH(1-39) concentration-steroidogenic response curves relative to monovalent antagonist analogs. The EC50 values measured in the presence of 0.5 microM monovalent antagonist were 110 +/- 28 pM for Cys25 ACTH(7-25)-S-N-ethylsuccinimide and 44 +/- 9 pM for Cys39 ACTH(7-39)-S-N-ethylsuccinimide. Some bivalent ACTH antagonists displayed much greater antagonist potency than their monovalent analogs, which supports the findings of Stolz and Fauchere (Helv Chim Acta 71: 1421-1428, 1988). The level of potency enhancement, however, was found to be dependent upon the spacer used to link receptor binding domains and the length of the ACTH peptide used in bivalent antagonist synthesis. The most potent inhibitor, bis(Cys25 ACTH(7-25)-S-succinimidopropionyl)2-hydroxy-1,3-propanediamine, was 28 times more potent than its monovalent analog, Cys25 ACTH(7-25)-S-N-ethylsuccinimide. However, a bivalent Cys25 ACTH(7-25) peptide containing two bis(succinimidopropionyl)2-hydroxy-1,3-propanediamine spacers that had been linked end-to-end via dithioerythritol showed no potency enhancement. Cys25 ACTH(7-25) based peptides containing one receptor binding domain and having the structure peptide-spacer-cysteine displayed no enhancement in antagonist potency. Bivalent Cys39 ACTH(7-39) linked by bis(succinimidopropionyl)2-hydroxy-1,3-propanediamine spacer exhibited only 4-fold enhancement in antagonist potency relative to Cys39 ACTH(7-39)-S-N-ethylsuccinimide. We therefore conclude that the potency enhancement observed with bivalent ACTH peptides: (1) is optimal with spacers less than approximately 40 A in length, (2) is not due to direct interactions between the spacer and cell surface, and (3) is dependent on the length of the ACTH peptide component. In addition, these results indicate that electrostatic interaction between bivalent ACTH peptides and plasma membrane lipids does not adequately account for the potency enhancements observed.

Adrenal Cortex↗
PubMed2002

Plasma concentrations of ACTH precursors correlate with pituitary size and resistance to dexamethasone in dogs with pituitary-dependent hyperadrenocorticism.

This study was performed to determine whether in dogs with pituitary-dependent hyperadrenocorticism (PDH) excessive release of adrenocorticotrophic hormone (ACTH) is accompanied by secretion of ACTH precursor molecules. In addition, we investigated whether the plasma ACTH precursor concentrations were correlated with the size of the pituitary gland and with the degree of resistance to negative glucocorticoid feedback. In 72 dogs with PDH, the plasma ACTH precursor concentration was determined by calculating the difference between the results of a radioimmunoassay (RIA) in which besides ACTH, ACTH precursors were also measured and a highly specific immunoradiometric assay (IRMA) using a polyclonal antibody against ACTH. The degree of resistance to glucocorticoid feedback was established by determining the effect of dexamethasone administration (0.1mg/kg) on the urinary corticoid/creatinine ratio. The pituitary height/brain area (P/B) ratio, determined by computed tomography, was used as a measure for the size of the pituitary gland. The plasma ACTH precursors concentration ranged from 18 to 2233ng/L (median 93ng/L). In 38 dogs, the pituitary was enlarged and plasma ACTH precursors concentrations in these dogs (median 130ng/L, range 24-2233ng/L) were significantly (P<0.05) higher than those in the dogs without pituitary enlargement (median 72ng/L, range 18-481ng/L). In concordance, P/B ratios correlated significantly with plasma ACTH precursor concentrations (r=0.35, P<0.01). In addition, the P/B ratios were significantly correlated with the degree of dexamethasone resistance (r=0.42, P<0.001). Plasma ACTH precursor concentrations in the dexamethasone-resistant dogs (median 210ng/L, range 24-628ng/L) were significantly higher (P<0.01) than those in the dexamethasone-sensitive dogs (median 72ng/L, range 18-2233ng/L). Similarly, the degree of dexamethasone resistance was also significantly correlated with the plasma ACTH precursor concentrations (r=0.33, P<0.01). Dogs with an elevated plasma alpha-MSH concentration (n=14) had significantly (P<0.001) higher plasma ACTH precursor concentrations (median 271ng/L, range 86-2233ng/L) than dogs with non-elevated alpha-MSH (median 73ng/L, range 18-481ng/L). In addition, the plasma concentrations of alpha-MSH correlated significantly with both plasma ACTH precursor concentrations (r=0.53, P<0.001) and P/B ratios (r=0.26, P<0.05). In conclusion, in all dogs with PDH the ACTH concentrations determined by the RIA were higher than the concentrations measured by IRMA indicating the presence of circulating ACTH precursors. High plasma ACTH precursor concentrations were especially found in dexamethasone-resistant dogs with large corticotroph adenomas, some of them probably of PI origin. In the association of large corticotroph adenoma, dexamethasone resistance and high plasma concentrations of ACTH precursors, the decreased sensitivity of the corticotroph cells to glucocorticoid feedback may play a pivotal role.

Adrenal Cortex↗
PubMed1976

Effects of ACTH and its O-nitrophenyl sulphenyl derivative on adrenocortical function in vivo.

Both ACTH and NPS-ACTH in which the single tryptophan residue of the hormone is modified were able to stimulate adrenal corticosterone concentration to the same extent in hypophysectomized rats, although a higher dose of NPS-ACTH was required. ACTH stimulated adrenal cyclic AMP levels 120-fold in hypophysectomized rats whereas NPS-ACTH caused a marginal increase. In the case of ACTH, low doses of the hormone capable of producing maximal stimulation of corticosterone synthesis did not produce any detectable change in cyclic AMP concentration. The rates of secretion of corticosterone induced by ACTH and NPS-ACTH in vivo were the same. NPS-ACTH was found to be 1.2% as potent as ACTH. The role of cyclic AMP in adrenal repair was investigated by administering equipotent doses of ACTH or NPS-ACTH to hypophysectomized rats. In adult rats both failed to produce a significant increase in adrenal weight. Adrenal function (measured by responsiveness to exogenous ACTH in vitro) was restored by NPS-ACTH but not to the same degree as ACTH. In hypophysectomized weanling rats, ACTH produced a small but significant increase in adrenal weight but NPS-ACTH did not. These results suggest that an increase in adrenal cyclic AMP may not be obligatory for the stimulation of steroidogenesis by ACTH and that some of the trophic actions of the hormone may be mediated by cyclic AMP.

Adenylyl Cyclases↗
PubMed1989

Gel chromatographic characterization of immunoreactive adrenocorticotropin in patients with ACTH hypersecretion.

We investigated the molecular size of circulating immunoreactive ACTH by gel chromatography in patients with ACTH hypersecretion due to various disorders of the hypothalamic-pituitary-adrenal axis. 4 patients with Addison's disease, 2 with Nelson's syndrome, 4 with Cushing's disease, 6 with the ectopic ACTH syndrome (2 bronchial carcinoma, 1 medullary carcinoma, 1 metastatic islett cell carcinoma, 1 benign bronchial carcinoid and 1 patient with occult ectopic Cushing's syndrome) and 1 patient with hypersecretion of ACTH from a clinically nonfunctioning pituitary adenoma were studied. Analysis of the molecular size of immunoreactive ACTH was performed by gel chromatography on a Sephadex G-75 column (superfine, 100 x 1.5 cm) equilibrated with 1% formic acid. 2 ml fractions were collected and evaporated to dryness. The ACTH content of the recovered samples was determined by RIA. In Addison's disease, Nelson's syndrome and Cushing's disease the plasma showed a single peak of ACTH immunoreactivity at the expected position of 1-39 ACTH. In the ectopic ACTH syndrome the plasma of 4 patients revealed at chromatography at least one other peak eluting between the void volume and 1-39 ACTH suggestive of a high molecular weight form of ACTH whereas plasma of 2 patients showed only a single ACTH peak at the position of labeled 1-39 ACTH. The patient with a clinically non-functioning pituitary adenoma revealed a gel filtration pattern similar to the patients with ectopic ACTH syndrome and secretion of high molecular weight ACTH. We conclude that secretion of high molecular weight forms of ACTH is not a unique feature of the ectopic ACTH syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

ACTH Syndrome, Ectopic↗
PubMed2003

Characterisation of ACTH related peptides in ectopic Cushing's syndrome.

Adrenocorticotrophin (ACTH) is derived by cleavage from the precursor, pro-opiomelanocortin (POMC), and depending on the degree of processing by the tissue or tumor, there is the potential for a number of ACTH-related peptides to be secreted from POMC expressing cells. Previous chromatographic approaches have indicated the presence of high molecular weight forms of ACTH in the human peripheral circulation. However a quantitative assessment of the degree of processing requires two-site immunoradiometric assays which distinguish ACTH precursors and ACTH. Using this approach, we have previously identified the precursors of ACTH (POMC and proACTH) in the circulation of normal subjects in the range 5-40 pmol/l, which suggests that processing in the normal pituitary cell is incomplete. This study aimed to examine the extent of POMC processing by tumors that give rise to Cushing's Syndrome as a means of evaluating its usefulness as a diagnostic marker. In a retrospective analysis of 86 patients with Cushing's Syndrome, 34/35 patients with pituitary tumors had low levels of ACTH precursors (below 100 pmol/l) and the mean ratio of ACTH precursors:ACTH was 5:1 which indicates that these tumors do process POMC to ACTH relatively efficiently. In ectopic Cushing's Syndrome, it is unlikely that the extra-pituitary tumor cells, process POMC as efficiently. Therefore increased prevalence of ACTH precursors in the circulation would be expected and this was substantiated by the large excess of ACTH precursors (139-18,000 pmol/l) in the circulation of the 51 patients with the ectopic ACTH Syndrome. The diagnostic accuracy of the measurement of ACTH precursors was then prospectively compared with a group of 62 patients undergoing the current "gold standard" test of inferior petrosal sinus sampling (IPSS). All those patients with ACTH precursors below a diagnostic cut-off of 100 pmol/l were subsequently shown to have pituitary tumors, whereas levels of >100 pmol/l were seen in the four patients with ectopic tumors. In comparison the IPSS had a specificity of 100% but a sensitivity of 93% and for these false negative results the ACTH precursors proved diagnostically useful. Therefore measurement of ACTH precursors offers a simple non-invasive diagnostic test for the differential diagnosis of Cushing's Syndrome which compares favourably with IPSS.

ACTH Syndrome, Ectopic↗
PubMed1986

The development and validation of a radioimmunoassay to measure plasma ACTH levels in salmonid fishes.

A radioimmunoassay (RIA) capable of determining blood ACTH levels in salmonid fishes was developed and validated. The RIA used an antibody raised against mammalian ACTH, iodinated human ACTH as tracer, and human 1-39 ACTH as standard. Incubation of the standard or unknown with antibody for 3 days before addition of as little high-specific activity tracer as practicable (1500 cpm; equivalent to 5 pg ACTH) produced a very sensitive RIA; the operating range was 5 to 200 pg ACTH/ml. Extracts of both pars distalis and neurointermediate lobe of the pituitary glands from a range of salmonid species diluted parallel to the ACTH standard in the RIA. There was always considerably more ACTH-immunoreactivity (ACTH-IR) in the pars distalis extracts than in the neurointermediate lobe. Generally plasmas also diluted parallel to the ACTH standard, with the exception only of the plasma from sexually mature female salmonids, which diluted very non-parallel to the standard, leading to unrealistically low estimates of the ACTH-IR level. The use of heparin as an anticoagulant during collection of samples caused problems when these plasmas were immunoassayed; instead EDTA was found to be a suitable anticoagulant. When the ACTH-IR was extracted from a pool of plasma obtained from acutely stressed salmon and chromatographed on a column of BioGel P6, followed by subsequent ACTH RIA of the fractions, only a single sharp peak of ACTH-IR was detected, which eluted in the position of authentic 1-39 ACTH. The plasma ACTH-IR level in unstressed fish was low, and near the detection limit of the RIA. An acute stress, produced by crowding and confinement for 30 min, increased ACTH-IR approximately 10-fold, and plasma cortisol levels 50-fold, but the plasma alpha-MSH level was not affected. Dexamethasone-treated fish did not respond to this stressor with any increase in either ACTH or cortisol levels.

Adrenocorticotropic Hormone↗
PubMed1983

Effects of ACTH on steroidogenesis in bovine adrenocortical cells in primary culture--increased secretion of 17 alpha-hydroxylated steroids associated with a refractoriness in total steroid output.

The long-term effects of ACTH on steroidogenesis in bovine adrenocortical cells maintained in primary culture have been investigated. Cells in monolayer culture were incubated in the presence or absence of ACTH for up to 72 h, and the steroid content of the incubation medium was assayed at 12 h intervals. During the first 12 h, adrenocortical cells incubated in the presence of ACTH (10(-9) M and 10(-6) M) produced substantially more cortisol and corticosterone than did cells incubated in the absence of ACTH. The production of steroidogenic intermediates such as pregnenolone, progesterone, and 17 alpha-hydroxypregnenolone, as well as 17 alpha-hydroxyprogesterone, 11-deoxycortisol, and 11-deoxycorticosterone also was increased by short-term (12 h) treatment with ACTH. Thereafter, corticosteroid production by cells incubated in the continued presence of ACTH decreased in a time and concentration dependent fashion. The maximal rate of cortisol production by cells incubated in the presence of ACTH (10(-9) M and 10(-6) M) for 72 h was only one third that of cells incubated in the presence of ACTH for 12 h. More dramatically, by 36 h, corticosterone secretion by cells incubated in the presence of ACTH (10(-6) M) declined to less than 20% of that of nontreated cells, and the production of 11-deoxycorticosterone was no longer detectable. ACTH also induced refractoriness in the production of other C21-steroids (pregnenolone, progesterone, 17 alpha-hydroxypregnenolone, 17 alpha-hydroxyprogesterone, and 11-deoxycortisol) as well as of C19-steroids (dehydroepiandrosterone, androstenedione, and 11 beta-hydroxyandrostenedione). The ACTH-induced refractoriness in the production of C21-steroids lacking a 17 alpha-hydroxyl group occurred earlier than that of 17-hydroxylated C21-steroids. Despite the decline in total corticosteroid production, the long term effect of ACTH was to enhance the relative secretion of 17 alpha-hydroxylated steroids and C19-steroids. Adrenocortical cells incubated for 72 h in the presence of ACTH continued to secrete cortisol, 17 alpha-hydroxyprogesterone, 11-deoxycortisol, and 11 beta-hydroxyandrostenedione in increased amounts. In fact, 11-deoxycortisol became a major secretory product of the ACTH-refractory adrenocortical cell. These results are indicative that ACTH acts in diverse manners on the bovine adrenocortical cell to affect corticosteroid secretion. The initial stimulation of corticosteroid production appears to be reflective of an increase in overall substrate (cholesterol) utilization and probably is mediated, in part, by an increase in cholesterol side chain cleavage activity. The secretion of 17 alpha-hydroxysteroids and C19-steroids is enhanced further by an action of ACTH to increase 17 alpha-hydroxylase activity and possibly also 17,20-lyase activity. The ACTH-induced refractoriness in corticosteroid production, on the other hand, appears to result primarily from a decline in precursor (cholesterol) utilization.

Adrenal Cortex↗
PubMed1984

The prolonged stimulatory effect of ACTH on 11 beta-hydroxylation, and its contribution to the steroidogenic potency of adrenocortical cells.

The mechanism of the prolonged stimulatory influence of corticotropin (ACTH) on the capacity of adrenocortical cells to produce cortisol in response to ACTH and more specifically the role of 11 beta-hydroxylation, was studied on guinea-pig adrenocortical cells dispersed from control and ACTH-treated animals. As a result of the previous in vivo exposure to ACTH, the net maximal production of glucocorticoids in response to ACTH (by 10(5) cells and 2 h incubation) increased from 660 +/- 33.9 ng (control group) to 1105 +/- 117.9 ng for cells from ACTH-treated animals (P less than 0.001), whereas the apparent affinity of the steroidogenic response remained unchanged. In addition there occurred an increased conversion of exogenous pregnenolone into cortisol by cells from ACTH-treated animals, indicating a prolonged stimulatory influence of ACTH on the post-pregnenolone pathway of cortisol biosynthesis. The activity of 11 beta-hydroxylation step was therefore examined by incubating the adrenocortical cells from control and ACTH-treated animals in the presence of increasing amounts of 11-deoxycortisol. The maximal capacity of 11-deoxycortisol conversion into cortisol was increased as a result of the in vivo exposure to ACTH, averaging 3423 +/- 211 ng cortisol formed from 5 micrograms 11-deoxycortisol by 10(5) cells from ACTH-treated animals vs 2074 +/- 185 ng for cells from control guinea-pigs (P less than 0.001). However, the conversion of lower amounts of 11-deoxycortisol into cortisol, reproducing quantitatively the maximal effect of ACTH on cortisol biosynthesis, was only barely increased in cells from ACTH-treated animals (P greater than 0.05). Therefore it was concluded that ACTH increases in a lasting way not only the overall steroidogenic capacity of adrenocortical cells but also the maximal efficiency of 11 beta-hydroxylation. Since the latter effect cannot account quantitatively for the magnitude of the lasting effect of ACTH on the maximal capacity of adrenocortical cells to produce cortisol in response to ACTH, it appears that the prolonged influence of ACTH on cortisol biosynthesis should also involve a stimulatory influence of the peptide on earlier step(s) of steroidogenesis.

Adrenal Cortex↗
PubMed2005

Plasma progesterone response following ACTH administration during mid-gestation in the pregnant Brahman heifer.

Previous reports of adrenal progesterone (P4) contributions during late gestation in cattle, and ACTH-induced P4 responses in the non-pregnant heifer, prompted a retrospective investigation to evaluate the plasma P4 response and the relative ratio of plasma cortisol (CT) to P4 following ACTH administration during mid-gestation in pregnant Brahman heifers. Twenty-three pregnant (139.0 +/- 5.0 days of gestation) Brahman heifers received one of the following treatments: 0 (saline; n = 5), 0.125 (n = 4), 0.25 (n = 5), 0.5 (n = 4), or 1.0 (n = 5)IU of ACTH per kg BW. Blood samples were collected at -15 and -0.5 (time 0), 15, 30, 45, 60, 75, 105, 135, 165, 195, and 255-min post-ACTH challenge. Plasma P4 and CT were quantified by RIA. Pre-ACTH P4 did not differ (P > 0.10) among ACTH treatment groups (pooled, 12.1 +/- 0.6 ng/mL). Among peak P4 values at 15-min post-ACTH infusion, control P4 (9.6 +/- 1.2 ng/mL) tended to be lower (P < 0.07) than 0.5 IU ACTH-treated heifers (13.3 +/- 1.1 ng/mL); and were lower (P < 0.02) than 0.25 and 1.0 IU ACTH-treated heifers (14.7 +/- 1.1 and 22.2 +/- 3.7 ng/mL, respectively). During the primary P4 response period (0 to 75-min post-ACTH), the area under the curve (AUC) was greater (P < 0.05) for 1.0 IU ACTH-treated heifers than all other groups. The CT:P4 ratios were lower (time x treatment, P < 0.01) for control heifers than all ACTH-treated heifers. Among ACTH-treated heifers, CT:P4 ratio response and CT:P4 ratio AUC were similar (P > 0.10) following ACTH challenge. In conclusion, acute increases in ACTH elevated plasma P4, likely of adrenal origin, in mid-gestation pregnant heifers, while the CT:P4 ratio (relative output) remained constant irrespective of ACTH dose (0.125-1.0 IU). Whether ACTH-induced increases in P4 in pregnant animals are of physiological significance (e.g., an accessory role in the maintenance of pregnancy during periods of acute stress) remains to be determined.

Adrenal Glands↗
PubMed1976

Immunoreactive alpha-MSH and ACTH levels in rat plasma and pituitary.

A radioimmunoassay is described for the measurement of alpha-melanocyte-stimulating hormone (alpha-MSH). The antibody was produced in rabbits by immunization with alpha-MSH coupled to bovine serum albumin with carbodiimide. The antibody did not react significantly with ACTH, beta-MSH, or 6 fragments of ACTH. The sensitivity and reliability of the assay were improved by employing a simple plasma extraction procedure. When applied to a 2 ml plasma sample, the detection limit of the radioimmunoassay was 6 pg/ml. ACTH was measured with a sensitive and specific radioimmunoassay previously described for humans and adapted for the rat. The anti-ACTH serum cross-reacted with the biologically active portion of alpha-p ACTH and not with alpha-MSH, beta-MSH or the alpha-p 17-39 and alpha-p 25-39 fragments of ACTH. The detection limit was 20 pg/ml. Plasma and pituitary alpha-MSH and ACTH had the same immunoreactivity as synthetic alpha-MSH and ACTH. alpha-MSH and ACTH contents of the rat neurointermediate lobe were 1398 +/- 360 (SE) ng and 28.2 +/- 2.9 ng, respectively, while in the anterior lobe they were 102 +/- 31 ng and 551 +/- 36 ng, respectively. The plasma alpha-MSH concentration at 8 AM in male rats was 64 +/- 8 pg/ml when the plasma ACTH concentration was 92 +/- 15 pg/ml. Over a 24-hour period two peaks of plasma alpha-MSH were observed, one at 4 AM (142 +/- 35 pg/ml) and the other at 4 PM (139 +/- 26 pg/ml). Plasma ACTH was higher at noon (151 +/- 43 pg/ml) and 4 PM (130 +/- 48 pg/ml). Short-term exposure to ether induced a transient increase in alpha-MSH level 5 min later and a rapid return to normal levels. Plasma ACTH increased significantly 2.5 min after the onset of ether stress and remained high for 30 min. Two hours' exposure to ether did not change plasma alpha-MSH, although a 3-fold increase in plasma ACTH was observed. Haloperidol injection was followed by a large increase in plasma alpha-MSH, whereas ACTH levels increased similarly after saline and Haloperidol injection. Corticoid administration reduced ACTH, but not alpha-MSH. Three weeks after adrenalectomy, alpha-MSH levels had not changed but ACTH levels had increased ten-fold. These data indicate that alpha-MSH is secreted in the rat, and that the regulation of its secretion is different from that of ACTH.

Adrenocorticotropic Hormone↗
PubMed1975

Studies of ACTH secretion control in 116 cases of Cushing's syndrome.

Plasma ACTH (normal value: 0.16 plus or minus mU/100 ml) was measured in 116 patients with Cushing's syndrome, using a bioassay including dynamic tests and sequential determinations. In 10 patients with adrenal tumors ACTH levels were nondetectable (ND) or low, and usually nonstimulatable. In 10 patients with ectopic ACTH secretion high levels (0.42 plus or minus 0.07 mU/100 ml) were measured. The extracts of 6 tumors yielded an ACTH-like substance. Forty-three patients with Cushing's disease (without pituitary tumor) had, before treatment, a mean ACTH level of 0.18 plus or minus 0.01 mU/100 ml, accompanied by high levels of plasma cortisol (32.1 plus or minus 1.9 mug/100 ml). Irregular nycthemeral variations occurred. ACTH rose to 0.30 mU/100 ml after incomplete adrenalectomy (20 patients) and to 1.14 mU/100 ml after total adrenalectomy (21 patients). Dexamethasone (8 mg per day) suppressed ACTH levels. Metyrapone induced a normal ACTH rise, but at abnormal times. Lysine-vasopressin (LVP) induced an ACTH mean relative increase of 120% before, and of 140% after adrenalectomy (i.e., within the normal range). Six nonadrenalectomized patients with pituitary tumors showed similar abnormalities of ACTH regulation. However, the ACTH rise after LVP was above 500%. When pituitary tumors occurred after adrenalectomy (12 patients) the mean basal ACTH level was 18 mU/100 ml. Dexamethasone induced a 90% decrease, and LVP a 416% increase in ACTH levels. In 6 patients with nodular adrenal hyperplasia, ACTH was undetectable before treatment. After adrenalectomy, ACTH rose to 0.4 mU/100 ml (11 patients) and the increase after LVP was 90%. Five additional patients developed pituitary tumors. These data confirm the abnormalities of ACTH feedback regulation in Cushing's disease. However, even when pituitary tumors occur, ACTH levels can be altered by metyrapone, dexamethasone and LVP. This last test is of particular interest for the detection of pituitary tumors. The follow-up pattern of treated nodular adrenal hyperplasia appears to be very similar to that of Cushing's disease.

Adrenal Gland Diseases↗
PubMed1986

Alpha-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock.

Hypovolemic shock was produced in rats by withdrawing about 50% of the estimated total blood volume. Following mean arterial pressure stabilization in the range of 15-25 mm Hg, with a pulse pressure of 7-12 mm Hg, the rats were given intravenous bolus injections either of ACTH fragments or of saline. The following ACTH fragments or analogs were used: ACTH-(4-10), alpha-MSH, ACTH-(1-16), ACTH-(1-17), ACTH-(1-18), [Nle4,D-Phe7]alpha-MSH, [beta-Ala1,Lys17]ACTH-(1-17)-4-amino-n-butilamide (alsactide). ACTH-(1-24) and human synthetic ACTH-(1-39) were used for comparison. All animals treated with saline died in 22.51 +/- 3.62 min. Treatment with ACTH fragments (160 micrograms/kg i.v.) increased blood pressure and pulse amplitude, the effect starting within a few minutes, gradually increasing, and reaching a maximum in 15-30 min. The blood and pulse pressure increases were sustained, remaining almost stable until the end of the 2 h recording. Two out of nine rats treated with alsactide, which was the least active, died within 2 h after treatment, while all rats treated with the other ACTH fragments or analogs were still surviving at that time. Both on a weight and on a molar basis, the most active was ACTH-(1-24), followed by ACTH-(1-16), by the alpha-MSH analog [Nle4,D-Phe7]ACTH-(1-13), by ACTH-(1-18) and by ACTH-(1-17). The present results show that melanocortins reverse otherwise fatal hypovolemic shock, and suggest a new therapeutic approach for shock treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Structure-activity relationships of monomeric and dimeric synthetic ACTH fragments in perifused frog adrenal slices.

The effect of synthetic monomeric and dimeric ACTH fragments on spontaneous and ACTH(1-39)-evoked steroidogenesis in frog interrenal tissue was studied in vitro. Infusion of ACTH fragment 11-24 (10(-6) M) or its dimeric conjugates, attached either by their N-terminal, Glu(11-24)2, or their C-terminal amino acid, (11-24)2Lys, had no effect on the spontaneous release of corticosteroids. The monomer ACTH(11-24) and the dimer Glu(11-24)2 were also totally devoid of effect on the steroidogenic response to ACTH(1-39) (10(-9)M). In contrast, the (11-24)2Lys conjugate (10(-6)M) significantly decreased ACTH-induced stimulation of corticosterone and aldosterone (-63 and -62%, respectively). The dimeric conjugate of the fragment ACTH(7-24), linked through the C-terminal ends, (7-24)2Lys (10(-6)M), was also completely devoid of effect on basal steroidogenesis but caused a marked decrease of ACTH-evoked corticosterone and aldosterone release (-72 and -80%, respectively). Conversely, infusion of the dimer (1-24)2Lys gave rise to a dose-related stimulation of corticosterone and aldosterone release. The time-course of the steroidogenic response to the dimer was similar to that of ACTH(1-24). The 1-24 conjugate was 70 times less potent than the monomers ACTH(1-24) and ACTH(1-39). These results suggest that amphibian adrenocortical cells contain only one class of ACTH receptor which recognizes the 11-24 domain of ACTH with an affinity which depends on the presence of a strong potentiator segment, located at the N-terminus end of ACTH(1-39). Since the ACTH-dimers are thought to induce cross-linking of the receptors, our results suggest that aggregation of ACTH receptors causes a down-regulation of the receptors.

Adrenal Glands↗
PubMed1994

Effects of protein kinase C activators upon the late stages of the ACTH secretory pathway of AtT-20 cells.

1. The mouse AtT-20/D16-16 anterior pituitary tumour cell line was used as a model system for the study of phorbol 12-myristate 13-acetate (PMA)-mediated enhancement of calcium-evoked adrenocorticotrophin (ACTH) secretion. 2. PMA stimulated ACTH secretion from intact cells in a concentration-dependent manner. Other phorbol esters; phorbol 12,13-dibutyrate (PDBu) and phorbol 12,13-didecanoate (PDD) and diacylglycerol analogues; 1-oleoyl-2-acetyl-sn-glycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG) also stimulated ACTH release from intact AtT-20 cells. This would suggest that activation of protein kinase C (PKC) stimulates ACTH secretion from AtT-20 cells. 3. Calcium stimulated ACTH secretion from electrically-permeabilized cells over the concentration-range of 10(-7) M to 10(-5) M. PMA (10(-7) M) enhanced the amount of ACTH secreted at every concentration of calcium investigated. The PKC inhibitor, chelerythrine (10(-5) M) blocked the PMA (10(-7) M)-evoked enhancement of calcium (10(-5) M)-stimulated ACTH secretion but did not alter significantly the calcium (10(-5) M)-evoked secretion itself. This suggests that PKC modulates the secretory response to increases in intracellular calcium but does not mediate the effects of calcium. 4. Guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S, 10(-5) M) stimulated ACTH secretion from permeabilized cells in the absence of calcium and was additive with calcium-evoked ACTH secretion up to a maximum value which could be achieved by calcium acting alone. This suggests that a GTP-binding protein mediates the secretory response to increases in the intracellular calcium. PMA (10-7 M) enhanced ACTH secretion stimulated by the combination of calcium and GTP-gamma-S (10-5 M).5. GTP-gamma-S stimulated ACTH secretion from permeabilized cells in a concentration-dependent manner with a threshold of 10-6 M. PMA (10-7 M) increased the amount of ACTH secretion evoked by every concentration of GTP-gamma-S investigated. Chelerythrine (10-s M) blocked the PMA (10-7 M)-evoked enhancement of GTP-gamma-S (10-4 M)-stimulated ACTH secretion but did not significantly alter GTP-gamma-S(10-4 M)-evoked secretion itself. This suggests that PKC modulates the secretory response to GTP-gamma-S but does not mediate the effects of GTP-gamma-S.6. GTP-gamma-S (10-8-10-4-M) stimulated ACTH secretion from permeabilized cells either in the presence or absence of ATP (5 mM) indicating that its effects on secretion are ATP-independent.7. The results of the present study support the hypothesis that, in AtT-20 cells, PMA is acting at some site distal to calcium entry which modulates the ability of an increase in cytosolic calcium concentration to stimulate ACTH secretion. This site of action is either at the level of or at some stage distal to a GTP-binding protein which mediates the effects of calcium upon secretion.8. PMA, unlike adenosine 3':5'-cyclic monophosphate (cyclic AMP) (Guild, 1991), can stimulate ACTH secretion from permeabilized cells in the absence of added calcium and guanine nucleotides which suggests that PMA and cyclic AMP are acting through distinct mechanisms at this post calcium site of action.

Adenosine Triphosphate↗
PubMed1975

The mechanism of ACTH stimulation of adrenal ornithine decarboxylase activity.

The mechanism of action of adrenocorticotrophin (ACTH) stimulation of rat adrenal orticotrophin (ACTH) stimulation of rat adrenal ornithine decarboxylase activity was investigated. ACTH induction or ornithine decarboxylase activity was not prevented by administration of drugs that inhibit adrenal steroid biosynthesis. A dose of ACTH that produced maximal levels of adrenal cyclic AMP did not induce ornthine decarboxylase activity. Ovine growth hormone, which caused no increase in adrenal cyclic AMP, stimulated adrenal ornithine decarboxyase activity. These observations suggest that the increase in adrenal ornithine decarboxylase activity stimulated by ACTH is not dependent upon steroidogenesis, nor is it dependent on the early peak of cyclic AMP, although it may be influenced by the sustained levels of tissue cyclic AMP that follow the administration of large doses of ACTH. Furthermore, it appears there may be a pathway of ornithine decarboxylase activation in the adrenal which is entirely independent of cyclic AMP mediation. The effects of hypophysectomy on adrenal ornithine decarboxylase response to ACTH were examined. In rats given ACTH 16 h after hypophysectomy, the increase in ornithine decarboxylase activity was delayed when compared with the response in animals given ACTH 1 h after hypophysectomy. Actinomycin D given during the first 3 h after ACTH in the 16 h hypophysectomized rat abolished the expected increase in ornithine decarboxylase activity. Thereafter, a progressive increase in ornithine decarboxylase activity was observed as the interval between ACTH and Actinomycin D administration was further increased. In contrast, Actinomycin D administered 15 min before ACTH in the 1 h hypophysectomized rat had no effect on the subsequent increase in ornithine decarboxylase activity, and actually progressively enhanced the response the longer its administration after ACTH was delayed. Cycloheximide abolished the response to ACTH in both the 1 h and the 16 h hypophysectomized rat. Thus, it appears that ACTH stimulates a post-transcriptional mechanism regulating ornithine decarboxylase activity in the acutely hypophysectomized animal, whereas, in the chronically hypophysectomized rat, ACTH must first stimulate transcription of new messenger RNA which is involved in regulation of adrenal ornithine decarboxylase synthesis.

Adrenal Glands↗
PubMed1976

[ACTH secretion and adrenocortical responsiveness in Cushing's syndrome due to adrenocortical hyperplasia (author's transl)].

A radioimmunoassay for plasma ACTH has been developed utilizing highly purified human ACTH (Li) labelled with 125I by the lactoperoxidase method as a tracer and an ACTH antibody produced by immunization of rabbits with ACTH-Z (Organon). The assay is highly specific, reproducible and sensitive to 20 pg of ACTH per ml. Utilizing this technique, endogenous ACTH secretion, adrenal responsiveness to endogenous ACTH and hypothalamic pituitary adrenal feedback mechanisms have been assessed in normal subjects and in patients with Cushing's syndrome due to adrenocortical hyperplasia and nodular cortical hyperplasia. The potential effect of a negative feedback mechanism on the circadian rhythmicity after SU-4885 administration was assessed by initiating SU-4885 either at 9 p.m. or 8 a.m. In normal subjects, the circadian rhythm of ACTH was persistent and independent of a decrease in cortisol. However, in a single case of Cushing's syndrome due to adrenocortical hyperplasia, the circadian rhythm was different from that of normal subjects, possibly influenced by a negative feedback mechanism when SU-4885 was initiated at 8 a.m. In Cushing's syndrome due to adrenocortical and nodular cortical hyperplasia, a significant correlation was observed between the mean plasma ACTH and urinary 17-OHCS values before and after SU-4885 administration (r=0.743, p less than0.01). A significant correlation was also obtained in normal subjects between plasma ACTH and urinary 17-OHCS values (r=0.889, p less than 0.01). However, there was quantitatively more 17-OHCS excreted in the urine for a given plasma ACTH level in patients with Cushing's syndrome than in normal subjects. To assess the relative biological activity of endogenous and exogenously administered ACTH, the ratio of daily 17-OHCS during SU-4885 administration and Cortrosyn-Z administration was expressed as the Cortrosyn Equivalent Quotient (C.E.Q.). The correlation between plasma ACTH and C.E.Q. was similar and significant for normal subjects and patients with Cushing's syndrome (r=0.670, p less than 0.01). These data suggest that there is hyper-responsiveness of the adrenal glands to endogenous ACTH in Cushing's syndrome due to adrenocortical hyperplasia and nodular cortical hyperplasia and that the adrenal hyperactivity is not engendered by a qualitative change in the ACTH release from the pituitary gland. To assess pituitary suppressibility, dexamethasone was administered 40 days or more later following total adrenalectomy in 9 patients with Cushing's syndrome, 6 with adrenocortical hyperplasia and 3 with nodular cortical hyperplasia. One day after discontinuation of substitution therapy, 2 mg of dexamethasone was administered orally followed on successive days by 4 and 8 mg doses. In each instance, dexamethasone was given at midnight and the plasma ACTH concentration was determined at 9:00 a.m. on the day before and after administration of the dexamethasone. A patient with Addison's disease was studied as a control...

17-Hydroxycorticosteroids↗
PubMed1992

Ectopic production of ACTH and corticotropin-releasing hormone (CRH).

The most common ectopic production of a pituitary hormone is the one of ACTH leading to Cushing's syndrome. Ectopic ACTH-hypersecretion is the cause of Cushing's syndrome in 10-15% of all cases. The ACTH-secreting tumours are often oat-cell carcinomas of the lung, less frequently pancreatic cancers, hypernephromas, or C-cell carcinomas of the thyroid. Some of these tumours may be benign or semi-benign as the rare carcinoid tumours and cause great problems in the differential diagnosis of ACTH-dependent hypercortisolism. Out of 173 of our patients with Cushing's syndrome observed in the last 12 years 21 were caused by ectopic ACTH-production. Of these 21 patients 13 have a small cell carcinoma of the lung. The ectopic ACTH-syndrome often has typical clinical features caused by the levels of ACTH and cortisol leading to hypocalcemic alkalosis with muscle weakness and wasting, carbohydrate intolerance, and hypertension with oedema. The survival time in many of these patients is not long enough to allow them to develop typical signs of Cushing's syndrome though they are often highly pigmented. These patients are easily diagnosed. However, patients with small tumours which do not cause very elevated ACTH-levels and who have the more typical clinical signs of full-blown Cushing's syndrome are difficult to recognize. For the differential diagnosis of ACTH-dependent Cushing's syndrome the corticotropin-releasing hormone (CRH) stimulation test and dexamethasone suppression test with high doses are helpful. In special cases the venous sampling procedure for ACTH-measurements is necessary, also CT or NMR is helpful. Ectopic CRH-production is a rare cause of ACTH-dependent Cushing's syndrome. Patients with ectopic CRH-production and consecutive ACTH-hypersecretion from the pituitary have not been studied extensively. There are especially no well documented results of the use of the CRH-stimulation test in vivo in this group of patients with Cushing's syndrome. On the other hand, in the documented cases, not only CRH-, but also ACTH-production was found in the tumours. So far, this rare cause of ACTH-dependent Cushing's syndrome has to be excluded or confirmed by the measurement of endogenous CRH-levels. But until now we have not been able to detect one single case of ectopic CRH-production using a sensitive homologous CRH-radioimmunoassay over a period of more than 8 years in which we have seen nearly 120 newly diagnosed patients with ACTH-dependent Cushing's syndrome. Only in the plasma and tumour tissue of two patients of other groups have we found high CRH-levels.

ACTH Syndrome, Ectopic↗
PubMedDate not supplied

Biphasic plasma aldosterone responses to four single-dose ACTH regimens.

Adrenocorticotropic hormone (ACTH) administration increases cortisol synthesis but produces a biphasic aldosterone response. Some investigators believe that the hypercortisolism from prolonged ACTH administration is responsible for this aldosterone response. The present study evaluated the plasma aldosterone response to four acute single-dose ACTH regimens that produced only a transient increase in plasma cortisol. Fourteen normal adult men received (1) 1-18 ACTH intravenous bolus (IV), (2) 1-18 ACTH intramuscular (IM), (3) 1-39 ACTH (IM), and (4) 1-24 ACTH (IV). The plasma aldosterone increased within one hour and tended to parallel the cortisol increment with all four ACTH regimens. With all of these ACTH regimens, the plasma aldosterone level decreased below placebo with 1-24 ACTH (IV) (24 hours), 1-39 ACTH (IM) (24 hours), and 1-18 ACTH (IV) and (IM) (48 hours) at a time when the cortisol had returned to normal. These results suggest that the delayed ACTH-induced aldosterone inhibition production are not directly related to cortisol production and do not require prolonged ACTH administration. These observations are consistent with ACTH induction of a nonaldosterone mineralocorticoid, which is independently suppressing aldosterone production.

Adrenocorticotropic Hormone↗