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PubMed1980

Responses of Y1 adrenocortical tumor cells to o-nitrophenyl sulfenyl ACTH.

NPS(o-nitrophenyl sulfenyl)-ACTH stimulated steroidogenesis in Y1 cells to the same maximum level as did ACTH, but with a 60-fold lower potency than the native hormone. NPS-ACTH also stimulated the extracellular accumulation of cAMP in Y1 cells with lower potency than the unmodified hormone. The amount of cAMP accumulated in the presence of NPS-ACTH approached 75% of the maximum with ACTH. In Y1 plasma membranes, NPS-ACTH was a partial agonist of adenylate cyclase activity, witn an efficacy dependent upon the type of guanyl nucleotide present. The steroidogenic responses of two Y1(Kin) mutants and two Y1(Cyc) mutants to NPS-ACTH paralleled their responses to ACTH and reflected closely their defects in cAMP-dependent protein kinase and ACTH-sensitive adenylate cyclase activity. These data imply an obligatory role for adenylate cyclase and cAMP-dependent protein kinase activities in stimulation of steroidogenesis in Y1 cells by NPA-ACTH.

Adenylyl Cyclases↗
PubMed1995

An inositol phosphoglycan from Trypanosoma cruzi inhibits ACTH action in calf adrenocortical cells.

We describe the effect of an inositol phosphoglycan (IPG) purified from Trypanosoma cruzi on the stimulation of aldosterone and cAMP production by ACTH in calf adrenocortical cells. T. cruzi IPG has two galactofuranose residues (Galf) which are not frequent in other IPGs. The effect of IPG with galactofuranose residues (IPG Galf) and IPG without these residues (IPG) was investigated. It was found that IPG Galf slightly decreased the stimulation of aldosterone and cAMP production by ACTH, whereas IPG significantly inhibited ACTH-mediated accumulation of both aldosterone and cAMP. The inhibition of aldosterone content in ACTH-treated cells by IPG was dose dependent. It was also found that the pretreatment of calf adrenocortical cells with IPG inhibited the accumulation of aldosterone provoked by ACTH and dibutyryladenosine-3',5'-cyclic monophosphate (db-cAMP). On the other hand, the activation of a GPI (glycosyl phosphatidylinositol)-phospholipase C by ACTH was evaluated. First it was found that the release of ceramide from a GPI-like molecule: a glycoinositol-phosphoceramide (LPPG) purified from T. cruzi is increased in ACTH-treated cells. Second, the release of alkaline phosphatase, a GPI-anchored enzyme, to the extracellular medium was increased in these cells by ACTH. These data suggest that ACTH activates a phospholipase C in calf adrenocortical cells, releasing IPG, which in turn may inhibit, or modulate ACTH action.

Adrenal Cortex↗
PubMed1992

Effect of ACTH on steroidogenic enzymes in guinea pig fasciculata-glomerulosa cells: changes in activity and mRNA levels.

Adrenocorticotropin (ACTH) is known to exert an acute effect on adrenal steroidogenesis as well as long-term effects by regulation of gene expression. In order to further study the long-term action of ACTH, guinea pig fasciculata-glomerulosa (FG) cells in primary culture were treated for up to 72 h with ACTH. The effects of this treatment on steroid secretion, enzyme activity and mRNA levels for steroid enzymes were measured. While the rate of 17-deoxy C-21 steroid secretion decreased over the 72-h period of incubation with ACTH, the 17-hydroxy C-21 steroid secretion rate remained constant for the first 24 h of incubation and declined thereafter; the rate of 4-ene C-19 steroid secretion increased over the 72-h incubation period. ACTH treatment increased 17-hydroxylase and 17,20-lyase activities and the maximal stimulation was reached after 48 h. In contrast, the activity of 21-hydroxylase (P450c21) steadily declined over the 72-h incubation period. ACTH also caused an increase in mRNA levels for P450c21, 17-hydroxylase and 17,20-lyase (P450c17), 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD) and cholesterol side-chain cleavage enzyme (P450scc). The maximal stimulation for the four mRNAs was observed after 18 h of incubation with ACTH, decreasing afterwards except for P450c17 mRNA levels which remained elevated over the 72-h incubation period. Despite the increase in mRNA levels for 3 beta-HSD and P450c21, no increase in their respective enzyme activities was observed and 21-hydroxylase activity even declined over the 72-h incubation period with ACTH, thus suggesting that mechanism(s) other than gene expression alone regulate steroid secretion in FG cells. In conclusion ACTH caused major changes in steroid distribution due to increased 17-hydroxylase and 17,20-lyase activities and decreased 21-hydroxylase activity in FG cells in culture. Moreover, our data revealed major differences in the induction of mRNAs for steroidogenic enzymes and their activities following ACTH treatment.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Impact of ACTH administration on the oviductal sperm reservoir in sows: the local endocrine environment and distribution of spermatozoa.

The objective of the study was to investigate if short-term stress in sows (simulated by injections of synthetic adrenocorticotrophic hormone (ACTH)) during standing oestrus had a negative effect on the local environment in the utero-tubal junction (UTJ) and isthmus and the distribution of spermatozoa in these segments. Fourteen sows were monitored for ovulation using ultrasonography in two consecutive oestruses. The sows were fitted with jugular catheters and, from onset of the second oestrus, blood samples were collected every second hour. In the 2nd oestrus, seven sows were given ACTH every second hour, from the onset of standing oestrus until the sow ovulated (ACTH-group), whereas the other seven sows remained as controls (C-group) and were given NaCl solution. The sows were artificially inseminated 16-18 h before expected ovulation. Six hours after ovulation the sows were anaesthetised, and blood samples were repeatedly taken from veins draining the uterus and the UTJ-isthmus, respectively. This oviduct was thereafter removed and divided in four adjacent sections consisting of: (i) the UTJ, (ii) the first, and (iii) the second isthmus segment prior to (iv), the ampullary-isthmic junction (AIJ) and the ampulla. The three first-mentioned segments were flushed to retrieve spermatozoa, whereas the last one was flushed to collect oocytes/ova. The number of spermatozoa attached to the zona pellucida was counted. The concentrations of cortisol in jugular blood of the ACTH-group sows during the time of ACTH-injections were significantly higher than of the C-group sows (p<0.05), as were the levels of progesterone (p<0.001). Progesterone and cortisol concentrations measured in the blood samples draining the UTJ-isthmic region 6 h after ovulation did not significantly differ between the groups, but the C-group displayed significantly higher concentrations of progesterone in the UTJ-isthmic region compared with the levels measured in parallel samples taken of jugular blood (p<0.01). The C-group, but not the ACTH-group, also displayed a significant elevation in progesterone concentration 6h after ovulation compared with the basal levels before ovulation (p<0.01). Numbers of retrieved spermatozoa were not significantly different between the C-group and the ACTH-group. However, there was a tendency for a larger number of spermatozoa among sows in the ACTH-group, especially in the isthmic segment adjacent to the AIJ. In conclusion, simulated stress induced by injections of ACTH during standing oestrus results in elevated concentrations of progesterone before ovulation and may interfere with the rise of progesterone after ovulation. However, ACTH-injections appeared to augment transport of spermatozoa through the female genital tract of pigs.

Adrenocorticotropic Hormone↗
PubMed2005

Comparison of two low dose ACTH therapies for West syndrome: their efficacy and side effect.

In order to clarify the appropriate usage of adrenocorticotropic hormone (ACTH), the efficacy and side effects of two different regimens of low dose ACTH therapy were compared. Thirty-four patients with West syndrome (WS) were treated with ACTH. The dose of synthetic ACTH-Z was 0.015 mg/kg/dose in 18 patients who were treated between 1996 and 1998 (regimen A), and 0.010 mg/kg/dose in 16 patients who were treated between 1999 and 2001 (regimen B). Patients were classified into cryptogenic and symptomatic groups. Efficacy and adverse effects of ACTH were compared between regimens A and B. Similar analyses were performed after stratification into cryptogenic and symptomatic groups. The efficacy of ACTH was not different between regimens A and B. However, among patients with symptomatic WS, the number of ACTH injections and the dose of ACTH until cessation of spasms were significantly smaller in regimen A than in regimen B. There was no significant difference in these variables between the regimens among those with cryptogenic WS. Adverse effects were not different between regimens A and B. 0.010 mg/kg per day of ACTH will be adequate for cryptogenic WS, but 0.015 mg/kg per day of ACTH is recommended for symptomatic WS.

Adrenocorticotropic Hormone↗
PubMed2004

ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells.

To identify genes that are induced by corticotropin (ACTH) in adrenal cortex cells, we carried out a differential hybridization screening of adrenal cortex cDNA libraries. Some of the clones we identified represented tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA. We examined ACTH dependence of the expression of TIMP-1 in vitro in cultured bovine adrenocortical cells, and in ACTH-treated rats. Northern blot analysis of total RNA from cells showed that the level of TIMP-1 mRNA increases sharply within 3h after ACTH stimulation. Since TIMP-1 inhibits some cell matrix metalloproteinases (MMPs) of the collagenase type, we examined the effect of ACTH on collagenase activity in bovine adrenocortical cells. Exposure of confluent cultures to ACTH for 24h showed dose-dependent inhibition of collagenase activity. Northern blot analysis of total RNA from rat adrenal zona fasciculata-reticularis and zona glomerulosa showed that in both of these zones TIMP-1 expression was induced within 12h after ACTH injection. Long-term (9 days) treatment with ACTH increased TIMP-1 mRNA levels nearly sixfold in zona fasciculata-reticularis. Overall, our results show that ACTH causes induction of TIMP-1 and suppression of collagenase activity, and suggest that ACTH may modulate the activities of MMPs and hence cell matrix remodeling.

Adrenal Cortex↗
PubMed1996

ACTH and AII differentially stimulate steroid hormone orphan receptor mRNAs in adrenal cortical cells.

NGFI-B and Ad4BP are steroid hormone receptor-like transcription factor that may control steroidogenesis, growth and differentiation in the adrenal cortex. We have studied the induction of NGFI-B and Ad4BP and mRNAs by the peptide hormones, ACTH, AII, IGF, FGF, and by KCl depolarization in cultured bovine adrenocortical cells. The mRNAs for these two transcription factors were most effectively but differentially induced by ACTH and AII. mRNA for NGFI-B was typically undetectable in unstimulated cells, but rapidly (< 30 min) accumulated in response to ACTH and AII. Peak increases occurred within 2-3 h after which mRNA levels declined. At maximally effective concentrations, AII produced increases in NGFI-B mRNA 2.7-fold larger than those triggered by ACTH (n = 7). In contrast to NGFI-B, Ad4BP mRNA was readily detectable in unstimulated cells. ACTH and AII induced smaller, slower and more sustained increases in Ad4BP mRNA. Peak values were obtained in 6-8 h and Ad4BP mRNA remained elevated for at least 18 h. ACTH produced increases in Ad4BP that were 2.6-fold larger than those stimulated by AII (n = 8). Antagonists of major signaling pathways that couple ACTH and AII receptors to cortisol secretion, including T-type Ca2+ antagonist Ni2+ and penfluridol, the CaM kinase antagonist KN-62, the A-kinase antagonist H-89 and the non-selective kinase antagonist staurosporine, all failed to suppress increases in NGFI-B and Ad4BP mRNAs triggered by these two peptides. Each of these agents effectively inhibited cortisol production stimulated by the peptides. Further, arguing against their proposed role as transcription factors for steroidogenic enzymes, ACTH- and AII-stimulated increases in steroid orphan receptor mRNAs were not correlated with corresponding increases in cortisol production measured over 24 h. The results show that NGFI-B and Ad4BP mRNAs are differentially regulated by ACTH and AII. Only NGFI-B is rapidly and transiently increased with kinetics common to immediate early genes. The lack of correlation between peptide-stimulated increases in orphan receptor mRNAs and cortisol production in combination with the apparent divergence in the associated signaling pathways argue against a primary role for these transcription factors in ACTH- and AII-stimulated steroidogenesis. The dual function of these peptide hormones as mediators of development and corticosteroid synthesis could necessitate the presence of separate, parallel signaling pathways.

Adrenocorticotropic Hormone↗
PubMed1997

A comparison of the insulin tolerance/glucagon test with the short ACTH stimulation test in the assessment of the hypothalamo-pituitary-adrenal axis in the early post-operative period after hypophysectomy.

OBJECTIVE: The insulin tolerance test (ITT) is the established reference test for assessing the hypothalamo-pituitary-adrenal (HPA) axis. Various authorities, however, have suggested that the 250 microgram short ACTH stimulation test may be used to assess the HPA axis in place of the ITT in suspected hypopituitarism, although a number of other studies have suggested that the test may be unreliable in this setting. In this study, the ITT (or glucagon test) has been compared with the 250 microgram short ACTH stimulation test in patients with pituitary tumours pre-operatively and within 2 weeks of trans-sphenoidal hypophysectomy. DESIGN: An ITT, or a glucagon test when the ITT was contraindicated, and the 250 micrograms short ACTH stimulation test, were performed in all the patients before (an ITT in 18 and a glucagon test in three patients) and within 2 weeks after trans-sphenoidal hypophysectomy (an ITT in 16 and a glucagon test in five patients). PATIENTS: Twenty-one patients with pituitary disorders (15 with acromegaly, one with a prolactinoma and five with non-functioning tumours) were studied; four had a microadenoma, two a mesoadenoma and 15 a macroadenoma. MEASUREMENTS: Serum cortisol was measured by radioimmunoassay. A normal response was defined as a rise in serum cortisol to 580 nmol/l or above for all the tests. RESULTS: Before surgery, three of 18 patients (17%) had a discrepancy between the ITT and the 30 minute short ACTH stimulation test and one of three between the glucagon test and the 30 minute short ACTH stimulation test. Combined together, pre-operatively, four of 21 patients (19%) had discrepant results. In the early post-operative period, the discrepancy between ITT and the 30 minute short ACTH stimulation test was higher with four of 16 patients (25%) showing discordant results; one of the five patients tested had a discrepancy between the glucagon test and the 30 minute short ACTH stimulation test. On combining the tests, the post-operative discrepancy was five of 21 patients (24%). CONCLUSIONS: The 250 microgram short ACTH stimulation test produces discordant results from the ITT in a clinically significant proportion of affected patients when assessing the HPA axis, although the rate of discordance varies according to the criteria used for normality for both the tests. We suggest that the ITT should remain the preferred test for assessing ACTH secretory capacity compared with the standard 250 microgram short ACTH stimulation test, both in the preoperative and in the early post-trans-sphenoidal hypophysectomy period.

Adenoma↗
PubMed2001

Elderly subjects show severe impairment of dehydroepiandrosterone sulphate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH(1-24).

OBJECTIVE: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ageing has been reported both in humans and in animals and may be involved in age-related changes in body composition, structure functions and metabolism, as well as in brain ageing. Despite the supposed HPA hyperactivity and its refractoriness to negative glucocorticoid feedback, low levels of dehydroepiandrosterone (DHEA) and its sulphate have been clearly demonstrated in human ageing and may suggest another cause of age-related changes in structure function and metabolism. Thus, our aim was to verify the adrenal responsiveness to various ACTH doses in normal elderly subjects. DESIGN: We studied cortisol (F), aldosterone (A) and DHEA responses to the sequential administration of very low, low and supramaximal ACTH1-24 doses (0.06 microg or 0.5 microg followed by 250 microg ACTH1-24 i.v. at 0 and +60 minutes) in healthy elderly subjects (ES) [six females and two males, aged 63-75 years, body mass index (BMI) 22-26 kg/m2]. The results in ES were compared with those recorded in healthy young subjects (YS) (six females and six males, aged 22-34 years, BMI 20-25 kg/m2). RESULTS: Basal DHEA levels in ES were lower (P < 0.05) than in YS, while F and A levels were similar in both groups. DHEA, F and A responses to ACTH were dose-dependent in both groups. In ES, however, DHEA levels showed no response to the 0.06 microg dose, a modest increase after 0.5 microg and a clearer rise after 250 microg ACTH; at any dose, the DHEA response in ES was clearly lower than in YS (P < 0.04). The F responses to 0.5 microg and 250 microg ACTH in ES were similar to those in YS; whereas, in ES, 0.06 microg ACTH elicited a non significant F increase which was significantly lower than in YS (P < 0.05). Similarly, the A responses to the highest ACTH doses were similar in both groups but, in ES, 0.06 microg ACTH elicited no increase in A secretion, which was clearly lower than in YS (P < 0.03). CONCLUSIONS: Normal elderly subjects show severe reduction of DHEA response to a wide range of ACTH doses, in agreement with peculiar impairment of the activity of the adrenal reticularis zone in ageing. In contrast to young adults, elderly subjects also show no cortisol and aldosterone response to a very low ACTH dose. This evidence indicates a reduced sensitivity to ACTH in the fasciculata and glomerulosa zones of the adrenal gland in ageing.

Adult↗
PubMed1995

Time-course of hypothalamic CRH and pituitary ACTH contents, and pituitary responsiveness to CRH stimulation after bilateral adrenalectomy.

The pituitary ACTH and hypothalamic CRH alterations at different periods after adrenalectomy (ADX) or Sham ADX were studied by measurement of ACTH and CRH contents by radioimmunoassay (RIA) in rats. We also studied the corticotroph alterations by immunohistochemistry and the in vitro pituitary responsiveness to CRH. Plasma ACTH presented a triphasic response after ADX. Anterior pituitary (AP) ACTH content decreased 3 h and 1 day after surgery, then rose over this period. Immunohistochemistry demonstrated an initial degranulation of the corticotrophs with a progressive increase in cells immunostained for ACTH and a positive correlation (r = 0.88) with AP ACTH content measured by RIA. Hypothalamic CRH content decreased after ADX, but returned to sham value 3 weeks later. Basal ACTH secretion in incubation medium was correlated with the AP ACTH content observed in vivo. The pituitary responsiveness to CRH was not the same at all times after ADX. It was absent 1 day after, presented an increase of 51%, 117% and 26% when compared with the basal ACTH output 3 h, 3 and 14 days after ADX, respectively. Our data suggest that after ADX the corticotroph undergoes a transitory decrease in ability to secrete ACTH after store depletion. During a later phase, however, there is a relative hyporesponsiveness of the corticotroph to CRH stimulation. These data indicate that CRH may be acting on a down-regulated pituitary or more additional factors play a role in the sensitization of the pituitary after ADX.

Adrenalectomy↗
PubMed1983

Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH.

Fifty-eight patients with severe, progressive multiple sclerosis were prospectively randomized to one of three treatments: 20 received intravenous ACTH, 20 received high-dose intravenous cyclophosphamide plus ACTH, and 18 were placed on a regimen consisting of plasma exchange, low-dose oral cyclophosphamide, and ACTH. The three groups were similar in age, sex, duration and type of disease, and degree of disability. Before treatment and six months and one year after treatment, a disability-status score, ambulation index, and functional-status score were determined, and a quantitative neurologic examination was performed. In the ACTH group, the number of patients stabilized or improved was 8 of 20 at six months and 4 of 20 at one year; in the cyclophosphamide-ACTH group, 18 of 20 at six months and 16 of 20 at one year; and in the plasma exchange group, 11 of 18 at six months and 9 of 18 at one year. High-dose cyclophosphamide plus ACTH was most effective in halting progression of the disease at both 6 and 12 months (at 12 months, cyclophosphamide-ACTH vs. ACTH, P = 0.0004; cyclophosphamide-ACTH vs. plasma exchange, P = 0.087). Thus, progressive multiple sclerosis may be stabilized by short-term, intensive immunosuppression with cyclophosphamide plus ACTH.

Administration, Oral↗
PubMed1996

ACTH-like bioactivity and immunoactivity in fetal lamb pituitaries at 0.65 and 0.95 gestation.

We wished to determine if the concentration of bioactive ACTH-like activity increased during development and if there was heterogeneity in ovine fetal anterior pituitary ACTH activity as measured by bioassay and radioimmunoassay (RIA). We obtained anterior pituitaries from eight sheep fetuses (four at 0.65 and four at 0.95 gestation; term 145 +/- 5 days) and extracted and homogenized them in ice-cold 5N acetic acid, 0.3% phenylmethanesulfonyl fluoride (PMSF) and 0.2% BSA. Fractionation of each pituitary extract was performed by size-exclusion chromatography using Sepadex G-50. The ACTH-like immunoactivity (ALI) profile for each pituitary showed two well-defined peaks. One eluted with human ACTH1-39 and the other eluted with the high molecular weight fraction in the void volume. Four fractions from the first peak representing the high molecular weight forms of ACTH activity and four fractions from the second peak representing the low molecular weight forms of ACTH activity were pooled separately. These two pools were subjected to reverse-phase chromatography (RPC) on a C-8 column using a linear gradient of 70% acetonitrile in 0.8% trifluoroacetic acid over a 60 min period. Based upon the RIA, the high molecular weight forms of ACTH from the G-50 column were resolved into three main fractions, one eluting similar to the standard ACTH1-39 and the remaining two eluting after that. The low molecular weight forms of ACTH from the G-50 column were resolved into three peaks, before, with, and after the standard. We used collagenase-dispersed rat adrenal cells to test the ACTH-like bioactivity (ALB) of the crude extracts and of the different fractions obtained from the RPC of the high and low molecular weight material. The concentration of ACTH-like bioactivity in the crude extracts was similar at the two stages of gestation. However, there was a trend for the low molecular weight peak to have more peptide eluting with human ACTH1-39 and higher ratios of ALB/ALI than did the high molecular weight peak. These results suggest that multiple ACTH molecular forms with different ALB/ALI ratios are present in the ovine fetal pituitary and that there is no selective increase in ACTH1-39 concentration in the fetal pituitary in late gestation.

Adrenocorticotropic Hormone↗
PubMed1976

The characterization of the ACTH produced by a primary pituitary tumour in a patient with Cushing's disease.

The nature of ACTH present in pituitary tumours associated with Cushing's disease has not been previously characterized nor correlated with the electron microscopic appearance. The present report describes the culture of tumour tissue obtained from a patient with a pituitary tumour associated with Cushing's disease, and the characterization of the ACTH content of tumour and media by bioassay, immunoassay, and Sephadex G-50 gel filtration. Electron microscopic studies were also performed. The pathological diagnosis was pituitary adenoma with basophilic PAS-positive granules. Electron microscopy showed uniformity of size and shape of the tumour cells, the presence of secretory granules of varying size and density, and disorganized tubular and vacuolar arrays of endoplasmic reticulum. The bioreactive ACTH content of the tumour was 0-29 mug/g, which is markedly below that seen in the normal pituitary, but within the range reported for ectopic ACTH-producing tumours. Immunoreactive ACTH when measured by a C-terminal antibody was five-fold higher than when measured by an N-terminal antibody; the latter gave a value of 1-24 mjg/g. On Sephadex G-50 gel filtration, 9% of the N-terminal immunoreactivity was present in the Vo fraction ('big' ACTH). This latter fraction had a greater percentage of bioreactivity (28%) than previously reported for this molecular species. Analysis of the tumour culture medium revealed a variation in molecular size similar to that seen in the tumour, although the percentage of ACTH of large molecular size was greater, suggesting increased secretion of a possible 'prohormone' by the tumour. Plasma ACTH was characterized by a 2:1 ratio of immunoreactivity (N-terminal) to bioreactivity, and a 4:1 ratio of C-terminal/N-terminal immunoreactivity. This report also appears to be the first of successful short-term tissue culture of a primary ACTH-producing tumour. The granule size was considerably larger than that reported for normal pituitary ACTH-containing cells.

Adenoma↗
PubMed1977

'Big ACTH' and calcitonin in an ectopic hormone secreting tumour of the liver.

A young man presented with rapidly developing Cushing's syndrome which was due to the ectopic secretion of ACTH and beta-MSH-like material from hepatic tumour deposits, possibly originating from biliary radicals. This association of the ectopic ACTH syndrome has not previously been described. During the 22 month course of the illness the plasma immunoreactive ACTH and 'beta-MSH' concentrations rose by logarithmic progression. The plasma calcitonin concentration was also raised but did not change during the last 12 months. At any stage of the illness the plasma concentration of the ecotopically produced hormones was stable except that after hydrocortisone there were inconstant variations. During the course of the illness the ectopic ACTH became biologically less potent. This ineffectural ACTH was present in the plasma, in the tumour, and in the medium in which the tumour was cultured, in a large molecular weight form. This 'big ACTH' differed from the normal ACTH found in the patient's pituitary and from authentic ACTH in its immunochemical character: the C-terminal antigenic determinant (33-39 region of ACTH) was masked in the large molecular weight form but was uncovered after extraction in neutral buffer and this 'big ACTH' was more readily extracted from the tumour at pH 7.0. The tumour tissue also contained immunoreactive beta-MSH-like material and immunoreactive calcitonin which resembled calcitonin M chromatographically.

Adolescent↗
PubMed1994

Plasma corticotrophin releasing hormone, vasopressin, ACTH and cortisol responses to acute myocardial infarction.

OBJECTIVES: We assessed the magnitude and duration of the response of hypothalamic-pituitary-adrenal hormones to the stress of myocardial infarction, in the presence and absence of angiotensin converting enzyme inhibitors. In particular, we wished to analyse the interrelationships between peripheral plasma levels of corticotrophin releasing hormone (CRH), vasopressin (AVP) and adrenocorticotrophin (ACTH), and also between ACTH and cortisol, during a prolonged medical stress. DESIGN: All hormones were measured within 6 hours of the onset of an acute myocardial infarction. Patients were randomly allocated to three different study groups according to a double blind procedure. PATIENTS: Group 1 (10 patients) received placebo treatment, Group 2 (13 patients) received a maintenance dose of captopril 25 mg three times daily, Group 3 (11 patients) received enalapril 5 mg three times daily. MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, and cortisol by ELISA. Reference ranges for all hormones were obtained from 40 or more volunteers from the electoral roll. RESULTS: At the start of the study, mean +/- SEM plasma AVP (27.9 +/- 4.6 pmol/l) was significantly (P < 0.001) raised above the mean for the reference range (1.82 +/- 0.09 pmol/l), and 12 patients had values > 50 pmol/l. Mean plasma cortisol (960 +/- 89.6 nmol/l) was also raised above the reference range mean (554 +/- 28 nmol/l, P < 0.001), as was mean plasma CRH (4.97 +/- 0.5 pmol/l, reference mean 1.52 +/- 0.09 pmol/l, P < 0.001). By contrast, mean ACTH (3.88 +/- 0.66 pmol/l) was significantly less than the reference mean (10.7 +/- 0.7 pmol/l, P < 0.001). During the 72-hour observation period there was a highly significant fall (P < 0.001) in plasma CRH, AVP and cortisol. By contrast, plasma ACTH rose, and the change with time of ACTH was significantly different from the fall in plasma CRH, AVP or cortisol (P < 0.001 for each comparison). No significant differences in plasma CRH, AVP, ACTH or cortisol responses to placebo, captopril or enalapril were observed. CONCLUSIONS: Within 6 hours of a myocardial infarction, mean plasma CRH, AVP and cortisol values were very significantly raised above mean control values, while ACTH was very significantly reduced. During the 3 days following an acute myocardial infarction, plasma CRH, AVP and cortisol fell substantially, and this pattern was not influenced by angiotensin converting enzyme inhibitors. By contrast, plasma ACTH showed a significant increase with time. This suggests that the usual relationships between CRH, AVP and ACTH, and between ACTH and cortisol are disturbed in patients admitted to hospital with myocardial infarction. Maximum levels of AVP observed in 12 patients exceeded 50 pmol/l, which may be sufficiently high to interfere with tissue perfusion. It is postulated that V1 AVP receptor antagonists may have a therapeutic application in limiting infarct size.

Adrenocorticotropic Hormone↗
PubMed1995

Differential dependence of ACTH secretion induced by various cytokines on the integrity of the paraventricular nucleus.

Effect of different cytokines, human recombinant interleukin-1 alpha and beta (IL-1 alpha, IL-1 beta), interleukin-6 and tumor necrosis factor-alpha (TNF) on adrenocorticotropin (ACTH) secretion was compared in sham-operated rats and those with lesions of the hypothalamic paraventricular nucleus. IL-1 alpha was less active than IL-1 beta in stimulating ACTH in sham-operated rats. Intravenous injection of IL-1 beta in sham-operated animals resulted in a rapid elevation of ACTH secretion. Five days after surgical lesion of the paraventricular nucleus, the main hypothalamic source of hypophysiotropic corticotropin-releasing factor-41, the response to IL-1 beta was attenuated but not abolished. This suggests involvement of extra-paraventricular releasing factors in mediation of ACTH-releasing activity of IL-1 beta, altered responsiveness of pituitary to CRFs, and/or direct action of IL-1 beta on the corticotrope cells. TNF resulted in a biphasic stimulation of ACTH concentration, with peaks at 15 min and 90 min. In paraventricular-lesioned, TNF injected rats both of these ACTH peaks disappeared, suggesting that CRFs from the paraventricular origin mediates ACTH-inducing activity of TNF. IL-6 elevated ACTH secretion much later than the other intravenously injected cytokines, the peak was at 1 h in sham-lesioned rats. Paraventricular lesion completely prevented the increase of ACTH plasma levels after IL-6 injection. These data suggest that: (1) Effect of TNF and IL-6 on hypothalamo-pituitary-adrenal axis is mediated through the hypothalamic paraventricular nucleus and (2) IL-1 beta is able to release ACTH even in the absence of hypothalamic drive.

Adrenocorticotropic Hormone↗
PubMed1992

Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats.

1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.

Adrenocorticotropic Hormone↗
PubMed1997

Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.

PURPOSE: To compare the efficacy and tolerability of vigabatrin (VGB) and adrenocorticotrophic hormone (ACTH) as first-line therapy in infantile spasms. METHODS: Forty-two infants (22 males, 20 females) aged 2-9 months with newly diagnosed infantile spasms, were included in the trial. Patients were randomized to receive VGB 100-150 mg/kg/day or Depot ACTH 10 IU/day. The alternative drug was given if spasms were not controlled within 20 days or in cases of intolerance to initial therapy. Twenty-three patients (7 cryptogenic, 16 symptomatic) received VGB as first-line therapy; 19 patients (8 cryptogenic, 11 symptomatic) received ACTH as the first drug. RESULTS: Cessation of spasms was observed in 11 (48%) of the patients randomized to VGB and in 14 (74%) of those randomized to ACTH. Response to VGB was observed within 1-14 days, but two-thirds of patients (7/11) responded within 3 days. In the group treated with VGB, side effects such as drowsiness, hypotonia and irritability were observed in 13% of patients, compared with 37% in the group treated with ACTH. VGB was more effective than ACTH as treatment for cerebral malformations or tuberous sclerosis, whereas ACTH proved more effective in perinatal hypoxic/ischemic injury. The efficacy of the two drugs was similar in cryptogenic cases. Disappearance of interictal EEG abnormalities occurred sooner in patients randomized to ACTH than in those who received VGB as initial therapy. During the second phase, the alternative drug was given to the resistant patients. Spasms ceased in 2 of 5 patients treated with VGB and in 11 of 12 patients treated with ACTH. After 3 months, relapses of spasms were observed in 6 patients treated with ACTH and in 1 treated with VGB. VGB produced a therapeutic response in nearly half the patients receiving this drug. CONCLUSIONS: Our data lend further support to the view that VGB may be considered a first-choice drug in the treatment of IS.

Adrenocorticotropic Hormone↗