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PubMed1989

Short loop adrenocorticotropin (ACTH) feedback after ACTH-(1-24) injection in man is an artifact of the immunoradiometric assay.

A recent report measured a decrease in plasma ACTH concentration by immunoradiometric assay (IRMA) during infusion of ACTH-(1-24) in humans. It was concluded that this decrease in ACTH concentration was due to short loop ACTH autoregulation. The present study demonstrates that the decrease in ACTH concentration measured by IRMA was due to an artifact of the IRMA. We injected 250 micrograms ACTH-(1-24), iv, into five normal male volunteers after overnight 2.5-g metyrapone administration. The ACTH concentration measured by IRMA decreased from 59.6 +/- 9.7 pmol/L before to 4.8 +/- 2.0 pmol/L 1 min after ACTH-(1-24) injection. The ACTH concentration measured by IRMA increased thereafter in a mirror image of the decline in ACTH-(1-24) measured by RIA. Addition of ACTH-(1-24) to plasma in vitro resulted in a decrease in the ACTH concentration measured by IRMA which was of similar magnitude to that observed in vivo. ACTH-(1-24) infusion in vivo or addition to ACTH-(1-39)-containing plasma in vitro decreased ACTH-(1-39) measured by IRMA by binding to N- but not C-terminal antibody without forming a detectable sandwich complex. We conclude that although ACTH short loop feedback may exist, it cannot be detected after ACTH-(1-24) injection with the use of a two-site IRMA.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Regulation of ACTH receptor mRNA and binding sites by ACTH and angiotensin II in cultured human and bovine adrenal fasciculata cells.

Human (HAC) and bovine (BAC) adrenal fasciculata cells express ACTH and angiotensin-II (A-II) receptors. In the present work, we have studied the effects of both hormones on ACTH receptor (ACTH-R) mRNA and binding sites. Both HAC and BAC expressed several ACTH-R transcripts. Although in both cell types, ACTH and A-II increased ACTH-R transcripts in a time- and dose-dependent manner, the maximal effects were different. Thus, ACTH at 10(-9) M enhanced 21- and 5-fold the level of ACTH-R mRNA and binding sites in HAC, whereas in BAC both parameters were enhanced only 3-fold. A-II at 10(-7) M increased 17- and 3.5-fold ACTH-R mRNA and binding sites in HAC, whereas in BAC, it caused only a 2-fold increase in ACTH-R mRNA and a small decrease in receptor number. In HAC, the stimulatory effects of both hormones on ACTH-R mRNA are mainly transcriptional, whereas in BAC they are mainly post-transcriptional, by decreasing the rate of degradation of ACTH-R mRNA. The stimulatory effects of ACTH on ACTH-R in both HAC and BAC were associated with an enhanced steroidogenic response to further hormonal stimulation. In contrast, specific species differences were observed with A-II. Thus, in HAC A-II increased ACTH-R mRNA and binding sites and the ACTH-induced cortisol production, whereas in BAC, A-II caused a slight decrease of ACTH binding sites and steroidogenic desensitization.

Adrenocorticotropic Hormone↗
PubMed1975

Interactions of adrenocorticotropic hormone with its adrenal receptors. Degradation of ACTH-1-24 and ACTH-11-24.

Crude membranes (20,000 times g pellet) prepared from human, rat, and ovine adrenals bind 125-I-corticotropin-(1-24)-tetracosapeptide (125-I-ACTH-1-24) and degrade unbound hormone. The degradation is dependent on temperature and the concentration of membrane proteins. The degradation of 125-I-[9-tryptophan(o-nitrophenylsulfenyl)]-corticotropin-(1-24)-tetracosapeptide (125-I-NPS-ACTH-1-24) is similar to 125-I-ACTH-1-24, but that of 125-I-corticotropin-(11-24)-tetradecapeptide (125-I-ACTH-1-24 is inhibited by ACTH-1-24 and corticotropin-(1-10)-decapeptide (ACTH-1-10), but ACTH-11-24 at the same molar concentration has no effect. On the other hand, the degradation of 125-I-ACTH-11-24 is protected by ACTH-11-24 and ACTH-1-24, but not by ACTH-1-10. This suggests two systems of degradation, one will have the NH-2-terminal sequence of ACTH-1-24 as substrate, and the other the 11-24 COOH-terminal sequence. The main label product from the degradation of the 125-I-ACTH-1-24 and 125-I-ACTH-11-24 behaves as [125-I]monoiodotyrosine on Sephadex G-50 and paper chromatography. The independence of ACTH binding to its receptor and degradation is demonstrated by the following facts. (a) Calcium and pancreatic trypsin inhibitor completely inhibit the binding at concentrations when the degradation is not altered; (b) the sequences of peptides of ACTH which inhibit the binding and degradation of 125-I-ACTH-1-24 are different.

Adenylyl Cyclases↗
PubMed2002

Single determination of plasma ACTH using an immunoradiometric assay with high detectability differentiates between ACTH-dependent and -independent Cushing's syndrome.

The purpose of this retrospective study was to elucidate the value of an ACTH assay with high detectability to differentiate between ACTH-dependent and -independent Cushing's syndrome. The study was based on the case records of 56 patients with Cushing's syndrome comprising 34 patients with ACTH-dependent Cushing's syndrome and 22 patients with ACTH-independent Cushing's syndrome. Basal morning plasma 1-39 ACTH was measured using an immunoradiometric assay (IRMA) with a normal range of 1.8-11 pmol/L. Peripheral corticotrophin-releasing hormone (CRH) tests were performed in 24 and 17 patients with ACTH-dependent and -independent Cushing's syndrome, respectively. Using a single ACTH measurement, a complete separation was observed between the two defined groups, with a cut-off value of 2.4 pmol/L. Mean ACTH concentration was 14.4 pmol L (range 2.5-47.7 pmol/L) in ACTH-dependent Cushing's syndrome and 0.6 pmol/L (range 0.2-2.2 pmol/L) in ACTH-independent Cushing's syndrome. The range of separation between the two groups was further increased by using two ACTH measurements in each patient or peripheral stimulation with CRH. It is concluded that in the majority of patients with Cushing's syndrome a single basal morning ACTH determination is sufficient to discriminate between ACTH-dependent and ACTH-independent Cushing's syndrome. In borderline cases with ACTH in the range 2-3 pmol/L, repeated measurements might be necessary. The peripheral CRH test was not superior to repeated ACTH measurements.

Adrenocorticotropic Hormone↗
PubMed1988

Vasopressin stimulation of adrenocorticotropin hormone (ACTH) in humans. In vivo bioassay of corticotropin-releasing factor (CRF) which provides evidence for CRF mediation of the diurnal rhythm of ACTH.

The diurnal response of ACTH release to intravenously administered arginine vasopressin was tested in normal volunteers given consecutively moderate doses of vasopressin every 15 min (0.1, 0.3, 1.0, and 3.0 IU) at 2200 h and again at 0700 h (PM/AM). This protocol was repeated 4 wk later with the times reversed (AM/PM). A dose-related increase in ACTH secretion was observed in all subjects. When the AM response of the AM/PM protocol was compared with the PM response of the PM/AM protocol, the release of ACTH was greater in the morning (P less than 0.05) as evaluated by the following criteria: peak value of ACTH (129.9 +/- 30.4 pg/ml in the AM vs. 57.1 +/- 20.2 in the PM); area under the curve (689 in the AM vs. 259 in the PM); and, sensitivity of the ACTH dose-response curve (first significant increase in ACTH with 1 IU of vasopressin in the AM but not significant even after 3 IU in the PM). In addition, when the AM vasopressin testing followed a previous evening stimulation (PM/AM protocol), there was a blunted ACTH response compared with the AM/PM protocol. Corticotropin-releasing factor (CRF) is probably the major ACTH secretagogue, but since vasopressin acts synergistically with CRF to produce an augmented release of ACTH, we suggest that the ACTH response to administered vasopressin depends upon the ambient endogenous level of CRF. We interpret our data and published data that CRF produces a lesser release of ACTH in the AM as follows: in the morning endogenous CRF is high and administered CRF produces little further release of ACTH, but administered vasopressin acting synergistically with high endogenous CRF causes a greater release of ACTH; conversely, in the evening endogenous CRF is low and administered CRF causes a greater release of ACTH, but vasopressin (a weak secretagogue by itself) gives a low ACTH response. We conclude that vasopressin stimulation of ACTH secretion can be used as an in vivo bioassay of endogenous CRF, and that there is a diurnal rhythm of CRF in hypophyseal portal blood.

Adrenocorticotropic Hormone↗
PubMed2000

Regulation by adrenocorticotropin (ACTH), angiotensin II, transforming growth factor-beta, and insulin-like growth factor I of bovine adrenal cell steroidogenic capacity and expression of ACTH receptor, steroidogenic acute regulatory protein, cytochrome P450c17, and 3beta-hydroxysteroid dehydrogenase.

The purpose of this study was to evaluate the time-course effect of a 36-h treatment with ACTH (10(-8) M), transforming growth factor-beta1 (TGFbeta1; 10(-10) M), angiotensin II (AngII; 10 (-7) M), and insulin-like growth factor I (IGF-I; 10(-8) M) on the steroidogenic capacity of bovine adrenocortical cells (BAC) and on messenger RNA (mRNA) levels of ACTH receptor, cytochrome P450c17, 3beta-hydroxysteroid dehydrogenase (3betaHSD), steroidogenic acute regulatory protein (StAR), and StAR protein. ACTH and IGF-I enhanced, in a time-dependent manner, the acute 2-h ACTH-induced cortisol production, whereas TGFbeta 1 and AngII markedly reduced it. ACTH, IGF-I, and AngII increased ACTH receptor mRNA, but the opposite was observed after TGFbeta1 treatment. ACTH and IGF-I increased P450c17 and 3betaHSD mRNAs, whereas AngII and TGFbeta1 had the opposite effects. However, the effects of the four peptides on ACTH-induced cortisol production appeared before any significant alterations of the mRNA levels occurred. The most marked and rapid effect of the four peptides was on StAR mRNA. The stimulatory effect of ACTH was seen within 1.5 h, peaked at 4-6 h, and declined thereafter, but at the end of the 36-h pretreatment, the levels of StAR mRNA and protein were higher than those in control cells. IGF-I also enhanced StAR mRNA levels within 1.5 h, and these levels remained fairly constant. The effects of AngII on StAR mRNA expression were biphasic, with a peak within 1.5-3 h, followed by a rapid decline to almost undetectable levels of both mRNA and protein. TGFbeta1 had no significant effect during the first 3 h, but thereafter StAR mRNA declined, and at the end of the experiment the StAR mRNA and protein were almost undetectable. Similar results were observed when cells were treated with ACTH plus TGFbeta1. A 2-h acute ACTH stimulation at the end of the 36-h pretreatment caused a higher increase in StAR mRNA and protein in ACTH- or IGF-I-pretreated cells than in control cells, which, in turn, had higher levels than cells pretreated with TGFbeta1, ACTH plus TGFbeta1, or AngII. These results and the fact that the stimulatory (IGF-I) or inhibitory (AngII and TGFbeta1) effects on ACTH-induced cortisol production were more pronounced than those on the ability of cells to transform pregnenolone into cortisol strongly suggest that regulation of StAR expression is one of the main factors, but not the only one, involved in the positive (IGF-I) or negative (TGFbeta1 and AngII) regulation of BAC for ACTH steroidogenic responsiveness. A high correlation between steady state mRNA level and acute ACTH-induced cortisol production favors this conclusion.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Developmental changes in adrenocorticotrophin (ACTH)-induced expression of ACTH receptor and steroid acute regulatory protein mRNA in ovine fetal adrenal cells.

OBJECTIVES: Adrenocorticotrophin (ACTH) plays an important role in mediating the increase in cortisol output in the late gestation sheep fetus. At the adrenal itself, heightened expression of ACTH receptor (ACTH-R) and steroid acute regulatory protein (StAR) appear to be important parallel changes. This study examined how ACTH affects ACTH-R and StAR mRNA expression, and cortisol production in adrenocortical cells isolated from fetuses of varying gestational age (dGA). We hypothesized that the ability of ACTH to stimulate its receptor and StAR mRNA expression would be greater close to term than earlier in development. METHODS: Adrenals were obtained from fetuses (100-105, 120, or 135-139 dGA), and the cortical cells were dispersed. After 3 days of culture, cells were stimulated with ACTH(1-24), and the cells and medium were collected at different time points (0, 3, 6, 9, 12, and 24 hours) for measurement of cortisol and ACTH-R and StAR mRNA. RESULTS: Cortisol secretion was increased after ACTH treatment in all three age cohorts. Cells from the 135-139 dGA group secreted the most cortisol, followed by the 100-105 and then the 120 dGA groups (P <.05). ACTH-R mRNA levels before and after ACTH were higher in the late compared to both earlier groups. StAR mRNA levels before and after ACTH were higher in the 100-105 and 135 than in the 120 dGA group. The time to peak ACTH-R mRNA response was age-dependent, with the 100-105 dGA cells taking longer to attain maximum levels. Maximal StAR mRNA levels were not age-related. CONCLUSION: The data suggest that ACTH-R and StAR are indeed key mediators of fetal adrenocortical responsiveness, and that ACTH is able to up-regulate responsiveness, and hence cortisol production, by increasing their expression.

Adrenal Glands↗
PubMed2003

Regulation of ACTH levels in anterior pituitary cells during stimulated secretion: evidence for aspartyl and cysteine proteases in the cellular metabolism of ACTH.

The regulation of cellular levels of adrenocorticotropin hormone (ACTH) in response to stimulated secretion was investigated to define the extent of cellular depletion of ACTH and subsequent increases to replenish ACTH levels in anterior pituitary cells (in primary culture). Treatment of cells with secretagogues for short-term incubation times (hours) resulted in extensive depletion of cellular ACTH. Corticotropin releasing factor (CRF) induced depletion of cellular levels of ACTH by 60-70% of control levels. The CRF-induced reduction of cellular ACTH was inhibited by the glucocorticoid dexamethasone. Phorbol myristate acetate (PMA), which stimulates protein kinase C (PKC), reduced ACTH levels by 50-60%. Forskolin, a stimulator of cAMP production, produced a moderate reduction in cellular ACTH. During prolonged incubation of cells (2 days) with these secretagogues, further reduction of ACTH levels by 70-80% was observed. However, increased cellular levels of ACTH occurred with continued treatment of cells with secretagogues, which provided nearly complete replenishment of cellular ACTH after 5 days treatment with secretagogues. Notably, the rising levels of cellular ACTH were inhibited by the aspartyl protease inhibitor acetyl-pepstatin A, and by the cysteine protease inhibitor E64d. These results demonstrate that depletion and recovery of ACTH levels are coordinately regulated, and that the increases in cellular levels of ACTH during the recovery phase involves participation of aspartyl and cysteine proteases. Thus, aspartyl and cysteine proteases may be involved in the cellular metabolism of ACTH.

Adrenocorticotropic Hormone↗
PubMed1999

Diagnosis of ACTH deficiency. Comparison of overnight metyrapone test to either low-dose or high-dose ACTH test.

Test sensitivity and accuracy of 250 microg/m(2) ACTH test, 1 microg/m(2) ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.

Adolescent↗
PubMed1977

Hormonal control of adrenocortical cell proliferation. Desensitization to ACTH and interaction between ACTH and fibroblast growth factor in bovine adrenocortical cell cultures.

A primary bovine adrenocortical cell culture system responsive to physiological concentrations of ACTH has been established. When added to cultures, ACTH inhibited DNA synthesis and cell division over the same concentration range required for stimulation of fluorogenic steroid production (0.01-10 nM). With chronic exposure to ACTH, cells became desensitized to the growth inhibitory effects of ACTH. Though cell growth was initially completely inhibited by ACTH, cells ultimately began to grow in its continued presence. The lag time to initiation of cell growth, the rate of growth, and the final density achieved depended on the ACTH concentration. Desensitization to ACTH(1-39) was not induced by monobutyryl cyclic AMP nor by ACTH(11-24). Specificity of desensitization was apparent because cells which had become desensitized to ACTH(1-39) remained fully responsive to monobutyryl cyclic AMP, prostaglandin E(1), and cholera toxin. Though the effects of ACTH on cell growth were readily reversible upon hormone removal, the desensitized response to readdition of ACTH persisted for at least 8 h. Fibroblast growth factor (FGF) stimulated both the growth rate and saturation density achieved. FGF did not alter the growth inhibitory effects of ACTH nor the reduced growth rate observed in desensitized cells maintained in ACTH. However, FGF greatly increased the saturation density achieved by cultures maintained with ACTH. Through the process of desensitization, adrenocortical cells are able to grow in the presence of high concentrations of ACTH and to respond to the effects of a growth factor by increasing the cell density achieved. This pattern of response may be a general one for growth control under the combined effects of antimitotic and mitotic factors.

Adrenal Cortex↗
PubMed1995

Intraoperative measurement of adrenocorticotropin (ACTH) during removal of ACTH-secreting bronchial carcinoid tumors.

The optimal treatment for ectopic ACTH syndrome is the complete removal of the tumor secreting ACTH. These tumors are often occult, with their location suggested but not proven with imaging techniques. The intraoperative measurement of ACTH by immunoradiometric assay in five patients with the occult ectopic ACTH syndrome during removal of suspicious intrapulmonary lesions is reported. A significant ACTH gradient was detected in the pulmonary veins of the affected lobes in two patients. ACTH had decreased significantly in all five patients by 10 and 15 min after tumor removal. All five patients had histologically proven ACTH-secreting bronchial carcinoid tumors, suppressed plasma ACTH by 24 h after tumor removal, and subsequent secondary adrenal insufficiency indicating successful surgical therapy (five of five true-positive). In one patient, previous surgery was not curative and did not result in a decrease in intraoperative measurement of ACTH (one of one true-negative). It was demonstrated that a rapid ACTH immunochemiluminescence assay with a 15-min incubation time has sufficient sensitivity and precision to detect decreases in ACTH described above. These results demonstrate that complete removal of ACTH-secreting bronchial carcinoid tumors can be detected intraoperatively by a decrease in arterial ACTH by 15 min. The modification of the ACTH immunochemiluminescence assay to 15 min incubation allows the documentation of a successful tumor removal in the operating room. It may also be used to locate the tumor intraoperatively by selective pulmonary vein sampling. This protocol may be applicable to the intraoperative measurement of ACTH during pituitary microadenomectomy for Cushing's disease.

Adrenocorticotropic Hormone↗
PubMed2000

A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery.

The short ACTH stimulation test is an easy, reliable, and extensively used test in the assessment of the hypothalamo-pituitary-adrenal (HPA) axis. However, its use immediately after pituitary surgery is a matter of debate. The insulin tolerance test (ITT) is the gold standard in the evaluation of the HPA axis, but it is not always without side effects and may be unpleasant early after pituitary surgery. Our aim was to investigate the value of the 1-microg ACTH test in the assessment of the HPA axis early after pituitary surgery. We also aimed to determine the value of the 1-microg and 250-microg ACTH tests and the ITT in the estimation of HPA axis status after 3 months postoperatively. Nineteen patients subjected to pituitary tumor surgery were included in the study, and the ITT and the 1-microg and 250-microg ACTH tests were performed between the 4th and 11th days of surgery. The tests were repeated at the first month in 3 patients with subnormal peak cortisol responses (454, 125, and 301 nmol/L) and in 18 patients at the third month postoperatively. ACTH stimulation tests were performed by using 1 microg and 250 microg ACTH iv as a bolus injection, and blood samples were drawn at 0, 30, and 60 min for measurement of serum cortisol levels. The ITT was performed by using iv regular insulin, and serum glucose and cortisol levels were measured. The 1-microg and 250-microg ACTH stimulation tests and the ITT were performed consecutively. At least 48 h were allowed between each test. A peak serum cortisol level of 550 nmol/L or greater was considered as a normal response for both the ITT and the ACTH tests. The serum cortisol level was measured by RIA using commercial kits. Serum glucose was determined by glucose oxidase method. There were correlations between the peak cortisol response to the ITT and the 1-microg ACTH test (r = 0.39, P < 0.05) in the early postoperative period. No correlation was found between the ITT and the 250-microg ACTH test responses. In the early postoperative period, two patients showed normal cortisol responses (> or =550 nmol/L) to the 1-microg ACTH test and five patients showed normal cortisol responses to the 250-microg ACTH test among the six patients with subnormal cortisol responses to the ITT. Three patients with subnormal cortisol responses to ITT and baseline cortisol values less than 240 nmol/L showed normal HPA axis at the end of the first month. In the late postoperative period, at the third month, all the patients showed normal HPA axis. In the early postoperative period of pituitary surgery, the 1-microg ACTH test results are more concordant than the 250-microg ACTH test in comparison with the ITT. Our results also indicate that HPA axis dysfunction shown by ACTH stimulation tests and the ITT in early postoperative period may be normalized 1-3 months after surgery. For this reason, we think that dynamic tests including the ITT may not be useful early after pituitary surgery.

Adrenocorticotropic Hormone↗
PubMed2004

A trial of intranasal ACTH(1-24) administration to a patient with isolated ACTH deficiency.

BACKGROUND: Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. Normally it could be used therapeutically as an alternative to glucocorticoid treatment in these patients. We investigated the possibility of therapeutic approach as intranasal ACTH replacement therapy in patients with ACTH deficiency. CASE REPORT: A 32-year-old woman with general fatigue, weakness of legs and loss of consciousness due to severe hyponatremia was admitted to our hospital. Endocrinological studies showed low levels of plasma ACTH and serum cortisol with the loss of circadian rhythm. Plasma ACTH and serum cortisol levels failed to respond after intravenous injection of human corticotropin releasing hormone (hCRH), however, serum cortisol showed a blunted response to ACTH(1-24) stimulation test. She was diagnosed isolated ACTH deficiency. We performed continuous intranasal administration of ACTH(1-24) to the patient. There were no cortisol, aldosterone and dehydroepiandrosterone (DHEA) responses to a single intranasal ACTH(1-24) administration while these levels increased 6 days after intranasal treatment of ACTH(1-24). CONCLUSIONS: These data demonstrate that adrenocortical steroids production are stimulated by intranasal administration of ACTH(1-24) in this patient with isolated ACTH deficiency. We suggest that intranasal administration of ACTH offers a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiologic than glucocorticoid replacement.

Administration, Intranasal↗
PubMed2006

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep.

The late-gestation plasma cortisol surge in the sheep fetus is critical for stimulating organ development and parturition. Increased adrenal responsiveness is one of the key reasons for the surge; however, the underlying mechanisms are not fully understood. Our recent studies suggest that ACTH-mediated increased expression of ACTH receptor (ACTH-R) and steroid acute regulatory protein (StAR) may play a role in enhancing responsiveness. Hence, we examined effects of ACTH infusion in fetal sheep on mRNA expression of these two mediators of adrenal responsiveness and assessed the functional consequences of this treatment in vitro. Fetuses of approximately 118 and 138 days of gestational age (dGA) were infused with ACTH-(1-24) for 24 h. Controls received saline infusion. Arterial blood was sampled throughout the infusion. Adrenals were isolated and analyzed for ACTH-R and StAR mRNA, or cells were cultured for 48 h. Cells were stimulated with ACTH, and medium was collected for cortisol measurement. Fetal plasma ACTH and cortisol concentrations increased over the infusion period in both groups. ACTH-R mRNA levels were significantly higher in ACTH-infused fetuses in both the 118 and 138 dGA groups. StAR mRNA increased significantly in both the 118 and 138 dGA groups. Adrenal cells from ACTH-infused fetuses were significantly more responsive to ACTH stimulation in terms of cortisol secretion than those from saline-infused controls. These findings demonstrate that increases in circulating ACTH levels promote increased expression of ACTH-R and StAR mRNA and are coupled to heightened adrenal responsiveness.

Adrenal Glands↗
PubMed1987

In vivo immunoreactive adrenocorticotropin (ACTH) production by human mononuclear leukocytes from normal and ACTH-deficient individuals.

Mononuclear leukocytes from 25 children (16 with normal pituitary ACTH production and 9 with ACTH deficiency) were examined for in vivo ACTH production by immunofluorescence with antiserum to ACTH-(1-13) amide. The protocol included 3 study periods: control, after administration of insulin, and after administration of typhoid vaccine (an interferon-alpha inducer). Plasma cortisol and mononuclear leukocyte ACTH immunofluorescence were measured before (0900 h) and 1, 2, 4, 6, 8, and 10 h after treatment on each of the 3 study days. In vitro studies with human leukocytes from normal subjects incubated with ACTH, insulin, or typhoid vaccine were also performed. Patients with normal pituitary ACTH production had an increase in the number of ACTH immunofluorescence-positive cells 1 h after insulin administration [25 +/- 5% (+/- SEM) to 44 +/- 6% P less than 0.05], and no change after typhoid administration. ACTH-deficient patients had no change after insulin administration and a significant rise 6 h after typhoid vaccine treatment (24 +/- 12% to 50 +/- 6%; P less than 0.05). The number of ACTH immunofluorescence-positive cells did not increase when mononuclear leukocytes were incubated in vitro with ACTH or insulin (with or without glucose deprivation). However, typhoid antigen enhanced this response from 8% to 55%. These data suggest that the number of human mononuclear leukocytes containing immunoreactive ACTH is increased by at least 2 stimuli: 1) a central factor(s), such as CRH, accounting for the in vivo rise 1 h after insulin administration in patients with an intact hypothalamic-pituitary axis, and 2) an interferon inducer (e.g. typhoid antigen), accounting for the typhoid antigen-induced rise in the number of ACTH-positive cells in vivo in ACTH-deficient patients and in vitro.

Adolescent↗
PubMed1999

Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests.

The efficacy of the standard high dose ACTH stimulation test (HDT), using a pharmacological 250-microg dose of synthetic ACTH-(1-24), in the diagnosis of central hypoadrenalism is controversial. The insulin hypoglycemia test is widely regarded as the gold standard dynamic stimulation test of the hypothalamo-pituitary-adrenal (HPA) axis that provides the most reliable assessment of HPA axis integrity and reserve. Alternatively, a prolonged infusion of ACTH causes a continuing rise in plasma cortisol levels that may predict the adrenals' capacity to respond to severe ongoing stress. In nine normal subjects, we compared plasma ACTH and cortisol levels produced by three i.v. bolus low doses of ACTH-(1-24) (0.1, 0.5, and 1.0 microg/1.73 m2; LDTs) with those stimulated by hypoglycemia (0.15 U/kg insulin) and with the cortisol response to a standard 250-microg dose of ACTH-(1-24). The normal cortisol response to an 8-h ACTH-(1-24) infusion (250 microg at a constant rate over 8 h) was determined using three modern cortisol assays: a high pressure liquid chromatography method (HPLC), a fluorescence polarization immunoassay (FPIA), and a standard RIA. In the LDTs, stepwise increases in mean peak plasma ACTH were observed (12.4 +/- 2.0, 48.2 +/- 7.2, 120.2 +/- 15.5 pmol/L for the 0.1-, 0.5-, and 1.0-microg LDTs, respectively; P values all <0.0022 when comparing peak values between tests). The peak plasma ACTH level after insulin-induced hypoglycemia was significantly lower than that produced in the 1.0-microg LDT (69.6 +/- 9.3 vs. 120.2 +/- 15.5 pmol/L; P < 0.0002), but was higher than that obtained during the 0.5-microg LDT (69.6 +/- 9.3 vs. 48.2 +/- 7.2 pmol/L; P < 0.02). In the LDTs, statistically different, dose-dependent increases in peak cortisol concentration occurred (355 +/- 16, 432 +/- 13, and 482 +/- 23 nmol/L; greatest P value is 0.0283 for comparisons between all tests). The peak cortisol levels achieved during the LDTs were very different from those during the HDT (mean peak cortisol, 580 +/- 27 nmol/L; all P values <0.00009. However, the mean 30 min response in the 1.0-microg LDT did not differ from that in the HDT (471 +/- 22 vs. 492 +/- 22 nmol/L; P = 0.2). In the 8-h ACTH infusion test, plasma cortisol concentrations progressively increased, reaching peak levels much higher than those in the HDT [995 +/- 50 vs. 580 +/- 27 nmol/L (HPLC) and 1326 +/- 100 vs 759 +/- 31 nmol/L (FPIA)]. Significant differences in the basal, 1 h, and peak cortisol levels as determined by the three different assay methods (HPLC, FPIA, and RIA) were observed in the 8-h infusion tests. Similarly, in the HDTs there were significant differences in the mean 30 and 60 min cortisol levels as measured by HPLC compared with those determined by FPIA. We conclude that up to 30 min postinjection, 1.0 microg/1.73 m2 ACTH-(1-24) stimulates maximal adrenocortical secretion. Similar lower normal limits at 30 min may be applied in the 1.0-microg LDT and the HDT, but not when lower doses of ACTH-(1-24) are administered. The peak plasma ACTH level produced in the 1.0-microg LDT is higher than in the insulin hypoglycemia test, but is of the same order of magnitude. The peak cortisol concentration obtained during an 8-h synthetic ACTH-(1-24) infusion is considerably higher than that stimulated by a standard bolus 250-microg dose, potentially providing a means of evaluating the adrenocortical capacity to maintain maximal cortisol secretion. Appropriate interpretation of any of these tests of HPA axis function relies on the accurate determination of normal response ranges, which may vary significantly depending on the cortisol assay used.

Adrenocorticotropic Hormone↗
PubMed2005

Malignant gastric carcinoid causing ectopic ACTH syndrome: discrepancy of plasma ACTH levels measured by different immunoradiometric assays.

Discrepancy of plasma ACTH levels measured by different immunoradiometric assays (IRMA) in a case with malignant gastric carcinoid causing ectopic ACTH syndrome was examined by gel chromatography and immunohistochemical analysis. A 49-year-old male was found to have a large gastric tumor, with muscle wasting, hypertension, diabetes and hypokalemia caused by hypercortisolemia. His plasma ACTH levels, although initially elevated, were found to be almost in normal ranges. The discrepancy of plasma ACTH levels was proven to be due to different IRMA kits used; the initial assay was performed by a kit that could recognize high-molecular weight (HMW) form as well as ACTH(1-39), but the later assay by another kit that could recognize only ACTH(1-39). Pathological examination of the gastric tumor was consistent with the diagnosis of malignant carcinoid. Immunohistochemical study revealed that immunoreactivity of proopiomelanocortin (POMC) was positive within the tumor cells, whereas those of ACTH and prohormone convertase 1/3 were negative. Molecular sieving analysis of patient's plasma by gel chromatography coupled with ACTH radioimmunoassay which could recognize HMW form and ACTH(1-39) and two different IRMAs revealed that the predominant form of ACTH was HMW form with a minor peak of ACTH(1-39). This is a rare case of ectopic ACTH syndrome caused by malignant gastric carcinoid with preferential production of HMW form of ACTH, possibly due to unprocessed POMC.

ACTH Syndrome, Ectopic↗
PubMed1994

ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell lines.

Corticotropin (ACTH) binds to specific receptors in the adrenal cortex and thereby regulates glucocorticoid and mineralocorticoid production. The number of ACTH binding sites on adrenocortical cells is increased by exposure of cells to activators of the cAMP pathway. The mechanism responsible for the increase in ACTH binding sites is not known. We therefore studied the levels of ACTH-R mRNA in mouse Y-1 and human NCI-H295 (H295) adrenocortical carcinoma cell lines. ACTH induced an increase in mouse ACTH-R mRNA in Y-1 cells that was time and dose dependent, increasing 6-fold over basal levels following exposure to 10(-8) M ACTH for 19-24 h. The amount of human ACTH-R mRNA in H295 cells increased 2-4-fold following a 24 h exposure to 10(-8) M ACTH, 1 mM dbcAMP, or 10(-5) M Forskolin. Treatment of H295 cells with angiotensin II (A-II) was found to dramatically increase the level of ACTH-R mRNA. These data indicate that regulation of ACTH-R mRNA levels is at least one mechanism by which ACTH and A-II elevate the number of ACTH binding sites in the adrenocortical cells.

Adrenal Cortex↗