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PubMed2000

Role of ACTH receptor in adrenocortical tumor formation.

Adrenocorticotrophin (ACTH) is the major regulatory hormone of steroid synthesis and secretion by adrenocortical cells. The actions of ACTH are mediated by its specific membrane receptor (ACTH-R). The human ACTH-R gene was recently cloned, allowing systematic determination of its sequence, expression and function in adrenal tumorigenesis. The presence of oncogenic mutations of the ACTH-R gene in adrenocortical tumors has been reported. Direct sequencing of the entire coding region of the ACTH-R gene of sporadic adrenocortical adenomas and carcinomas did not reveal constitutive activating mutations, indicating that this mechanism is not frequent in human adrenocortical tumorigenesis. Recent studies demonstrated allelic loss of the ACTH-R gene in a subset of sporadic adrenocortical tumors using a PstI polymorphism located in the promoter region of the ACTH-R gene. Loss of heterozygosity of the ACTH-R was analyzed in 20 informative patients with a variety of benign and malignant adrenocortical tumors. Three of them showed loss of heterozygosity of the ACTH-R gene. In addition, Northern blot experiments demonstrated reduced expression of ACTH-R mRNA in these three tumors with loss of heterozygosity, suggesting the functional significance of this finding at the transcriptional level. Deletion of the ACTH-R gene seems to be involved in a subset of human adrenocortical tumors, contributing to cellular dedifferentiation.

Adrenal Cortex Neoplasms↗
PubMed1978

A new approach to the preparation of ACTH antibody by immunization of the rabbit with an antigen-antibody complex.

Immunization with antigen-antibody complex of ACTH produced sensitive ACTH antibody applicable to the radioimmunoassay. The antibody prepared by immunization with the synthetic 1-24 ACTH was mixed with the antigen porcine ACTH, and the mixture was incubated to form the antigen and antibody complex. Two rabbits were initially immunized with this complex, then further immunized with only the porcine ACTH. Both rabbits produced the ACTH antibody with a titer of 1:25,000, which could detect ACTH of 5 pg per tube when applied to the radioimmunoassay of the human ACTH. This antibody showed a strong crossreaction with synthetic 1-24 ACTH, which was confirmed by radioimmunoassay method and immunostaining technique. On the other hand, control animals immunized with only procine ACTH from the beginning showed no production of ACTH antibody. It was concluded that addition of ACTH antibody to the antigen for the first immunization took an important role in eliciting production of the antibody. Possible roles of the antigen-antibody complex for immunization were discussed.

Adrenocorticotropic Hormone↗
PubMed1999

The influence of plasma on basal and ACTH-stimulated in vitro adrenocortical steroidogenesis.

Early descriptions of in vitro ACTH bioassays all emphasised the need to use extracted plasma samples due to interference by an unidentified component. The aim of these studies was to elucidate the effects of whole plasma on ACTH steroidogenic activity in vitro and to identify the responsible factor. A sensitive in vitro dispersed bovine adrenocortical cell bioassay was established. The addition of 10% ACTH-depleted human pooled plasma to the incubation media resulted in basal steroidogenesis equivalent to that achieved with 10(-9) M ACTH1-24 and potentiated the steroidogenic activity of 10(-9) M ACTH1-24 by 7.8-fold. This potentiation was dependent on the concentration of both ACTH and plasma in the media, but did not result from the mitogenic effect of plasma. A pituitary source was excluded and the potentiating activity was not extractable by Vycor glass. Column chromatography demonstrated two peaks of activity corresponding to molecular weights of 650 and 220x10(3) Da. These peaks did not correspond to the plasma binding of 125I-ACTH which resulted from non-specific binding to albumin. Lipoprotein-deficient serum had no effect on either basal or ACTH-stimulated steroidogenesis, but both were restored by the addition of purified lipoproteins. However, novel findings demonstrated a differential effect of low (LDL) and high (HDL) density lipoproteins on basal and ACTH-stimulated steroid production; thus, LDL exerted a greater effect on the former, whilst HDL potentiated the steroidogenic activity of added ACTH more than LDL. The addition of the lipoproteins to lipoprotein-deficient serum restored its basal and ACTH potentiating effects, the cholesterol concentrations of the chromatographic fractions exactly paralleling their ACTH potentiating effect. These findings suggest that not only are lipoproteins the plasma factor(s) which potentiates ACTH steroidogenic activity in in vitro bioassays, but also that they exert differential effects on basal and ACTH-stimulated steroid production.

Adrenocorticotropic Hormone↗
PubMed2001

The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus.

To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450(scc)), 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 17alpha-hydroxylase (P450(C17)) in the fetal adrenal gland. ACTH(1-24) infusion (14.7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysectomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approximately 50% following the removal of the pituitary gland. ACTH(1-24) infusion to HX fetuses failed to restore levels of SF-1 mRNA to that seen in intact animals. P450(scc) and 3betaHSD mRNAs were increased by ACTH(1-24) infusion for 18 days in intact animals, although no effects of the infusion were seen on P450(C17) mRNA levels. For all three of these mRNAs, there was a significant increase in their abundance between 132 days of gestation and term in intact fetuses. By term, ACTH(1-24) infusion was without any additional effect on their abundance. HX decreased the expression of P450(scc), 3betaHSD and P450(C17) mRNAs, while ACTH(1-24) infusion to HX fetuses increased the expression of these mRNAs to levels seen in intact animals. There were significant correlations between the abundance of the mRNA for P450(scc), 3betaHSD and P450(C17), but not MC2R and SF-1, and premortem plasma cortisol concentrations. These results emphasise the importance of the pituitary gland and ACTH in the regulation of the enzymes involved in adrenal steroidogenesis. Factors in addition to ACTH may also play some role, as the infusion was not always effective in increasing the abundance of the mRNAs. Surprisingly, the mRNA for MC2R and SF-1 did not appear to be regulated by ACTH in the late-gestation ovine fetus, though a pituitary-dependent factor may be involved in the regulation of SF-1 mRNA abundance.

Adrenal Glands↗
PubMed1988

Characterization of 12-O-tetradecanoyl-phorbol-13 acetate mediated ACTH release.

Activation of calcium-activated, phospholipid-dependent protein kinase C by phorbol esters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) has been shown to mediate release of hormones in many systems. To investigate the role of protein kinase C in the mechanism of pituitary ACTH release, we studied the effect of the following conditions on TPA mediated ACTH release in primary rat pituitary cultures; corticotropin releasing hormone (CRH), different concentrations of extracellular calcium (Ca+2), nifedipine (a calcium channel blocker), PGE2 and cortisol (regulators of ACTH secretions). TPA induced ACTH release in a dose dependent fashion with an ED50 of 4.2 x 10(-10) M. The maximal amount of ACTH release individually induced by TPA (10(-8) M) and CRH (10(-8)) were identical. TPA (10(-8)) potentiated the amount of ACTH release from cells already maximally stimulated with CRH (4 x 10(-8) M). TPA mediated ACTH release was dependent on extracellular calcium and inhibited by nifedipine, to a maximum of 35%. Cortisol decreased the amount of ACTH individually released by TPA and CRH in a similar and dose dependent fashion with maximal inhibition of 47% occurring at 10(-7) M. PGE2 caused a dose dependent reduction of TPA mediated ACTH release. In conclusion, the pathways of ACTH release induced by CRH and TPA are not entirely the same but may share a common regulatory pathway. Extracellular calcium and calcium cell influx may be important for maximal ACTH release induced by TPA. Protein kinase C activation may play an important role in CRH stimulated ACTH release.

Adrenocorticotropic Hormone↗
PubMed1992

ACTH hypertension in the rat: role of sodium chloride.

Adrenocorticotrophin (ACTH) produces adrenally dependent increases in both blood pressure and salt (NaCl) appetite in the rat. The present study examines the effect of free access to a high intake of NaCl on ACTH hypertension in the rat to test the hypothesis that high NaCl intake would amplify the rise in blood pressure. Either water or 1%NaCl were offered to sham or ACTH treated Sprague-Dawley rats. Subcutaneous injections of synthetic ACTH (0.5 mg/kg/day) for 10 days caused large increases in the intake of both 1%NaCl (+240 +/- 6 ml/day) and water (+45 +/- 4 ml/day), urine volume (1%NaCl + ACTH +182 +/- 4 ml/day, ACTH + water +36 +/- 2 ml/day), adrenal weight (ACTH + water 176 +/- 18, ACTH + 1%NaCl 367 +/- 129 mg/100 g body weight) and maximum systolic blood pressure (SBP) (ACTH + water +18 +/- 5 mmHg; 1%NaCl + ACTH +16 +/- 3 mmHg). Some ACTH + 1%NaCl rats developed severe edema. Thus, free access to NaCl in ACTH treated Sprague Dawley rats did not potentiate the hypertension, but was associated with edema in some animals.

Adrenal Glands↗
PubMedDate not supplied

[Simultaneous and bilateral catheterization of inferior petrosal sinuses in the diagnosis of Cushing's syndrome: basal multiple sampling and after ACTH-releasing hormone test].

In 22 patients with ACTH-dependent Cushing's syndrome we have performed multiple ACTH evaluations, baseline and after ACTH-releasing hormone (CRH), during simultaneous bilateral inferior petrosal sinus sampling. The basal inferior petrosal sinus/periphery ratio for ACTH was > 2 in 11/22 patients, CRH challenge caused the appearance of an inferior petrosal sinus/periphery ratio > 3 in 6 other patients. An ACTH-secreting adenoma was surgically proven in 17 patients with ACTH inferior petrosal sinus/periphery ratio > 2 basally or > 3 after CRH and in 1 patient with an inferior petrosal sinus/periphery ratio < 2 basally or 3 after CRH. In 4 patients the very high peripheral ACTH levels, the inferior petrosal sinus/periphery ratio and the lack of ACTH increase after CRH indicated the presence of an ectopic ACTH syndrome. An ACTH intersinus gradient > 1.4 was found in 11 patients. Among these patients the adenoma was correctly localised in 6 and wrongly in 5 patients. In conclusion, the diagnostic accuracy of the inferior petrosal sinus sampling was of 95.4% (21/22 cases) considering basal and CRH-stimulated ACTH levels. The multiple basal ACTH evaluation does not seem to be necessary associated with CRH-test, but may be helpful in some cases.

Adenoma↗
PubMed1986

Immunoreactive forms of ACTH released by the adenohypophysis of the rat during the perinatal period in vivo and in vitro studies.

Immunoreactive ACTH levels were determined in whole plasma, eluate fractions of plasma and perfusates of anterior lobe extracts subjected to chromatography on Sephadex G-50 fine. In the fetal plasma, ACTH levels were higher on day 19 than on days 17, 18, 20 and 21. After birth, ACTH concentrations dropped to reach the lowest values in one week old newborns; thereafter they increased until weaning on day 21. They were then similar to those of non pregnant adult females. Three peaks of immunoreactive ACTH were present in all the chromatograms; the first one eluted near the void volume ("big" ACTH, PM approximately 44,000), the third one coeluted with human ACTH (1-39) ("little" ACTH, PM approximately 4,500) and the second one eluted midway between the 2 previous peaks ("intermediate" ACTH, PM approximately 13,000). During the last days of pregnancy, the proportion of the "little" form of ACTH in the fetal plasma showed a gradual increase whereas that of the "big" one decreased. On days 17, 19 and 21 of gestation the anterior lobes of fetal pituitary glands released in vitro these 3 forms of immunoreactive ACTH in the same proportions as those observed in the anterior lobes. In contrast, the proportions of the circulating forms of ACTH were quite different; the "little" one gradually increased and the "big" one decreased as gestation progressed. In vitro controlled tryptic digestion of the isolated "big" form led to the appearance of "intermediate" and "little" forms suggesting some transformations in the circulation of the ACTH forms released by the fetal hypophysis in vivo.

Adrenocorticotropic Hormone↗
PubMed1980

Plasma glucocorticoid and circulating blood leukocyte responses in cattle after sequential intramuscular injections of ACTH.

Nine Holstein-Friesian cows in the same stage of lactation were randomly given IM injections of saline solution, 100 IU of ACTH, or 200 IU of ACTH for a period of 3 days at 0800 and 1600 hours on one day and at 0100 hours the next day. A dose of 100 IU of ACTH represented the amount of ACTH released during physiologic stress and 200 IU of ACTH represented a therapeutic dose. Blood samples were obtained from indwelling jugular catheters for total circulating leukocyte and total plasma corticosteroid determinations at -1, 0, 0.25, 0.50, 1, 1.50, 2, 4, 6, and 8 hours after the 0800-hour ACTH injections. Concentrations of blood leukocytes and total plasma corticosteroids were affected significantly (P < 0.05) by treatment, cow within treatment, day of injection, treatment by day interaction, time, treatment by time interaction, and day by time interaction. Total plasma corticosteroids were 5.6 ng/ml (saline), 38.9 ng/ml (100 IU of ACTH), and 59.8 ng/ml (200 IU of ACTH). Mean corticosteroid concentrations from 0.5 to 8 hours were 29.2 ng/ml on day 1, 42.5 ng/ml on day 2, and 32.7 ng/ml on day 3. Blood leukocytes were 8,545 cells/mm3 (saline, 11,241 cells/mm3 (100 IU of ACTH) and 9,777 cells/mm3 (200 IU of ACTH). When compared with basal circulating leukocyte concentrations (within cow), this represented increases of 20.7% for 100 IU of ACTH and 24.5% for 200 IU. Mean circulating leukocyte concentrations from 0.5 to 8 hours were 8,900 cells/mm3 on day 1, 10,500 cells/mm3 on day 2, and 10,000 cells/mm3 on day 3. These data indicate that the adrenal gland responded less on day 3 and that continuous stimulation of bovine adrenal glands by ACTH at physiologic and therapeutic concentration could lead to reduced synthesis or release of adrenal corticosteroids (or both) with concomitant reduction in the concentration of total circulating leukocytes.

Adrenocorticotropic Hormone↗
PubMed1996

[Determination of ACTH in the inferior petrosal sinuses in the examination of patients with hypercortisolism].

BACKGROUND: Differential diagnosis of the etiology of ACTH-dependent hypercortisolism is very difficult in some cases. The uncertainty, whether there is a central or ectopic etiology, is also strengthened by the fact that even nuclear magnetic resonance (MR) sometimes does not prove the pituitary adenoma. A more precise differential diagnosis under these conditions has been made, over the last years, by selective determination of ACTH levels bilaterally in sinus petrosi inferiores (SPI) and by their comparison with the level in peripheral blood. The confirmation of central etiology makes a decision about neurosurgical intervention easier. This intervention, due to the present microsurgery technique, makes it possible to detect otherwise undetectable microadenoma and enables its selective excision with maintaining healthy hypophysis tissue and all its functions. METHODS AND RESULTS: In the last two years the authors indicated 11 patients (10 women, one man at the age of 17-54 years, mean age 33.5 year) with proved ACTH-dependent hypercortisolism to the determination of ACTH in SPI. Their CT or NMR examination did not prove a hypophysis tumour unequivocally. Only in one female patient the catheterization was not possible for anomalous vascular bed with aplasia of internal jugular vein on the left and hypoplasia of internal jugular vein on the right. In 8 patients the determination of the ratio of ACTH levels between SPI and periphery (7.78 +/- 1.54, mean +/- S.E.) has shown that even the basal levels indicated central etiology of hypercortisolism. This has been confirmed by the ratio of the values of ACTH after stimulation with corticotrophin releasing hormone (CRH). The diagnosis was confirmed in all patients by surgery, by histology and post-operation course. In two female patients the ratio of basal levels of ACTH, SPI/periphery did not prove useful for the diagnosis of the Cushing's disease. In the first patient the CRH stimulation was not yet performed routinely and the ratio of basal levels of ACTH, SPI/periphery gave a false negative result, as shown by the finding of adenoma of hypophysis during the operation. The operation was indicated on the basis of hormonal examinations and repeated MR with a finding of suspected microadenoma and the diagnosis was then confirmed by further clinical development. The determination of the levels of ACTH after CRH stimulation would give more precision in this case, as shown by analysis of the results of large cohorts in literature, which we perform at present as well. In the other patient the CRH stimulation test was done, changing the ratio from 1.1 to 5.7 and thus confirmed central etiology of the Cushing's syndrome. In agreement with literature this method did not contribute to lateral localization of the tumour. CONCLUSIONS: The determination of basal levels of ACTH in SPI and levels after CRH stimulation enables to differentiate between central and ectopic overproduction of ACTH in the ACTH-dependent Cushing's syndrome.

Adenoma↗
PubMed1997

Metyrapone pre-treated inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful investigative technique in the differential diagnosis of ACTH-dependent Cushing's syndrome. Diagnostic accuracy is improved by the administration of corticotrophin releasing-factor (CRF) during the procedure to stimulate ACTH secretion. We hypothesized that, given the unavailability of CRF in Australia, stimulation of ACTH secretion from tumorous corticotrophs with metyrapone treatment before IPSS may be useful. AIMS: To describe our clinical experience with a novel diagnostic test, and to compare results between IPSS with and without metyrapone pre-treatment. SETTING: Metropolitan, Australian university teaching hospital. PATIENTS: 18 patients were studied on 21 occasions: three with Cushing's disease without metyrapone treatment prior to IPSS (M-), 11 with Cushing's disease with metyrapone pretreatment (M+), three with ectopic ACTH syndrome, and one with pseudo-Cushing's syndrome. TREATMENT: Patients received oral metyrapone, median dose 750 mg 6 hourly, for 24 h before IPSS. RESULTS: No major side effects were noted. Metyrapone increased serum 11-deoxycortisol concentration to a median of 400 nmol/l (range 36-1310) on the morning of the test. Radiological confirmation of correct catheter placement was shown in 36/42 inferior petrosal sinuses (86%). Median peak central: peripheral ACTH ratios were 9.8 for M- pituitary adenomas (range 5.7-13.6), 12.9 for the technically successful M+ pituitary adenomas (range 8-54.1), and 1.6 for M+ ectopic ACTH syndrome cases (range 1.2-3.4). Repeat studies in unoperated patients with ectopic ACTH syndrome showed ratios < 1.6. IPSS showed median peak ACTH concentrations of 190 ng/l for M- pituitary adenomas (range 83-205), 595 ng/l for the technically successful M+ pituitary adenomas (range 80-7630; P = 0.035 compared to M-), and 62 ng/l for M+ ectopic ACTH syndrome cases (range 47-220). IPSS correctly identified the pituitary source of ACTH production in all cases of Cushing's disease (except one technical failure where MRI revealed a lesion). MRI scanning correctly identified a lesion in 3/14 operated Cushing's disease cases. IPSS correctly lateralized 1/3 M- and 7/8 M+ Cushing's disease cases where the procedure was technically successful and surgical descriptions adequate. Pituitary exploration revealed a visible lesion in 75% of cases corresponding to the side predicted by IPSS; 'blind' hemi-hypophysectomy was performed on the side predicted from IPSS in the remainder. All cases of Cushing's disease were cured or improved following surgery, with a median follow-up of 2.8 years (range 0.7-5.9). CONCLUSIONS: Metyrapone pre-treated inferior petrosal sinus sampling is safe, and appears to induce high ACTH output from pituitary corticotroph adenomas. The technique has allowed accurate localization and treatment of pituitary corticotroph microadenomas.

ACTH Syndrome, Ectopic↗
PubMed2007

The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome.

OBJECTIVE: Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin-releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH-dependent Cushing's syndrome. DESIGN: A retrospective case-record study. PATIENTS: Fifty-six patients with confirmed ACTH-dependent Cushing's syndrome underwent BIPSS with desmopressin stimulation when presenting negative pituitary tumour imaging. MEASUREMENTS: Central to peripheral (CEN:PER) ACTH gradient, lateralization of the ACTH source and surgical tumour confirmation were evaluated. RESULTS: A CEN:PER ACTH gradient was found in 40 patients under basal conditions (CEN:PER >or= 2) and in 47 patients after desmopressin stimulation (CEN:PER >or= 3). Ectopic ACTH-producing tumours (three lung carcinoid tumour, one thymus carcinoid tumour and one thymus hyperplasia) were confirmed in five out of nine patients without the CEN:PER ACTH gradient, and four cases were false negative for Cushing's disease. Lateralization (IPS:IPS >or= 1.4) was observed in 80.8% of patients under basal conditions (38/47) and in 97.8% after desmopressin (46/47), and it was surgically confirmed in 78.7%. There were no false-positive cases. Sensitivity and specificity were 92.1% and 100%, respectively. CONCLUSIONS: Desmopressin improves the differential diagnosis of ACTH-dependent Cushing's syndrome by amplifying the CEN:PER and IPS:IPS ACTH gradients, and is therefore a useful ACTH secretagogue in BIPSS.

ACTH Syndrome, Ectopic↗
PubMed2002

Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.

ACTH Syndrome, Ectopic↗
PubMed1994

[Synthesis and release of CRF and ACTH in ectopic CRF/ACTH-producing tumors].

To differentiate between ectopic ACTH syndrome and Cushing's disease, we examined the gene expression of CRF, POMC and glucocorticoid receptor in pituitary adenomas and in ectopic ACTH-producing tumors. CRF increased plasma ACTH levels in all patients with Cushing's disease and in some patients with ectopic ACTH syndrome whose tumors contained CRF and CRF mRNA. In CRF non-responders, no CRF was detected in tumors that contained no CRF mRNA or contained only long-size CRF mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in the patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRF increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRF mRNA, PMA-induced POMC gene expression, two ectopic ACTH syndrome subtypes (tumors containing ACTH with CRF and tumors without CRF), and Dex-induced decrease in ACTH release and POMC mRNA levels in some bronchial carcinoid.

ACTH Syndrome, Ectopic↗
PubMed1976

Multiple forms of corticotropin (adrenocorticotropic hormone, ACTH) and their significance.

Big corticotropin (adrenocroticotropic hormone, ACTH), an immunoreactive form of ACTH with low biological activity and which elutes in the void volume on Sephadex G-50 gel filtration, is found in plasma and extracts of human pituitary and tumour. Controlled tryptic digestion of big ACTH releases a product with full corticotropic activity which is indistinguishable from the (1-39) ACTH with respect to size, charge and susceptibility to tryptic digestion. Immunoreactive ACTH, predominantly in the big form, is found in virtually all tissue extracts of carcinoma primary to or metastatic from the lung, but not of carcinoma metastatic to the lung, and even in precancerous lung lesions. The absence of clinical Cushing syndrome in patients with carcinoma of the lung and moderate elevation of plasma concentrations of ACTH is due to the low biological activity of big ACTH. Prolonged survival (for more than two years) of patients with lung carcinoma has been observed only in those whose plasma ACTH is low before therapy or after resection of the lung tumour. Rabbit, rat and mouse pituitaries contain an intermediate sized ACTH but the usual 1-39 peptide predominates in the pituitaries of monkey, sheep, dog, cat and guinea pig, as well as man. The hormonal form of ACTH appears to be an important factor regulating the cortisol/corticosterone ratio in mammalian adrenal corticoid secretion because administration of porcine ACTH to rabbits alters the adrenal secretory pattern so as to decrease corticosterone production and increase cortisol production.

Addison Disease↗
PubMed1998

Evidence for Ah receptor mediation of increased ACTH concentrations in primary cultures of rat anterior pituitary cells exposed to TCDD.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to increase plasma ACTH concentrations in male Sprague-Dawley rats and in male rat primary anterior pituitary cell cultures. The present study examined whether the anterior pituitary effects observed after TCDD exposure are mediated via the Ah receptor (AhR). Primary anterior pituitary cell cultures were prepared from normal 180- to 220-g male rats and the cultures treated with alpha-naphthoflavone (ANF), an antagonist; beta-naphthoflavone (BNF), an agonist; BNF + TCDD; 3,3',4,4',5-pentachlorobiphenyl (PCB), which is known to bind to the AhR; and 2,2',4,4',5,5'-hexachlorobiphenyl (HCB), which does not bind the AhR. Support for the TCDD-AhR-mediated increases in ACTH concentrations is provided by the following observations: (1) ANF inhibited both the 1.3- to 2-fold TCDD-induced increase in basal medium and intracellular ACTH concentrations and the 30% TCDD-induced decrease in medium ACTH levels and the 1.2-fold increase in intracellular ACTH levels in corticotropin-releasing hormone (CRH)-stimulated cells, (2) BNF increased basal medium (1.7-fold) and intracellular (1.3-fold) ACTH concentrations, (3) BNF + TCDD demonstrated additivity by increasing basal medium (2.4-fold) and intracellular (1.7-fold) ACTH concentrations, (4) PCB increased basal medium (1.8- to 2.1-fold) and intracellular (1.3- to 1.8-fold) ACTH concentrations and inhibited medium ACTH secretion in CRH stimulated cells by 24-43%, and (5) HCB did not effect basal or CRH stimulated medium and intracellular ACTH concentrations. From this study it appears that TCDD-induced changes in ACTH secretion and synthesis by cultured anterior pituitary cells is mediated through the Ah receptor.

Adrenocorticotropic Hormone↗
PubMed1997

Regulation of the 11 beta-hydroxysteroid dehydrogenase in the rat adrenal. Decrease enzymatic activity induced by ACTH.

Patients with ectopic ACTH syndrome often develop hypertension and hypokalemic alkalosis with an abnormal increase in the ratio of plasma cortisol to cortisone, indicating that 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity is inhibited. Inhibition of 11 beta HSD allows access of cortisol or corticosterone to the mineralocorticoid receptor where it act as a mineralocorticoid. Two isozymes, 11 beta HSD-1 and 11 beta HSD-2, have been cloned and characterized. The rat adrenal expresses the mRNAs for 11 beta HSD-2 and, in lesser amounts, 11 beta HSD-1. We investigated the effect of ACTH on the 11 11 beta HSD-2 activity in the rat adrenal. Rat adrenal cells zone fasciculata (ZF) were dispersed and incubated separately with increasing concentrations of ACTH for 90 min, and secretion of corticosterone (B) and 11-dehydrocorticosterone (A) in the media was measured by enzyme-linked immunoabsorbent assays (ELISA). The conversion of [3H]B to [3H]A in the presence of 0.5 mM NAD+ was evaluated in microsomes prepared from dispersed cells preincubated for 30 min with cyanoketone and metyrapone followed by incubation for 30 min with the same inhibitors, with and without 10 nM ACTH. The dispersed cells of the ZF produced significant amounts of A which increased with ACTH. The basal B/A ratio was 0.97 +/- 0.05. ACTH caused a concentration-dependent increase in the ratio of B/A with a maximum ratio of 9.58 +/- 0.20. ACTH also inhibited the conversion of [3H]B to [3H]A in microsomes in which endogenous B production was inhibited by cyanoketone and metyrapone. ACTH did not change the K(m) for B conversion, but the Vmax was reduced significantly (1.73 +/- 0.43 pmol/min. mg protein), indicating that ACTH suppressed the 11 beta HSD-2 in a noncompetitive fashion. Dibutyryl cyclic AMP (dcAMP) also produced a concentration-dependent increase in the B/A ratio, but various concentrations of calcium did not affect the enzyme activity. In summary, adrenal cells treated with ACTH results in a significant increase in the ratio of B/A in the ZF owing a noncompetitive inhibition of the 11 beta HSD-2 via the ACTH receptor.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

CRH and AVP-induced changes in synthesis and release of ACTH from the ovine fetal pituitary in vitro: negative influences of cortisol.

During late gestation in sheep, fetal plasma adreno-corticotrophin (ACTH) and cortisol levels increase, and these are associated with increased pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary. Corticotrophin-releasing hormone (CRH) and vasopressin (AVP) are the primary hypophysiotrophic factors regulating ACTH secretion from the fetal sheep pituitary corticotroph, but previous reports with term fetal tissue have failed to show effects on levels of POMC mRNA. The objectives of the present study were to establish the effects of CRH and AVP on both synthesis and secretion of ACTH before term, and to determine how cortisol affects these responses. Fetal pituitaries were removed at d 138 of gestation (term approximately d 147), the anterior pituitary was separated, and the cells dispersed and placed in monolayer tissue culture. After 4 d, cells were treated for 18 h with several different concentrations (10(-6)-10(-9) M) and combinations of CRH, AVP, and cortisol. Following incubation, the medium was removed for ACTH analysis, and the cells fixed for POMC mRNA measurement and immunoreactive (ir)-ACTH localization. Separately, CRH and AVP significantly (p < 0.05) stimulated ACTH secretion in a dose-dependent manner. Simultaneous treatment of maximally stimulating levels of CRH and AVP augmented (p < 0.05) the output of ACTH. Cortisol did not affect basal (nonstimulated) ACTH output, but attenuated the neuropeptide-induced increases in ACTH secretion. This effect of cortisol was more pronounced in cells treated with CRH than in cells treated with AVP. POMC mRNA levels were increased by both CRH and AVP treatments in a dose-dependent manner, though there was no further increase in POMC mRNA when CRH and AVP were added together. Cortisol attenuated (p < 0.05) the neuropeptide-induced increases in POMC mRNA, though AVP-stimulated POMC mRNA levels were significantly higher than in cells treated with cortisol alone. Cortisol failed to alter non-stimulated POMC mRNA levels. We conclude that in late gestation: 1) Fetal pituitary corticotrophs respond to CRH and AVP by increasing POMC mRNA levels and ACTH secretion 2) AVP is more potent than CRH at the level of ACTH secretion, but not POMC transcription 3) Cortisol attenuates the synthetic and secretory responses to CRH and AVP, but has little effect in the non-stimulated state.

Adrenocorticotropic Hormone↗