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PubMed2004

Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson's syndrome compared with Cushing's disease.

OBJECTIVE: As described originally, Nelson's syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing's disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelson's syndrome and untreated Cushing's disease. PATIENTS AND METHODS: To address this pathophysiological issue, we studied nine patients fulfilling the criteria of Nelson's syndrome receiving glucocorticoid and mineralocorticoid replacement; nine patients with untreated pituitary-dependent Cushing's disease and nine gender- and age-matched controls. ACTH release was appraised by monitoring plasma ACTH concentrations in blood samples collected every 10 min for 24 h. ACTH secretion rates and endogenous decay were quantified by multiparameter deconvolution analysis. The orderliness of the ACTH release process was delineated by the approximate entropy (ApEn) statistic. Diurnal variation in ACTH secretion was appraised by cosinor analysis. RESULTS: Basal ACTH secretion was increased sixfold and pulsatile secretion ninefold in patients with Nelson's syndrome compared with Cushing's disease (P </= 0.01 and P </= 0.001, respectively). The increase in pulsatile secretion was due to an eightfold augmentation of burst mass. Event frequency was comparable in both patient groups (32 +/- 1 vs. 28 +/- 2 pulses/24 h), and higher than in normal controls (22 +/- 1 pulses/24 h, P < 0.0001). Paradoxically, the consistency of subordinate patterns of serial ACTH release, albeit disrupted in active Cushing's disease, was normal in Nelson's syndrome (P = 0.014). Normal ACTH secretory-process regularity in Nelson's syndrome was attributable to a more reproducible (lower ApEn) succession of ACTH secretory-burst mass denoting more uniform amplitude evolution over 24 h (P = 0.007, Nelson vs. Cushing). However, the quantifiable regularity of serial interburst intervals (waiting times) was unexpectedly elevated in Nelson's syndrome (P = 0.022). Nelson patients maintained a significant diurnal rhythm in ACTH release, which was marked by a 15-fold greater amplitude (P = 0.0018 vs. Cushing's) and a 4-h acrophase (maximum) delay (P = 0.037 vs. control). CONCLUSION: The present detailed analyses delineate marked ACTH secretory-burst mass amplification and (amplitude-independent) anomalous regularity of successive pulse size and timing in Nelson's syndrome compared with Cushing's disease or controls. We postulate that the foregoing novel distinctions are due to unique tumoural secretory properties, concurrently required glucocorticoid replacement and/or hypothalamic injury associated with prior radiotherapy in Nelson's syndrome.

Adrenalectomy↗
PubMed1995

Involvement of multiple protein kinase C isozymes in the ACTH secretory pathway of AtT-20 cells.

1. The mouse AtT-20/D16-16 anterior pituitary tumour cell line was used as a model system for the study of protein kinase C (PKC)-mediated enhancement of calcium- and guanine nucleotide-evoked adrenocorticotrophin (ACTH) secretion. 2. A profile of the PKC isozymes present in AtT-20 cells was obtained by Western blotting analysis and it was found that AtT-20 cells express the alpha, beta, epsilon and zeta isoforms of PKC. 3. PKC isozymes were activated by the use of substances reported to activate particular isoforms of the enzyme. The effects of these substances were investigated in both intact and electrically-permeabilized cells. Phorbol 12-myristate 13-acetate (PMA, EC50 = 1 +/- 0.05 nM, which activates all isozymes of PKC, except the zeta isozyme), thymeleatoxin (TMX, EC50 = 10 +/- 0.5 nM, which activates the alpha, beta and gamma isozymes) and 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA, EC50 = 3 +/- 0.5 nM, a beta 1-selective isozyme activator) all stimulated ACTH secretion from intact cells in a concentration-dependent manner. Maximal TMX stimulated ACTH secretion was of a similar degree to that obtained in response to PMA but maximal dPPA-stimulated ACTH secretion was only 60-70% of that obtained in response to PMA or TMX. 4. Calcium stimulated ACTH secretion from electrically-permeabilized cells over the concentration-range of 100 nM to 10 microM. PMA (100 nM), TMX (100 nM) but not dPPA (100 nM) enhanced the amount of ACTH secreted at every concentration of calcium investigated. PMA (100 nM) and TMX (100 nM)significantly enhanced ACTH secretion in the effective absence of calcium (i.e. where the free calcium concentration is nM).5. GTP-gamma-S stimulated ACTH secretion from permeabilized cells in a concentration-dependent manner with a threshold of 1 micro M. PMA (100 nM), TMX (100 nM) but not dPPA (100 nM) increased the amount of ACTH secretion evoked by every concentration of GTP-gamma-S investigated.6. The PKC inhibitor, chelerythrine chloride (10 micro M), blocked the PMA (100 nM)-evoked enhancement of calcium- and GTP-micro-S-stimulated ACTH secretion but did not significantly alter calcium- or GTP-micro-S-evoked secretion itself.7. The present paper indicates that AtT-20 cells express multiple isoforms of PKC and that these act at different sites in the secretory pathway for ACTH secretion. The alpha and epsilon isozymes of PKC can act distal to calcium entry to modulate the ability of increased cytosolic calcium concentrations to stimulate ACTH secretion. This site of action is either at the level of, or at some stage distal to, a GTP-binding protein which mediates the effects of calcium upon ACTH secretion. The beta isozyme of PKC may act ata stage early in the secretory pathway to regulate the cytosolic calcium concentration.

Adrenocorticotropic Hormone↗
PubMed1984

Adrenocorticotropin radioimmunoassay: properties of antisera against synthetic ACTH(1-24) and its clinical application.

Two antisera against synthetic ACTH(1-24) developed in rabbit showed strikingly different affinities toward the ACTH molecule. Both antisera (A-6 and A-7) were highly specific for the COOH-terminal region of ACTH(1-24). Antisera A-6 recognized ACTH(1-39) poorly. Radioimmunoassays (RIAs) using these antisera permitted the rapid (less than or equal to 18 h) quantitation of ACTH(1-24) (A-6) or ACTH(1-39) (A-7) at picogram levels. ACTH levels were determined on silicic acid extracts of rat and human plasma samples by the RIA specific for mid-region of ACTH(1-39) (A-7) and compared with that obtained by an ACTH(34-39) (C-terminal) RIA. In nearly all cases the C-terminal/mid-region ACTH ratios were less than 1.0, indicating that C-terminus of ACTH is more readily degraded by tissue or blood peptidases than are internal sequences. A solid-phase immunoadsorbent RIA specific for the extreme COOH-terminus of ACTH(1-24) was developed by coupling antiserum (A-6) to Sepharose 4B. This assay exhibited the same specificity as the soluble antiserum, yet tolerated relatively high concentrations of protein. Although the assay was suitable for rapid quantitation of ACTH(1-24), a decrease in sensitivity was observed in comparison to a conventional assay.

Adrenocorticotropic Hormone↗
PubMed1984

Electron microscopic immunocytochemistry by the protein A-gold method of two types of rat anterior pituitary ACTH cells.

Immunocytochemical detection of ACTH using the protein A-gold method was performed in the adult male rat anterior pituitary gland after simple glutaraldehyde fixation and double fixation with glutaraldehyde and osmium tetroxide. Immunoreactive ACTH cells of the rat anterior pituitary can be classified into two groups: typical and atypical ACTH cells. The typical ACTH cells are small stellate cells extending slender processes, and contain secretory granules aligned in a single row along the cell surface. The atypical ACTH cells are rather fat, polygonal or oval cells with a few stout processes. Secretory granules are very numerous and fill the entire cytoplasm, and are not limited to the cell periphery. The latter cell's granules vary widely in electron density after glutaraldehyde and osmium. Among these variable secretory granules, the dense ones are strongly labeled with ACTH-reactive colloidal gold particles, but less dense ones are not. The typical ACTH cells reported here correspond to the Type II ACTH cells, while the atypical ones are the Type I ACTH cells previously reported. The results of protein A-gold immunocytochemistry of ACTH favor the view that two types of ACTH cells are present in the rat anterior pituitary. An intermediate type of ACTH cells was also observed, suggesting a transition between the above mentioned two types of ACTH producers.

Adrenocorticotropic Hormone↗
PubMed2000

Administration of ACTH to restrained, pregnant sows alters their pigs' hypothalamic-pituitary-adrenal (HPA) axis.

This study was designed to examine the physiology and behavior of pigs whose dams were snared and then injected with ACTH during gestation. Administration of ACTH to dams during pregnancy has been shown to replicate the effects of prenatal stress in other species. Control sows (n = 8) were given no treatment, whereas the treatment sows (ACTH, n = 8) were immobilized by snaring the snout and then administered an i.v. injection of ACTH (1 IU/kg BW) weekly from 6 to 12 wk of gestation. A pig was killed from each sow at 1, 30, and 60 d of age. The hypothalamus, pituitary gland, adrenal glands, and liver were immediately obtained to determine the amounts of corticotropin-releasing hormone (CRH), beta-endorphin, and mRNA for pro-opiomelanocorticotropin (POMC), the ACTH receptor (ACTH-R), and insulin-like growth factor I (IGF-I). Pituitary corticotrope and somatotrope cell numbers and adrenal cortex-to-medulla area ratios (CORT:MED) were also determined. Pigs' behaviors were recorded at 6 and 8 wk of age. At 75 d of age, a blood sample was taken and a biopsy puncture was created on one pig from each litter, then pigs were stressed by mixing. Blood was sampled every other day for 10 d to determine plasma cortisol concentrations and differential leukocyte counts. Biopsy damage was evaluated for healing. At 1 d of age, control pigs tended to weigh more (P = .09), have a lower expression of ACTH-R mRNA (P = .01) and IGF-I mRNA (P = .01), and a lower CORT:MED (P = .04) than ACTH pigs. At 30 d of age, control pigs had a greater concentration of beta-endorphin (P = .01) and tended to have a lower concentration of CRH (P = .09) and IGF-I mRNA (P = .10) than ACTH pigs. At 60 d of age, control pigs tended to have lighter pituitary glands (P = .08), a lower expression of POMC mRNA (P = .02), and a CORT:MED (P = .003) than ACTH pigs. At 8 wk of age, control pigs performed a higher frequency of belly nosing (P = .07) and oral vice behaviors (P = .01) than ACTH pigs. In response to mixing stress, control pigs had lesser concentrations of plasma cortisol (P = .03) and healed faster (P = .006) than ACTH pigs. Thus, exogenous ACTH and restraint during gestation alters the HPA axis of the sow's offspring, and during stressful situations later in life health, and therefore welfare, may be compromised.

Adrenal Glands↗
PubMed2002

Plasma adrenocorticotropin (ACTH) concentrations and clinical response in horses treated for equine Cushing's disease with cyproheptadine or pergolide.

Plasma ACTH levels have been variable in horses with a positive clinical response for therapy for equine Cushing's Disease (ECD). Therefore, our purpose was to determine the value of monitoring plasma adrenocorticotropin (ACTH) levels during treatment of equine Cushing's disease (ECD) with either cyproheptadine (n = 32) or pergolide (n = 10). First, we validated the chemiluminescent ACTH assay (specificity, precision, accuracy, intra-assay and interassay variations) and tested methods of handling the whole blood from the time of collection to when the ACTH was assayed. The sensitivity and specificity of high plasma ACTH levels for detecting ECD was determined in a retrospective study on hospitalised horses (n = 68). Surveys were sent to veterinarians who submitted equine ACTH levels that were high initially and had at least 2 ACTH samples to determine the value of monitoring ACTH levels during therapy of ECD. The ACTH chemiluminescent assay was valid. The ACTH was stable when whole blood was collected and held in plastic tubes for 8 h before separating the plasma. The sensitivity and specificity of plasma ACTH levels for detecting ECD were 84% (n = 19,95% CI 60,97) and 78% (n = 49,95% CI 63,88), respectively. Treated horses generally showed a decrease in plasma ACTH. Plasma ACTH levels may be helpful when monitoring therapy of ECD, although improvement in clinical signs should be considered most important. There were no differences between cyproheptadine and pergolide in terms of improvements in any of the clinical signs.

Adrenocorticotropic Hormone↗
PubMed2002

The relationship between morning serum cortisol and the short ACTH test in the evaluation of adrenal insufficiency.

BACKGROUND: Morning serum cortisol examinations and short corticotropin (ACTH) tests are popular screening tests for unstressed patients suspected of having adrenal insufficiency. However, the correlation between morning serum cortisol and the peak cortisol response in the short ACTH test after intravenous injection of ACTH has not been studied before. This retrospective study examined the relationship among the mean basal morning cortisol level, the single random morning cortisol level and the peak cortisol level in the short ACTH test in evaluation of adrenal insufficiency. METHODS: In this retrospective study, we examined the relationship among the mean basal morning cortisol level and the peak cortisol level stimulated by intravenous injection of 250 microg synthetic ACTH in 106 unstressed patients with proven or suspected hypothalamic-pituitary-adrenal disease. Plasma cortisol levels were determined by radioimmunoassay. The correlation of the basal morning cortisol to the short ACTH test was determined by linear regression analysis. The ACTH test was analyzed using the receiver operating characteristic (ROC) curve method, and the cut-off points for various sensitivity and specificity were calculated. RESULTS: The mean basal is highly correlated to peak cortisol response in the ACTH test (r = 0.7724, p < 0.0001). Iatrogenic Cushing's syndrome, caused by ingestion of herbs with illegal steroid additives, was the most common cause (60%) of adrenal insufficiency in the 52 patients with subnormal result. A mean basal morning serum cortisol of > or = 300 nmol/L excluded the possibility of adrenal insufficiency, and a level of < 110 nmol/L suggested adrenal insufficiency. A mean basal cortisol level of > or = 234 nmol/L predicted a normal cortisol response in the ACTH test with optimal sensitivity (80.6%) and specificity (91.4%). CONCLUSIONS: The mean morning cortisol level is a cost-effective screening test in predicting the results of the ACTH test. A mean morning cortisol level > or = 300 nmol/L in suspicious cases of adrenal insufficiency which are not due to acute central etiologies excludes the possibility of subnormal cortisol response to ACTH; whereas a level < 110 nmol/L is likely to have subnormal cortisol response to ACTH. The short ACTH test or insulin tolerance test should be performed in patients with a morning cortisol level 300 nmol/L or with clinical symptoms highly suggestive of adrenal insufficiency.

Adolescent↗
PubMed1989

Transforming growth factor beta treatment decreases ACTH receptors on ovine adrenocortical cells.

Transforming growth factor beta (TGF beta) is a potent inhibitor of adrenocortical cell differentiated functions, whereas corticotropin (ACTH) is the main physiological hormone which acts positively on these functions. We have studied the effects of both TGF beta and ACTH on ovine adrenocortical cell ACTH receptors. Ovine adrenocortical cells contained specific high affinity (Kd = 2.7 +/- 1.6 x 10(-10) M) and low capacity (1190 +/- 120 sites/cell) ACTH receptors. Pretreatment of cells with TGF beta resulted in a time- and dose-dependent (ED50 = 50 pg/ml) decrease of 125I-ACTH1-39 binding. The observed decrease in ACTH binding was due to a 2-3-fold decrease in the number of binding sites without modification of the binding affinity. On the contrary, pretreatment of cells with ACTH caused a 4-4.5-fold increase in the number of ACTH binding sites without an effect on the Kd. When cells were pretreated with both ACTH and TGF beta, TGF beta blocked completely the positive trophic effect of ACTH on its own receptors. The variations in ACTH receptor number were associated with parallel changes on acute ACTH-induced cyclic AMP production. Thus, the effects of TGF beta on ACTH receptor content are likely another important negative action of this peptide on adrenocortical cell differentiation. Moreover, these results suggest that regulation of ACTH receptor number may be one mechanism by which hormones and growth factors control adrenocortical differentiation.

Adrenal Cortex↗
PubMed1985

Cerebrospinal fluid ACTH as a marker of central nervous system metastases from small cell carcinoma of the lung.

Adrenocorticotrophic hormone (ACTH) concentrations were measured in the plasma and cerebrospinal fluid (CSF) of 107 consecutive patients with known or suspected central nervous system (CNS) metastases secondary to small cell carcinoma of the lung. The combined results of computerized tomography scans, neurologic examination, and autopsy were used to determine the presence or absence of CNS metastases. On the basis of such an assessment, definitive conclusions were possible in 77 patients. CNS metastases were present in 52 cases and absent in 25. The median CSF ACTH level was 30 ng/ml in both groups. None of five patients with very high CSF ACTH concentrations had elevated ACTH concentrations in plasma. Considering the 95th percentile of patients without CNS metastases as the upper limit of normal, 12 patients with metastases and one without had an elevated CSF ACTH value. Eleven patients with leptomeningeal carcinomatosis (MC) did not constitute a special subgroup in this respect. The median ratio of CSF ACTH and plasma ACTH was 1.0 in patients with CNS metastases and 0.4 in those without (P less than 0.05). Patients with MC had a median ratio of 1.3, which was significantly different from that of both of the other groups (P less than 0.05). Ten patients with CNS metastases (one with MC) and one without exceeded the upper 95th percentile of the CSF/plasma (ACTH) ratio in patients without CNS metastases. The significance levels of these findings disappeared, however, when patients with signs of an elevated ACTH concentration in plasma were excluded. Patients with ectopic ACTH production into CSF do not necessarily have ectopic ACTH production outside the CNS, despite the presence of extracerebral metastases. With the criteria employed in this study, an elevated level of CSF ACTH diagnosed too few patients for the authors to recommend its determination as a single test in diagnosing CNS metastases or MC secondary to small cell carcinoma of the lung.

ACTH Syndrome, Ectopic↗
PubMed1992

Failure of somatostatin analogue to control Cushing's syndrome in two cases of ACTH-producing carcinoid tumours.

OBJECTIVE: To determine the effectiveness of somatostatin analogue (octreotide) in controlling hypercortisolism in two patients with ectopic ACTH-producing carcinoid tumours, and to review the literature. DESIGN: The two patients were treated with octreotide administered by subcutaneous injection, for 5 days with 150 micrograms three times daily and for 7 days with 100 micrograms three times daily respectively. They were subsequently treated with oral metyrapone 250 mg three times daily. PATIENTS: Patient 1 had a metastatic carcinoid tumour but the primary was not identified. Patient 2 had a pulmonary carcinoid. Cushing's syndrome due to ectopic ACTH syndrome was established by demonstration of failure of cortisol suppression by dexamethasone, elevated ACTH levels, and immunoperoxidase staining for ACTH within the tumours. MEASUREMENTS: Urinary free cortisol (UFC) was measured on consecutive days during treatment with octreotide. Serum cortisol and ACTH levels were taken daily in patient 2, and on days 0 and 3 in patient 1. RESULTS: Patient 1 had a baseline 24-hour urinary free cortisol of 5340 nmol/24 h, serum cortisol of 915 nmol/l, and serum ACTH of 163 ng/l (ACTH ng/l x 0.23 = pmol/l). After 3 days of octreotide, serum cortisol was 782 nmol/l and ACTH 164 ng/l. Twenty-four hour urinary free cortisol was 4136 nmol/24 h after 7 days of treatment. Metyrapone, however, resulted in a rapid fall in urinary free cortisol to 290 nmol/24 h, with marked clinical improvement. Patient 2 had a baseline 24-hour urinary free cortisol of 2520 nmol/24 h, serum cortisol of 747 nmol/l, and ACTH of 103 ng/l. Urinary free cortisol rose to 2970 nmol/24 h on day 6 of treatment with octreotide. Serum cortisol and ACTH levels fell slightly to 611 nmol/l and 70 ng/l respectively. On changing to metyrapone, the urinary free cortisol fell to 821 nmol/24 h in 4 days. CONCLUSIONS: Octreotide failed to significantly reduce 24-hour urinary free cortisol, serum cortisol and ACTH in the two patients reported. We conclude that it should probably not be regarded as primary treatment for control of hypercotisolism in patients with ACTH-producing carcinoids, but reserved as adjunctive therapy.

ACTH Syndrome, Ectopic↗
PubMed2005

Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion.

The hypothalamo-pituitary-adrenal axis is a stress-adaptive neuroendocrine ensemble, in which adrenocorticotropin (ACTH) drives cortisol secretion (feedforward) and cortisol restrains ACTH outflow (feedback). Quantifying direction- and pathway-specific adjustments within this and other interlinked systems by noninvasive means remains difficult. The present study tests the hypothesis that forward and reverse cross-approximate entropy (X-ApEn), a lag-, scale-, and model-independent measure of two-signal synchrony, would allow quantifiable discrimination of feedforward (ACTH --> cortisol) and feedback (cortisol --> ACTH) control. To this end, forward X-ApEn was defined by employing serial ACTH concentrations as a template to appraise pair-wise synchrony with cortisol secretion rates and vice versa for reverse X-ApEn. Coupled hormone profiles included normal ACTH-normal cortisol, high ACTH-high cortisol, and high ACTH-low cortisol concentrations in 35 healthy subjects, 21 patients with tumoral ACTH secretion, and 9 volunteers given placebo and a steroidogenic inhibitor, respectively. We used forward and reverse X-ApEn analyses to identify marked and equivalent losses of feedforward and feedback linkages (both P < 0.001) in patients with tumoral ACTH secretion. An identical analytical strategy revealed that ACTH --> cortisol feedforward synchrony decreases (P < 0.001), whereas cortisol --> ACTH feedback synchrony increases (P < 0.001), in response to hypocortisolemia. The collective outcomes establish precedence for pathway-specific adaptations in a major neurohormonal system. Thus quantification of directionally defined joint synchrony of biologically coupled signals offers a noninvasive strategy to dissect feedforward- and feedback-selective adaptations in an interactive axis.

Adolescent↗
PubMed2005

Galectin-3 Expression in Functioning and Silent ACTH-Producing Adenomas.

Galectin-3 (Gal-3), a beta galactoside-binding protein, has been implicated in a variety of biological functions including cell growth, differentiation, tumor cell adhesion, angiogenesis, tumor progression, and metastasis. We recently reported that Gal-3 was expressed in a subset of normal pituitary cells and tumors including PRL, ACTH, and in folliculo-stellate (FS) cells and tumors and that Gal-3 had an important regulatory role in pituitary cell proliferation. We further investigated the expression of Gal-3 protein in ACTH- and PRL-producing tumors and the expression of various galectin mRNAs by RT-PCR in pituitary adenomas and normal pituitary. Most silent ACTH subtypes 1 and 2 adenomas were negative or only focally positive for Gal-3 expression compared to functioning ACTH tumors from patients with Cushing's disease and Nelson's syndrome. In the normal pituitary, Gal-3 was expressed in less than 1% of the basophil-invading cells (ACTH cells present in the posterior pituitary) and in a subset of the anterior lobe ACTH-positive cells. RT-PCR analyses showed that many members of the galectin family including galectins 1, 2, 3, 4, 5, 6, 7, 8, and 9 were expressed in normal pituitary and in functioning ACTH- and PRL-producing tumors. These results indicate that Gal-3 is associated with functioning ACTH and PRL tumors and is expressed infrequently in silent ACTH adenomas, suggesting that Gal-3 protein and/or gene is altered in non-functioning ACTH tumors. The use of ACTH and Gal-3 immunostaining should help in the diagnosis of silent ACTH adenomas.

ACTH-Secreting Pituitary Adenoma↗
PubMed1978

Existence of a common precursor to ACTH and endorphin in the anterior and intermediate lobes of the rat pituitary.

Extracts of rat anterior and intermediate-posterior pituitary were fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for immunoactive ACTH and endorphin. In both lobes the major forms of immunoactive ACTH have apparent molecular weights of 31,000 (31K), 20--21K, 14K, and 4.5K, and the major forms of immunoactive endorphin have apparent molecular weights of 31K (coincident with the peak of immunoactive ACTH), 13K (a betaLPH-like peptide), and 3.5K (a beta-endorphin-like peptide). However, the quantitative distribution of immunoactivity among the various forms differs greatly between the lobes. Assays using an extreme COOH-terminal ACTH antiserum indicate that the 31K ACTH/endorphin molecule in rat anterior and intermediate pituitary is similar to the pro-ACTH/endorphin molecule from mouse pituitary tumor cells. A radioimmunoassay that is specific for the NH2-terminal non-ACTH, nonendorphin segment (referred to as 16K fragment) of the mouse pro-ACTH/endorphin molecule was used to assay extracts of rat pituitary. In addition to detecting material at 31K and 20--21K, the 16K fragment radioimmunoassay detects significant amounts of cross-reactive material with an apparent molecular weight of 16K in extracts of both lobes. This result also suggests that the structure and processing of the rat 31K ACTH/endorphin molecule is similar to that of mouse tumor cell pro-ACTH/endorphin. Cell suspensions were prepared from the anterior and intermediate lobes of the rat pituitary and maintained in culture for a 24-h period. The isolated cells from both lobes incorporate [3H] phenylalanine into immunoprecipitable ACTH- and endorphin-containing molecules. By sequential immunoprecipitation with ACTH and endorphin antisera, it is possible to demonstrate directly that a single molecule (31K ACTH/endorphin) has antigenic determinants for both ACTH and endorphin. Significant amounts of 31K ACTH/endorphin are released into the culture medium by isolated anterior lobe and intermediate lobe cells. The isolated intermediate lobe cells synthesize and secrete relatively large amounts of a beta-endorphin-like molecule; the isolated anterior lobe cells secrete significant amounts of both a betaLPH-like molecule and a beta-endorphin-like molecule. These same quantitative differences between anterior and intermediate lobe tissue were observed in immunoassays of extracts of the separated lobes and probably reflect differences in the processing of the common precursor. The isolated anterior lobe cells can be stimulated to release increased amounts of immunoprecipitable ACTH and endorphin by incubation with a cyclic AMP analog and a phosphodiesterase inhibitor.

Adrenocorticotropic Hormone↗
PubMed2002

Intra- and postoperative plasma ACTH concentrations in patients with Cushing's disease cured by transsphenoidal pituitary surgery.

BACKGROUND: The optimal treatment of choice for ACTH-producing pituitary adenomas is their complete removal by the transsphenoidal surgical approach. ACTH-producing pituitary adrenomas are, however, often small in size not detectable with neuro-imaging techniques, which may result in difficulties during their surgical removal. With the advent of rapid methods for plasma ACTH measurement, a few neurosurgical centers introduced intra-operative plasma ACTH determinations in peripheral and central blood samples to help improve the outcome of pituitary surgery in patients with Cushing's disease. METHOD: To evaluate the usefulness of this new method, we performed, under standardized conditions, intra-operative plasma ACTH measurements with a rapid immunochemiluminometric method at different stages of transsphenoidal pituitary surgery in 7 patients with Cushing's disease. FINDINGS: We found that from the beginning of anesthesia until the end of operation, ACTH concentrations in venous plasma were highly variable by both the rapid and the standard methods. In most cases the changes in venous plasma ACTH concentrations that occurred until the end of surgery failed to indicate the removal of the ACTH-producing pituitary adenoma. However, a more than 50% decrease of venous plasma ACTH concentrations by the rapid assay was observed 2 h after completion of the operation in all but one of the patients. As evidenced by a long-term hormonal and clinical remission, these changes in plasma ACTH levels in all patients were accompanied by a complete removal of the ACTH-producing pituitary adenoma. INTERPRETATION: These findings indicate a slow disappearance of ACTH from the circulation after a successful pituitary surgery in patients with Cushing's disease.

Adenoma↗
PubMed1994

Dissociation between plasma bioactive and immunoactive ACTH concentrations in depressed patients.

Previous studies have reported dissociations between plasma cortisol and immunoactive adrenocorticotropic hormone (ACTH) concentrations in both normal controls and in patients with major depression. In order to investigate this issue further, placebo and dexamethasone (DEX) were administered to normal controls and depressed patients at 11 PM, and plasma cortisol and ACTH were measured the following morning at 7 AM. Plasma ACTH concentrations were quantitated by both immunoassay (I-ACTH) and by bioassay (B-ACTH). In 10 normal controls, DEX (0.25, 0.5, and 1.0 mg, PO, elixir) produced a dose-related suppression of cortisol, I-ACTH and B-ACTH, with all three hormones significantly suppressed by DEX (0.5 and 1.0 mg) (p < or = 0.01). In 20 depressed patients, 7 AM plasma ACTH and cortisol concentrations were assessed following a single dose of DEX (0.5 mg). Fifteen patients were classified as suppressors and five as escapers, as reflected by mean (+/- SEM) cortisol concentration of 19.9 +/- 3.0 ng/ml and 81.2 +/- 7.0 ng/ml, respectively. Mean I-ACTH concentrations were comparable in both the escapers (8.6 +/- 1.6 pg/ml) and in the suppressors (7.0 +/- 1.0 pg/ml). In contrast, the mean B-ACTH concentration was more than two-fold higher in the escapers (4.5 +/- 0.5 pg/ml) than in the suppressors (2.2 +/- 0.3 pg/ml) (p < or = 0.001). Eleven of the 20 patients received both placebo and DEX (0.5 mg) on two separate occasions. Although DEX significantly suppressed both cortisol (p < or = 0.0001) and B-ACTH (p < or = 0.01) concentrations, I-ACTH was not significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1984

The enhancement of pregnenolone production as the main mechanism of the prolonged stimulatory effect of ACTH on cortisol production by guinea-pig adrenocortical cells.

The prolonged stimulatory influence of corticotropin (ACTH) on the adrenocortical steroidogenic response to ACTH was studied in guinea-pig adrenocortical cells harvested from control and ACTH-treated animals (ACTH1-24, 50 micrograms s.c. twice daily on the day preceding the in vitro experiment). The maximal capacity to produce cortisol in response to ACTH (by 10(5) cells and 2 h incubation) was increased from 341.8 +/- 36.3 ng (control group) to 663.3 +/- 37.6 ng for cells obtained from guinea-pigs treated in vivo with ACTH. In the presence of trilostane, added to the cells in order to block the conversion of pregnenolone to cortisol, the net maximal output of pregnenolone and 17-hydroxypregnenolone in response to ACTH was significantly increased in adrenocortical cells from ACTH-treated animals (449.5 +/- 35.8 ng pregnenolone and 85.7 +/- 10.5 ng 17-hydroxypregnenolone vs 269.1 +/- 36.3 ng pregnenolone and 43.7 +/- 8.51 ng 17-hydroxypregnenolone for cells from control guinea-pigs). It appeared therefore that the total production of pregnenolone (as estimated by the sum of pregnenolone and 17-hydroxypregnenolone produced by the cells incubated with trilostane) nearly reached the level of the maximal production of cortisol in response to ACTH and was also significantly enhanced for cells from ACTH-treated animals (532.2 +/- 38.4 ng vs 312.8 +/- 40.0 ng for cells from control group). By contrast, no effect was documented on 17 alpha-hydroxylase activity since 17 alpha-hydroxylation index was similar for both types of adrenocortical cells (16.3 +/- 2.05% for ACTH-treated animals and 14.2 +/- 2.83% for control group). It was concluded therefore that the prolonged stimulatory influence of ACTH on pregnenolone production is the main mechanism of the enhancement of cortisol synthesis by guinea-pig adrenocortical cells previously stimulated by ACTH.

17-alpha-Hydroxypregnenolone↗
PubMed1995

The kinetics of ACTH expression in rat leukocyte subpopulations.

The pro-opiomelanocortin (POMC) gene encodes a family of peptides originally identified in the pituitary gland. An important POMC-derived peptide hormone, corticotropin (ACTH), is also produced by leukocytes and modulates in vitro immune functions. The present investigation was undertaken to determine the kinetics and cellular distribution of ACTH immunoreactivity (ACTH-ir) in vitro in rat splenic leukocyte subpopulations. Cells were cultured with Concanavalin A (ConA), lipopolysaccharide (LPS), or media alone. ACTH-ir was identified with a specific antiserum raised against ACTH 1-24. Double indirect-immunofluorescence was done at 0, 21, and 48 h for B, t-helper (Th), and T-cytotoxic (CTL) cells. Initial kinetic studies demonstrated peak ACTH-ir in all cell types at 18-21 h for both ConA and LPS treatments. A few leukocytes (1-2%) expressed ACTH-ir at 0 h and these were found to be macrophages (MO). Lymphocyte ACTH-ir is 0% at 0 h and rises to 90 +/- 5% and 75 +/- 6% at 21 h with ConA and LPS, respectively. This sharply contrasts with 9 +/- 4% of each cell type positive in media alone at 21 h. The percent immunoreactivity among the three lymphocyte subpopulations did not significantly differ at any single treatment at a single time point. However, there were significant differences in the intensity levels among the subpopulations. At 48 h of ConA or LPS treatment only 10 +/- 4% of B, Th and Tc were positive, while none were positive in media alone. Stimulated peritoneal MO also increase positivity for ACTH-ir (85 +/- 5%). These results indicate that rat splenic B, CTL, and Th lymphocytes can be immunologically stimulated to express the peptide hormone ACTH and that basal ACTH expression in macrophages is distinct from that in lymphocytes. Thus, lymphocyte-derived ACTH may be a paracrine or autocrine regulator of immune function.

Adrenocorticotropic Hormone↗
PubMed2005

Cerebrospinal fluid ACTH and cortisol in opsoclonus-myoclonus: effect of therapy.

Opsoclonus-myoclonus syndrome is one of a few corticotropin (ACTH)-responsive central nervous system disorders of childhood. We measured cerebrospinal fluid ACTH and cortisol in 69 children with opsoclonus-myoclonus and 25 age- and sex-matched control subjects to determine endogenous levels and look for hypothesized differential hormonal effects of ACTH and corticosteroid treatment. Cerebrospinal fluid cortisol was 10-fold higher with ACTH treatment (n = 26), but was unchanged with oral steroid treatment (n = 18) or no treatment (n = 25). It was significantly higher in children receiving daily high-dose ACTH than alternate day ACTH. In ACTH-treated children, cerebrospinal fluid and serum cortisol were highly correlated (r = 0.96, P = 0.0001), with a mean ratio of cerebrospinal fluid to serum cortisol of approximately 1:10. Cerebrospinal fluid ACTH concentration did not differ significantly between untreated opsoclonus-myoclonus and control subjects but was lower with ACTH (-29%) or steroid treatment (-36%), suggesting feedback inhibition of ACTH release. These data delineate differences in the central effects of ACTH and corticosteroid therapy, as well as between high and low ACTH doses, and support the integrity of the brain-adrenal axis in pediatric opsoclonus-myoclonus.

Adrenocorticotropic Hormone↗