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At least 163 records · Page 9Linked to original sources
PubMed1989

ACTH receptors in nervous tissue. High affinity binding-sequestration of [125I]Phe2,Nle4]ACTH 1-24 in homogenates and slices from rat brain.

We have demonstrated specific, high affinity binding of a biologically active Tyr23-monoiodinated derivative of ACTH, [125I][Phe2,Nle4]ACTH 1-24, in rat brain homogenates. Similarly, in metabolically inhibited and noninhibited rat whole brain slices there is a specific "binding-sequestration" process that is dependent on time, protein concentration, and pH. In homogenates, binding curves were best described by a two-site model and provided the following parameters: Kd1 = 0.65 +/- 0.47 nM, Bmax1 = 21 +/- 41 fmol/mg protein; Kd2 = 97 +/- 48 nM, Bmax2 = 3.5 +/- 1.8 pmol/mg protein. In metabolically viable brain slices, concentration-competition curves of [125I][Phe2,Nle4]ACTH 1-24 binding-sequestration can be described by three components (Kd1 = 14 +/- 24 nM, Bmax1 = 50 +/- 95 fmol/mg protein; Kd2 = 2.4 +/- 1.9 microM, Bmax2 = 44 +/- 49 pmol/mg protein; Kd3 = 0.16 +/- 1.0 mM, Bmax3 = 5.3 +/- 54 nmol/mg protein). Metabolic inhibition, by removal of glucose and addition of 100 microM ouabain, abolishes the lowest affinity, highest capacity binding-sequestrian component only (Kd1 = 7.1 +/- 14 nM, Bmax1 = 8.7 +/- 16 fmol/mg protein; Kd2 = 7.4 +/- 4.49 microM, Bmax2 = 37 +/- 27 pmol/mg protein). The two binding-sequestration parameter estimates obtained from metabolically inhibited tissue slices are not significantly different from those of the two higher affinity components obtained with noninhibited tissue. Thus, metabolic inhibition permits demonstration of ACTH receptor binding only, unconfounded by sequestration or internalization of ligand:receptor complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1995

Responses of immunoreactive ACTH and bioactive ACTH to large hemorrhage and resuscitation in conscious dogs.

We studied the effect of fluid resuscitation on immunoreactive adrenocorticotropic hormone (irACTH) and bioactive ACTH (bioACTH) after hemorrhage in conscious dogs. Animals (n = 7) were bled 30% (approximately 25 ml/kg) over 3 min and 30 min later were either resuscitated [43.3 ml/kg 0.9% NaCl (1.8 times hemorrhage volume) over 10 min] or not. Blood was reinfused after 210 min. Animals had both treatments (> 4 days apart). irACTH, bioACTH, cortisol, angiotensin II, and aldosterone increased rapidly after hemorrhage. Resuscitation increased blood volume and cardiac output to resting values, but arterial hypotension persisted. bioACTH and irACTH decreased 40-90 min after hemorrhage in both groups, but each decreased more rapidly after resuscitation. The elimination half-life of bioACTH was shorter than that of irACTH, but neither was affected by resuscitation. The ratio of bioACTH to irACTH followed the same pattern with or without resuscitation. Angiotensin II and aldosterone remained increased without resuscitation but decreased promptly after resuscitation. In conclusion, 1) saline infusion at 1.8 x hemorrhage volume provides effective cardiovascular resuscitation, with resolution of hormonal responses to hemorrhage; 2) although ACTH responses resolved with or without resuscitation, resuscitation produced more rapid resolution without changing the parameters of ACTH elimination; 3) the dynamics of the resolution of the ACTH response to hemorrhage are similar whether induced by stimulus removal or feedback inhibition.

Adrenocorticotropic Hormone↗
PubMed1975

ACTH and prostaglandin receptors in human adrenocortical tumors. Apparent modification of a specific component of the ACTH-binding site.

The failure of certain adrenal tumors to respond to ACTH was investigated in vivo be administration of corticotropin-(1-24)-tetracosapeptide (ACTH1-24) and dexamethasone and in vitro by studying the binding properties of ACTH1-24 and prostaglandin E1 (PGE1) and their effect on adenylate cyclase activity of the tumors' crude membranes; in addition, in five cases the stimulation of cortisol production in isolated adrenal cells by both hormones and dibuttyryl cyclic adenosine 3',5'-monophosphate (cAMP) was also studied. The results obtained in 13 hormone-producing tumors of the human adrenal cortex, i.e. 10 carcinomas and 3 adenomas, were compared with those found in normal human adrenal glands. According to the adenylate cyclase responses to ACTH1-24 and PGE1, the tumors fall into different categories. In the first group are six rumors in which the adenylate cyclase was stimulated by both ACTH1-24 and PGE; in addition specific binding could be demonstrated for the two hormones in all six. The binding affinity for 125I-ACTH1-24 was found to be about 10 times higher than that for 125I-ACTH11-24. In the one tumor in which the experiment was performed, bound 125I-ACTH1-24 was displaced by ACTH1-10. These results are similar to the ones found in normal human adrenal preparations. For two rumors of the group in which ACTH did not increase steroidogenesis in vivo, the biochemical abnormality might be located beyond cAMP formation. A second group encompasses six tumors in which the steroidogenesis in vivo and the adenylate cyclase activity were insensitive to ACTH1-24 but in which the enzyme was stimulated by PGE1 and NaF. However, these preparations bound 125I-ACTH1-24 and 125I-ACTH11-24, the binding affinity being similar for both peptides but 10 times lower than the one found in normal adrenal cortex for 125I-ACTH1-24. In the only case of this group where it was tested, ACTH1-10 did not displace bound 125I-ACTH1-24. This result strongly suggests the possibility of a modification or a loss of the receptor site that binds the N-terminal sequency (1-10) of ACTH, the biologically active part of the molecule. In the last tumor, both PGE1 and ACTH were unable to stimulate adenylate cyclase activity and steroid production in a preparation of isolated adrenal cells, although steroidogenesis was stimulated by dibutyryl though steroidogenesis was stimulated by dibutyryl cAMP. No specific binding for PGE1 could be demonstrated. However, 125I-ACTH1-24 and 125I-ACTH11-24 were found to be bound to the tumor with the same affinity.

Adenoma↗
PubMed2005

Absence of adrenocorticotropin (ACTH) neurosecretory dysfunction but increased cortisol concentrations and production rates in ACTH-replete adult cancer survivors after cranial irradiation for nonpituitary brain tumors.

CONTEXT: For the first time, physiological cortisol secretion has been studied in ACTH-replete adult cancer survivors to explore any discrepancy between stimulated (during insulin-induced hypoglycemia) and spontaneous cortisol secretion and, in particular, the possible existence of ACTH neurosecretory dysfunction that might explain the excessive fatigue suffered by some cancer survivors. STUDY SUBJECTS: Cortisol profiling at 20-min intervals over 24 h during the fed state was undertaken in 34 patients (10 females), aged 17-53.7 yr (median, 21.5 yr), 2-29 yr (median, 11.5 yr) after receiving conventional cranial irradiation for nonpituitary brain tumors or leukemia (n = 5) and in 33 age-, gender-, and body mass index-matched normal controls, of whom 23 patients and 17 controls were also profiled in the last 24 h of a 33-h fast. RESULTS: The fed profile mean cortisol concentration (mean +/- sem) was significantly increased (by 14%) in the patients compared with that in normal subjects (213 +/- 6.9 vs. 187 +/- 6.7 nmol/liter; P = 0.009), with all individual values above the lowest seen in normal subjects. Multiparameter deconvolution analysis revealed a parallel increase (by 20%) in cortisol secretion rates (1.8 +/- 0.09 vs. 1.5 +/- 0.08 nmol/liter.min; P = 0.03) due to selective augmentation of the cortisol mass released per burst with no changes in burst frequency (12/24 h) or half-life. No significant differences were observed between males and females, after short-term fasting, or between female patients and normal females. Thus, in the light of total group comparisons, male patients had even higher values than normal males, and more so during fasting (mean cortisol and cortisol secretion increased by 20 and 29% in the fed state and by 41 and 32% in the fasting state, respectively; P < 0.05). CONCLUSIONS: This study has demonstrated that radiation-induced ACTH neurosecretory dysfunction does not exist and, thus, resolved the clinical dilemma as to whether cortisol replacement should be considered in those patients with excessive fatigue and normal stimulated cortisol responses. On the contrary, cranial irradiation causes activation of the corticotrope-adrenal axis, and in the absence of ACTH deficiency, this activation is manifested by parallel increases in circulating cortisol levels and cortisol production rates without any change in cortisol half-life. The lack of cortisol increase in female patients may be attributed to the adverse effect of their higher body mass index on cortisol secretion or may reflect a genuine gender dichotomy.

Adolescent↗
PubMed1991

The nocturnal serum thyrotropin surge is abolished in patients with adrenocorticotropin (ACTH)-dependent or ACTH-independent Cushing's syndrome.

TSH secretion was evaluated in 10 patients with ACTH-dependent (pituitary microadenoma, n = 5) or ACTH-independent [adrenal adenoma (n = 4) or carcinoma (n = 1)] Cushing's syndrome, and in 12 normal controls matched for age and sex. Serum TSH concentration was assayed at night, from 2200-0200 h, and in the morning, both basally and 30 min after iv injection of 200 micrograms synthetic TRH. Patients with hypercortisolism showed significantly reduced serum total T4 and T3 and free T3 concentrations and increased serum reverse T3 levels. Their mean baseline serum TSH concentration in the morning, albeit slightly lower, did not significantly differ from those of controls. The mean peak TSH value after TRH was significantly reduced, and a blunted TSH response to TRH was found in 4 out of 10 patients. At variance with normal controls, who showed nighttime TSH values 63-228% higher than morning values, 9 out of 10 patients had nighttime levels not different from or even lower than those in the morning; the remaining patient had nighttime TSH values marginally (33%) higher than in the morning. An inverse relationship (r = 0.80, P less than 0.001) was found between serum cortisol and TSH values both at night and in the morning. No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. These results show a substantial impairment of TSH secretion, and in particular the loss of the nocturnal surge of the hormone, in patients with Cushing's syndrome. Although the origin of the nocturnal TSH rise is probably multifactorial, cortisol, at least when secreted in excess, appears to play an important role in its regulation.

Adrenocorticotropic Hormone↗
PubMed1987

ACTH and adrenal aerobic glycolysis. I: Effects of O-nitrophenylsulphenyl and other ACTH analogues, vasoactive intestinal peptide and human parathyroid hormone(1-34) on lactic acid, steroid and cyclic AMP production by mouse adrenocortical cells.

The structural requirements in the ACTH molecule for evocation of the glycolytic response in suspensions of mouse adrenal cells were investigated by examining the effects of analogues containing modifications at positions 8, 9 and 10 and of peptides containing homologies with the amino-terminal segment of ACTH. Introduction of a nitrophenylsulphenyl (NPS) group into the tryptophan moiety at position 9 of ACTH(1-24) greatly reduced both the potency and the capacity for maximal glycolytic response. It also virtually abolished cyclic AMP formation. In contrast, the capacity for a maximal steroidogenic response remained unimpaired in the NPS derivative, although steroidogenic potency was reduced to 0.4% of that of ACTH(1-24). Replacement of the tryptophan moiety with phenylalanine had intermediate inhibitory effects on glycolysis and steroid output; replacement with alanine virtually abolished both these responses. Replacement of arginine in position 8 with lysine in the Phe9 analogue caused a fifty-fold increase in glycolytic potency, but rendered it steroidogenically inactive. Cyclic AMP production was abolished in the Ala9 analogue and greatly impaired in the Phe9 and Lys8,Phe9 analogues. Replacement of the glycine moiety in position 10 with L-alanine, D-alanine, beta-alanine or alpha-aminoisobutyric acid had little or no effect on steroidogenic or glycolytic capacity, although potency was reduced with all substitutions excepting L-alanine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1977

Sarcoidosis therapy with cortisone and ACTH--the role of ACTH therapy.

Out of 58 sarcoidosis patients 55 were treated successfully with a prednisolone therapy lasting one to two years. The high initial dosis of 40 mg daily has been maintained for at least 3 months. In case of intolerance or inefficiency of corticosteroid therapy a treatment with synthetic ACTH either in combination with corticosteroids or only ACTH was applied to 23 patients. The positive experiences of other authors were confirmed. Synthetic ACTH (1 mg) injected intramuscularly every third day did not cause any side-effects. ACTH can be employed not only in combination with corticosteroids, but it can also substitute them in special clinical cases.

Adrenocorticotropic Hormone↗
PubMed1982

[Structure-function organization of ACTH: fragment ACTH 11-24--a functionally important site of the hormone molecule].

The steroidogenic and lipolytic activities of ACTH fragments (ACTH11-24--I, ACTH11-19--II, ACTH11-16--III and ACTH 17-24--IV) were studied. Fragments I--IV exert a steroidogenic effect in isolated fasciculata rat adrenal cells at concentrations of 1--500 micrograms/ml. The inner activity (alpha) and concentration at which a half-maximum effect is achieved (EC50) for fragments I and IV are 0.64+/-0.09 and 0.5--2.0 micrograms/ml, for fragment III--0.49+/-0.07 and 0.7 microgram/ml, respectively. Fragments I--IV have no effect on the lipolysis in isolated rat fat cells. The results obtained are indicative of the functional importance of fragment ACTH11-24 in manifestation of steroidogenic action of ACTH and suggest that the second active site of ACTH is enclosed within this amino acid sequence.

Adipose Tissue↗
PubMed1998

[ACTH receptor, ACTH receptor anomaly, and familial glucocorticoid deficiency].

Familial glucocorticoid deficiency (FGD) is an autosomal recessive syndrome with hereditary adrenocortical unresponsiveness to ACTH. After the cloning of ACTH receptor or melanocortin-2 receptor (MC-2R) cDNA, several kinds of mutations in the receptor genes have been reported. However, the apparently normal ACTH receptor gene in some affected children suggests that the etiology of FGD is heterogeneous. In this short review, we describe the recent advances in the molecular biology of ACTH receptor genes, its post-receptor signal transduction in the adrenocortical cells, and the molecular genetics of the FGD and a related syndrome, Allgrove syndrome. We also discuss that this kind of work will help us to understand better about the molecular mechanism of the glucocorticoidogenesis in the human being.

Glucocorticoids↗
PubMed1987

Identification of ACTH-producing intrathoracic tumors by measuring ACTH levels in aspirated specimens.

Three patients with Cushing syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production underwent direct 22-gauge needle aspiration of bronchial (two cases) and mediastinal (one case) carcinoid tumors. High levels of ACTH were measured in all three tumors. This technique permits absolute identification of an ectopic source of ACTH before surgery.

ACTH Syndrome, Ectopic↗
PubMed1978

ACTH-like immunoreactivity in the gastrin cell. Independent changes in gastrin and ACTH-like immunoreactivity during ontogeny.

Rat antral gastrin cells have been shown to contain ACTH-like immunoreactivity. Studies on the ontogeny of the antral gastrin cells reveal that these cells start to store gastrin before they contain detectable quantities of ACTH-like immunoreactivity. At no stage studied were duodenal gastrin cells found to contain ACTH-like peptides. The data indicate that the G cells synthetizes and/or releases the two hormonal peptides independently.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Isolated ACTH deficiency confirmed by ACTH radioimmunoassay.

A 28 year old woman presented with symptoms and biochemical findings suggesting hypoglycemia. Detailed endocrine investigations indicated secondary adrenocortical insufficiency with no rise in plasma ACTH or plasma cortisol following insulin-induced hypoglycemia or vasopressin infusion. The adrenal glands however produced cortisol normally following prolonged stimulation with depot tetracosactrin. Other anterior pituitary hormones were released normally following appropriate stimulation tests. The literature on isolated ACTH deficiency is briefly reviewed, and this case represents one of the few reports in which the diagnosis has been substantiated by ACTH radioimmunoassays.

Adrenocorticotropic Hormone↗
PubMed1989

Bilateral and simultaneous venous sampling of inferior petrosal sinuses for ACTH and PRL determination: preoperative localization of ACTH-secreting microadenomas.

We report our experience on venous sampling of the inferior petrosal sinuses for basal and CRH-stimulated ACTH and PRL gradients in 8 patients with surgically proven Cushing's disease who had normal preoperative neuroradiological studies. In 7 patients basal plasma ACTH concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral sinus; the gradients were enhanced by oCRH administration. In one out of two patients who had previously undergone unsuccessful pituitary microsurgery, neither basal nor oCRH-induced ACTH increases led to correct localization of the microadenoma within the pituitary. In 4 out of 7 patients basal serum PRL concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral; only two out of 4 showed an increase in PRL levels after oCRH injection. Our study confirms that simultaneous and bilateral venous sampling of inferior petrosal sinuses is a valuable means to identify the site of microadenomas in patients with Cushing's disease without neuroradiological evidence of the tumor. This procedure may give misleading results in patients previously operated on. Unilateral or predominant increases of PRL concentration during catheterization of the inferior petrosal sinuses, when present, always lateralize to the side of the corticotroph adenoma, providing a possible additional signal of the presence of the tumor.

Adenoma↗
PubMed2000

Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH.

We report a 30-year-old female with adrenal unresponsiveness to ACTH. Her clinical features included no adrenal crisis despite poor drug compliance, poor pubic hair development (Tanner stage 2), well-developed breasts (Tanner stage 5), and regular menstrual cycles. Endocrinological data included blood ACTH 1500 pmol/l, cortisol 18 nmol/l, dehydroepiandrosterone sulphate below 0.26 micromol/l, activated renin 0.37 pmol/l, and aldosterone 3.4 nmol/l. Direct sequencing and allele-specific amplification revealed two novel mutations in the ACTH receptor gene. One was transition from guanine to adenine at nucleotide position 1002, resulting in substitution of aspartate for asparagine at codon 103, and the other was transition from cytosine to thymine at nucleotide 1104, leading to substitution of arginine for tryptophan at codon 137. The present findings lend additional credence to the notions that adrenal androgens play an important role in female pubic hair development and that ovarian development takes place independently of adrenarche.

Adrenal Gland Diseases↗
PubMed1995

A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome.

Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 families with triple A syndrome. The proband with IGD was a homozygote for an A-->G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome.

Adenine↗
PubMed1983

A possible role of "steroidogenic factor" in the corticoidogenic response to ACTH; effect of ACTH, cycloheximide and aminoglutethimide on the content of cholesterol in the outer and inner mitochondrial membrane of rat adrenal cortex.

The role of a "steriodogenic factor" in the corticoidogenic response to adrenocorticotropic hormone (ACTH) was studied in this experiment. ACTH caused an accumulation of cholesterol within the adrenocortical mitochondria in rat after pretreatment with either cycloheximide (CH) or aminoglutethimide (AG). The cholesterol distribution in these cholesterol-rich mitochondria was examined by measuring the cholesterol concentrations in the outer and inner mitochondrial membranes. In the case of pretreatment with CH, cholesterol was accumulated in the outer membrane and not in the inner membrane. In contrast, in the case of pretreatment with AG, cholesterol was accumulated in the inner membrane and not in the outer membrane. It could be concluded from the presented data that the function of a "steroidogenic factor" in the corticoidogenic response to ACTH might take place at the step of cholesterol translocation from the outer mitochondrial membrane to the inner membrane.

Adrenal Cortex↗
PubMed1990

Effects of ACTH, epinephrine and Met-enkephalin on brain beta-endorphin-like immunoreactivity, and of ACTH, epinephrine, Met-enkephalin and naloxone on retention, in normal and in protein-malnourished rats.

Rats raised and maintained on a normal-protein diet (25% protein) responded to the ip administration of ACTH-(1-24), epinephrine or Met-enkephalin with a decrease in hypothalamic beta-endorphin-like immunoreactivity, which is attributable to a release of this substance. This effect was not seen in rats raised and maintained on a low-protein diet (8% protein). In the normal animals, the pre-test administration of ACTH, epinephrine or Met-enkephalin and the post-training administration of naloxone enhanced retention-test performance of a step-down inhibitory avoidance task. These behavioral effects were absent in the protein-malnourished rats. Previous studies have shown that the behavioral effect of post-training naloxone is secondary to the release of brain beta-endorphin during training, and that the pre-test effect of the hormones is due to a release of brain beta-endorphin induced by the substances themselves. Since it is not likely that the differences were caused by hyperreactivity to the aversive stimuli employed, the suggested interpretation is that protein-malnourished rats present a dysfunction in the brain beta-endorphin system which renders it unresponsive not only to novel training experiences, but also to the pre-test retrieval enhancing effects of ACTH, epinephrine and Met-enkephalin.

Adrenocorticotropic Hormone↗
PubMed1983

Comparison between adrenal steroid secretion after stimulation with two synthetic analogues of corticotropin : ACTH 1-24 and ACTH 1-17.

Chemical manipulations of the native ACTH (1-39) molecule led to the synthesis of a newly characterized compound which shows several interesting features, such as an enhanced half-life, an increased resistance against enzymic degradation and lower immunogenic activity. This study aimed at comparing the adrenal steroidogenetic response of the 1-17 analogue and of the other commercially available synthetic ACTH (1-24). Results suggest that ACTH 1-17 has a more pronounced and prolonged activity, which is confined to glico- and mineralocorticoid secretion.

17-Hydroxycorticosteroids↗