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PubMed1980

Transient brain shrinkage in infantile spasms after ACTH treatment. Report of two cases.

This is the report of two cases of infantile spasms, manifesting transient brain shrinkage in computerized tomography (CT) after ACTH treatment. ACTH was given for 8 weeks to a 8-months-old Japanese girl with infantile spasms. First CT performed at 2 weeks after the final ACTH injection, displayed moderate brain shrinkage. Second CT at 4 months showed marked diminution of the shrinkage. ACTH was also given for 8 weeks to a 14 months old Japanese boy with infantile spasms. First CT, just before ACTH treatment, showed mild cortical atrophy, the second at 7 days after the final ACTH injection revealed marked brain shrinkage and moderate ventricular dilatation, and the third at 2 months, disclosed mild improvement of the shrinkage. ACTH or corticoateroid has widespread effects on the developing nervous system. In animal experiments, ACTH or steroids interfere with brain growth of young rats. CT findings of transient brain shrinkage in a child with infantile spasms might suggest that intensive treatment with ACTH or steroids in infancy interferes with brain growth as seen in the results of animal experiments.

Adrenocorticotropic Hormone↗
PubMed1989

Cortisol feedback on ovine fetal ACTH secretion during the last fifth of gestation.

This study investigates the development of the feedback relationship between cortisol and ACTH in ovine fetuses at 117-119 (n = 5), 130-134 (n = 4) and 140-143 (n = 6) days of gestation. During the last 2 h of a 24 h cortisol (100 micrograms h-1) or saline (0.19 mL h-1) infusion, the fetal ACTH response to bolus oCRH injection (10 micrograms) was tested after the collection of basal ACTH and cortisol samples. Basal ACTH concentrations in un-infused or saline-infused fetuses were observed to progressively increase after 117-119 days of gestation. In contrast, a prepartum increase in cortisol concentrations could not be detected until after 130-133 days. Cortisol infusion significantly inhibited basal ACTH values at 130-133 and 140-143 but not at 117-119 days. In the two youngest age groups, cortisol infusion significantly inhibited the fetal ACTH response to oCRH. At 140-143 days, ACTH values after oCRH injection, were elevated to a similar extent during the saline or cortisol infusion. However, at 140-143 days there was evidence to suggest that the ACTH response to oCRH administered during the saline infusion was blunted when compared with earlier stages of gestation. This study suggests that the circulating, basal concentrations of both ACTH and cortisol increase during the last fifth of gestation in the ovine fetus. The exact nature of the prepartum feedback relationship that develops between these two hormones remains to be fully elucidated.

Adrenal Glands↗
PubMed2005

The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E2.

The adrenal cortex is a major stress organ in mammals that reacts rapidly to a multitude of external and internal stressors. Adrenocorticotropin (ACTH) is the main stimulator of the adrenal cortex, activating corticosteroid synthesis and secretion. We evaluated the mechanism of action of ACTH on adrenals of male rats, preserving the architecture of the gland in vitro. We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because Nomega-nitro-l-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release. Corticosterone content in adrenals after incubation with ACTH or NP was lower than in control glands, indicating that any de novo synthesis of corticosterone during this period was not sufficient to keep up with the release of the stored hormone. The release induced by ACTH or NP depleted the corticosterone content in the adrenal by approximately 40% compared with the content of glands incubated in buffer. The mechanism of rapid release is as follows: NO produced by NO synthase activation by ACTH activates cyclooxygenase, which generates PGE(2), which in turn releases corticosterone stored in microvesicles and other organelles.

Adrenal Cortex↗
PubMed2000

A bovine adrenocortical Kv1.4 K(+) channel whose expression is potently inhibited by ACTH.

We have cloned a bovine adrenal cortical (bKv1.4) K(+) channel cDNA whose expression is rapidly inhibited by adrenocorticotropic hormone (ACTH). The 4386-nucleotide cDNA is homologous to other voltage-gated, rapidly inactivating Kv1.4 channels, and includes a 1986-nucleotide coding region and large 5'- and 3'-untranslated regions. Bovine Kv1.4-specific mRNA from adrenal zona fasciculata (AZF) cells was rapidly and potently reduced by ACTH, with a t(12) of approximately 1 h and an IC(50) of 1.2 pm. The membrane-permeable cAMP analog 8-pcpt-cAMP also reduced bKv1.4 mRNA expression with kinetics similar to that observed with ACTH. Reduction of bKv1.4 mRNA expression by ACTH and 8-pcpt-cAMP was only partially inhibited by the selective protein kinase A antagonist H-89. Consistent with their effect on bKv1.4 mRNA, ACTH and 8-pcpt-cAMP both dramatically reduced the expression of bKv1.4-associated A-type current measured over 72 h. These results demonstrate that bovine AZF cells synthesize a Kv1.4-type channel whose expression is inhibited at the pretranslational level by ACTH and 8-pcpt-cAMP by a mechanism that is partially dependent on the activation of protein kinase A. The rapid, potent reduction of bKv1.4 mRNA produced by ACTH and 8-pcpt-cAMP indicates that the expression of this K(+) channel is under tonic inhibitory control of the hypothalamic-pituitary-adrenal axis. The basic electrical properties of AZF cells might be tightly regulated at the transcriptional level by the normal diurnal pattern of ACTH secretion, and altered during bouts of stress by the enhanced release of this pituitary peptide. Under conditions of prolonged stress or adrenal insufficiency, persistent ACTH-induced changes in the electrical properties of AZF cells could be coupled to parallel changes in cortisol secretion.

Adrenal Cortex↗
PubMed1981

Coordinate, equimolar secretion of smaller peptide products derived from pro-ACTH/endorphin by mouse pituitary tumor cells.

The secretion of peptide products derived from pro-ACTH/endorphin was examined with several radioimmunoassays and with polyacrylamide gel analyses of immunoprecipitates of radioactively labeled peptides. In studies using a mouse pituitary tumor cell line the accumulation of each of the four molecular forms of adrenocorticotropic hormone (ACTH) in tissue culture medium was shown to be a linear function of time. No evidence for self inhibition of secretion by accumulated, secreted peptides (i.e., ultra-short feedback) was found. Furthermore, synthetic human ACTH and synthetic camel beta-endorphin did not alter secretion of peptides when added to the culture medium at levels up to 10,000 times physiological. Stimulation of the release of ACTH-, endorphin-, lipotropin-, and 16k fragment immunoreactive material by norepinephrine was fully blocked by cobalt; by this criterion, stimulated release was calcium dependent. All the smaller molecules derived from the pro-ACTH/endorphin common precursor were secreted in equimolar amounts under all circumstances tested, within the precision of these studies (+/- 11%). Norepinephrine and cobalt did not significantly alter the secretion of pro-ACTH/endorphin and ACTH biosynthetic intermediate. The stimulation of secretion by norepinephrine and inhibition of secretion by cobalt was restricted to the lower molecular weight products derived from pro-ACTH/endorphin: glycosylated and nonglycosylated ACTH(1-39); beta-lipotropin, beta-endorphin, and gamma-lipotropin; and 16k fragment.

Adrenocorticotropic Hormone↗
PubMed1999

Haemodynamic mechanisms of corticotropin (ACTH)-induced hypertension in the rat.

OBJECTIVES: To investigate the roles of cardiac output and systemic and regional resistances in corticotropin (ACTH)-induced hypertension in the rat METHODS: This study consisted of three series of experiments with eight groups of male Sprague-Dawley rats (n = 132). Series 1 comprised groups 1-4, where group 1 = sham (0.9% NaCl, subcutaneous (s.c.) injection); group 2 = ACTH (0.5 mg/kg per day, s.c.); group 3 = atenolol + sham; group 4 = atenolol + ACTH treatments. Series 2 comprised groups 5 and 6, where group 5 = minoxidil + sham and group 6 = minoxidil + ACTH treatments. Series 3 comprised groups 7 and 8, where group 7 = ramipril + sham and group 8 = ramipril + ACTH treatments. Systolic blood pressure, water and food intakes, urine volume, and body weight were measured every second day. After 10 days of treatment, mean arterial blood pressure was measured by intra-arterial cannulation, and cardiac output (CO), and renal, mesenteric and hindquarter blood flows (RBF, MBF and HBF) determined using transonic small animal flowmeters. RESULTS: ACTH treatment increased blood pressure (P < 0.001) with a rise in CO (P < 0.01) and renal vascular resistance (RVR, P < 0.05), but did not affect total peripheral resistance (TPR). Atenolol blocked the rise in CO without affecting the rise in blood pressure produced by ACTH treatment Minoxidil lowered TPR, but did not prevent the rise in blood pressure or renal vascular resistance. Ramipril blunted the rise in RVR and blood pressure without significantly affecting TPR. CONCLUSION: Neither preventing rise in CO nor lowering TPR altered the ACTH-induced rise in blood pressure in the rat However, both the hypertension and rise in RVR were prevented by ramipril. These data suggest that increase in RVR may play a role in the pathogenesis of ACTH-induced hypertension in the rat.

Adrenocorticotropic Hormone↗
PubMed1987

Intrinsic pulsatility of ACTH release from the human pituitary in vitro.

An in-vitro perifusion system was used to investigate spontaneous ACTH release from human fetal (21-23 weeks gestation) and adult pituitaries. The pattern of ACTH release from fetal pituitaries (n = 7) exhibited a remarkable pulsatile character with a mean (+/- SEM) pulse interval of 11.3 +/- 0.8 min. The mean pulse amplitude was 49.7 +/- 6.3 pg, with a nadir to peak increment of 90.7 +/- 10.4%. The mean ACTH release rate was 87.2 +/- 13.3 pg/2 min. Addition of the calcium chelator EGTA (4 nM) to the perifusion medium induced a significant (P less than 0.01) decrease in both ACTH release rate (from 102.0 +/- 8.5 to 52.0 +/- 9.9 pg/2 min) and ACTH pulse amplitude (from 57.7 +/- 2.8 to 31.3 +/- 4.6 pg) (n = 3). Administration of either 2 nM corticotrophin releasing factor (CRF) or 56 mM KCl induced 10- and 2-fold increases in ACTH secretion, respectively (n = 2). Quarters of adult human pituitaries (n = 6) also secreted ACTH in a pulsatile fashion, with a pulse interval of 14.8 +/- 1.7 min, pulse amplitude of 86.7 +/- 10.0 pg, nadir to peak increment of 84.5 +/- 9.8%, and overall release rate of 167.2 +/- 8.8 pg/2 min. These studies demonstrate that ACTH release from the isolated human pituitary in vitro is characterized by high frequency/low amplitude pulses, independent of hypothalamic stimulation. Accordingly, this spontaneous calcium-dependent pulsatile ACTH release apparently reflects the activity of an intrinsic intrapituitary pulse-generating mechanism.

Adrenocorticotropic Hormone↗
PubMed1991

Episodic ACTH and cortisol secretion in normal children.

The aim of this study was to determine the normal relationship between ACTH and cortisol secretion in children. Fourteen children (nine male, five female; median age 11.3 years) were hospitalized and blood samples were taken every 20 min for 24 h. A circadian rhythm was observed with median 0900 h and midnight ACTH values of 1.80 and less than 0.97 pmol/l, and for cortisol 296 and 62 nmol/l respectively. The median (range) areas under the curve for ACTH and cortisol were 29.7 (9.0-53.8) pmol/l/h and 5114 (3562-8630) nmol/l/h respectively. There were no significant differences detected for ACTH and cortisol secretion between males and females, or between prepubertal (n = 9) and pubertal subjects (n = 5). Using a novel form of time series analysis we have shown that both ACTH and cortisol are secreted with a dominant periodicity of 0.7-1.0 h, representing 24-34 secretory episodes of ACTH and cortisol in 24 h. For cortisol, but not ACTH, there is a significant secondary periodicity of 2-3.2 h. To look for shared periodicities we have used the technique of coherency. This reveals that for six of the children ACTH and cortisol are secreted with a significant shared periodicity of 0.8-1.0 h, and for a further five children a similar secondary shared periodicity is present. Therefore in normal children ACTH and cortisol secretion are interdependent and episodic but are not influenced by either pubertal status or gender.

Adolescent↗
PubMed1994

Effect of atrial natriuretic factor infusion on basal and CRH-stimulated ACTH, cortisol and aldosterone levels in patients with Cushing's or Addison's disease.

OBJECTIVE: While it has been shown that atrial natriuretic factor (ANF) is able to inhibit CRH-stimulated ACTH secretion in vitro, in normal men conflicting results on its effect on ACTH/cortisol responses to insulin and CRH have been reported. Since no data are available concerning the possible influence of ANF on the hypothalamic-pituitary-adrenal axis in states of ACTH hypersecretion, the effect of ANF on pituitary-adrenal function in basal conditions and after CRH stimulation has been investigated in patients with Cushing's (n = 4) and Addison's disease (n = 4). DESIGN: On two different days all patients underwent the following procedures: (a) alpha-human ANF was infused, after a priming dose of 100 ng i.v., at a rate of 0.01 microgram/kg/min over 5 hours. After 120 minutes of ANF infusion, oCRH (1 microgram/kg) was i.v. injected as a bolus; (b) vehicle infusion was given over 5 hours and at 120 minutes oCRH was injected. Plasma ANF, ACTH, cortisol, aldosterone, renin activity and K+ were measured; heart rate and blood pressure were monitored. RESULTS: In Cushing's disease plasma ANF rapidly increased within 30 minutes of the exogenous peptide infusion (from 27 +/- 5 to 73 +/- 14 pmol/l; mean +/- SE), whereas in the vehicle study its concentration was unchanged. During the first 2 hours of both tests no significant modifications in ACTH levels were observed. After CRH the plasma ACTH peak was unchanged. Serum cortisol levels progressively declined during the first 2 hours of ANF infusion (from 778 +/- 150 to 461 +/- 48 nmol/l; P < 0.05), whereas no changes were observed during vehicle. After CRH serum cortisol rose to similar peaks. Plasma aldosterone levels were significantly reduced during the first 2 hours of ANF infusion (from 81 +/- 20 to 35 +/- 7 pmol/l P < 0.05), whereas no changes were found during vehicle. A similar aldosterone rise was induced by CRH during either vehicle or ANF. Mean plasma renin activity slightly declined and the changes were similar on both occasions. In Addison's disease ANF levels rose within 30 minutes of the peptide infusion (from 12 +/- 1 to 49 +/- 8 pmol/l), while they were unchanged during vehicle. A slight decline in ACTH levels in the first 2 hours was observed during either vehicle or ANF infusion. After CRH the plasma ACTH peaks were similar. Mean plasma renin activity was unaffected by vehicle, while ANF caused a decline during the first 2 hours (from 13.4 +/- 0.8 to 7.7 +/- 0.3 ng/ml/h). In all patients, heart rate, blood pressure and K+ were only slightly affected on both occasions. CONCLUSIONS: (1) In patients with corticotrophin hypersecretion ANF does not influence basal and CRH-stimulated ACTH secretion; (2) in Cushing's disease ANF inhibits cortisol and aldosterone basal secretion; this effect is not mediated by ACTH and is over-ridden by CRH stimulation.

Addison Disease↗
PubMed1995

Increased 17 alpha-hydroxyprogesterone response to ACTH in silent adrenal adenoma: cause or effect?

OBJECTIVE: Recent studies suggest a possible connection between silent adrenal nodules and mild forms of 21-hydroxylase deficiency. It remains unclear whether the enzymatic deficiency is generalized or intrinsic to the adrenal mass. To help to clarify this, we have studied 17 alpha-OH-progesterone (17OH-P) response to ACTH stimulation in a group of patients with adrenal 'incidentaloma' in comparison with normal subjects. In patients who underwent surgical treatment, the test was repeated to evaluate possible modifications in 17OH-P behaviour after resection of the adrenal mass. SUBJECTS AND METHODS: Fifteen subjects with incidentally discovered asymptomatic adrenal masses were studied. Basal hormone evaluations were normal, with normal cortisol suppression after low-dose dexamethasone. Iodocholesterol scanning, performed in 12 patients, showed normal bilateral adrenal uptake in 2 subjects and an increased uptake on the side of the lesion in 10 subjects. In every patient, ACTH stimulation was performed to evaluate the secretory response of cortisol, 17OH-P, progesterone and dehydroepiandrosterone sulphate. An identical test was performed in 10 control subjects with normal adrenal glands, matched for age and sex. In six patients with an adrenal lesion > 3.5 cm, the ACTH stimulation test was repeated one month after surgery. RESULTS: The 17OH-P response to ACTH stimulation was significantly higher in subjects with adrenal 'incidentaloma' than in controls (P < 0.01). In particular, 10 subjects out of 15 (66%) evidenced a 17OH-P peak > 18 nmol/l at 60 minutes. No differences were seen in baseline 17OH-P or cortisol levels or in cortisol response to ACTH between the two groups. Dehydroepiandrosterone sulphate concentrations were significantly lower in patients with adrenal 'incidentaloma' than in normals. In six patients who had an increased 17OH-P response to ACTH on initial evaluation, the ACTH test was repeated one month after surgery. In five of these patients, 17OH-P response to ACTH was clearly reduced, suggesting that in these cases the enzymatic defect was restricted to the adenoma. In the other patient, however, stimulated 17OH-P levels remained unchanged. In this case, therefore, all of the adrenal tissue seems to be involved, suggesting a late-onset 21-hydroxylase deficiency. No significant modifications in cortisol response to ACTH were observed. CONCLUSION: It seems therefore that in some cases of incidentaloma the steroidogenic enzymatic defect may be secondary to the adenomatous proliferation, while in others such defects may induce the development of silent adrenal nodules.

17-alpha-Hydroxyprogesterone↗
PubMed2005

An update on the biochemical diagnosis of congenital ACTH insufficiency.

OBJECTIVE: Congenital ACTH insufficiency due to disorders of the hypothalamo-pituitary axis is life threatening. However, the optimal method for establishing the diagnosis remains controversial. The standard Synacthen test (SST) is safe and easy to perform in infancy, but its performance has not been well evaluated in infants and children with ACTH insufficiency. DESIGN, PATIENTS AND MEASUREMENTS: We aimed to determine the value of the SST by comparing the 30-min SST cortisol concentration with physiological (spontaneous) cortisol secretion (2-hourly measurements for 24 h) in 28 patients (13 male; age range 0-5.1 years) with one or a combination of optic nerve (25) midline forebrain (17) and other pituitary hormone (17) abnormalities. Spontaneous cortisol secretion (mean < 145 nmol/l) was arbitrarily used as the 'gold-standard' in the diagnosis of ACTH insufficiency as it offered a reflection of endogenous cortisol mileu. A normal SST was defined as a 30-min serum cortisol > 540 nmol/l. RESULTS: The SST basal, 30-min and 60-min serum cortisol concentrations were significantly (P < 0.001) lower in patients with ACTH insufficiency (mean spontaneous cortisol < 145 nmol/l). 3/13 patients without and 12/15 patients with ACTH insufficiency failed the SST (specificity 76.9%; sensitivity 80%). Two out of three patients with ACTH insufficiency who passed the test were symptomatic with fatigue, poor growth and hypoglycaemia that resolved with hydrocortisone treatment. An 08:00 h serum cortisol cut-off of 175 nmol/l provided a sensitivity of 93.3% and a specificity of 92.3% as compared with spontaneous cortisol secretion. The 30-min increment and the 60-min SST cortisol concentrations although highly specific (100%) had reduced sensitivity (40% and 60%, respectively). CONCLUSIONS: A normal SST does not rule out ACTH insufficiency and measurement of physiological cortisol secretion may be required to confirm the diagnosis. A combination of 08:00 h serum cortisol > 175 nmol/l and a 30-min SST serum cortisol > 540 nmol/l to exclude ACTH insufficiency (sensitivity 69%, specificity 100%) would ensure that no child with ACTH insufficiency would be missed and hence would prevent serious consequences, although it may lead to over-diagnosis in some cases.

Adrenocorticotropic Hormone↗
PubMed1981

Seasonal, circadian and episodic variations of human immunoreactive beta-MSH, ACTH and cortisol.

The 24-hour profile of plasma levels of immunoreactive beta-MSH (IR-beta MSH), ACTH and cortisol was obtained at 15-min intervals in six normal males in summer and winter. In the radioimmunoassay used, dilution curves of human beta-MSH and human beta-LPH were not parallel. A seasonal variation in basal pituitary-adrenal secretion, with higher levels in winter than in summer, was demonstrated. A circadian rhythm was found to be significant for ACTH, IR-beta MSH and cortisol in all investigations. Whereas ACTH and cortisol patterns were largely concordant in all studies, there was a significant desynchronization of the circadian rhythm of IR-beta MSH as compared to ACTH in five cases. Eighty-three percent of the secretory spikes of cortisol but only 68% of the IR-beta MSH spikes were concomitant with an ACTH spike. Correlations between maximal levels of concomitant spikes were higher during the quiescent period of pituitary-adrenal secretion (22.00--04.00) for ACTH-cortisol whereas for ACTH-IR-beta MSH, highest correlations were found during the active early morning secretory phase (04.00--10.00). For the three plasma constituents studied, longer apparent half-lives were found to occur when the basal level before spiking was already elevated, suggesting that ACTH, beta-LPH and cortisol are secreted in bursts superimposed on a continuous basal secretion. Absolute increments of concentration appeared to be relatively independent of the level before spiking. It is suggested that the dissociations between ACTH and IR-beta MSH fluctuations in plasma observed here result from in vitro proteolysis of beta-LPH.

Adrenocorticotropic Hormone↗
PubMed2005

Effect of ACTH administration on biochemical and immune measures in boars.

The effects of stress induced by adrenocorticotropic hormone (ACTH) on biochemical and immune changes in Swedish Landrace boars aged approximately 6-7 months were observed during ACTH administration and for 16 days after the cessation of treatment. Adrenocorticotropic hormone treated animals (n = 7) were given intravenously 10 microg/kg body mass of ACTH for 3 days. Control group of animals (n = 7) received intramuscularly 1 ml of sterile 0.9% saline. Total protein and globulin levels were significantly elevated during the induced stress period and for the next 16 days (P < 0.01 to P < 0.0001, respectively). Also, serum immunoglobulin IgG concentration was significantly elevated during and after ACTH injection (P < 0.001 to P < 0.0001). Adrenocorticotropic hormone treatment had no effect on serum albumin, IgA and IgM concentrations. Glucose concentration was significantly decreased on the second day of ACTH administration (P < 0.001) and on day 9 after treatment (P < 0.001). Calcium level was significantly decreased only for 24 h after the last ACTH dosage (P < 0.01). Also, serum phosphorus level was significantly decreased on the first (P < 0.05) and third (P < 0.001) days of ACTH challenge but remained unaffected after the cessation of ACTH treatment. It is concluded that the administration of ACTH to boars results in immune humoral and biochemical changes during stress and the post-stress period.

Adrenocorticotropic Hormone↗
PubMed1988

Inhibition of serotonin-induced ACTH release in man by clonidine.

1. Clonidine, an alpha 2-adrenergic agonist, is thought to inhibit noradrenergic neuronal activity (NNA) in the central nervous system (CNS) by a presynaptic alpha 2-receptor mechanism. Central NNA is thought to be the primary monoaminergic stimulus to pituitary ACTH release. Fenfluramine, a serotonin releasing agent and uptake inhibitor, causes ACTH release in normal man. 2. The present study investigated the effect of clonidine on fenfluramine-induced ACTH release in six normal volunteers. Four protocols were used: 1.5 mg/kg body weight oral fenfluramine; 4.3 micrograms/kg body weight oral clonidine; oral clonidine + oral fenfluramine 1 h later; placebo clonidine. Plasma ACTH and cortisol were measured at intervals for 5 h after clonidine and for 4 h after fenfluramine. 3. The mean plasma ACTH and cortisol levels and the mean maximal changes in these levels were significantly lower during the clonidine + fenfluramine test than during fenfluramine alone. Plasma ACTH and cortisol levels were not lowered significantly more by clonidine than by placebo. 4. In conclusion, clonidine blocked the ACTH-releasing activity of fenfluramine in normal humans. This inhibition of active ACTH release may result from clonidine blockade of fenfluramine-induced activation of central NNA. Clonidine alone was no more effective than placebo in lowering plasma ACTH and cortisol.

Adolescent↗
PubMedDate not supplied

Effect of sodium valproate on naloxone-stimulated ACTH and cortisol release in humans.

1. Gamma-aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAA agonist, blocks naloxone-induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA-mediated, SV should also inhibit naloxone-stimulated ACTH release. 2. We studied five healthy volunteers in randomized, double-blind, placebo-controlled afternoon studies with SV 400 mg, given 180 min before i.v. naloxone 125 micrograms/kg bodyweight. Plasma concentrations of ACTH, cortisol and SV were measured at intervals during the experiments. 3. SV had no effect on the mean integrated ACTH and cortisol responses to naloxone; ACTH: 165 +/- 21 versus 284 +/- 40 pmol.min per L, P = 0.08; cortisol: 10.5 +/- 1.9 versus 12.8 +/- 1.2 nmol.min per L-3, P = 0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cortisol levels were also not significantly altered by SV (P > 0.30). Mean SV levels were not significantly different between SV/nal and SV/placebo studies (P > 0.50). 4. In conclusion, SV had no effect on naloxone-induced ACTH and cortisol release in normal humans at the dose and plasma drug concentrations studied. This contrasts with the potent inhibitory effect of alprazolam, and suggests that the effect of SV on the human hypothalamic-pituitary-adrenal axis may not be through a GABAA-mediated mechanism. Alternatively, higher plasma SV levels or more sustained exposure to SV may be necessary to inhibit hypothalamic secretion of CRH.

Adrenocorticotropic Hormone↗
PubMed1995

The effects of calyculin A upon calcium-, guanine nucleotides- and phorbol 12-myristate 13-acetate-stimulated ACTH secretion from 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 phosphatase involvement in the late stages of the secretory pathway for adrenocorticotrophin (ACTH) secretion. The effects of the type 1 and 2 phosphatase inhibitor calyculin A upon calcium-, guanine nucleotide- and phorbol 12-myristate 13-acetate (PMA)-stimulated ACTH secretion from electrically-permeabilized AtT-20 cells were studied. 2. Calyculin A (1 nM-1 microM) inhibited both calcium (10 microM)- and guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) (100 microM)-evoked ACTH secretion from permeabilized cells in a concentration-dependent manner. These effects were maximal with 100 nM calyculin A. 3. ACTH secretion was stimulated from electrically-permeabilized cells when the cytosolic free calcium ion concentration, controlled by calcium-EGTA buffers, was raised over the concentration range of 100 nM to 10 microM. This calcium-stimulated ACTH secretion was inhibited by co-incubation with calyculin A (100 nM). 4. GTP-gamma-S (10 nM-100 microM) stimulated ACTH secretion from permeabilized cells at concentrations greater than 1 microM GTP-gamma-S. Co-incubation with calyculin A (100 nM) inhibited this stimulation of ACTH secretion observed at these concentrations of GTP-gamma-S. 5. PMA (100 nM) significantly stimulated ACTH secretion from permeabilized cells in the absence of either calcium and guanine nucleotides and this action was enhanced by calyculin A (100 nM). Furthermore, an inhibition of GTP-gamma-S (100 microM)-stimulated ACTH secretion observed in the presence of calyculin A (100 nM) was not observed in the presence of PMA (100 nM). 6. The results of the present study indicate that dephosphorylation by phosphatases plays an important role in stimulus-secretion coupling in AtT-20 cells and is involved in mediating the effects of GE upon the secretory apparatus in these cells. Furthermore, the point of regulation of the secretory response by PKC which underlies the ability of PKC to amplify the calcium/GE system may lie distal to both GE and these phosphatases.

Adrenocorticotropic Hormone↗
PubMed2005

Effect of ACTH therapy for epileptic spasms without hypsarrhythmia.

PURPOSE: We analyzed the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for patients with epileptic spasms (ESs) who did not meet the criteria of West syndrome (WS). METHODS: The subjects were 30 patients, including 13 boys and 17 girls, who had received ACTH therapy between 1970 and 2003. We excluded patients with WS, but included those with a history of WS who no longer showed hypsarrhythmia at the period of ACTH therapy. The age at onset of ESs and at ACTH therapy ranged from 2 to 82 months with a median of 18 months, and from 11 to 86 months with a median of 29 months, respectively. RESULTS: Excellent and poor responses were obtained in 19 (63%) and 11 (37%) patients, respectively, as a short-term effect. Although the patients could be subclassified into five subgroups according to the previous reports, no difference was seen in short- term response to ACTH. Among 17 of the 19 patients with excellent short-term outcomes and a follow-up of >1 year after the ACTH therapy, eight patients have continued to be seizure free (29%; excellent long-term effect), whereas the remaining nine patients had a recurrence of seizures (complex partial seizures, four; generalized tonic seizures, three; ESs, two) at 9 months to 198 months (median, 49 months) after ACTH therapy. In addition, nine of the 17 patients demonstrated a localized frontal EEG focus after the ACTH therapy, although most of these had previously shown diffuse epileptic EEG abnormality. CONCLUSIONS: ACTH therapy is worth trying for patients with resistant ESs, even without features of WS. However, the long-term effect is uncertain because recurrences of various types of seizures, including focal, were frequently observed.

Adolescent↗
PubMed1970

On the mode of action of ACTH on the isolated perfused adrenal gland.

1. Isolated cat adrenal glands were perfused with Locke solution, and the corticosteroid outputs in response to adrenocorticotrophin (ACTH) were studied.2. Steroid outputs varied with the ACTH concentration, as well as with the duration of exposure to a given ACTH concentration.3. Omission of calcium from the perfusion medium markedly depressed ACTH-evoked steroid release. The steroid output was directly related to the extracellular calcium concentration up to 0.5 mM.4. During a constant exposure to ACTH, steroid output was maintained for at least 2-3 hr, provided that calcium was present in the perfusion medium.5. Strontium, but not barium or magnesium, replaced calcium in maintaining the secretory response to ACTH.6. Magnesium depressed ACTH-evoked secretion in the presence of calcium, and this depression of secretion was antagonized by increasing the calcium concentration.7. Prolonged perfusion with sodium-free or potassium-free solutions did not markedly inhibit steroid output in response to ACTH. Excess potassium (56 mM) did not produce a consistent or marked increase in spontaneous steroid output and did not affect the response to ACTH.8. The steroid content of adrenal glands perfused with Locke solution and exposed to ACTH was about 10% of the amount which was secreted. By contrast, adrenal glands perfused with calcium-free media and exposed to ACTH contained much higher amounts of steroid, despite the negligible amount secreted.9. These data suggest that calcium plays a critical role in the mechanism of corticosteroid secretion from the adrenal cortex.

Adrenal Cortex Hormones↗