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PubMed1992

Direct effect of ACTH on renin release in isolated perfused guinea-pig kidneys with adrenal glands.

To investigate the direct effect of corticotropin (ACTH) on the renin-angiotensin-aldosterone system, isolated guinea-pig kidneys with adrenal glands were perfused with various doses of ACTH (0.1-1000 micrograms/l) and 0.3 mmol/l of dibutyryl cyclic AMP (cAMP) through each cannula inserted into the abdominal aorta and the inferior caval vein. Perfusate renin activity was increased in a dose-dependent manner by the addition of ACTH in a range of 0.1-1000 micrograms/l, and reached a plateau at 20 min with each dose. The perfusate cAMP level was dose-dependently increased with 10-1000 micrograms/l of ACTH. Perfusate renin activity was also markedly increased by the addition of dibutyryl cAMP. The same effects of ACTH on renin and cAMP secretions were observed in the kidney perfusion model from which the adrenal glands were excluded. Aldosterone secretion failed to respond to 0.1 micrograms/l of ACTH, and was increased by higher concentrations (1-1000 micrograms/l) in the same experiments. These results demonstrate that ACTH has a direct effect on renal renin release in a physiological concentration (0.1 micrograms/l), and that the action of ACTH is probably mediated by cAMP. The sensitivity of renin release to ACTH stimulation is no less than that of aldosterone secretion during ACTH infusion, so it is possible that ACTH is an important stimulator of the renin-angiotensin system.

Adrenal Glands↗
PubMed2005

Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression.

BACKGROUND: The ACTH receptor (ACTH-R) is a member of the seven transmembrane domain receptor super-family. In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low. However, no inhibitory factor for ACTH-R expression has been defined to date. DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1) is a general repressor of steroid production, inhibiting steroidogenic factor-1 (SF-1)-dependent expression of multiple steroidogenic enzymes. The aim of this study was to investigate whether ACTH-R gene transcription is affected by DAX-1 and whether this mechanism is involved in down-regulation of ACTH-R expression in adrenocortical tumors. METHODS: We screened 22 adrenocortical tumors for ACTH-R and DAX-1 mRNA expression by Northern blot. For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid. These experiments were also performed using ACTH-R promoter 5'-deletion constructs and constructs mutated at the SF-1-binding sites. RESULTS: We found a negative correlation between DAX-1 and ACTH-R mRNA expression (R=-0.47, P<0.02). Accordingly, in vitro expression of DAX-1 significantly reduced hACTH-R and mACTH-R promoter activity by 89 and 55% respectively. DAX-1 inhibition was also present in the shortest construct of a series of 5'-deletion constructs of the human promoter extending from -64 to +40 bp relative to the transcription start site. Mutation of the SF-1-binding sites within the hACTH-R promoter resulted in reduced or abolished DAX-1 inhibition, arguing for a mechanism that involves SF-1 for DAX-1 inhibition. CONCLUSIONS: These data support the concept that DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo.

Adenoma↗
PubMed1993

Factors affecting ACTH release from perifused equine anterior pituitary cells.

The multifactorial control of ACTH is well established. We wished to establish and characterize an in-vitro perifusion system, using equine anterior pituitary cells and physiological concentrations of secretagogues, to investigate factors which affect the dynamics of ACTH secretion. Anterior pituitary tissue was divided for dispersion into cells with collagenase, trypsin or dispase, or by mechanical dispersion. After dispersal followed by 18-h incubation, cells were perifused and the ACTH response to 10-min pulses of arginine vasopressin (AVP; 100 nmol/l), corticotrophin-releasing hormone (CRH; 0.01 nmol/l), and AVP (100 nmol/l) plus CRH (0.01 nmol/l) determined. ACTH responses to these secretagogues were lower (P < 0.05) in cells prepared using the enzymes dispase and trypsin than with the enzyme collagenase. Cells prepared by mechanical methods were not responsive. Collagenase-prepared cells were used in subsequent experiments. In dose-response studies (10-min pulse length), a steep CRH-ACTH dose-response curve was obtained with the minimum effective concentration of CRH between 0.001 and 0.01 nmol/l, and a maximum effective concentration of 1.0 nmol/l. A less steep AVP-ACTH dose-response curve was obtained with a minimum effective concentration of AVP between 0.5 and 5 nmol/l, and no plateau in response up to 5000 nmol AVP/l. Increasing the incubation time between cell preparation and stimulation with AVP from 18 h to 90 h significantly (P < 0.01) increased the ACTH response. Repeated stimulation by AVP (100 nmol/l) or CRH (0.01 nmol/l) (5-min pulses every 30 min for 23 pulses) produced ACTH responses which decreased in an approximately exponential curve with time. When AVP and CRH were given at physiological concentrations, pulse lengths and pulse frequency, the ACTH response to repeated 1-min pulses of AVP, measured as height above basal secretion, was potentiated by the addition of CRH (1, 2.5, 5, 10 and 20 pmol/l) as a constant perifusion at all AVP concentrations tested (1 nmol AVP/l, P < 0.02; 10 nmol AVP/l, P < 0.0005; 25 nmol AVP/l, P < 0.0005). During the 1-min AVP pulse, the AVP concentration at the level of the cells was 30% of the expected concentration. Potentiation was increased both by increasing AVP concentration (P < 0.00005) and by increasing CRH concentration (P < 0.00005) up to 5 pmol CRH/l. The ACTH height response to repeated AVP stimulation significantly (P = 0.034) decreased with time, independent of CRH and AVP concentration. There was a significant (P = 0.014) decrease in ACTH response to CRH infusion with time, independent of CRH concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed2001

Suppression of lipid peroxidation in adrenal microsomes following ACTH administration to guinea pigs.

Previous studies demonstrated high levels of lipid peroxidation (LP) in the guinea pig adrenal cortex. The present studies were done to determine if adrenal LP activity was influenced by ACTH, the major hormonal regulator of the gland. Guinea pigs were treated with ACTH for 1, 3 or 7 days. In addition, some guinea pigs received ACTH for 7 days and were killed 3 or 7 days later. After treatment, adrenal microsomal fractions were prepared and incubated in vitro with 1 mM ferrous sulfate to initiate LP. ACTH treatment caused a progressive decrease in adrenal LP; activity was almost totally inhibited within 3 days. The inhibitory effects of ACTH on LP were dose-dependent. Following cessation of ACTH treatment, adrenal LP gradually returned toward control levels. Microsomal concentrations of linoleic acid, a major substrate for adrenal LP, were increased by ACTH administration and then also returned to control levels after cessation of treatment. There were no significant changes in adrenal alpha-tocopherol or beta-carotene concentrations resulting from ACTH treatment. The results indicate that ACTH has a role in the regulation of adrenal LP. The actions of ACTH cannot be attributed to an increase in adrenal content of the antioxidants, alpha-tocopherol and beta-carotene, or to a decrease in LP substrate. The actions of ACTH to inhibit LP may contribute to an increase in adrenal hormone production by protecting steroidogenic enzymes from peroxidative degradation.

Adrenal Cortex↗
PubMed2001

Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone gene expression.

The hormone corticotropin (ACTH) is employed as therapy for diverse neurological disorders, but the mechanisms for its efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system (CNS) have been attributed to activation of glucocorticoid receptors. However, in several human disorders, ACTH has therapeutic actions that differ qualitatively or quantitatively from those of steroids. This study tested the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors and focused on the effects of ACTH on the expression of corticotropin-releasing hormone (CRH), a neuropeptide involved in neuroimmune functions and in certain developmental seizures. The results demonstrated that ACTH potently reduced CRH expression in amygdala neurons. This down-regulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced down-regulation of CRH expression. Taken together, these data indicate that ACTH activates central melanocortin receptors to modulate CRH gene expression in amygdala, supporting the notion that direct, steroid-independent actions of ACTH may account for some of its established clinical effects on the CNS.

Adrenocorticotropic Hormone↗
PubMed2001

The stimulatory effect of vasoactive intestinal peptides on the cortisol production of guinea pig Zona fasciculata cells: an extra-ACTH regulatory model of the adrenocortical function.

The effect of vasoactive intestinal peptide (VIP) on cortisol production was studied in a primary culture enriched with guinea pig Zona Fasciculata (ZF) cells. In ZF cells, VIP stimulates cortisol secretion and enhances the steroidogenic action of ACTH. Compared to ACTH on an equal molar basis, the cortisol-stimulatory effect of VIP is at least 10-fold less potent. As VIP exhibits a wide range of biological actions with widespread distribution in the body, the steroidogenic action of VIP on the adrenal glands is not tissue-specific. There are VIP receptors in ZF cells. With the aid of a VIP receptor antagonist, we found that ACTH and VIP mutually bind each other's receptors with an affinity-ranking order of ACTH > VIP receptor antagonist > VIP. VIP stimulates cortisol production most likely through the cyclic AMP (cAMP) signaling pathway. Both ACTH receptors and the VIP receptors bind VIP receptor antagonist more avidly than VIP, but the bindings do not lead to a consequential effect on cAMP production and cortisol secretion. However, the VIP receptor antagonist counteracted ACTH and VIP to lower both cAMP and cortisol production. In addition, ASIF and BNP-32, which are the proven ACTH receptor antagonists, reduced the cortisol-stimulatory effect of ACTH and VIP. These results suggest that besides ACTH, VIP be an important factor in regulating the cortisol secretion from the adrenal cortex at the site of ACTH receptors. In cases with hypercortisolemia being detected concomitantly with normal or low ACTH levels, we may need to investigate the influential role of VIP.

Adrenal Cortex↗
PubMed1992

[Physiological analyses of secretory kinetics of adrenocorticotropic hormone (ACTH) from anterior pituitary cells: development and application of a microperfusion system].

A microperfusion system was developed to study detailed kinetics of adrenocorticotropic hormone (ACTH) secretion by dispersed rat anterior pituitary cells responding to various ACTH secretagogues. The system approaches hydrodynamics to square-wave stimuli and enables kinetic analysis of ACTH secretion with intervals as short as 5 sec. ACTH secretion initiated within 5 sec of exposure of the cells to corticotropin-releasing factor (CRF), arginine vasopressin (AVP), oxytocin (OT) or angiotensin II (A-II) and reached a maximum within 20-40 sec. CRF induced a plateau-shaped secretion of ACTH which remained constant as long as CRF was perifused. In contrast, the ACTH secretion responding to AVP, OT and A-II rose rapidly to a peak and fell to the baseline despite continued perifusion of these agents. There were two components of ACTH secretory response to AVP and OT. AVP had synergistic effect with CRF only if it was perifused simultaneously with CRF or immediately after CRF was stopped. The ACTH secretory response to A-II was greatly diminished when cells were exposed to AVP or OT before A-II perifusion. Prior exposure to A-II had no effect on the magnitude of the ACTH secretory response to either AVP or OT. Epinephrine, nor-epinephrine, gastrin-releasing peptide, atrial natriuretic factor and cholecystokinin stimulated no significant ACTH secretion in the microperfusion system, although some of them induced ACTH secretion by same cell preparation in static culture systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed2005

[Clinical efficacy of shortened ACTH therapy --an individualized method for minimization of adverse effects--Part 1. The short-term outcome].

To minimize adverse effects and to get good efficacy of ACTH therapy against West syndrome, we tried a new 2-steps therapeutic protocol consisting of the shortened ACTH therapy and the additional ACTH therapy. In a prospective multi-institutional study, 20 patients with newly diagnosed West syndrome who had failed to respond to high-dose vitamin B6 and zonisamide were treated by this shortened ACTH therapy. Synthetic corticotropin (ACTH-Z 0.025 mg/kg/dose, max 0.25 mg) was administrated intramuscularly seven times on every other day for 14 days. At 1 month after discontinuing corticotropin, spasms and hypsarrhythmia disappeared in 10/20 (50%) and 13/17 (59%) patients respectively. Subsequently, 9 out of the 10 patients with persistent spasms received additional therapy for 1 or 2 weeks with daily intramuscular ACTH-Z, which was tapered off over a few weeks. Including the additional ACTH therapy, the disappearance of spasms and hypsarrhythmia were found in 13 patients (65%) and 13 patients (76%). Adverse effects during the shortened ACTH therapy were fewer than additional ACTH therapy but not statistically significant. Severe adverse effects were not observed in both ACTH therapy. In the 2-steps therapeutic protocol according to the response to ACTH, favorable results were obtained in seizure control, EEG findings and the degree of adverse effects.

Adrenocorticotropic Hormone↗
PubMed1991

Quantification and characterization of ACTH-related peptides produced by human peripheral blood mononuclear cells.

We have used a sensitive radioimmunoassay to quantify and characterize PBMC-associated immunoreactive ACTH (ACTH-IR). Mean ACTH content of freshly isolated human PBMCs was 3.8 +/- 0.72 pg (SEM) per 10(6) cells. During 3 days of incubation ACTH-IR in conditioned media of control PBMCs increased significantly, p less than 0.02. Gel filtration chromatography revealed a minor peak of ACTH-IR coeluting with ACTH (1-39) and a major peak coeluting with ACTH (11-24). Treatment with 15 nM CRH did not alter the amount of ACTH-IR secreted or its gel pattern. Synthetic ACTH (11-24), was radioiodinated and was used for binding experiments that demonstrated specific high- and low-affinity binding sites for ACTH (11-24) on a human T cell line. These results add support for a role of ACTH and related peptides in immune regulatory systems and suggest that cell-specific post-translational processing of POMC may generate an expanding number of biologically active moieties.

Adolescent↗
PubMedDate not supplied

[ACTH of lymphocytic origin under normal and pathological conditions].

Evidence has accumulated that human peripheral blood mononuclear cells (PBMC) may release adrenocorticotropic hormone (ACTH) and endorphin-like peptides into the culture medium when stimulated with different substances such as Newcastle disease virus and the lipopolysaccharide of Escherichia coli. However, to our knowledge, no quantitative assessment of ACTH-LIR (like-immunoreactivity) in human PBMC has been reported. We thus utilized a radioimmunoassay for ACTH to find a median of 30 pg of ACTH-LIR in 10(7) PBMC of 11 normal subjects. ACTH-LIR was also detected in 7 different cell lines derived from patients with lymphoid and myeloid malignancies, two of them, JM and U937, showed values of 135 and 108 pg/10(7) cells respectively. Stimulation with IL-1 beta at the concentration of 1000 U/mL induced, after 48 h, a significant increase of intralymphocytic ACTH levels when compared to basal and 24 h values. The chromatographic characterization of this ACTH-LIR showed, at least, three molecular forms of immunoreactive ACTH; molecular weights were 31 kD POMC, 22 kD ACTH and 4.5 kD ACTH. We used northern blotting with human genomic DNA probe for POMC gene to evidence specific mRNA in PBMC; mRNA was also observed in a T lymphocyte cell line derived from a patient with lymphoma. We conclude that PBMC produce ACTH-LIR which may act as a paracrine immunomodulator similar to lymphokine and/or may signal the adrenal gland to secrete glucocorticoids.

Adrenocorticotropic Hormone↗
PubMed1991

Correlation between plasma levels of ACTH and cortisol in basal states and during the CRH test in normal subjects and patients with hypothalamo-pituitary disorders.

Using a new ACTH-immunoradiometric assay (IRMA), we measured plasma ACTH levels in the basal states and during CRH test in normal subjects and the patients with hypothalamo-pituitary disorders. The basal levels of plasma ACTH in 76 normal young (25-45 yr) and 140 elderly (60-85 yr) subjects were 23.1 +/- 13.6, and 17.5 +/- 11.2 pg/ml, respectively. The plasma ACTH levels were less than detection limit (5 pg/ml) in 3 patients with isolated ACTH deficiency, and less than 10 pg/ml in 6 of 7 patients with hypopituitarism. A significant correlation was observed between the basal levels of plasma ACTH and of cortisol in two age groups, with almost the same regression line, showing no age-related decline in the plasma levels of ACTH and cortisol. In 2 normal subjects and 2 patients with Cushing's disease, synchronized secretions of ACTH and cortisol were observed between 0800h and 1800h. In normal subjects and the patients with pituitary disorders, a significant correlation was observed between the Area Under the Curve's for plasma ACTH and cortisol during the CRH test. The correlation constant was higher in normal subjects, but lower in the patients with acromegaly, non-functioning pituitary tumor, and Cushing's disease in this order, suggesting low sensitivity of the pituitary-adrenal axis in these patients. These results suggest that the ACTH-IRMA kit provide reliable data for clinical investigation, and that the secretions of ACTH and cortisol correlate each other in basal states and during the CRH test in the patients with pituitary disorders as well as in normal subjects.

Adolescent↗
PubMed1978

[Possible consequence of ACTH-like peptides for human mental performance (author's transl)].

ACTH affects behavior of rats. The results of the reported experiments suggest that ACTH effects on conditioned behavior are the result of an improved motivation or attention. The ACTH fragments, ACTH 4--10 and ACTH 4--9, have the behavioral effects of ACTH but are devoid of endocrine activities. The ACTH 4--9 analog H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) has behavioral activity after oral administration. ACTH-like-peptides restore the behavioral deficiencies of hypophysectomised rats and delay extinction of conditioned behavior of normal rats independent of the type of conditioning. So is extinction of pole jump avoidance and extinction of conditioned tast aversion delayed after Org 2766. Moreover ACTH-like peptides reduce the behavioral deficit in rats with amnesia even when the treatment is given two weeks after the induction of amnesia. In man the administration of a single dose of ACTH 4--10 on Org 2766 reduces the duration of lapses as well as the number of errors of volunteers in a continuous performance task. These and similar observations suggest that ACTH-like peptides may be of practical consequence for the therapy of patients with impairments of cognitive processes.

Adrenocorticotropic Hormone↗
PubMed1987

Evaluation of plasma aldosterone concentrations before and after ACTH administration in clinically normal dogs and in dogs with various diseases.

Plasma aldosterone concentrations were measured in response to adrenocorticotropic hormone (ACTH) gel administration in clinically normal dogs, in dogs with hypoadrenocorticism, and in dogs (with electrolyte abnormalities) that did not have hypoadrenocorticism. Baseline plasma aldosterone concentrations were determined from specimens obtained every 10 minutes for 3 hours from 2 dogs and every 30 minutes for 7.5 hours from 2 other dogs. During the evaluation period, plasma aldosterone concentrations varied by at least 50% in each dog. A randomized crossover design was used to compare changes in plasma aldosterone concentrations after administration of ACTH gel and physiologic NaCl solution. Dogs had significantly (P = 0.002) higher plasma aldosterone concentrations after administration of ACTH gel than after administration of NaCl solution. Plasma cortisol concentrations increased as expected after ACTH gel administration. Analysis of cortisol and aldosterone concentrations in the same specimens obtained at 7 sample collection times did not reveal significant linear correlation, and scatterplots did not indicate a nonlinear association. In addition, plasma aldosterone concentrations were determined in response to ACTH administration alone and to ACTH combined with a high dose of dexamethasone (0.1 mg/kg, IV). The plasma aldosterone response to ACTH alone was not significantly different from the response to ACTH combined with dexamethasone. For both tests, plasma aldosterone concentrations at 60 and 120 minutes after ACTH administration were significantly (P less than 0.0005 and P = 0.0001, respectively, increased, compared with base-line values. Six dogs with adrenocortical hypofunction, as determined by plasma cortisol concentrations before and after ACTH administration, had plasma aldosterone concentrations that were diminished or did not increase after ACTH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Insufficiency↗
PubMedDate not supplied

[ACTH response to 24 hours oral metyrapone test in normal children (author's transl)].

A study of ACTH response to orally given metyrapone were carried out with 32 normal subjects aged 18 months to 15. Effectiveness of adrenal inhibition was supported by delta F > 5 microgram or cortisol level after metyrapone < 3 microgram/100 ml. The strong positive correlation between delta F and delta ACTH indicates the high sensibility of delta ACTH as an index of the responsiveness. No correlation was found between delta ACTH and weight, height, or age. Mean level (M +/- 2 SEM) are established: plasma ACTH level at 8 before metyrapone = 32,1 +/- 7,5 pg/ml; plasma ACTH level at 8 after metyrapone = 271,8 +/- 57 pg/ml; delta ACTH = 240 +/- 6 pg. Including these considerations, biological ACTH variability, and reproductibility of determinations, an abnormal response seems to be proved by plasma ACTH level at 8 after metyrapone < 100 pg/ml or/and delta ACTH < 70 pg. A normal response is established by delta ACTH > 150 pg.

17-Hydroxycorticosteroids↗
PubMedDate not supplied

Clinical chronopharmacology of ACTH 1-17. I. Effects on plasma cortisol and urinary 17-hydroxycorticosteroids.

The aim of the investigation was to study the effects of ACTH 1-17 on both plasma cortisol and urinary 17-OHCS in health adult young males with regard to the time (clock hours) at which this polypeptide was injected. Eight healthy adults (males from 18-30 years) volunteered for the study. They were synchronized with a diurnal activity from 0700 to 0000 and a nocturnal rest. Each week, during 6 consecutive weeks (January 19 to February 25, 1980), a 3-day test was performed on Saturday, Sunday and Monday. On Sundays 3 control-tests and 3 ACTH-tests were programmed during which either saline or 100 micrograms ACTH 1-17 were injected i.m. at respectively 0700, 1400 and 2100. During each 3 day-test (72 h) the urinary excretion of 17-OHCS was determined every 4 h at fixed clock hours. In addition, on Sundays, venous blood was sampled prior to control or ACTH injections at respectively 0700, 1400, and 2100 and 20, 40, 60, 90, 120, 150 and 180 min thereafter. Plasma cortisol (radioimmunoassay) was determined in samples thus collected. Both conventional and cosinor methods were used for statistical analyses. A strong and statistically significant rise of plasma cortisol was observed after all of the ACTH 1-17 injections. The obtained mean response curves were observed after all of the ACTH 1-17 injections. The obtained mean response curves were similar in form and parallel. The highest plasma cortisol curve corresponded to ACTH injected at 0700, the lowest to ACTH injected at 2100. The curve corresponding to ACTH injected at 1400 went in-between. The 24-h urinary excretion of 17-OHCS after ACTH 1-17 was approximately 4 times greater than the control value when injected at 0700, approximately 3 times greater than control when injected at 1400 and only twice greater than control when injected at 2100. In terms of changes in plasma cortisol and 17-OHCS the greatest best benefit of ACTH 1-17 is achieved when this polypeptide is injected at 0700, rather than at 1400 or 2100 in diurnally active subjects.

17-Hydroxycorticosteroids↗
PubMed1982

[The changes of human plasma ACTH, immunoreactive-beta-endorphin and cortisol during pregnancy, labor and delivery (author's transl)].

Immunoreactive (IR)-beta-endorphin, ACTH and cortisol from the plasma of 88 pregnant women during gestation, and 28 women with spontaneous labor were measured. The concentrations of ACTH, IR-beta-endorphin and cortisol gradually increased during gestation. There were significant correlation between ACTH and IR-beta-endorphin (r = 0.79, p less than 0.0001), as well as between ACTH and cortisol (r = 0.54, p less than 0.0001) during gestation. Maternal ACTH and IR-beta-endorphin concentrations rapidly increased during the course of labor, peaked immediately after delivery at 671.3 +/- 136.1 and 513.9 +/- 85.5 pg/ml, respectively, and then decreased two hours later. There was a highly significant correlation (r = 0.89, p less than 0.0001) between ACTH and IR-beta-endorphin during labor. The levels of cortisol were elevated during labor and showed no difference during labor, or two hours later. However, there was no significant relationship between ACTH and cortisol (r = 0.24) during labor. Chromatographic analysis was performed on the pooled plasma extracts from pregnant women at the various stage of labor. In ACTH analysis, a single peak was seen at the position of native ACTH in each case. All detectable immunoreactivities eluted in two peaks at the position of beta-LPH and beta-endorphin. However, beta-LPH to beta-endorphin ratio was almost the same in each case. These results suggest that 1) ACTH and IR-beta-endorphin are secreted concomitantly, probably by the maternal pituitary gland during gestation as well as in response to the stress of labor; 2) the lack of correlation between ACTH and cortisol is due to the difference in metabolic clearance rate of these hormones during labor; 3) neither peripheral nor intrapituitary conversion of beta-LPH to beta-endorphin is seen during gestation and labor.

Adolescent↗
PubMed1998

Influence of nitric oxide synthase inhibitors on the ACTH and cytokine responses to peripheral immune signals.

Nitric oxide (NO) is an unstable gas that participates in the response of the hypothalamic-pituitary-adrenal (HPA) axis to a variety of immune signals, including turpentine-induced tissue damage and the systemic injection of the pro-inflammatory cytokine interleukin 1-beta (IL-1beta). Studies that have investigated the role of this gas in the intact rat have relied on blockade of NO formation with the NO synthase (NOS) inhibitor N(omega)nitro-L-arginine-methylester (L-NAME). They have suggested that endogenous NO blunts the ACTH response to intravenous (i.v.) IL-1beta in part by exerting an inhibitory influence on the release of hypothalamic peptides such as corticotropin-releasing factor (CRF) from nerve terminals in the median eminence. It must nevertheless be noted that, at present, evidence for this mode of action remains circumstantial. Significant controversy remains regarding the specificity of the compounds used to block NO formation, the characteristics of their effect in terms of dose and timing of administration, the possibility that their effect is restricted to IL-1beta or can be expanded to other pro-inflammatory cytokines, and the question of whether the possibility that they might also influence ACTH release by altering circulating levels of tumor necrosis factor-alpha (TNF-alpha) and IL-6. The purpose of the present study was to elucidate these points. In the first series of experiments, we determined the i.v. IL-1beta-induced ACTH response to various doses of systematically injected L-NAME (1-100 mg/kg). At 10-100, but not 1 mg/kg, L-NAME significantly (P<0.01) augmented the ACTH response to IL-1beta, with a maximum effect observed at 30 and 100 mg/kg. At the 30 mg/kg dose, L-NAME was equally effective in augmenting the ACTH response when administered between 5 and 240 min prior to the cytokine. The effect of L-NAME was fully mimicked by equivalent doses of other arginine derivatives such as N(omega)-monomethyl-L-arginine (L-NMMA) or N(omega)-nitro-L-arginine (L-NNA), indicating that controversy in the published literature concerning the influence of NO on CRF secretion does not appear to be due to the use of different arginine derivatives. The ability of other cytokines such as TNF-alpha and IL-6 to release ACTH and corticosterone was significantly (P<0.01) augmented by blockade of NO formation in a manner similar to that found with IL-1beta. To test the hypothesis that L-NAME might alter ACTH secretion at least in part by modifying the secretion of pro-inflammatory cytokines, we measured plasma concentrations of TNF-alpha and IL-6 following endotoxin injection in the presence or absence of L-NAME. Blockade of NO formation reduced TNF-alpha but increased IL-6 levels in rats administered the lipopolysaccharide (25 microg/kg i.v.). As L-NAME augments the ACTH response to TNF-alpha as well as IL-6, it is improbable that changes in TNF-alpha and IL-6 secretion during immune stimulation represents an important mechanism mediating the inhibitory influence of endogenous NO on the HPA axis activity. Collectively, these results indicate that the systemic injection of L-NAME very quickly augments the stimulatory effect of pro-inflammatory cytokines on ACTH secretion, and does so for at least 4 h. Other arginine derivatives known to block the activity of constitutive NO syntheses, such as L-NMMA and L-NNA, exert an effect that is virtually identical to that of L-NAME. The ability of L-NAME to increase the ACTH response to i.v. IL-1beta is also observed in rats injected with TNF-alpha and IL-6. Because of the opposite effects of L-NAME on the levels of these two cytokines, the influence of arginine derivatives on ACTH release is probably not due to changes in cytokines produced during immune stimulation such as endotoxemia.

Adrenocorticotropic Hormone↗
PubMed2003

A case of ACTH-producing pheochromocytoma associated with pregnancy.

Ectopic ACTH syndrome is rarely caused by pheochromocytoma. We report a case of a 28-year-old woman with Cushing's syndrome due to ACTH-producing adrenal pheochromocytoma. She had delivered preterm baby at 32nd week of gestation with 'severe preeclampsia'. After delivery, persistent hypertension accompanied by severe headache led her to being misdiagnosed as Cushing's syndrome due to right adrenal adenoma (normal plasma ACTH level) and cerebral vasculitis of unknown etiology. She was referred to our hospital for surgical treatment. Repeated biochemical studies suggested coexistence of ectopic ACTH syndrome and pheochromocytoma. To reverse her clinical deterioration, right total and left subtotal adrenalectomy was performed with presumptive diagnosis of 1) right adrenal pheochromocytoma causing ectopic ACTH syndrome or 2) coexistence of ACTH-dependent Cushing's syndrome and right adrenal pheochromocytoma. Pathologic examination of right adrenal mass revealed pheochromocytoma which showed strong immunostaining for ACTH. Plasma ACTH and urinary cortisol excretion normalized after surgery, but she succumbed to multiple cerebral infarcts and disseminated intravascular coagulation. Pregnancy and inappropriately low plasma ACTH at initial evaluation might have hampered early diagnosis. To our knowledge, this is the first description of a case with ectopic ACTH syndrome due to pheochromocytoma associated with pregnancy.

ACTH Syndrome, Ectopic↗