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PubMed2002

Hypothalamus-pituitary-adrenal axis in central diabetes insipidus: ACTH and cortisol responsiveness to CRH administration.

A strong relationship has been found between arginine-vasopressin (AVP) and hypothalamus-pituitary-adrenal axis in humans. The aim of the current study was to evaluate baseline and CRH-stimulated ACTH and F levels in patients with central diabetes insipidus (CDI), before and after replacement therapy with desamino-D-AVP (DDAVP). Twenty-five patients with CDI, and 25 sex- and age- and BMI-matched healthy subjects entered the study. A standard CRH test (measurement of plasma ACTH and serum F before and every 15 min for 2 h after the administration of 100 microg of human CRH) was performed in all subjects. In patients with CDI, CRH test were repeated after 1 week of DDAVP at standard doses. At study entry, ACTH and F levels were significantly higher in patients with CDI than in controls either at baseline (ACTH: 45.5+/-4.8 vs 18.5+/-3.3 ng/l, p<0.05; F: 375.1+/-55.7 vs 146.6+/-19.4 microg/l, p<0.05) or after CRH test considered as a peak (ACTH: 90.8+/-14.4 vs 42.5+/-7.4 ng/l, p<0.05; F: 501.6+/-65.7 vs 226.3+/- 25.6 microg/l, p<0.05) and AUC (ACTH: 3997.0+/-571.7 vs 2136.0+/-365.8 ng/l/120 min, p<0.05; F: 31,489.0+/-4299.4 vs 14,854.5+/-1541.5 microg/l/120 min, p<0.05). In patients with CDI, 1 week of replacement with DDAVP brought down ACTH (peak: 56.9+/-9.3 ng/l; AUC: 2390.7+/-480.7 ng/l/120 min) and F (peak: 310.3+/-39.5 microg/l; AUC: 17,555.5+/-2008.7 microg/l/120 min) responses to CRH to normal but did not significantly modify baseline hormone levels (ACTH: 29.6+/-3.6 ng/l; F: 239.0+/-32.3 microg/l). In conclusion, CDI is associated to increased baseline ACTH and F levels and increased responsiveness of ACTH and F to CRH administration. In addition, replacement treatment with DDAVP normalized CRH-induced but not baseline ACTH and F secretion.

Adolescent↗
PubMed2003

GHRP-6 is able to stimulate cortisol and ACTH release in patients with Cushing's disease: comparison with DDAVP.

It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing's disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing's disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing's disease (8 female, 2 male; age: 36.7 +/- 4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2 microg/kg iv) and DDAVP (10 micro g i.v.) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean +/- SE; basal: 15.5 +/- 1.7 vs peak: 45.1 +/- 9.3) and cortisol values (nmol/l, basal: 583.0 +/- 90.8 vs peak: 1013.4 +/- 194.6). ACTH AUC (pmol/l min(-1)) and cortisol AUC (nmol/l min(-1)) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0 +/- 1.4 vs peak: 50.5 +/- 16.2) and cortisol levels (basal: 572.5 +/- 112.7 vs peak: 860.5 +/- 102.8. AUC values for ACTH and cortisol were 1627.6 +/- 639.8 and 18364.7 +/- 5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1 +/- 9.3 vs 50.5 +/- 16.2; AUC: 1235.4 +/- 424.8 vs 1627.6 +/- 639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r = 0.87, p = 0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing's disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.

Adolescent↗
PubMed2005

ACTH enhancement of T-lymphocyte cytotoxic responses.

1. Corticotropin (ACTH) was one of the first neuropeptides shown to bind to receptors on leukocytes and modulate immune responses. Generally ACTH inhibits immune responses, but certain functions can be enhanced. The present study was performed to determine the effects of ACTH on cytotoxic T-lymphocyte responses, the components, and the major phenotypes of the participating cells. 2. The action of ACTH on cytotoxicity was measured in vitro, in assays utilizing T-lymphocytes that had been previously sensitized in vivo. The cells were then cultured with ACTH and target cells bearing the appropriate stimulatory major histocompatiblity antigens. 3. ACTH did not significantly affect a primary mixed lymphocyte reaction whereas it enhanced a secondary (memory) cytotoxic response up to 100% following 2 days of ACTH treatment. The effect was a shift in the kinetics of effector cell generation so that ACTH-treated cultures demonstrated an augmented cytotoxic activity on day 2, that was not as pronounced on day 3 as cytotoxic activity in control cultures became maximal. ACTH also inhibited Concanavalin A-stimulated T-lymphocyte mitogenesis. Immature thymocyte mitogenesis was inhibited more than that of mature thymocytes. 4. The finding that IFN-gamma was elevated in the cultures suggested that ACTH may enhance memory cytotoxic responses through a combination of mechanisms such as direct cell alterations or synergy with regulatory cytokines. While corticosteroids are probably the most recognized neuroendocrine, stress hormone to affect immune functions, our study illustrates that other neuroendocrine factors such as ACTH, also directly affect immune functions.

Adrenocorticotropic Hormone↗
PubMed1986

Dopaminergic modulation of ACTH-induced grooming.

ACTH-(1-24)-induced grooming was studied after administration of the peptide into the substantia nigra or intracerebroventricularly (i.c.v.). The modulation of dopamine receptors in neostriatum (with haloperidol and apomorphine) and nucleus accumbens (with 3,4-dihydroxyphenylamino-2-imidazoline hydrochloride; DPI and ergometrine) was investigated. In the nucleus accumbens, the modulatory effects of ergometrine and DPI on ACTH-(1-24)-induced grooming were based on their affinity for dopamine receptors and not on their affinity for adrenoceptors. Intrastriatal application of dopaminergic agents inhibited i.c.v. ACTH-(1-24)-induced excessive grooming, whereas the grooming score was enhanced if ACTH-(1-24) was administered into the substantia nigra. The finding of differential effects of dopaminergic agents on ACTH-induced excessive grooming depending on the route of administration indicate that i.c.v. ACTH-induced excessive grooming is not mediated solely through the substantia nigra. The increase in grooming behavior seen after the intrastriatal administration of dopaminergic agents - when ACTH was injected into the substantia nigra - suggests the involvement of the striato-nigral GABAergic pathway. Local injections of ACTH-(1-24) into the periaqueductal gray also induced excessive grooming. Since a second injection of ACTH-(1-24) into the periaqueductal gray did not lead to a grooming response, irrespective of where the first injection of ACTH-(1-24) was given (i.c.v. into the nigra or via the periaqueductal gray) it is suggested that this structure seems to play a primary role in the induction of excessive grooming. Therefore the modulatory effects of the dopaminergic influence on ACTH-(1-24)-induced grooming may be exerted via the striato-nigro-collicular pathway.

Adrenocorticotropic Hormone↗
PubMed1987

ACTH regulation of cholesterol movement in isolated adrenal cells.

Confluent bovine adrenal cell primary cultures respond to stimulation by adrenocorticotropin (ACTH) to produce steroids (initially predominantly cortisol and corticosterone) at about one-tenth of the output of similarly stimulated rat adrenal cells. The early events of steroidogenesis, following ACTH stimulation, have been investigated in primary cultures of bovine adrenal cortical cells. Steroidogenesis was elevated 4-6-fold within 5 min of exposure to 10(-7) M ACTH and increased linearly for 12 h and declined thereafter. Cholesterol side-chain cleavage (SCC) activity was increased 2.5-fold in mitochondria isolated from cells exposed for 2 h to ACTH and 0.5 mM aminoglutethimide (AMG), even though cytochrome P-450scc only increases after 12 h. Mitochondrial-free cholesterol levels increased during the same time period (16.5-25 micrograms/mg of protein), but then both cholesterol levels and SCC activity declined in parallel. More prolonged exposure to ACTH prior to addition of AMG caused the elevation in mitochondrial cholesterol to more than double, possibly due to enhanced binding capacity. Early ACTH-induced effects on cellular steroidogenesis result from these changes in mitochondrial-free cholesterol. The maximum rate of cholesterol transport to mitochondria in AMG-blocked cells was consistent with the maximum rate of cellular steroidogenesis. Cycloheximide (0.2 mM) rapidly blocked (less than 10 min) cellular steroidogenesis, cholesterol SCC activity, and access of cholesterol to cytochrome P-450scc without affecting mitochondrial-free cholesterol. Exposure of confluent cultures to the potent environmental toxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (10(-8) M), for 24 h prior to ACTH addition decreased the rates of ACTH- and cAMP-stimulated steroidogenesis but did not affect the basal rate. In both cases, the effectiveness of TCDD increased with time of exposure to the stimulant. Although cholesterol accumulated in the presence of ACTH and AMG (13-28 micrograms/mg), pretreatment of cells with TCDD caused a decrease in mitochondrial cholesterol (13-8 micrograms/mg). The effect of TCDD was produced relatively rapidly (t1/2 approximately 4 h). Since even in the absence of TCDD, the mitochondria of ACTH-stimulated cells also eventually lose cholesterol (after 2 h) TCDD pretreatment may increase the presence of a protein(s) that cause this mitochondrial-cholesterol depletion following stimulation by ACTH or cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗
PubMed1989

Microtubules, organelle transport, and steroidogenesis in cultured adrenocortical tumor cells. 1. An ultrastructural analysis of cells in which basal and ACTH-induced steroidogenesis was inhibited by taxol.

In adrenocortical cells, the first step in the enzymatic processing of cholesterol to steroid end products occurs in the mitochondria. ACTH increases mitochondrial cholesterol and steroidogenesis. In cultured mouse adrenocortical tumor cells, microtubule-based organelle motility may increase the proximity of mitochondria to the SER, lipid droplets and endoscome-derived lysosomes, thereby facilitating the transfer of cholesterol from these organelles to the mitochondrial outer membrane. ACTH may increase opportunities for the transfer by promoting organelle motility and by increasing the number of lysosomes. Taxol, a microtubule polymerizer, inhibits basal and ACTH-induced steroidogenesis in these cells, presumably at the step where mitochondria obtain cholesterol. We examined the ultrastructure of taxol-treated, unstimulated and ACTH-stimulated cells, seeking alterations which conceivably could interefer with the proposed organelle transport and encounters, and thus correlate with taxol's inhibition of steroidogenesis. Primary cultured cells were incubated in serum-containing medium for 4 hr with and without ACTH (10 mU/ml), with 10 micrograms/ml and 50 micrograms/ml of taxol, and with ACTH and taxol 10 or taxol 50 simultaneously. Culture media were analyzed for the presence of secreted steroids at the end of 1, 2, and 4 hr of incubation. At the end of the fourth hour, unstimulated cells and cells treated with ACTH, taxol 50, and both agents simultaneously, were fixed and processed for EM. Taxol inhibited basal and ACTH-induced steroidogenesis in a dose-dependent fashion. In both unstimulated and ACTH-stimulated cells, taxol 50 formed numerous microtubule bundles, but did not markedly change the distribution of mitochondria and lipid droplets. SER tubules, and clusters of Golgi fragments, endosomes, and lysosomes appeared to be translocated towards the cell periphery along some of the microtubules. Taxol permitted an ACTH-induced cell rounding and microfilament rearrangement considered to facilitate organelle motility. Our data indicate that taxol disrupts the formation of lysosomes by these adrenal cells, but it seemed unlikely that taxol's ultrastructural effects could prevent organelle transport proposed to cause meetings between mitochondria and the SER or lipid droplets, or prevent ACTH-caused increases in these encounters. Taxol may instead prevent the transfer of lipid droplet or SER-contained cholesterol to adjacent mitochondria, by a means not detectable in our electron micrographs.

Adrenal Cortex Hormones↗
PubMed1989

ACTH modulation of nerve development and regeneration.

(1) The availability of short amino acid sequences of the naturally occurring ACTH 1-39 molecule has made it possible to separate the corticotropic characteristics of the parent molecule from its neurotrophic effects. Potent neurotrophic fragments are ACTH 4-10, an analog of ACTH 4-9 (Org 2766), and alpha-MSH (ACTH 1-13), peptide fragments that do not evoke corticosteroid secretion, yet clearly affect both the development and regeneration of peripheral nerve. (2) Early postnatal administration of either ACTH 4-10 or Org 2766 accelerates the neuromuscular development of the immature rat, increasing the contractile strength of the EDL muscle and inducing more rapid muscle contractions. Grasping strength and motor activity are increased; these are all changes indicative of more rapid neuromuscular maturation. Prenatal peptide treatment elicits a more complex pattern of response since administration early in gestation (GD 3-12) accelerates neuromuscular development whereas later administration (GD 13-21) decelerates maturation. (3) ACTH peptides have a similar accelerating effect on the morphology of the developing neuromuscular junction. At two weeks of age, nerve arborization is conspicuously increased by postnatal administration of either ACTH 4-10 or Org 2766, as is nerve terminal branching within the endplate itself. However, this is preceded by an initial depression of nerve branching in the 7-day-old rat pup. We conclude that while the developing neuromuscular system is sensitive to ACTH peptides, this susceptibility is age-related. The crucial role of these peptides may be limited to very brief, defined periods during which the peptides may interact with trophic or growth-associated substances, each of which may have its own decisive, circumscribed time frame of influence. (4) Perinatal administration of ACTH peptides affects CNS development. One measurable indication of this is an acceleration of eye opening. Early exposure to ACTH peptides has long-lasting effects on behavior, apparent when these animals are tested as adults. Increased spontaneous motor activity, heightened states of arousal and agitation, and changes in social behavior have been reported. Certain avoidance responses and tests of visual discrimination in male rats are improved by neonatal treatment with alpha-MSH. Overall motor activity is increased and the normal period of hyperactivity is initiated earlier. Male sexual behavior is decreased and sexually dimorphic behaviors in males are eliminated. alpha-MSH may alter the development of its own dopaminergic feedback circuitry while ACTH affects serotonin levels in the preoptic nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed2004

ACTH enhances chondrogenesis in multipotential progenitor cells and matrix production in chondrocytes.

The association of melanocortin peptide overproduction with enhanced linear growth prompted the current investigation of adrenocorticotropin hormone (ACTH) effects on multipotential chondroprogenitor populations and committed chondrocytes in culture. Two multipotential progenitor populations, rat bone marrow stromal cells (BMSC) and the clonal multipotential cell line RCJ3.1, and two committed chondrocyte populations, resting chondrocytes (RC) isolated from the rib of young rats and the chondrocyte restricted cell line RCJ3.1C5.18 (C5.18), were cultured in differentiation medium plus or minus ACTH. Alcian blue stain was used to quantitate proteoglycan matrix production in all populations treated with a range of ACTH concentrations. Changes in proliferation due to ACTH treatment of all cell types were measured using 3H-thymidine incorporation. Differences in matrix production of ACTH-treated and -untreated RC and C5.18 cells were determined using 3H-proline incorporation. Relative transcript expression of the chondrocyte matrix proteins collagen type II (COLL II) and aggrecan (AGR) in treated and untreated cells was analyzed by Northern blot. Collagen type X (COLL X), a marker of hypertrophic differentiation, was measured in committed chondrocytic populations. Western analysis was used to detect the melanocortin-3 receptor (MC3-R), which was a suspected mediator of the ACTH signal. Matrix deposition was dose-dependently increased by ACTH in all cell populations as measured by alcian blue stain. ACTH treatment increased proliferation in multipotential progenitor populations (BMSC and RCJ3.1) while proliferation was decreased in committed chondrocyte populations (RC and C5.18). Total protein and total cell-associated collagen production were significantly increased by ACTH treatment in committed populations. Relative COLL II and AGR transcript expressions were significantly increased in both the RC- and C5.18-committed population and very significantly increased in the progenitor populations. Additionally, collagen type X expression was detected earlier and in greater abundance in ACTH-treated committed chondrocyte populations. Finally, the melanocortin-3 receptor was detected in all examined cell types by Western blot. These data show that ACTH promotes the development of the chondrocyte phenotype from multipotential mesenchymal progenitor populations and increases matrix production and differentiation of committed chondrocytes. These findings, together with the detection of the MC3-R in all of these cell types, indicate a role for the melanocortin system in chondrogenesis.

Adrenocorticotropic Hormone↗
PubMed2006

Adrenal cortical responses to low- and high-dose ACTH(1-24) administration in major depressives vs. matched controls.

Increased hypothalamo-pituitary-adrenocortical (HPA) axis activity occurs in 30-50% of patients with major depression. This includes normal-to-increased adrenal cortical hormone (cortisol) secretion in spite of reduced corticotropin (ACTH) stimulation. A possible explanation is increased adrenal responsiveness to ACTH. Supporting this possibility is the finding of increased adrenal volume, which reverts to normal with successful treatment. Eight female and six male patients with major depression, and eight female and six male individually matched controls, underwent two test sessions 5-7 days apart. On the first day, a low ACTH(1-24) dose (0.014 microg/kg i.v.), equivalent to 1 microg in a 70-kg individual, was given. On the second day, a supramaximal stimulating dose (250 microg i.v.) was given. Serial blood samples were analyzed for immunoreactive (IR-)ACTH, ACTH(1-39), and cortisol. There were no significant sex or patient-control differences in IR-ACTH areas under the curve (AUCs) following low-dose ACTH(1-24), and the correlation between patient and matched control AUCs was +0.71, indicating good correspondence in the amount of circulating ACTH(1-24) available for adrenal stimulation. There were no significant sex or patient-control differences in cortisol response and no significant interaction between dose and subject group, indicating that patients did not differ from controls in their cortisol responses to either low- or high-dose ACTH(1-24). These findings do not indicate increased adrenal cortical responsiveness in patients with major depression. Neurochemical/neurohormonal and neural stimulatory factors other than ACTH might be responsible for the increased adrenal gland size and cortisol secretion, in spite of reduced pituitary ACTH secretion, that has been reported in this illness.

Adrenal Glands↗
PubMed1998

Serotonergic involvement in stress-induced ACTH release.

We investigated the involvement of serotonin (5-HT) and 5-HT receptors in mediation of stress-induced ACTH secretion in adult male rats, which were pretreated by 5-HT antagonists before restraint-, ether-, cold swim-stress or endotoxin. All stressors potently increased plasma ACTH. Lesion of 5-HT neurons with 5, 7-dihydroxytryptamine injected intracerebroventricularly, into the paraventricular nucleus or into the raphe nuclei, inhibited the restraint stress-induced ACTH response by 50%. Restraint increased the content of 5-HT and its metabolite 5-hydroxyindole acetic acid, in the raphe nuclei, whereas the other stressors had no such effect. Pretreatment with the 5-HT1A receptor antagonist WAY 100635 inhibited the restraint stress- and endotoxin-induced ACTH secretion by 50%. The 5-HT1+2 antagonist methysergide or the 5-HT2 antagonist ketanserin inhibited the restraint- or ether stress-induced ACTH response, and eliminated the endotoxin-induced ACTH response. The 5-HT2 receptor antagonist LY 53857 blocked only the endotoxin-induced ACTH response. Pretreatment with the 5-HT3 receptor antagonist ondansetrone had no effect on stress-stimulated ACTH secretion. The 5-HT3+4 receptor antagonist tropisetrone inhibited the restraint- and ether stress-induced response. The ACTH response to swim stress was not affected by any of the antagonists used. It is concluded that the 5-HT1A, the 5-HT2A and the 5-HT2C receptor, but not the 5-HT3 receptor are involved in the stress-induced ACTH secretion. An involvement of the 5-HT4 receptor is possible. Furthermore, that serotonergic neurons in the raphe nuclei are activated during restraint stress, and that these neurons and neurons in PVN of the hypothalamus, are important for the mediation of the restraint stress-induced ACTH response.

Adrenocorticotropic Hormone↗
PubMed1998

Large and invasive silent corticotroph-cell adenoma with elevated serum ACTH: a case report.

BACKGROUND: A silent corticotroph-cell adenoma (SCCA) is defined as evidence of immunoreactive ACTH in tumor cells of a pituitary adenoma that is not associated with symptoms of Cushing's disease. Most previous reports have discussed the etiology of this unique entity; however, the precise mechanisms of its "silence" are not clear yet. We discuss the pitfalls of endocrinological diagnosis and surgical management of SCCA. METHODS: A 63-year-old man, without the symptoms of Cushing's disease, demonstrated elevated serum levels of ACTH, but normal levels of cortisol. ACTH was measured by newly developed immunoradiometric assays (RMA), which are more specific for biologically active ACTH than conventional radioimmunoassay (RIA). The tumor was more than 3 cm in diameter and invaded both the cavernous sinus and the sphenoid sinus. RESULTS: Two different types of IRMAs revealed elevated serum ACTH levels. The tumor was removed successfully by staged operations. The high levels of serum ACTH were normalized after the second operation. CONCLUSION: The cause of the silence of SCCA is not clear yet. The elevated serum ACTH levels in the present case were not attributable to "Big ACTH." We suggest one possibility: the cause of the silence might be a minor variant of ACTH, detected by IRMA, leading to less biological activity of ACTH. This type of adenoma is invasive in nature and can potentially grow large because it is free of endocrinological symptoms. We emphasize the appropriate surgical strategy to normalize the serum levels of ACTH in case of SCCA.

Adenoma↗
PubMed2000

Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD).

Although in utero maternal stress has been shown to have lasting effects on rodent offspring, fetal effects of chemically-induced alterations of the maternal hypothalamic-pituitary-adrenal axis (HPA) have not been well studied. This study examined the effects of in vivo 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on pituitary-adrenal function in the male rat, pregnant female rat and pregnant female mouse. The secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) in pituitary and adrenal glands, respectively, was assessed in ex vivo perifusion cultures. Male and pregnant female (gestation day 8) Sprague-Dawley rats were gavaged once with 10 microgram/kg TCDD, pregnant female mice once with 24 microgram/kg TCDD, and euthanized 10 days later. Hemi-pituitary (rat) or whole anterior pituitaries (mice) and right adrenal glands from the same animal were quartered, perifused under baseline and stimulated conditions. In both males and pregnant females, TCDD did not affect corticotropin releasing hormone (CRH)-stimulated ACTH secretion. Neither total pituitary ACTH nor plasma ACTH was altered in either sex or species by TCDD treatment. ACTH-stimulated CORT secretion was not affected by TCDD in either sex or species, and adrenal tissue and plasma CORT levels were unchanged in males and pregnant females by TCDD. However, the plasma ACTH:CORT ratio was decreased about 46% in male rats treated with TCDD. Plasma CORT levels were 23-fold higher and plasma ACTH levels were 1.5-fold higher in pregnant females than in male rats. In male versus female rats, adrenal CORT and anterior pituitary ACTH tissue levels were about 7.5- and 1.75-fold higher and ACTH, respectively. Female mouse adrenal tissue CORT was about 4-fold greater than female rat. The reduced plasma ACTH:CORT ratio in the male rat suggests that TCDD disturbs HPA function. Exposure of male rat to a 5-fold higher dose in earlier studies clearly demonstrated effects of TCDD on male rat HPA. The present study identified substantial HPA performance differences between male and pregnant female rats. The failure to detect a response to TCDD in pregnant female rat and mouse could be a function of both TCDD dose and the high level of secretion of both ACTH and CORT in pregnant animals. For the rat or mouse, a single exposure to TCDD during pregnancy does not appear sufficient to induce maternally-mediated developmental, reproductive and behavioral toxicity via the HPA axis.

Adrenal Glands↗
PubMed1982

Circulating ACTH and related peptides in lung cancer.

The prevalence of high levels of circulating ACTH-like immunoactivity was determined in 134 patients with lung cancer, using reference ranges from 52 age- and sex-matched patients with non-malignant lung disease. Two studies used ACTH radioimmunoassays with different specificities. Study A used an unextracted plasma or serum assay for total ACTH immunoactivity. High serum ACTH levels occurred in 24% of patients with small-cell carcinoma and 3% of patients with non-small-cell cancer. In patients with small-cell carcinoma, levels were high in 12% with limited disease and 32% with extensive disease. Study B used an ACTH assay after plasma extraction by porous glass, which measured mainly regular 1-39 ACTH. Here no lung-cancer patient had levels above the reference range, suggesting that the high levels in Study A may be due to plasma ACTH components which are poorly extracted by porous glass. It is concluded that high circulating ACTH immunoactivity occurs in a minority of patients with lung cancer, particularly those with extensive small-cell carcinoma. Indirect evidence suggests that the high ACTH levels detected with assays for total ACTH are due to molecular forms other than 1-39 ACTH, probably high-mol.-wt species.

Adrenocorticotropic Hormone↗
PubMed1997

Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche.

OBJECTIVE: The mechanism of adrenarche is controversial, and there have been competing claims that its origin is in the hypothalamo-pituitary axis or in the adrenal gland itself. ACTH is proposed inducer of adrenarche so patients with ACTH resistance due to be familial glucocorticoid deficiency syndrome provide a model to clarify the degree to which ACTH is involved in the regulation of adrenal androgen secretion during adrenarche. DESIGN: Random analysis of plasma adrenal androgens and urinary adrenal androgen output in treated patients with familial glucocorticoid deficiency. PATIENTS: Eleven patients (6 males and 5 females, aged 6.5-21.6 years, 4 prepubertal, minimum bone age 9 years) with familial glucocorticoid deficiency were studied. In 6, mutations, in the coding region of the ACTH receptor are the cause of their ACTH resistance. In the remaining 5 the receptor was normal. MEASUREMENTS: Physical examination, basal serum cortisol, basal plasma ACTH, serum cortisol after stimulation with 250 micrograms ACTH(1-24), plasma dehydroepiandrosterone-sulphate (DHEAS) and plasma androstenedione (A4), total urinary androgen excretion and single-stranded sequencing of the coding region of the ACTH receptor. RESULTS: DHEAS was undetectable in 8, and detectable but below the age-matched reference values in 3 patients. A4 was measured in 10 patients, and in 3 patients (2 in late puberty) was found to be subnormal whereas in the remaining 7 patients A4 was normal for age and pubertal stage consistent with the gonadal contribution to peripheral A4 levels. Significantly diminished output of urinary adrenal androgen metabolites in 3 patients confirmed the results found in serum. The lack of adrenarche was independent of the presence of a mutation within the ACTH receptor and of the severity of glucocorticoid deficiency. Despite adequate glucocorticoid replacement therapy ACTH levels remained elevated in 10 of the 11 patients. CONCLUSIONS: Although reduced adrenocortical inner zone cell number may contribute to the lack of adrenarche, in some patients there appears to be a discrepancy between partial glucocorticoid deficiency and significantly diminished adrenal androgen secretion. These data imply a significant contribution of ACTH to the regulation of adrenarche in normal children either by having a priming effect on the adrenal gland or by acting in concert with other adrenal androgen stimulating factors.

Adolescent↗
PubMed1998

Pulsatile secretion of ACTH and cortisol in premenopausal women: effect of obesity and body fat distribution.

OBJECTIVE: There is emerging evidence that women with visceral obesity may have hyper-responsiveness of the hypothalamic-pituitary-adrenal axis. There are no studies on basal daily secretory pattern of ACTH and cortisol in subjects with different obesity phenotypes. DESIGN AND PATIENTS: In this study we examined daytime pulsatile secretion of ACTH and cortisol in two groups of premenopausal obese women with visceral (V-BFD) (BMI 37.1 +/- 1.7) and subcutaneous (S-BFD) (BMI 38.8 +/- 1.5) body fat distribution (measured by CT scan) and in a group of normal weight healthy controls (BMI 21.1 +/- 0.5). After an overnight fast, blood samples were taken at 15-minute intervals for 12 h (49 samples, from 0800 h until 2000 h). All women avoided breakfast but had a normal lunch and dinner, both containing similar food, energy and nutrient composition. ACTH and cortisol responses to mixed meals at noon and in the evening were also investigated. RESULTS: Mean values of ACTH and cortisol did not differ between the groups. However, ACTH pulse frequency was significantly higher in V-BFD (P < 0.06) and S-BFD (P < 0.02) obese women than in controls, without any significant differences between the two obese subgroups. Mean ACTH pulse amplitude was lower in the V-BFD than in S-BFD obese (P < 0.02) and control (P < 0.05) groups. Cortisol episodic characteristics did not differ between V-BFD and S-BFD obese and controls. All differences in ACTH pulsatile parameters between obese and controls and between the two obese subgroups were evident only in the morning, with no further significant differences during the early and late afternoon. There were no significant differences in cortisol parameters during the three periods of the day between the various groups, apart from late afternoon cortisol pulse frequencies, which were significantly lower in V-BFD than in controls. After lunch, ACTH and cortisol levels significantly increased in all groups, but the cortisol increase tended to be more rapid in V-BFD than in the other two groups. After dinner, ACTH significantly increased in V-BFD and controls but not in the S-BFD group, whereas cortisol rose significantly in all groups, but significantly less in S-BFD than in V-BFD and controls. CortisolAUC (but not ACTHAUC) after lunch was significantly higher than after dinner in all groups. ACTH response after each meal was similar in all groups, but cortisolAUC after dinner was significantly lower in S-BFD than in V-BFD women. CONCLUSION: This study demonstrates that in premenopausal women, obesity, particularly the visceral phenotype, is associated with several abnormalities of ACTH pulsatile secretion, particularly in the morning. On the contrary, no major differences were present in either blood concentrations, diurnal rhythm or secretory pattern of cortisol between obese and controls. The responses to meals seem to indicate a much more rapid cortisol response after lunch in women with visceral obesity and a reduced activation of the hypothalamic-pituitary-adrenal axis after dinner in women with subcutaneous obesity.

Adrenocorticotropic Hormone↗
PubMed2000

Disrupted cortisol-ACTH relationships in elderly women given corticotrophin-releasing hormone two weeks after proximal femur fracture.

OBJECTIVE: In elderly women with hip fractures plasma cortisol is persistently higher than in healthy elderly women, possibly causing undesirable catabolic effects. A lack of corresponding changes in plasma ACTH or in the cortisol response to exogenous ACTH has prompted us to study cortisol-ACTH relationships after giving corticotrophin-releasing hormone (CRH) to such subjects. SUBJECTS: Seventeen women aged 70-90 years who had sustained a hip fracture about two weeks previously were compared with 19 healthy women aged 68-85 years. MEASUREMENTS: 100 microg CRH was injected into each subject and ACTH and cortisol concentrations were measured at intervals for 90 minutes beforehand and 180 minutes afterwards. The concentrations of vasopressin and various cytokines and related peptides were also measured during the baseline period. RESULTS: Under baseline conditions plasma cortisol was higher and plasma ACTH lower in the injured patients than in the healthy subjects. The patients showed smaller incremental ACTH and cortisol responses to CRF but because of the higher baseline value the peak cortisol concentration was enhanced. A strong correlation between the cortisol and ACTH responses in the healthy subjects was completely lost in the patients and the slope of the ACTH-cortisol dose-response relationship varied greatly between individuals, with no overall increase. The concentrations of vasopressin, interleukin-1 receptor antagonist and soluble tumour necrosis factor receptors were higher in the patients but did not correlate with the responses to CRH. CONCLUSIONS: The results are not consistent with increased sensitivity to ACTH and suggest an independent stimulus to the adrenals of hip-fracture patients. Its identity is unknown as the non-ACTH stimuli proposed hitherto are reported to enhance sensitivity to ACTH.

Adrenocorticotropic Hormone↗
PubMed2005

Intranasal administration of ACTH(1-24) stimulates catecholamine secretion.

Previously, we reported that intranasal (IN) ACTH(1-24) administration stimulates adrenocortical steroid secretion in normal subjects. To determine the efficiency of transmucosal absorption of ACTH into the adrenal medulla, we measured serum cortisol, aldosterone, epinephrine, norepinephrine and dopamine levels after IN vs. intravenous (IV) administration of 250 microg ACTH(1-24) in 7 healthy adult men (mean age 21.7 +/- 1.2 yr; range, 21 - 24 yr). Blood was collected at 0, 30, 60 and 120 min after administration of ACTH(1-24), and the levels of adrenocortical steroids and catecholamines were measured by specific RIA and HPLC methods, respectively. There were no side effects associated with IN or IV ACTH administration. Consistent with the previous study, serum cortisol and aldosterone increased after IN administration of ACTH(1-24), peaking 30 min after administration. Sixty minutes after IN and IV administration of ACTH, epinephrine levels increased by 41.9 +/- 13.1 % and 63.3 +/- 11.8 %, respectively, and remained elevated throughout the sampling period. Thirty minutes after IN or IV administration of ACTH(1-24), plasma norepinephrine levels increased by 55.9 +/- 13.4 % and 73.7 +/- 15.0 %, respectively, peaking 30 min after ACTH(1-24) administration, and decreasing to basal levels within 60 min. Plasma dopamine levels did not change after IN administration of ACTH(1-24). Adrenocortical steroid and catecholamine levels did not increase after IN administration of saline. These results demonstrate that IN administration of ACTH(1-24) not only stimulates adrenocortical steroids, but also epinephrine and norepinephrine.

Administration, Intranasal↗
PubMed1991

Differential ACTH response of immunodetectable HMG CoA reductase and cytochromes P450(17 alpha) and P450(21) in guinea pig adrenal outer zone cell types, zona glomerulosa and zona fasciculata.

In the guinea pig adrenal the cells of the outer zone secrete high levels of steroid and respond to ACTH with increased synthesis of cholesterol and steroid. The outer zone consists of two cell types: zona fasciculata (ZF) and zona glomerulosa (ZG). To determine the relative contribution of ZF and ZG to the outer zone's ACTH response, purified populations of each cell type were prepared from ACTH-treated and control animals. Levels of proteins potentially involved in the ACTH response were measured by ELISA. HMG CoA reductase, the rate limiting enzyme of cholesterol synthesis, and two cytochrome P450s, P450(17 alpha) and P450(21), were studied. P450(17 alpha) is required for production of cortisol, but not for corticosterone or aldosterone. P450(21) is required for production of all of these corticosteroids. ZF cells had 4-5 fold greater concentration of all three proteins, but the proteins in ZG cells showed a greater response to ACTH (approximately 3 fold). The response of ZG cells to ACTH and their possession of P450(17 alpha) is consistent with observations made in vitro that ZG cell populations synthesize cortisol and respond to ACTH with increased output of cortisol as well as of corticosterone and aldosterone. In ZG cells to a greater extent than ZF cells, the response to ACTH involved increases in levels of enzymes of both cholesterol and steroid synthesis, suggesting that new protein synthesis is an important component of their ACTH response. On the other hand, the fact that ZF cells can increase steroid output in response to ACTH with a lesser increase in these proteins suggests a different mechanism of regulation. Mobilization of stored cholesterol may be more important in the ACTH-responsiveness of the lipid-filled ZF cells than in the lipid-poor ZG cells.

Adrenal Cortex↗