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PubMed1977

High molecular weight forms of human ACTH are glycoproteins.

The RIA-ACTH in a normal human pituitary, 2 ectopic ACTH-secreting tumors and plasma from a patient with Nelson's syndrome and one with ectopic ACTH syndrome was divided into 3 molecular weight classes after gel exclusion chromatography. The largest component appeared in or near the void volume and was designated "big" RIA-ACTH. The second, designated "intermediate" RIA-ACTH, eluted between the void volume and standard human 1-39 ACTH (mol. wt. 4,541). An immunoreactive material designated "little" ACTH-coeluted with standard human ACTH. A significant fraction (29-61%) of "big" RIA-ACTH from the tumors bound to concanavalin A-agarose and was eluted with 0.2 M alpha-methyl-D-mannopyranoside. An additional 16-22% of "big" RIA-ACTH was more tightly bound to the concanavalin A, but could be purged from the column with 0.1 M acetic acid. A smaller total percent of "big" RIA-ACTH from the pituitary (20%) and plasmas (5-10%) bound to the lectin and was similarly eluted and purged. Relatively little (less than 8%) of "intermediate" RIA-ACTH from all sources bound to concanavalin A, with the exception of that in the pitull sources was essentially excluded (greater than 93%) from the column. These data indicate that a significant fraction of human "big" RIA-ACTH is a glycoprotein and that human "intermediate" RIA-ACTH may be also.

Adenoma, Islet Cell↗
PubMed1978

Cyproteroneacetate and ACTH adrenal function.

Cyproteroneacetate, an antiandrogenic and gonadotropin-inhibiting steroid, has a marked ACTH suppressive effect. In rats, adrenal atrophy and severe impairment of ACTH and corticosterone responses to stress are induced by a 10-day treatment with 3-0.75 mg/100 g BW cyproteroneacetate/day. Two weeks after cessation of treatment, the ACTH adrenal system has not yet recovered. The ACTH suppression is evident 6 h after a single dose. In 25 human volunteers, a single dose of 200 mg cyproteroneacetate impaired their ACTH and 11-deoxycorticosteroid response to 1 g metyrapone. A similar impairment was seen in 12 women on sequential treatment with cyproteroneacetate and ethinyl estradiol. In 4 out of 11 children treated for precocious puberty, random plasma ACTH and cortisol measurements, cortisol responses to ACTH, and ACTH and cortisol responses to insulin-induced hypoglycemia revealed severely impaired ACTH adrenal function. Questionable impairment was found in 2 out of 11 and normal function in 5 out of 11 children. In 10 patients with endogenous elevated plasma ACTH, 10 days of treatment with cyproteroneacetate, in addition to the steroid substitution, diminished the morning plasma ACTH levels. It is concluded that cyproteroneactate has a pronounced ACTH-suppressive effect. The individual susceptibility of treated patients varies and the effect is dose dependent. A cortisol-like effect must be assumed, because cyproteroneacetate-treated animals and patients under therapy can withstand stress situations without signs of adrenal insufficiency. ACTH adrenal function must, however, be closely watched in treated patients and steroid cover must be considered in conditions of stress. Great care has to be taken when the drug, with its own "stress-protective" effect, is withdrawn. The recovery of ACTH adrenal function may take several months.

Adrenal Cortex↗
PubMed1995

Effects of cocaine and corticotropin-releasing factor on pulsatile ACTH and cortisol release in ovariectomized rhesus monkeys.

Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood samples were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak amplitude, percentage increase in peak amplitude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse amplitude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH response to CRF challenge suggests that the CRF sensitivity and the ACTH release capacity of the anterior pituitary corticotroph cells were intact. The lack of stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal axis in OVX monkeys, in contrast to normal male monkeys, may reflect the absence of gonadal steroids.

Adrenocorticotropic Hormone↗
PubMed1995

Adrenocorticotropic hormone (ACTH) increases the expression of its own receptor gene.

Regulation of the ACTH receptor (R) in the adrenal gland by its own ligand "ACTH" has been a matter of controversy. In the present study, whether ACTH regulates the expression of mRNA for its own receptor in the adrenal gland was studied in human subjects and in rats in vivo. In the human study, adrenal adenoma tissues as well as adjacent normal tissues were obtained at surgery from two patients with typical Cushing's syndrome. Northern blot analysis revealed two ACTH-R mRNA species with 4.0 kb and 2.0 kb. ACTH-R mRNAs in the adenoma tissues were much more abundant than those in the normal tissues from the two patients, suggesting that the mRNA in normal adrenal tissue is either suppressed by cortisol excess or the absence of ACTH. To examine the mechanism involved in ACTH-R mRNA regulation, the changes in the receptor mRNA caused by ACTH were studied in dexamethasone-treated rats. Administration of dexamethasone for 5 days resulted in a marked decrease in ACTH-R mRNA to an undetectable level. A bolus administration of ACTH1-24 intravenously or ACTH-Z1-24 intramuscularly to the dexamethasone-treated rat did not cause any significant change in ACTH-R mRNA from 0.5 to 12 h after the administration. However, a significant increase in the receptor mRNA was observed at 24 h after the ACTH-Z1-24 and the level was further increased until 48 h followed by a sustained increase at 72 h when it was given once every 24 h. These data suggest that the ACTH-receptor is increased by ACTH at a pretranslational level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1999

On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis.

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

Adrenocorticotropic Hormone↗
PubMed1993

The effect of cortisol on the secretion of ACTH by anterior pituitary cells of the horse in culture.

Perifused equine anterior pituitary cells were used to investigate the effect of cortisol on the ACTH response to pulses of corticotrophin-releasing hormone (CRH; 0.01 nmol/l) and arginine vasopressin (AVP; 100 nmol/l), given for 5 min every 30 min for 690 min and ACTH measured in 5-min fractions. At the fourth pulse of secretagogue (0 min), a constant perifusion with cortisol began (0 nmol/l (control), 100, 200, 500, 5000 and 50,000 nmol/l) and continued until the ninth pulse (150 min). For each pulse of secretagogue, the amount of ACTH (pmol) secreted in response to each pulse (ACTH response area), the highest concentration of ACTH (microgram/l) measured after each pulse (peak height) and the mean ACTH in the three prepulse fractions (ACTH baseline) were determined. Data from control columns in each experiment were fitted by least squares to an exponential function to produce a mean control value for each end-point; results in all columns were expressed as a percentage of the mean control values. The addition of cortisol had a highly significant negative effect on ACTH response area, peak height and baseline at all times from +30 to +240 min (columns given cortisol compared with the mean of control column values by t-test). Analysis of variance of the data showed that the higher the cortisol concentration, the quicker the ACTH response area (P = 0.0072) and peak height (P = 0.002) decreased to < 50% of mean control, and the greater the maximum percentage change (suppression) in ACTH response area (P < 0.0001) and peak height (P < 0.0001). The maximum percentage change (suppression) in baseline was independent of cortisol concentration. At +30 min after the start of cortisol perifusion, the ACTH response area in CRH columns was significantly lower than in AVP columns (P = 0.0088), and remained lower 90 min after the end of perifusion (P = 0.0084) but the maximum percentage change (suppression) was not different between secretagogues. ACTH peak height was significantly (P < 0.0268) lower in CRH than in AVP columns (from +30 min until 180 min after the end of cortisol perifusion) and the maximum percentage change (suppression) was also greater (P = 0.0011) in CRH columns. This study shows the effect of different concentrations of cortisol on CRH- and AVP-induced ACTH secretion by equine anterior pituitary cells, and the time-course for ACTH responses to be inhibited by, and recover from, cortisol perifusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Normal values for a short-time ACTH intravenous and intramuscular stimulation test in women in the reproductive age.

Normal values in endocrine testing are the most important precondition for the recognition of disorders of the endocrine system. To establish a reference range for adrenocorticotropic hormone (ACTH) stimulation tests, an intravenous and intramuscular ACTH stimulation test was conducted in 29 female volunteers without hyperandrogenism. A total of 25 IU of ACTH were administered intravenously or intramuscularly and blood sampling was performed before, 1 h and 2 h after ACTH injection. The test was performed on days 3-5 of the menstrual cycle. The following steroid hormones were assessed in the serum: 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone, dehydroepiandrosterone, testosterone, free testosterone and 5 alpha-dihydrotestosterone. The normal range was defined by the interval between the 5th and 95th percentiles; additionally the 1st, 25th, 50th, 75th and 99th percentiles are reported. A significant increase of serum hormone levels after ACTH administration could be observed for the following hormones: cortisol, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. There was no rise after ACTH application for testosterone, 5 alpha-dihydrotestosterone and free testosterone. It could be shown for all hormones that there was no significant difference between the serum levels that were reached after intravenous and intramuscular ACTH injection. Neither could we find a significant difference in the relative increase of the serum hormones when stimulation values were related to basal values. Since in most studies with ACTH stimulation tests, only the serum values 1 h after ACTH application are measured, we investigated whether the measurement of steroid hormones 2 h after ACTH application gave further information. We could demonstrate that for most measured serum hormones the majority of the volunteers had the maximal response 2 h after ACTH application, no matter whether ACTH was injected intramuscularly or intravenously. As a conclusion, we recommend the measurement of the respective hormones not only 1 h but also 2 h after ACTH stimulation. Since there is no increase after ACTH stimulation for total testosterone, free testosterone and 5 alpha-dihydrotestosterone, it is sufficient to assess the basal values of these hormones. Excessive adrenal response is reflected by dehydroepiandrosterone, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and cortisol.

17-alpha-Hydroxypregnenolone↗
PubMed1992

ACTH: a structure-activity study on pilocarpine-induced epilepsy.

Intracerebroventricularly applied pilocarpine (2.4 mg/2 microliters) immediately produced symptoms of epilepsy, ranging from akinesia to motor seizures, in rats. Whereas ACTH-(1-39), ACTH-(1-24), ACTH-(1-18), ACTH-(1-16) and ACTH-(18-39) were not active, subcutaneous pretreatment with smaller ACTH-like fragments, such as ACTH-(4-9), ACTH-(4-10), ACTH-(4-10)(7D-Phe), ACTH-(7-16), and Org2766, reduced the severity of the epilepsy. Moreover, fewer rats developed motor seizures. Thus, ACTH fragments devoid of peripheral endocrine activity reduce pilocarpine-induced epileptiform activity in rats. A narrow bell-shaped dose-response relationship was found. Except for ACTH-(7-16), which was active in a dose of 1 and 10 micrograms/rat s.c., the other fragments were only active at one dose (10 micrograms/rat). The anti-epileptic properties appeared to reside in the sequence 1-16, and more specifically in the sequences 4-7 and 7-16, of the ACTH molecule.

Adrenocorticotropic Hormone↗
PubMed1990

Differential modulation of ACTH-stimulated cortisol and androstenedione secretion by insulin.

Results of previous clinical studies suggested counter regulatory actions between insulin and DHEA(S). The present studies were performed using primary monolayer cultures of bovine fasciculata-reticularis cells to test the hypothesis that insulin directly affects adrenal androgen secretion. Although having no independent effect, insulin exhibited complex time- and concentration-specific actions on ACTH-stimulated secretion of both C21 (cortisol) and C19 (androstenedione) corticosteroids. In the presence of low concentrations (0.05-0.1 nM) of ACTH, cortisol secretion during a 2 h incubation was about 2-fold greater in the presence than in the absence of insulin (0.01-100 ng/ml). In the presence of a maximal concentration (10 nM) of ACTH, on the other hand, cortisol secretion was not affected by insulin at concentrations less than or equal to 0.1 ng/ml, but was decreased at higher insulin concentrations. ACTH-stimulated androstenedione secretion was not significantly affected by insulin during a short-term (2 h) incubation. During a prolonged (24 h) incubation, insulin produced a concentration-dependent inhibition of ACTH-stimulated cortisol secretion. At an insulin concentration of 100 ng/ml, ACTH (10 nM)-stimulated cortisol secretion declined to a level only 30% of that produced by ACTH alone. In contrast, insulin exhibited biphasic effects on the secretion of androstenedione by cells maintained in the presence of ACTH for 24 h; an effect that was most dramatic in the presence of a maximal concentration of ACTH. At an insulin concentration of 0.1 ng/ml, androstenedione secretion by cells maintained in the presence of 10 nM ACTH was increased approximately 2.5-fold. At higher concentrations of insulin, ACTH-stimulated androstenedione secretion was inhibited to an extent comparable to that in cortisol secretion. The effects of insulin on ACTH-stimulated cortisol and androstenedione secretion could not be accounted for by changes in steroid degradation or a loss in 11 beta-hydroxylase activity. These results indicate that insulin interacts with ACTH to modulate the secretion of both C21 and C19 corticosteroids and that physiological concentrations (less than or equal to 1 ng/ml) of insulin may have a long-term effect to enhance selectively adrenal androgen secretion. These data are consistent with a servo mechanism between insulin and DHEA(S) in vivo and indicate that the correlations observed clinically result, at least in part, from a direct action of insulin to modulate the rate of adrenal androgen production.

Adrenal Glands↗
PubMed1995

Ectopic ACTH syndrome.

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

Adrenal Glands↗
PubMed2005

Effects of ACTH and cAMP on steroidogenic acute regulatory protein and P450 11beta-hydroxylase messenger RNAs in rainbow trout interrenal cells: relationship with in vitro cortisol production.

Steroidogenic acute regulatory protein (StAR) transfers cholesterol over the inner mitochondrial membrane, thereby making the molecule available for cholesterol side-chain cleavage enzyme, which carries out the first conversion in the steroidogenic pathway. In mammals, StAR controls this rate limiting step in steroidogenesis, and both StAR protein and StAR mRNA levels become rapidly elevated in response to tropic hormone stimulation. The relationship between StAR gene expression and steroid production in fish has not yet been well explored. We investigated the relationship between adrenocorticotropic hormone (ACTH)- and cAMP-stimulated cortisol production in vitro and levels of StAR transcripts in interrenal cells of rainbow trout. To assess the effect of ACTH on mRNA levels of a downstream steroidogenic enzyme, we also investigated the effects of ACTH on transcripts encoding 11beta hydroxylase (P450 11beta). In a series of experiments, juvenile rainbow trout head kidney tissue containing interrenal cells was incubated with either ACTH or dibutyryl cyclic AMP (dbcAMP). Cortisol in incubation media were measured by radioimmunoassay and total RNA was isolated from the tissue for Northern analysis or for quantitative real-time PCR. Incubation of tissue with 150 ng/mL ACTH for 1-18 h induced a progressive increase in cortisol accumulation in media, but StAR mRNA levels increased modestly and mostly insignificantly over 18 h, irrespective of treatment. Exposure of tissue for 18 h to 5, 150, 500 or 1,500 ng ACTH/mL resulted in a strong increase in cortisol production, with a peak response (15-fold increase over controls) achieved with 150 ng/mL ACTH. Although there was a trend towards a dose-response effect, mean StAR mRNA levels were only significantly affected by the highest concentration of ACTH used (1,500 ng/mL), which induced a less than 2-fold increase in StAR transcripts. However, there was a significant linear relationship between StAR mRNA levels and ACTH-induced cortisol accumulation in media (p<0.001, r(2)=0.55). Incubation of tissue with 5mM dbcAMP for 6 or 18 h induced large increases in cortisol accumulation in media over controls, but had no significant effect on StAR mRNA levels. By contrast, ACTH induced a clear dose-dependent increase in P450 11beta transcripts, with 150 ng/mL ACTH inducing an 8-fold increase in levels compared to control; nonetheless, only a weak correlation existed between transcript levels and ACTH-induced cortisol secretion (p<0.003, r(2)=0.26). Thus, despite the relatively high degree of conservation of StAR proteins in vertebrates, we have been unable to demonstrate that a rapid, acute increase in transcription of the StAR gene is the dominant mechanism supporting flow of cholesterol to the mitochondria during acute increases in cortisol production in rainbow trout. The strong stimulation of P450 11beta gene transcription by ACTH probably enhances biosynthetic capacity during longer term chronic ACTH stimulation.

Adrenocorticotropic Hormone↗
PubMed2002

ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability.

The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies. However, the mechanisms for this efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors. The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH--compared with steroids--for this disorder are the focus of this chapter. First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed. This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain. This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions. Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH. Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented. This downregulation 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 downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS.

Adrenocorticotropic Hormone↗
PubMed1999

Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing's syndrome and simple obesity.

OBJECTIVE: The desmopressin test has recently been introduced in clinical practice as an adjunctive tool in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). It has been reported that the majority of patients with pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no such response is usually observed in other forms of this syndrome. In the present study, the responsiveness of the HPA axis to desmopressin was studied in a group of obese subjects. In addition, the ability of desmopressin administration to differentiate between patients with obesity and the various forms of Cushing's syndrome was investigated. DESIGN AND SUBJECTS: Cortisol and ACTH responses to the administration of desmopressin (10 microg bolus i.v.) were examined in 20 consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7 kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients, either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg 6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for the exclusion of Cushing's syndrome. Three of eight subjects showed failure of cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on further testing with the formal 2-day test. All but two of the remaining subjects had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low-dose, dexamethasone suppression test. For comparison, desmopressin responses were also tested in 33 patients with CS of varied aetiologies (25 patients with pituitary-dependent CS, three patients with occult ectopic ACTH secretion and five patients with primary adrenal CS). A positive response was considered to be an increment greater than 20% and 50% from baseline levels of cortisol and ACTH, respectively. RESULTS: Mean cortisol (F) and ACTH levels did not differ from the baseline at any time point following desmopressin administration in the obese group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5 +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult ectopic or primary adrenal CS. In contrast, in the group of patients with CD, there was a significant rise in the mean ACTH and F levels from baseline (basal F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8, peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of the obese patients. With regard to ACTH, increments greater than 50% over baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%) of the obese patients. As previously reported, none of the patients with occult ectopic ACTH secretion or primary adrenal CS had a positive response. CONCLUSIONS: The prevalence of subjects who met the criteria adopted to define positive cortisol and ACTH responses to the desmopressin test was significantly higher in the group of patients with Cushing's disease than in the group of patients with obesity. It is therefore suggested that this test may be occasionally useful in the differentiation between simple obesity and the pituitary-dependent form (but not other forms) of Cushing's syndrome.

Adrenocorticotropic Hormone↗
PubMed2000

Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease.

OBJECTIVE: The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently. DESIGN AND PATIENTS: We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition. RESULTS: With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P<0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose-response relationship between ACTH and cortisol in the patients resembled a dose-response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1-39). CONCLUSIONS: The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substitution is a discretionary decision.

Adolescent↗
PubMed2001

C-terminal fragments of ACTH stimulate feeding in fasted rats.

Peptides derived from pro-opiomelanocortin, including alpha-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [alpha-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide alpha-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.

Adrenocorticotropic Hormone↗
PubMed2004

ACTH modulates ERK phosphorylation in the adrenal gland in a time-dependent manner.

ACTH is known to act through the activation of cAMP/PKA in adrenocortical cells, but it has been suggested that it could also act via other pathways such as the ERK 1/2 cascade. To determine the effects of ACTH administration at sequential time points on the activation of ERKs 1/2, groups of rats (n = 6/group) were subjected to i.p. injections of either ACTH (Synacthen Depot-0.2 mg/Kg), or saline (Ct). The animals were sacrificed and the adrenal glands collected at different timings after ACTH injection (2 h, 18 h and 24 h). Two additional groups were injected daily until sacrifice (3 days and 15 days). Blood was collected for analysis and the adrenals were used for immunohistochemistry or Western Blot (WB) analysis. Immunoreactivity was scored by counting the mean number of zonae fasciculata (ZF) and reticularis (ZR) positive cells/section (mean +/- SEM). Adrenal weight was increased by ACTH in comparison with Ct. Corticosterone levels, as expected, were higher in ACTH treated animals than in Ct. The number of pERK positive cells increased in a time-dependent manner until 3d, and declined although not significantly in the 15 days animals (Control--48.13 +/- 9.0; ACTH 2 h--125.93 +/- 14.5; ACTH 18 h-139.46 +/- 10.0; ACTH 24 h--185.28 +/- 13.3; ACTH 3 days--198.47 +/- 18.6; ACTH 15 days--158.58 +/- 15.1). Comparable results were obtained with WB analysis. Our data shows that ACTH induces the activation of the MAPK/ERKs 1/2 cascade, especially in the ZF, consistent with this zone being more responsive to ACTH.

Adrenal Glands↗
PubMed1977

Lung tumours and ACTH production.

ACTH levels measured by N- and C-terminal immunoassays and cytochemical bioassay, were measured in fourteen lung tumours not associated with the ectopic ACTH syndrome and in macroscopically normal lung tissue taken from the same patients at thoracotomy. Significant concentrations of immunocative (greater than 3 ng/g wet weight) and bioactive (greater than 0.2 ng/g wet weight) ACTH were found in all the carcinoid and oat cell tumours (n=9), a combined tumour (poorly differentiated adenocarcinoma with large cell carcinoid elements), and a poorly differentiated squamous cell tumour. All the carcinoid tumours contained more C- than N-terminal ACTH immunoactivity. The squamous cell tumours (n=2), anaplastic tumours (n=2) and adenocarcinoma contained insignificant ACTH levels. There was a good correlation between the ACTH levels and the presence of secretory granules in the tumours examined ultrastructually. All the macroscopically normal samples of lung tissue contained immuno and bioactive ACTH-like material, the levels of which correlated well with ACTH levels in the tumour tissue. It is suggested that all lung tumours of carcinoid or oat cell type synthesize ACTH-like materials although clinical evidence of the ectopic ACTH syndrome may be absent. The presence of ACTH-like materials in non-tumorous lung tissue in patients with lung cancer may indicate a low level of ACTH production throughout the lung or sequestration of ACTH containing granules secreted by the tumour.

Adenocarcinoma↗
PubMed1993

The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy.

OBJECTIVES: We compared the responses of the stress hormones, cortisol, ACTH, vasopressin (AVP), corticotrophin releasing hormone (CRH) and catecholamines to elective conventional and laparoscopic cholecystectomy. DESIGN: A right upper quadrant transverse incision was used for conventional cholecystectomy, and four 1-2-cm incisions for the laparoscopic procedure (for insertion of surgical instruments, diathermy, fibreoptic telescope and light source, and carbon dioxide insufflation). Blood was sampled immediately prior to premedication (temazepam), after induction of anaesthesia (fentanyl and thiopentone) and at 10-minute intervals until the end of the procedure (N2O maintenance, vecuronium relaxation). A blood sample was taken after reversal, and then at 10-minute intervals for 50 minutes. Plasma sodium and blood pressure were measured at similar intervals. Results are expressed as mean +/- standard error. PATIENTS: Twelve patients were studied (six in each group). MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and catecholamines by HPLC. RESULTS: The mean premedication hormone values for the conventional and laparoscopic procedures did not increase significantly after induction of anaesthesia. Within 10 minutes of the first incision, however, there was a marked concordant rise in mean plasma ACTH and AVP levels for both procedures (conventional: ACTH, from a premedication value of 10.2 +/- 1.7 to 80.1 +/- 14.3 pmol/l, AVP from 1.2 +/- 0.4 to 117 +/- 24 pmol/l, P < 0.01 for both hormones; laparoscopic: ACTH from 5.8 +/- 2.6 to 55.1 +/- 26.0 pmol/l, AVP from 1.6 +/- 0.11 to 49.2 +/- 27.09 pmol/l). At the end of both types of operation mean levels of ACTH and AVP were still elevated, although the ACTH: AVP ratio had increased. Greater variability in ACTH and AVP responses was seen in the laparoscopic than in the conventional procedure, three patients showing a relatively small response to surgery. Total secretion of ACTH during both types of surgery was not significantly less both during (P < 0.05), and after (P < 0.01) laparoscopic surgery. For both procedures, the timing of AVP and ACTH peaks was significantly related (P < 0.002). A small but significant rise in CRH was observed 30 minutes after the start of surgery for both procedures P < 0.05). The timing of CRH and ACTH peaks was unrelated. The maximum mean plasma cortisol level for the conventional procedure (1268 +/- 147 nmol/l) was reached 20 minutes after reversal of anaesthesia and remained at this level until the end of sampling. The cortisol response was comparable during the laparoscopic procedure but was beginning to fall at 60 minutes post-operatively. Plasma adrenaline responses to the two types of surgery were not significantly different, but the plasma total noradrenaline response to laparoscopic surgery as indicated by the response area during the first 20 minutes was significantly increased (P < 0.02). Plasma sodium, renin activity and initial systolic blood pressure fall were not significantly different during the two procedures. CONCLUSIONS: For both procedures, the peak of ACTH secretion after incision is likely to be AVP dependent, and the timing of peak levels of these two hormones was significantly related. Subsequent ACTH secretion may be the result of an interaction between AVP and CRH. Laparoscopic cholecystectomy results in a smaller AVP rise than does the conventional procedure, and plasma AVP falls more rapidly post-operatively. During the period of observation, ACTH, CRH, cortisol and adrenaline responses were not significantly lessened by the laparoscopic approach, but there was a significant increase in the noradrenaline response. Stress hormone monitoring may assist further improvements in surgical technique.

Adrenocorticotropic Hormone↗