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PubMed1990

ACTH stimulation tests and plasma dehydroepiandrosterone sulfate levels in women with hirsutism.

BACKGROUND: Hirsutism in women is a clinical manifestation of excessive production of androgens. The source of the excess androgen may be either the ovaries or the adrenal glands, and distinguishing between these sources may be difficult. METHODS: To determine whether measurements of plasma dehydroepiandrosterone (DHEA) sulfate and ACTH stimulation tests, both widely used in the evaluation of hirsutism in women, provide useful information, we performed both tests in 22 normal women and 31 female patients with hirsutism. The hormones measured in plasma during the ACTH stimulation tests were progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, androstenedione, 11-deoxycortisol, and cortisol. RESULTS: The women with hirsutism were divided into four groups based on their individual responses to ACTH stimulation: patients with a possible 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency, those with a possible 21-hydroxylase deficiency, those with a possible 11 beta-hydroxylase deficiency, and those with no apparent defect in steroidogenesis. The results in 19 patients (61 percent) suggested subtle defects in adrenal steroidogenesis. There was no significant correlation between the basal plasma DHEA sulfate levels and the hormonal response to ACTH, nor were the basal levels of hormones predictive of the levels after ACTH stimulation. Eleven patients had significantly elevated basal levels of plasma DHEA sulfate; only 5 of these 11 had responses to ACTH suggestive of compromised steroidogenesis. Thirteen patients who had responses suggestive of defective steroidogenesis had DHEA sulfate levels within the normal range. CONCLUSIONS: A substantial proportion of women with hirsutism have mild defects in adrenal steroidogenesis, revealed by an ACTH stimulation test, that are indicative of late-onset (nonclassic) congenital adrenal hyperplasia. Measurements of basal steroid levels are not helpful in differentiating among the causes of increased androgen production in such patients and may be misleading.

17-alpha-Hydroxypregnenolone↗
PubMed1982

Pattern of cortisol release in sheep following administration of synthetic ACTH or imposition of various stressor agents.

This paper describes experiments with sheep, in which changes in plasma cortisol, after imposition of various stressor agents, were compared to the changes following administration of synthetic ACTH. The influence of stress associated with shearing, yarding, oestrogen administration (30 microgram oestradiol benzoate, i.v.), feeding and fasting on the plasma concentration of cortisol was monitored in four mature Merino ewes. They were placed in the experimental environment for 21 days before monitoring began. The ewes were treated in pairs, each pair being visually and acoustically isolated from the other. One pair of ewes was exposed to the particular stress and the remaining pair acted as their own controls. The treatments were reversed 2 days later. In the second part of the experiment, 0, 0.01, 0.1, 1.0 or 10.0 i.u. synthetic ACTH were injected as an intravenous bolus, after endogenous secretion had been suppressed by administration of synthetic glucocorticoid. All blood samples were taken via an indwelling jugular catheter. A comparison of cortisol release--estimated from a plot of cortisol in plasma versus time--following imposition of various stressor agents and administration of synthetic ACTH, allowed stress to be defined in terms of synthetic ACTH equivalents. The most severe stress was associated with shearing (0.84 i.u. synthetic ACTH equivalents), less stress was imposed by yarding and handling (0.45 i.u.), and there appeared to be no effect attributable to feeding, fasting or oestrogen administration. The similarity in the pattern of cortisol release following ACTH administration offers the possibility of defining acute, but not chronic, stress in terms of ACTH equivalents.

Adrenocorticotropic Hormone↗
PubMed1975

Adrenal cells in tissue culture the effects of choleragen and ACTH on steroid and cyclic-AMP metabolism.

Primary cultures of mouse adrenocortical tumors provide a sensitive system for investigating the effects of the enterotoxin of the V. cholerae (choleragen) on cyclic-AMP metabolism in the intact cell. Like ACTH, the toxin stimulates the synthesis and release of steroids from these cells but its mode of action differs from that of ACTH. The steroidogenic response to ACTH is immediate and of limited duration. The initial rate of steroidogenesis is the highest. In contrast, the steroidogenic response to choleragen is preceded by a 30-240 minute lag period which is inversely related to the concentration of the toxin. Whereas prolongation of the response to a single dose of ACTH requires hormone concentrations above those producing maximal initial steroidogenic activity, persistent steroidogenesis is induced at all levels of the toxin. Steroidogenic responses are detectable with 10 pg/ml of choleragen or less. The respective effects of ACTH and choleragen on cyclic-AMP synthesis and release into the medium parallel those on steroidogenesis. Intracellular cyclic-AMP levels in ACTH-treated cells reach a peak within 20-30 minutes and decline to normal levels within 2-4 hours. In choleragen-treated cells, after the lage period, the levels of intracellular cyclic-AMP remain above control levels indefinitely. The effects of ACTH and choleragen on cyclic-AMP biosynthesis are additive at all levels of the two compounds. The effects of choleragen are blocked by prior treatment of the toxin with a five-fold molar excess of ganglioside GM1, a presumed constituent of the toxin-binding site.

Adrenal Cortex↗
PubMed1996

Regulation of growth by ACTH in the Y-1 line of mouse adrenocortical cells.

Y-1 adrenal cells were cell cycle arrested by serum starvation to characterize a G0-->G1-->S transition in these cells. Cycle arrested Y-1 cells start to enter S phase 8h after serum feeding, reaching more than 90% cells synthesizing DNA by 24h. ACTH displays a dual effect in the G0-->G1-->S transition: 2h ACTH treatment stimulates DNA synthesis initiation, but longer treatments inhibit S phase entry. This dual effect of ACTH is similar to the antagonistic actions of PMA (phorbol-12-miristate-13-acetate) on the G0-->G1-->S transition. However ACTH and PMA are likely to have different mechanisms of action. ACTH inhibitory effect requires PKA, whereas PMA inhibitory effect is not dependent on PKA. ACTH induces the proto-oncogenes c-fos and c-jun, but inhibits the expression of the c-myc proto-oncogene. PMA, on the other hand, induces equally well c-fos, c-jun and c-myc. We hypothesize that ACTH promotes G0-->G1 transition by induction of c-fos and c-jun and blocks G1-->S transition by c-myc inhibition.

3T3 Cells↗
PubMed1999

Acute in vivo effects of ACTH by exo utero microinjection on differentiation, steroidogenesis and proliferation of fetal mouse adrenocytes.

Mouse embryos on embryonic day (E)13 or 14 were treated with ACTH1-24 by exo utero microinjection and the adrenal was examined after 16 and 32 h. Light microscopic morphometry showed that the ACTH treatment increased cell size and decreased cell density of the adrenocortical cells. Bromodeoxyuridine-labeling index did not alter significantly after the ACTH treatment. By immunohistochemistry, both number of cells expressing 11beta-hydroxylase and the staining intensity increased in the ACTH-treated glands compared to controls whereas expression of aldosterone synthase was detectable in neither the treated nor control groups. Ultrastructurally, the adrenocytes of the inner cortical zone of the ACTH-treated glands were characterized by strikingly increased content of the smooth endoplasmic reticulum, increased mitochondria with more vesicular cristae, lipid droplets with a much higher electron density along with the distribution altered from that in controls. All of the significant differences between the ACTH-treated and control glands occurred at 16 h but not at the 32 h interval. The present results indicated that the mouse fetal adrenocytes are already sensitive to ACTH during early period (E13 and 14) of their functional differentiation. In vivo acute treatment of ACTH stimulates cell-size, increase of fetal adrenocytes but not proliferation, and may directly or indirectly regulate multiple steps of the steroidogenic process of the fetal mouse adrenal.

Adrenal Cortex↗
PubMed1997

Regulation of human thought by neuropeptide ACTH 4-10: an analysis of the EEG's dimensional complexity.

The neuroactive 4-10 fragment of adrenocorticotropin (ACTH 4-10) has been found to impair electroencephalographic (EEG) signs of selective attention in previous studies. It was hypothesized that this effect reflects a more general influence of the peptide weakening the mutual inhibition among frontocortical neuronal networks. Therefore, ACTH 4-10 was expected to loosen attentional control not only over external input but also over internal thoughts. This study examined the effects of ACTH 4-10 on the dimensional complexity of the EEG recorded while subjects solved tasks of convergent analytical thinking and of divergent creative thinking and during mental relaxation. Subjects were tested 30 min after i.v. administration of placebo or ACTH 4-10 (2 mg). ACTH 4-10 enhanced dimensional complexity of the EEG. The effect primarily concerned frontocortical recordings during convergent thinking, which, following placebo, was associated with the lowest EEG dimension. ACTH 4-10 also impaired behavioral performance on tasks of convergent thought, when presented verbally. Results suggest that ACTH 4-10 counteracts the inhibitory control among cortical neuronal networks necessary for orderly analytical thinking.

Adrenocorticotropic Hormone↗
PubMed1983

Application of ACTH stimulation to adrenal imaging with radioiodocholesterol.

ACTH-stimulation adrenal imaging (ACTH-I) was performed in 14 patients after baseline imaging (B-I) was performed. In six patients with no adrenal diseases in whom the findings of B-I were equivocal, morphologic normality of the adrenals was confirmed by ACTH-I because of increased adrenal uptake of radioiodocholesterol. In three patients with cortisol-producing tumors, visualization of contralateral glands by ACTH-I provided indirect evidence for autonomous cortisol secretion of the tumors. In three patients with pheochromocytoma or cyst, ACTH-I increased adjacent cortical radioactivity to more clearly delineate the lesions. In two patients with primary adrenocortical insufficiency, exogenous ACTH had no effect on adrenal uptake of the tracer. Correlation was observed between response of the adrenal net counts and urinary excretion of 17-OHCS and 17-KS. ACTH-I is useful when B-I does not provide sufficient diagnostic information or further information is needed due to low or absent radioiodocholesterol uptake by the adrenal gland(s).

17-Ketosteroids↗
PubMed1982

Refractory Cushing's disease caused by multinodular ACTH-cell hyperplasia.

A patient with pituitary-dependent hypercortisolism, unresponsive to resection of nodules in the anterior lobe, is described. Histochemical stains of the nodules showed multiple, focal, cellular expansions of the fibrovascular stroma. Transitions between normal and expanded adenohypophysial acini were present. Immunoperoxidase stains for ACTH and other pituitary hormones revealed that these multiple foci contained an excess of ACTH-positive cells. Less than 10% of the cells in these foci were negative for ACTH and positive for other hormones. Serial sections showed that these foci of predominantly ACTH-producing acini were not connected. Clinical, morphological, and immunohistochemical data indicated that ACTH-cell hyperplasia caused Crushing's disease in this patient. Pathologic study of individual cases should concentrate on determining whether hyperplasia or adenoma exist at the time of surgical exploration of the pituitary gland, since this determination is important to proper treatment. Tentative criteria to recognize ACTH-cell hyperplasia are: 1. Multiple foci of ACTH laden cells. 2. A minor subpopulation of cells of alternate hormone series. 3. Expansion without destruction of acini in the adenohypophysis.

Adenoma↗
PubMed2003

Interaction between alcohol and nitric oxide on ACTH release in the rat.

BACKGROUND: This work was designed to determine whether alcohol increased nitric oxide (NO) levels within the hypothalamic-pituitary (HP) axis, whether endogenous NO participated in the known ability of alcohol to release ACTH and, conversely, whether prior alcohol treatment altered the ACTH response to NO. METHODS: In a first group of experiments, intact adult male rats were injected with the vehicle or alcohol intragastrically (4.5 g/kg). The effect of alcohol on NO was studied by measuring nitrite + nitrate levels, as well as NOS activity, as indexes of formation of this gas. The role of endogenous NO then was studied by blocking the activity of NO synthase, the enzyme responsible for formation of this gas, and determining whether this treatment altered the ACTH response to alcohol. Finally, we investigated the influence of alcohol on the ACTH response to NO. These studies were done in rats exposed to alcohol vapors (4 hr/day for 1-5 days) to avoid the confounding influence of HP axis stimulation by acutely injected alcohol. RESULTS: The acute intragastric injection of alcohol significantly (p < 0.01) increased NO levels in the paraventricular nucleus of the hypothalamus, the anterior pituitary, and peripheral blood. The ACTH response to acute intragastric alcohol injection was significantly (p < 0.01) decreased by the arginine derivative N omega-nitro-L-arginine-methylester, which nonspecifically blocks NOS activity, as well as by the specific neuronal NOS antagonist 7-nitroindazole. A 5 but not 1 or 3 day exposure to intermittent alcohol vapors interfered with the ACTH response to the intracerebroventricular injection of the NO donor 3-morpholino-sydnonimine. CONCLUSION: Acute alcohol injection increases NO levels in blood and the HP axis, and these responses seem to facilitate the ACTH response to alcohol. Reciprocally, prolonged (5 days) exposure to ethanol vapors blunts the HP axis response to centrally administered NO.

Adrenocorticotropic Hormone↗
PubMed1979

Suppression of plasma ACTH concentration by angiotensin II infusion in normal humans and in a subject with a steroid 17 alpha-hydroxylase defect.

Six healthy subjects were infused with angiotensin II and plasma concentrations of angiotensin, ACTH and cortisol were measured before, during and after the infusion. In all cases the plasma ACTH concentration fell as plasma angiotensin increased and rose again, sometimes to higher than basal levels, when the angiotensin infusion was terminated. These effects were most marked at the highest rate of infusion (8 pmol/kg/min) and, at the lower rates (2 and 4 pmol/kg/min), there was some recovery of ACTH levels during the infusion period in some subjects. Plasma ACTH concentrations also fell when angiotensin was infused into a patient with high ACTH levels due to a steroid 17 alpha-hydroxylation defect. The inhibition of ACTH secretion is not due to a rise in plasma cortisol operating a negative feedback inhibition. It could be a direct effect of the infused angiotensin on the brain-hypothalamus-pituitary complex or an effect on the metabolism of ACTH.

Adrenal Hyperplasia, Congenital↗
PubMed1980

The dose-response relationship of ACTH and cortisol in Cushing's disease.

The dose-response relationship between plasma ACTH and plasma cortisol was examined in normal subjects, patients with Addison's disease and patients with Cushing's disease. Plasma cortisol and ACTH levels were measured every half-hour from 06.00 h to 10.00 h and from 16.00 h to 18.00 h during a control day and during 1 to 3 days of continuous cortisol infusion. A plot of mean morning plasma ACTH versus the log of mean plasma cortisol revealed a similar dose-response relationship in normal and Addisonian subjects. Total plasma cortisol was four times more potent in suppressing mean morning ACTH in normal and Addisonian subjects, than in patients with Cushing's disease. When plasma cortisol was undetectable, there was no significant difference between mean morning ACTH concentrations in Addisonian patients and in adrenalectomized Cushing's patients. The glucocorticoid feedback control of ACTH in Cushing's disease had dose-response characteristics similar to those in Addison's disease and normal subjects, except for decreased sensitivity to cortisol feedback suppression of ACTH.

Addison Disease↗
PubMed1981

Patterns of plasma cortisol and ACTH concentrations in patients with Addison's disease treated with conventional corticosteroid replacement.

Plasma cortisol and adrenocorticotrophin hormone (ACTH) profiles were estimated in twelve patients with Addison's disease following randomized oral administration of either cortisone acetate (25 mg) or hydrocortisone (20 mg) alternately, at 0900 h on consecutive days. Normal corticosteroid replacement therapy was discontinued from 1200 h on the day prior to the study period. In four patients elevated basal plasma ACTH concentrations were not suppressed to the limit of detection following the administration of either drug, and in three of these no suppression was found following the prolonged administration of pharmacological doses of dexamethasone. Diminished sensitivity of pituitary ACTH secretion to cortisol inhibition may result from chronic loss of negative feedback before and/or after diagnosis and treatment. In three patients elevated basal plasma ACTH concentrations were suppressed adequately during the administration of either drug, but in five, low basal ACTH concentrations following corticosteroid withdrawal suggested chronic inhibition of anterior pituitary corticotrophs by over-replacement with glucocorticoid. However, further study is necessary to determine whether the estimation of ACTH profiles is a more accurate reflection of the adequacy of corticosteroid replacement than the estimation of cortisol profiles alone, and whether this estimation leads to an improvement in patient management. Hydrocortisone (20 mg) achieved higher mean cortisol levels and lower mean ACTH levels than cortisone acetate (25 mg), but either drug may be suitable for glucocorticoid replacement provided the dose is tailored to the individual needs.

Addison Disease↗
PubMed1983

Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing's disease.

Up to one-third of subjects who have had bilateral adrenalectomy for treatment of Cushing's disease will develop Nelson's syndrome. To examine the value of pre-operative ACTH assays in predicting outcome, we have studied fifteen cases of Cushing's disease treated by bilateral adrenalectomy and pituitary irradiation. Three patients developed Nelson's syndrome. There was no significant correlation between preoperative ACTH level, either 8 am 'basal' or during metyrapone testing, and ACTH concentration post-treatment. Plasma ACTH concentration in the first year after treatment, however, showed a highly significant correlation with the latest postoperative value (n = 14, r = 0.684, P less than 0.01), even more marked when subjects with duration of follow-up less than 3 years were excluded (n = 11, r = 0.836, P less than 0.002). In nine of fifteen patients, plasma ACTH showed either no change or a definite fall during subsequent follow-up. We conclude that plasma ACTH measurement in the first post-operative year is a good indicator of eventual outcome. The continued fall in plasma ACTH shown in many patients after the first year of treatment suggests an effect of irradiation on the pituitary.

Adolescent↗
PubMed1985

ACTH and cortisol responses to ovine corticotrophin-releasing factor in patients with primary and secondary adrenal failure.

The ACTH and cortisol responses to an intravenous bolus injection of 100 micrograms ovine CRF were studied in 19 patients with adrenal failure. In all eight patients with primary adrenal failure, plasma ACTH levels increased from a mean basal level of 1494 +/- 431 (SEM) pg/ml to peak value of 2601 +/- 1220 pg/ml at 10 min. In comparison with healthy subjects absolute ACTH increments after ovine CRF were significantly augmented in the patients with Addison's disease (P* less than 0.001), and the absolute ACTH responses after ovine CRF were positively correlated with the basal plasma ACTH levels. The 11 patients with secondary adrenal insufficiency could be subdivided into two groups: (A) those having little or no ACTH and cortisol response to ovine CRF (five patients) and (B) those having prolonged and pronounced ACTH responses with a biphasic pattern and a delayed second peak (six patients), followed in all patients by a marked cortisol increase. These data demonstrate that the CRF-test can discriminate between hypothalamic and pituitary causes of secondary adrenal failure.

Addison Disease↗
PubMed1985

Pituitary ACTH dependent Cushing's syndrome due to ectopic production of a bombesin-like peptide by a medullary carcinoma of the thyroid.

A 41-year-old man presented with Cushing's syndrome and the biochemical features of ectopic ACTH production. Investigation revealed mediastinal metastases from a medullary carcinoma of the thyroid. The peripheral plasma contained grossly elevated levels of bombesin-like immunoreactivity (irBombesin) as well as calcitonin; blood sampling via a venous catheter confirmed a gradient of irBombesin, but not of ACTH, in the mediastinal vein draining the tumour. On extraction the tumour contained a bombesin-like peptide, but not vasopressin or corticotrophin releasing factor and only very low levels of ACTH; immunohistochemical studies showed positive immunostaining for bombesin and calcitonin but none for ACTH or CRF. No ACTH was released from dispersed tumour cells in vitro. However an extract of the tumour stimulated ACTH release in vitro from perifused dispersed rat anterior pituitary cells. This is the first reported case of Cushing's syndrome due to ectopic production of a bombesin-like peptide, causing excessive pituitary ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1988

Selective bilateral and simultaneous catheterization of the inferior petrosal sinus: CRF stimulates prolactin secretion from ACTH-producing microadenomas in Cushing's disease.

Bilateral, selective and simultaneous catheterization of the inferior petrosal sinus with measurements of ACTH after stimulation with ovine corticotrophin-releasing factor (CRF) is now frequently used to establish the differential diagnosis in patients with Cushing's disease and to determine the side of the microadenoma in the pituitary. To investigate whether CRF has any effect on other pituitary hormones, we also determined prolactin (PRL) concentrations in the samples obtained during this procedure. Fourteen patients under evaluation for Cushing's syndrome and one patient with a hormonally inactive pituitary tumour were catheterized. Baseline PRL levels in the peripheral veins were within the normal range before and after CRF in all patients (3.7-16.0 ng/ml). In 10 patients ACTH- and PRL concentrations lateralized to one side of the pituitary and could both be stimulated by CRF. The gradient of PRL between inferior petrosal sinus and periphery ranged from 7 to 147 ng/ml after CRF. There was no correlation between ACTH and prolactin increase in response to CRF. In three patients with no ACTH-gradient but a positive response to CRF, no tumours could be found during transsphenoidal surgery; they had no PRL-gradient and showed no PRL response to CRF. One patient with the ectopic ACTH syndrome had no ACTH- and no PRL response to CRF. The patient with the inactive pituitary tumour showed a normal ACTH-, but no PRL response to CRF. These data demonstrate for the first time that in normo-prolactinaemic patients with Cushing's disease, in contrast to patients bearing no microadenoma, PRL is secreted in response to CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1990

The effect of cyproheptadine and/or bromocriptine on plasma ACTH levels in patients cured of Cushing's disease by bilateral adrenalectomy.

Cyproheptadine and bromocriptine have been reported to be therapeutic in suppressing ACTH levels in Cushing's disease and Nelson's syndrome. However, there have been only scattered reports of their effect in suppressing raised ACTH levels found in patients cured of Cushing's disease by bilateral adrenalectomy. In order to assess whether these agents could prove beneficial in such patients we studied 12 patients previously treated with bilateral adrenalectomy alone for Cushing's disease before and after 3 weeks of cyproheptadine and/or bromocroptine therapy. All had raised plasma ACTH values but no patient had evidence of a pituitary macroadenoma. Plasma ACTH and cortisol were sampled 2-hourly for 24 h. Neither drug regime led to any change in plasma levels of cortisol for 24 h after a 20 mg dose of oral hydrocortisone. Plasma ACTH (mean +/- SEM) showed a small but significant overall reduction (523 +/- 45 vs 392 +/- 34 ng/l; P less than 0.05) while on bromocriptine alone (5 mg given at 0800 and 1800 h, n = 5). When each time point was analysed individually this reduction was significant at only five out of 13 time points. At 0400 h plasma ACTH (mean +/- SEM) was 758.4 +/- 298.1 vs 380.2 +/- 166.6; 0600 h, 795 +/- 288.7 vs 477.8 +/- 191.7; 1200 h, 266.8 +/- 106.2 vs 187.0 +/- 80.3; 1400 h, 470.0 +/- 239.0 vs 302.0 +/- 135.9; 1600 h, 548.6 +/- 262.5 vs 394.2 +/- 178.5 ng/l (P less than 0.05). There was no significant change in plasma ACTH during treatment with the combination of bromocriptine and cyproheptadine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1989

Potentiation of fenfluramine-induced ACTH release in man by naloxone.

1. This study set out to compare the effect of the combination of fenfluramine (Fen) and naloxone (Nal) on ACTH and cortisol release with each of these agents alone in six normal volunteers. Three protocols were used: 1.5 mg/kg bodyweight oral Fen; 125 micrograms/kg bodyweight i.v. Nal; oral Fen plus i.v. Nal 135 min later. Plasma ACTH and cortisol were measured at intervals of 285 min over each test. 2. The mean peak levels and mean peak changes from basal in plasma ACTH and cortisol were significantly greater in the combination test (Fen/Nal) than in either the Fen alone or the Nal alone tests. Fen and Nal given together cause a synergistic release of ACTH and cortisol as determined by the areas under the ACTH-time and cortisol-time curves for Fen/Nal compared to the sums of Fen alone plus Nal alone curves for ACTH and cortisol. 3. We conclude that Fen and Nal acting synergistically work through different and potentiating mechanisms at the hypothalamic, central nervous system and/or pituitary levels to cause ACTH release.

Adrenocorticotropic Hormone↗