Source Of ACTH Research Articles

Activity of the pituitary-adrenal system in rat fetuses subjected to encephalectomy in early or late stages of pregnancy.

The corticostimulating activity of the fetal rat hypophysis was studied on day 21, in fetuses deprived of their hypothalami by total removal of the brain (encephalectomy) in early (day 16) or late (day 19) stages of gestation. On day 19, the fetal manipulation was performed either on intact or adrenalectomized dams. The data show that: (1) Compared to controls, encephalectomy does not alter pituitary ACTH content in fetuses of intact mothers but that pituitary ACTH content does not significantly increase in encephalectomized fetuses of adrenalectomized mothers whereas it does in the littermate control fetuses. (2) Compared to controls, circulating ACTH levels are reduced by encephalectomy on both day 16 and day 19; an increase in ACTH levels occurs in both fetal groups in response to maternal adrenalectomy. Decapitation removes this fetal source of ACTH. (3) Adrenal glands are not as much atrophied by encephalectomy as by decapitation on day 16, whereas adrenal weight is decreased to the same extent by encephalectomy and by decapitation on day 19. However, the marked increase in circulating ACTH in both control and encephalectomized fetuses caused by maternal adrenalectomy is probably the cause of the significant increase in adrenal weight in these groups. (4) Adrenal corticosterone content in all the groups but not always adrenal weight, is a fairly accurate reflection of the ACTH levels measured. The results suggest that: (1) Pituitary ACTH content is not a sensitive measure of dynamic changes in synthesis and secretion in rat fetuses. (2) Changes in basal plasma ACTH in response to fetal encephalectomy show the presence of both an autonomous corticotropic function and a cephalic regulation of the corticotropic function from day 16 of fetal life and beyond. Pituitary autonomy seems higher in earlier than in later stages of gestation. (3) There is feedback of corticosterone into the pituitary of fetal rats; a marked increase in ACTH release is caused by the removal of the maternal corticosteroids.

Cushing's syndrome with small cell carcinoma of the uterine cervix

A 28 year old white woman was found to have a cervical tumor in the 25th week of pregnancy. Pathologic examination revealed a nonkeratinizing small cell carcinoma. After delivery by cesarean section, pelvic lymph node exploration was carried out, and all 15 nodes were free of tumor. Her condition was staged as II-A, and she was treated with local radiation. Metastatic disease became manifest almost a year later and was histologically similar to her primary disease. A Cushingoid appearance was noticed and plasma cortisol levels were elevated. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) and 17-ketosteroid (17-KS) levels were elevated and failed to suppress with dexamethasone. Plasma adrenocorticotropin (ACTH) level was elevated. Electron microscopic examination of the tumor tissue revealed neurosecretory granules. Immunoperoxidase stains for ACTH were positive. The patient's course was one of progressive decline and eventual death. A literature review revealed two other cases in which carcinoma of the uterine cervix was considered to be the source of ectopic ACTH. Some small cell carcinomas of the cervix may arise from cells of the APUD series. Small cell carcinoma of the uterine cervix may behave differently from the more commonly encountered keratinizing and large cell nonkeratinizing carcinomas of the cervix and may not respond as well to standard therapy. Ectopic hormone production, production of abnormal peptides or of vasoactive amines may be more common in small cell carcinoma of the cervix than is currently recognized, and these products may be clinically useful as tumor markers.

Source of ACTH in Cushing's Disease

Source of ACTH in Cushing's Disease

THE CELLS OF ORIGIN OF ACTH IN MAN

The evidence from ACTH-producing tumors, from the morphologic effects of excess glucorticoids on the hypophysis, and from immunocytochemistry all points to the predominant "basophils" of the human anterior lobe, the intensely PAS-possitive beta(R) cells, as the source of ACTH. Similar cells often also occur, sometimes in large numbers, in the pars nervosa. beta(R) cells can be immunostained with antibodies against alphaMSH and betaMSH, but it is likely that they actually contain the precursor molecule(s) of betaMSH, betaLPH (and may be gammaLPH). Once this is satisfactorily documented, the functional term corticolipotrops should replace the provisional name beta(R) cells. Electron microscopically, these cells contain randomly arranged granules with a maximum diameter of 300-500 nm, and occasionally small amounts of filamentous material, which increases dramatically in response to excess glucocorticoids. In the beta (R) cells of adults, a single set of granules stains for ACTH and with antibodies to betaMSH. In fetal life, ACTH cells appear early and material reactive with anti-betaMSH accumulates in them (and possibly also in cells not containing ACTH) only later. The posterior lobe beta(R) cells can be immunostained with both anti-betaMSH and antibodies against the COOH-terminal portion of ACTH, but the presence of bioactive ACTH in them remains to be shown.

ECTOPIC ACTH SYNDROME AND MEDULLARY THYROID CARCINOMA

ABSTRACT A 40 year old patient with medullary thyroid carcinoma subsequently developed Cushing's syndrome with presumably ectopic ACTH formation. The immunoreactive calcitonin in the plasma was greatly and ACTH slightly increased. Despite the excessively high calcitonin concentration the patient finally developed a serious osteoporosis which presumably resulted from Cushing's syndrome. In this case at least, a raised endogenous plasma calcitonin level did not prevent an osteoporosis caused by hypercortisolism. The autopsy revealed a bilateral hyperplasia of the adrenal cortex and a normal pituitary gland suggesting that Cushing's syndrome was probably caused by an ectopic ACTH source. Twenty-two additional cases of medullary thyroid carcinoma with Cusing's syndrome reported in the literature have been reviewed. Eighteen out of 23 patients were alkalotic which is typical of an ectopic ACTH production. In these patients the characteristic clinical signs of hypercortisolism were nearly as frequently observed (70 %) as in patients with non-ectopic Cushing's syndrome (91 %). An ectopic Cushing's syndrome occurs only in 2–4 % of advanced cases of medullary thyroid carcinoma and is a serious complication. Among the 23 patients 18 died with an average survival time of only 4.5 months after the diagnosis of Cushing's syndrome was established.

Plasma immunoreactive corticotrophin and lipotrophin in Cushing's syndrome and Addison's disease.

Plasma immunoreactive corticotrophin (ACTH) and lipotrophin (LPH) were measured in patients with raised circulating concentrations from a pituitary or an ectopic source. They were measured again in seven patients after they had received hydrocortisone. Plasma ACTH concentrations were higher than LPH concentrations in patients with a pituitary source of their hormones, whereas this relation was reversed when the source was ectopic. After hydrocortisone administration the half life of immunoreactive ACTH was 40 minutes and that of LPH 95 minutes, resulting in a reversal of the normal relation of ACTH to LPH. The use of two antisera with different specificities for measuring LPH has further shown that pituitary LPH differs from ectopic LPH. Relatively less gamma-LPH than beta-LPH was produced from ectopic sources, the relation being reversed in patients with a pituitary source for their raised concentrations. Measuring plasma LPH as well as ACTH might therefore help in deciding whether a patient with Cushing's syndrome has a pituitary or ectopic source of ACTH, which sometimes presents a difficult clinical problem.

DEMONSTRATION OF CORTICOTROPHIN-RELEASING ACTIVITY IN RAT AND HUMAN PERIPHERAL BLOOD

Corticotrophin-releasing activity of rat or human peripheral blood was examined with a sensitive in vitro CRF bioassay, using cultured rat adenohypophyseal cells and ACTH measurement by radioimmunoassay. A dose-related ACTH secretion into the medium occurred in response to plasma or serum obtained from unstressed rats or humans. The minimum effective dose was 2.5 mul (0.1% of the medium concentration). No concomitant release of TSH occurred, indicating that cellular destruction was not the source of ACTH in the medium. As previously found with hypothalamic extract, 50% of the maximum ACTH secretion produced by a given quantity of plasma occurred within 1-5 min. Fifty per cent of CRF activity was retained after plasma was boiled for 5 min. CRF activity of serum was not different in intact, 1-10 min ether-stressed, adrenalectomized, hypophysectomized or dexamethasone-treated rats. There was no significant difference in CRF activity between serum from intact rats and those with complete forebrain removal and hypophysectomy, indicating that serum CRF originates from a source outside the forebrain or pituitary. Because of the lack of correlation of blood CRF activity with conditions in which there are marked differences in in vivo ACTH concentration, it is possible that the blood CRF activity we measure is non-specific.

Secretion of ACTH and β-MSH by an Adrenal Medullary Paraganglioma

A 41-yr-old woman with Cushing's syndrome was shown to have a right adrenal medullary tumor and bilateral adrenocortical hyperplasia by adrenal venography. Her cortisolism was very marked and was unaffected by administration of ACTH, metyrapone, or dexamethasone. She had elevated plasma ACTH and β-MSH without an apparent normal circadian rhythm. Plasma samples obtained by selective venous catheterization suggested that the tumor was the source of ACTH and β-MSH and that the hyperplastic adrenal cortex was the source of cortisol. The tumor was found on postmortem examination to be a non-chromafnn paraganglioma which contained immunoreactive ACTH. Clinical and biochemical evidence of catecholamine excess was absent.

The effects of hypophysectomy on adrenocortical function in the duck (Anas platyrhynchos).

SUMMARY The general effect of chronic hypophysectomy on organ and body weights, liver glycogen, blood glucose, peripheral plasma corticosterone concentrations, and blood pressure in the duck were similar to those described for several mammalian species. The disappearance and distribution of radioactivity after the administration of [1,2-3H]corticosterone and [1,2-3H]aldosterone was studied according to a single compartment model system. When compared with sham-operated ducks, the apparent volumes of distribution and the biological half-lives of radioactivity in hypophysectomized ducks were significantly increased, and the estimated metabolic clearance rates of [1,2-3H] corticosterone and [1,2-3H]aldosterone were significantly decreased. The patterns of distribution of radioactivity and the rate of metabolism of both hormones returned towards normal when the chronically hypophysectomized ducks were treated with corticotrophin (ACTH). Fourteen days after hypophysectomy the peripheral plasma concentration of corticosterone and the estimated rate of corticosterone secretion by the adrenal fell to 10 and 4%, respectively, of the values observed in sham-operated birds. Examinations of the peripheral plasma corticosterone concentration during the first 30 min after the removal of the adenohypophysis indicated a mean biological half-life for endogenous corticosterone of 13·7 min. The rates of appearance of radioactivity in the bile, intestine and cloaca of the hypophysectomized birds suggested substantial declines in the rates of aldosterone and corticosterone metabolism. These declines could not be accounted for by the reduced rate of glomerular filtration in the hypophysectomized bird. Replacement therapy with ACTH restored the excretory patterns of both steroids towards normal. The quantitative similarities between the effects of hypophysectomy in the duck and several mammalian species make it unnecessary to postulate either a high degree of adrenal autonomy or an extrahypophysial source of ACTH in the control of adrenocortical function in the duck.

Cytological and cytochemical investigations of the adenohypophysis of the sheep.

Six types of cells were identified in the pars distalis of the sheep adenohypophysis using various tinctorial methods and cytochemical reactions: They were two types of acidophils (alpha and epsilon), two types of amphophils (zeta and delta 1) and two types of basophils (beta and delta 2). Various experiments such as castration, thyroidectomy and adrenalectomy were carried out to examine the changes in each cell type.The alpha cells were stained orange with orange G in trichrome or tetrachrome methods and showed acid hematein positive but PAS negative reaction. They were located throughout the gland except the zona tuberalis.The epsilon cells were stained red with acid fuchsin, azocarmine or erythrosin and showed positive reaction for the acid hematein test and PAS method. They were larger than the alpha cells and were distributed throughout the pars distalis especially in its peripheral area.The zeta cells were amphophilic cells stained purple with aniline blue and acid fuchsin in trichrome method. Their granules were PAS positive, but AF and AT negative, and were R type after the PFA/AB/PAS/OG method. The zeta cells were large, irregular or polygonal cells distributed in the central portion of the pars distalis. They were considered to be the only source of ACTH, since they increased in number and size and showed a marked degranulation after adrenalectomy.The beta cells were large polygonal basophils which were confined to the zona tuberalis. The PAS positive granules of the beta cells were stained selectively by AF and alcian blue but not by AT or methyl blue. The beta cells were considered to be thyrotrophs, because, after thyroidectomy, they became enlarged and degranulated cells identical with thyroidectomy cells.The delta 1 cells were small, round or oval amphophilic cells stained reddish purple with both aniline blue and acid fuchsin in the trichrome method. They were distributed throughout the pars distalis. Their granules were coarse and stained blue-black or purple in AT, purple in PAS and methyl blue, but not stained by AF.The delta 2 cells were large, oval or rounded basophilic cells and were stained light blue with aniline blue in the trichrome method. The granules of delta 2 cells showed a weak positive reaction for PAS and AT but not for AF. After castration, the delta 1 and delta 2 cells increased in number and size, degranulated, and developed into castration cells, which contained larger or smaller vacuoles in their cytoplasm. These cells were considered to be gonadotrophs.

DISTRIBUTION OF ADRENOCORTICOTROPHIC HORMONE IN THE PITUITARY GLAND

The highly vascular, anteromedial zone of hog and beef pituitary glands, which is rich in basophilic cells, contains a concentration of ACTH from 4 to 13 times that found in the rest of the adenohypophysis. The concentration of ACTH can be correlated (r = 0.96) with the relative proportion of basophilic cells, supporting the view that the pituitary basophiles are the source of ACTH. The distribution of both basophiles and ACTH in the rat adenohypophysis is more uniform than in hog or beef glands. The posterior lobe of all species examined (rat, hog, beef, and man) contains small, but significant, amounts of ACTH.

DISTRIBUTION OF ADRENOCORTICOTROPHIC HORMONE IN THE PITUITARY GLAND

The highly vascular, anteromedial zone of hog and beef pituitary glands, which is rich in basophilic cells, contains a concentration of ACTH from 4 to 13 times that found in the rest of the adenohypophysis. The concentration of ACTH can be correlated (r = 0.96) with the relative proportion of basophilic cells, supporting the view that the pituitary basophiles are the source of ACTH. The distribution of both basophiles and ACTH in the rat adenohypophysis is more uniform than in hog or beef glands. The posterior lobe of all species examined (rat, hog, beef, and man) contains small, but significant, amounts of ACTH.