Adrenal Cortical Stimulation Research Articles

Preferential Preservation of Bone Mineralisation by LHRH Agonists in the Treatment of Metastatic Prostate Cancer

Histomorphometric measurements of tumour-free bone have been undertaken in a closely matched group of patients with metastatic prostate cancer treated either by subcapsular orchidectomy (SCO) or luteinising hormone-releasing hormone (LHRH) agonists. Age, fasting morning urine hydroxyproline/creatinine ratios, alkaline and acid phosphatase levels and elapsed time after hormonal manipulation were similar in those receiving SCO (n = 8) as compared to LHRH therapy (n = 8). Results indicated that osteoid surface and mineralisation rate were significantly reduced in the SCO group (p less than 0.05); other indices were also lower in the SCO patients but failed to reach statistical significance. These changes, possibly due to increased adrenal cortical stimulation secondary to elevated gonadotrophin levels following orchidectomy suggest that medical castration by gonadotrophin inhibition may avoid unnecessary morbidity due to treatment-induced bone dysfunction.

The effect of heat-stable extract from bovine sublingual salivary glands on the carbohydrate metabolism of the rabbit

This extract (SLF 3) caused hyperglycaemia when injected intraperitoneally (i.p.) into rabbits (20 mg/kg body wt) which was maximal at 0.5 h and took 2 h to return to the initial value. SLF 3 also produced a two-fold increase in corticosteroid levels compared to controls, so the increase in blood glucose was probably mediated by adrenal cortical hormone stimulation.

Computed tomography in untreated adults with virilising congenital adrenal cortical hyperplasia

Thirteen adult patients with biochemically proven congenital adrenal hyperplasia (CAH) were examined by computed tomography (CT). Six patients had never received glucocorticoid therapy. In three of those six patients, CT revealed a tumorous transformation in one of the hyperplastic adrenal glands. In the seven patients with CAH who were treated since childhood, no mass could be demonstrated on CT. The development of an adrenocortical tumour due to chronic adrenal cortical stimulation by excessive adreno-cortico-trophic hormone (ACTH) production in adult patients with untreated CAH may not be a rare occurrence, as is demonstrated in this series. It is important not to confuse this entity with a primary virilizing adrenal tumour which requires a different form of treatment. In case of tumorous transformation in untreated adults with CAH, suppressive therapy with CT control should be favoured over surgery, as long as the tumour is ACTH-dependent. Moreover, these observations illustrate the desirability of lifelong glucocorticoid therapy in patients with CAH, including adult males who biochemically may not require suppression of steroid androgen excess.

Activity of [des-Aspartyl1]-Angiotensin II in Primary Aldosteronism

This study describes the effects of [des-Aspartyl(1)]-angiotensin II ([des-Asp]-AII) on blood pressure and aldosterone production in patients with primary aldosteronism due to aldosterone-producing adrenal adenoma (APA) and idiopathic adrenal hyperplasia (IHA), and in normotensive control subjects. 10 patients with primary aldosteronism, 7 with APA and 3 with IHA, and 6 normotensive control subjects were placed on a constant 150-meq sodium diet for 4 days. [des-Asp]-AII was infused for 30 min at 6, 12, and 18 pmol/kg per min. Three groups of patients were identified on the basis of aldosterone response to [des-Asp]-AII. Group I, composed of normotensive control subjects, showed incremental increases in plasma aldosterone concentration from 6+/-1 to 14+/-3 ng/100 ml (P < 0.01) with [des-Asp]-AII infusion. Group II, composed of patients with primary aldosteronism, showed incremental increases in plasma aldosterone concentration from 33+/-8 to 65+/-13 ng/100 ml (P < 0.05) with 12 pmol/kg per min of [des-Asp]-AII. Group III, also composed of patients with primary aldosteronism, showed no increase of plasma aldosterone concentration with [des-Asp]-AII. Groups I and II showed similar percentage increases in plasma aldosterone concentration (P = NS). Group III showed significantly lower aldosterone responses than group I (P < 0.01). Group II included all patients with IHA and two patients with APA. Group III included only patients with APA. The blood pressure responses to [des-Asp]-AII of subjects in group I did not differ significantly from those of groups II or III.Thus, patients with IHA and a subgroup of patients with APA showed responsiveness to [des-Asp]-AII which was limited to adrenal cortical stimulation of aldosterone biosynthesis. This suggests that adrenal responsiveness to angiotensin is a major control mechanism in some forms of primary aldosteronism. The differential adrenal responsiveness to [des-Asp]-AII in patients with APA indicates either that there are two distinct subpopulations of APA, or that alteration in tumor response to angiotensin occurs during the natural progression of the disease history.

Inhibition of Hepatocarcinogenesis by Adrenocorticotropin in Aflatoxin B1-Treated Rats2

We examined whether hormones would modify the carcinogenic action of aflatoxin B1 (AFB1). Four groups of inbred Fischer rats received AFB1, 125 mug per animal, weekly per os. In three of the groups, certain hormones were administered simultaneously: One group received 1 U growth hormone (GH) sc weekly, another was given 4 U adrenocorticotropin (ACTH) weekly, and a third received 0.5 U insulin weekly sc. AFB1, ACTH, and insulin were given for 20 weeks; GH was given for only 10 weeks. The control group did not receive hormone adjuvant. In each group, 4 animals were killed at 7, 14, 21, 28, and 35 weeks; the remaining rats were killed at 77 weeks. Their livers were carefully examined and samples prepared for light and electron microscopy. Animals receiving AFB1 and ACTH failed to exhibit hepatocellular carcinoma. On the other hand, malignant lymphoma appeared at 56 weeks in 3 of the 6 surviving males on this regime. AFB1, alone or when given with insulin or GH, caused hepatocellular carcinoma in all animals; in these, lymphoma was not observed. Lymphoma comprised two cell types, each with similar neclear characteristics but differing in their nucleocytoplasmic ratios and in the amount and distribution of cytoplasmic organelles. Alterations leading to hepatocellular carcinoma were examined at various stages of development. "Basophilic hyperplasia" reflected an increase in free ribosomes. "Hyperplastic nodules" were composed of hepatocyte aggregates with characteristics similar to those encountered in the earlier stage. Both the "neoplastic nodules" and hepatocellular carcinomas were formed by cells containing large, "smooth fingerprints" and free ribosomal aggregates. These features supported the concept that AFB1 impairs ribosomal binding to endoplasmic reticulum membranes. The failure of ACTH-treated animals to develop hepatocellular carcinoma was ascribed to the effect of adrenal cortical stimulation upon membrane-polysome binding.

BLOOD GLUCOSE LEVEL IN MICE

ABSTRACT The hypoglycaemic effect of synthetic tetraicosapeptide corticotrophin was investigated in NMRI mice in order to determine its physiological significance as well as its mechanism of action. It was found that in normal non-fasting mice corticotrophin produced a maximal hypoglycaemic response at a dose level of about 5 μg per 20 g mouse (1250 milliunits per 20 g mouse). The ED50 of the hypoglycaemic effect was about 1000 times larger than the ED50 for adrenal cortical stimulation. Immunoassayable insulin was markedly increased 15 minutes following 5 μg of corticotrophin, whereas following a maximal steroidogenic dose (1.6 nanogram) or following ether stress the plasma insulin levels were normal. In adrenalectomized mice the administration of 5 μg of corticotrophin had practically no effect on the blood glucose level, whereas pretreatment with a glucocorticosteroid in adrenalectomized mice markedly restored the hypoglycaemic response. Acutely hypophysectomized mice showed a hypoglycaemic response to corticotrophin indistinguishable from that found in normal mice, whereas animals hypophysectomized 3–7 days before corticotrophin injection showed a smaller response. Corticotrophin in a dose of 5 μg per 20 g mouse had no hypoglycaemic effect in mice with manifest alloxan diabetes. Corticotrophin injected 5 minutes following a diabetogenic dose of alloxan hardly had any measurable effect on the acute initial alloxan hyperglycaemia, whereas the latter was greatly reduced when corticotrophin was given 5 minutes before alloxan administration. Pretreatment with corticotrophin did not change the frequency or intensity of the ensuing diabetic condition in mice. It is concluded that the corticotrophin induced hypoglycaemia is dependent on 1) the presence of normally functioning pancreatic beta-cells; and 2) the presence of glucocorticosteroids. It is doubtful whether the observed hypoglycaemia has any physiological significance.

FETAL-MATERNAL ADRENAL CORTICAL RESPONSE TO STRESS IN THE INTACT AND HYPOPHYSECTOMIZED RAT.

The secretion of ACTH in response to stress was studied in both maternal and fetal rats. The stress response of the hypophysectomized pregnant rat was also investigated. In intact pregnant rats there was an adrenal ascorbic acid depletion (–27%) and corticosterone increase (+144%) which did not occur in the stressed hypophysectomized pregnant rats. Fetuses from intact and hypophysectomized pregnant rats showed no evidence of adrenal cortical stimulation in response to histamine injection, surgery, explantation in vitro for 40 min or ether anesthesia of the mother. It is concluded that 1) placental ACTH is not mobilized in response to stress, and 2) the fetal rat does not exhibit an adrenal cortical response to stress. (Endocrinology74: 737, 1964)

Effect of acute alcohol intoxication on steroid output of rat adrenals in vitro.

Ethyl alcohol, 2 g/kg in 20% solution, was given to rats by gavage and the adrenals were removed 1 1/2 hr later and incubated in vitro. Their corticosteroid production was not significantly different from that of glands from water-treated or untreated controls. However, when this dose of alcohol was administered by intraperitoneal injection, a significant elevation in adrenal steroid output was observed. Increasing the dose of alcohol to 4 g/kg by stomach tube also evoked an increased adrenocortical response, but when this total dose was divided into two spaced doses, each one of 2 g/kg by stomach tube, 1 1/2 hr apart, no significant alteration in adrenocortical production was observed, despite higher blood alcohol levels and equally deep intoxication. Thus, although the blood alcohol level attained may influence the activity of the adrenal cortex, the rate of change in blood and tissue alcohol levels also seems to be a significant factor in determining whether adrenal cortical stimulation will occur. None of the treatments appeared to modify the relative proportions of the various steroids released.

THE EFFECT OF REPEATED ALCOHOLIC INTOXICATION ON ADRENAL ASCORBIC ACID AND CHOLESTEROL IN THE RAT

Groups of adult male and female albino rats received daily gavage of 1.25 ml of water or of 20% ethanol per 100 g body weight for a period of 1 month, and were killed either 1.5 hours or 24 hours after the last dose. Such daily treatment with either water or alcohol, ending 24 hours before death, did not result in any significant change from control values in the relative weight of the adrenal glands, or their ascorbic acid and cholesterol contents. No changes in these values were found in animals which received an additional dose of water or alcohol 1.5 hours before death. The female rats showed lower values for adrenal ascorbic acid content than the males in corresponding groups, but did not differ from the males with respect to the effects of the various treatments. A similar experiment with male rats only, carried on for 2 months, also showed no significant differences among any of the treatment groups.Measurements of the degree of intoxication produced by single doses of ethanol were carried out by means of the inclined-plane test. Intraperitoneal injection of 2 g/kg produced much more rapid and marked intoxication than did gavage with either 2 or 4 g/kg.It was concluded that daily gavage for 1-2 months with ethanol in a moderately intoxicating dose (2 g/kg) does not constitute a stimulus to adrenal cortical activity or result in exhaustion atrophy of the adrenal cortex, and that adrenal cortical stimulation is not an invariable accompaniment of acute or chronic alcoholic intoxication.

THE EFFECT OF REPEATED ALCOHOLIC INTOXICATION ON ADRENAL ASCORBIC ACID AND CHOLESTEROL IN THE RAT

Groups of adult male and female albino rats received daily gavage of 1.25 ml of water or of 20% ethanol per 100 g body weight for a period of 1 month, and were killed either 1.5 hours or 24 hours after the last dose. Such daily treatment with either water or alcohol, ending 24 hours before death, did not result in any significant change from control values in the relative weight of the adrenal glands, or their ascorbic acid and cholesterol contents. No changes in these values were found in animals which received an additional dose of water or alcohol 1.5 hours before death. The female rats showed lower values for adrenal ascorbic acid content than the males in corresponding groups, but did not differ from the males with respect to the effects of the various treatments. A similar experiment with male rats only, carried on for 2 months, also showed no significant differences among any of the treatment groups.Measurements of the degree of intoxication produced by single doses of ethanol were carried out by means of the inclined-plane test. Intraperitoneal injection of 2 g/kg produced much more rapid and marked intoxication than did gavage with either 2 or 4 g/kg.It was concluded that daily gavage for 1-2 months with ethanol in a moderately intoxicating dose (2 g/kg) does not constitute a stimulus to adrenal cortical activity or result in exhaustion atrophy of the adrenal cortex, and that adrenal cortical stimulation is not an invariable accompaniment of acute or chronic alcoholic intoxication.

Induction of Mammary Secretion in Rats by Electrical Stimulation.

SummaryMature virgin female rats were injected subcutaneously with 10 μg estradiol daily for 10 days to produce mammary lobule-alveolar development. For the following 5 days, all except 10 controls were electrically stimulated twice daliy for periods of 30 seconds on head, lumbar region, nasal mucosa and nipples. Control rats showed regression of the mammary glands to a bare duct system and no secretion, whereas almost all of the electrically stimulated rats showed variable degrees of mammary secretion and maintenance of lobule-alveolar structure. Adrenal cortical stimulation in all electrically-stimulated groups was indicated by significant decreases in thymus weight. It is concluded that electrical stimulation of these areas in the rat induces release of both prolactin and ACTH, probably through autonomic and CNS pathways.

Serum lipoprotein and cholesterol changes in nephrectomized dogs maintained by peritoneal dialysis.

The serum lipoproteins and cholesterol were studied in dogs after bilateral nephrectomy. In most cases the animal's life was prolonged by dialysis. Cholesterol and the lower density lipoproteins increased and remained elevated while the high density –S 1–10 fraction usually decreased moderately. Dogs fed a high protein diet exhibited similar but more pronounced lipid changes and arteriolar necrosis, and no correlation was found between elevation of blood pressure and lipid concentration. Ureteral ligation elicited qualitatively similar lipid changes to arenal dogs fed raw kidneys. As one control, well nourished dogs unfed for 5 days showed no significant serum lipid changes. It is suggested that, by analogy, the postnephrectomy lipid pattern may be in part due to action of products of adrenal cortical stimulation.

THE SUBCUTANEOUS ASSAY OF CORTICOTROPHIN A

In 1953 it became evident (Wolfson, 1953), that the classical assay of corticotrophin, the so called Sayers test (Sayers, 1948) does not give much information about adrenal cortical stimulation after subcutaneous or intramuscular administration of the hormone therapeutically since it cannot measure the degree of extravascular inactivation of corticotrophin, which may vary according to the chemical treatment of the pituitary glands in the process of purification. The United States Pharmacopoeia, fifteenth revision (U. S. P. XV, 1955), therefore prescribes the application of a subcutaneous assay method for corticotrophin devised for extravascular use. This method is essentially the same as the Munson modification of the Sayers test (Munson, 1948) with the exceptions, that corticotrophin is administered subcutaneously at higher dose levels in 15 % gelatine in 0.5 % phenol, and that the time elapsing between injection and adrenalectomy is three hours. In a previous paper (Rerup, 1957) it was shown that quantitative comparative

Effect of stimulation of adrenal cortex on blood pepsinogen in animals and man.

SummaryBlood pepsinogen levels were measured in cats, dogs, rats, and man following acute and chronic administration of adrenocorticotrophic hormone and/or cortical steroids. Despite demonstration of adrenal cortical stimulation, pepsinogen activity did not increase. The data indicate that blood pepsinogen activity does not constitute an index of adrenal cortical activation.

Metabolic significance of nervous symptoms due toattacks of vomiting with ketosis in children

Summary The metabolic study of fourteenchildren with severe nervous disorders, secodary to attacks of vomiting with ketonuria, showed that the clinical picture was related once to plasma hypotonia, twice to acidosis with ketosis, and eleven times to hypokaliemic alkalosis. Thus hypokaliemic alkalosis may coexistwith severe ketosis and, in our patients, was the most common cause of the severe symptoms. Its clinical aspect is variable. When hypokaliemia is moderate, tetany due to alkalosis with superficial breathing is common. Under 2.5 meq. per liter, coma or lethargy, muscular hypotonia or flaccid paralysis, edema of the extremities, paralytic ileus, superficial respiration, and urine retention are the clinical features noted. Laboratory determinations confirm pH and bicarbonate increase and the fall of chloride and potassium in blood. The ECG record shows changes related to hypokaliemia. Clinical and biological recovery is achieved within several days under the administration of potassium chloride at a dosage of 200 to 400 mg. per kilogram of body weight daily. The pathogenesis of hypokaliemic alkalosis is complex: digestive loss of chloride and potassium, adrenal cortical stimulation, fasting, and chiefly excessive administration of sodium bicarbonate and citrate in the treatment of the attacks of vomiting with ketosis. The coexistence of ketosis and of ametabolic alkalosis raises interesting metabolic problems: potassium deficiency may favor the occurrence of ketosis through impairment of carbohydrate metabolism; on the contrary, ketosis modifies the urinary syndrome of hypokaliemic alkalosis and is useful to a point because it balances a partial alkalosis by anions. The EEG study of children with hypokaliemic alkalosis and ketosis shows impressive diffuse and symmetric slow waves which disappear, with a short lag, when the metabolic disorders are controlled. These EEG changes are likely to be directly related to alkalosis and impaired hydration of the brain cells. From the practical viewpoint, the relative frequency of hypokaliemic alkalosis in the course of the nervous disorders, secondary to vomiting with ketosis, in contrast to the uncommon occurrence of ketoacidosis, leads to a cautious establishment of the therapeutic measures. The best clinical sign of diagnostic value is the type of the respiration: superficial respiration in alkalosis, hyperpnea in acidosis with ketosis. Nevertheless, chemical determinations, ECG and EEG records are necessary to establish the type and degree of the electrolyte and acid-base imbalance and the management to be used: sodium bicarbonate in acidosis, potassium chloride in hypokaliemic alkalosis.

Studies in histochemistry: quantitative histological distribution of cholesterol in adrenal glands of the cow, rat and monkey, and effects of stress conditions, ACTH, cortisone and desoxycorticosterone.

AS PART of a broader program dealing with the quantitative histochemical basis for the functions of the adrenal gland, this study on cholesterol extends recent work on ascorbic acid (Bahn and Glick, 1954a, b), potassium and lipid (Glick et al., 1955), phenolsulfatase (Glick et al., 1954), enzymatic conjugation of m-aminophenol with sulfate and glucuronate (Glick and Stecklein, 1954), β-glucuronidase (Wattenberg and Glick, 1953; Nayyar and Glick, 1955), and coenzyme A (Malmstrom and Glick, 1954). The fall in the cholesterol content of the adrenal cortex, like that of ascorbic acid, has been taken as an indication of adrenal cortical stimulation and, as with ascorbic acid, the previous quantitative work on cholesterol dealt with analyses of whole glands or whole cortices (Long, 1947). The present investigation was designed to carry the analyses to the individual zones so that a histological differentiation of the quantitative effects could be made.

The intranasal use of hydrocortisone alcohol.

THE RECENT reports of Bordley and his co-workers* concerning the changes in the tissues of the upper air passages under adrenal cortical stimulation following the intramuscular administration of corticotropin (ACTH) and the oral administration of cortisone were received enthusiastically by otolaryngologists. The authors observed that under treatment with these hormones the allergic nasal mucous membranes lose their swelling, develop a slate pink color, and are covered with a layer of clear mucus. Polyps lose their translucence, begin to shrink, and, in many instances, disappear completely. These changes correlated with the initial eosinopenia developing under corticotropin therapy; in one patient, an intranasal spray of cortisone caused a slow but definite regression of polyps. Dill and Bolstead3found that a local application of cortisone resulted in a marked improvement in 12 (48%) of 25 patients treated and some, but doubtful, improvement in 6 patients (24%); the rest (28%) showed no change

Changes in blood-clotting time and blood-sugar levels in relation to electroshock therapy.

Summary Sixteen psychotic patients were studied under stress. Electroshock therapy was used as stressor. These patients were divided into three groups: Group 1 was subjected to EST according to hospital routine; Group 2 was handled in identical fashion, with the exception that no electric current was applied; and Group 3 consisted of patients who were suddenly subjected to EST without anticipating it. Blood-sugar levels and the bloodclotting time were determined before and after EST, or, in Group 2, anticipated EST. It was shown that there was a marked shortening of the bloodclotting time and elevation of the blood-sugar level preceding and following EST, which was most marked immediately before and after EST, when the accompanying anxiety and excitement were at their peak. The changes in the bloodclotting time and blood-sugar level were practically identical in Groups 1 and 2, indicating that the application of electric current to the brain had no direct influence on the changes of these values. There was no significant deviation from normal in Group 3 where electrical current was applied, but anxiety and anticipation was at a minimum. The deviations of the BCT and the BS indicate some adrenomedullary stimulation, which we have shown to be independent of EST, but produced by anticipation and anxiety. It was further speculated that the adrenocortical stimulation, which has been shown to follow EST, is not a direct action of electricity on the hypothalamus and pituitary, but rather follows the stimulation of the pituitary by adrenalin to produce ACTH. The electroshock therapy then probably is nonspecific as far as the adrenal medullary and cortical stimulation is concerned, and may be replaced by any noxious stimulus which produces severe anxiety and excitement.

Quantitative evaluation of primary adrenal cortical deficiency in man

1. 1. A method designed to afford a quantitative appraisal of adrenal cortical functional capacity has been devised. It consists of a two-fold test: (1) a standard metabolic regimen capable of provoking acute adrenal insufficiency in the severely adrenal-deficient individual; and (2) powerful adrenal cortical stimulation by means of intravenous corticotrophin. 2. 2. Classification of patients into one of four separate grades of adrenal cortical functional capacity is proposed on the basis of multiple criteria of response to each portion of the test. Intrinsic and extrinsic grounds for confidence in the accuracy of the method are presented.

The effect of ACTH on the blood level of 17-hydroxycorticosteroids and the circulating eosinophils in man.

In clinical practice the intramuscular route of administration of ACTH remained the method of choice until Gordon et al. (1950) demonstrated the usefullness of the intravenous route, using a continuous infusion extending over a period of days. In order to maintain a continuous activation of the adrenal cortex the intramuscular administration of ACTH must be repeated several times a day. The continuous intravenous administration of ACTH is an effective and economical method of inducing adrenal cortical stimulation in clinical cases but has the disadvantage of many hours of immobilization.