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On dairy calves (totally 35 animals; 14 male; 21 female) measurements of rectal temperature, heart rate and blood values (acid-base balance, Hb, Hk, MCHC, gas content and gas pressure, hemoglobin derivatives, cortisol, total protein, albumin, blood urea, creatinine, glucose, lactate, Ca, Mg, P, Fe) and of salivary cortisol were done before and after i.v. ACTH application and liquid feed intake at 5, 15, 40 and 60 days of life age. Mean values of P-cortisol, S-cortisol, heart rate and COHb were elevated and those of total protein, albumin, Mg, Hb, Hk, O2CAP were decreased after i.v. ACTH and feed intake. Mean glucose and P concentration changed differently in younger and older calves after ACTH and liquid feed intake. Changes of Ca and Fe concentration were not significant at all age points. Effects of gender could be found for cortisol, O2CONT, MCHC, total protein, creatinine, lactate, Mg, and Ca at some age points. Initial P-cortisol levels were higher at 5 and 15 days than at 40 and 60 days of life, the levels after stimulation were higher at 5 days than at 15, 40 and 60 days. Initial levels of S-cortisol were significantly different between all age points, the levels after stimulation were not different. Female calves had significantly greater P-cortisol values at 40 and 60 days as male calves and at 40 days greater S-cortisol values too. Significant correlations between P-cortisol and S-cortisol could be found before stimulation (5 days: r = 0.626; 15 days: r = 0.366; 60 days: r = 0.357) not thereafter. All measures except P-cortisol, S-cortisol, O2SAT, and HHb had significant correlations before and after ACTH and liquid feed intake indicating great interindividual variation and individual specificity of reaction within this growth period. Results were discussed under the viewpoint of reactivity of adrenocortex and steroid distribution concerning organ specific effects of steroids in calves.

Statistical analysis of normally occurring cortisol levels in serum and urine of horses served to recommend thresholds for this corticosteroid in these body fluids, as application of exogenous cortisol as well as ACTH may elevate the cortisol concentrations above the proposed threshold. The present study contributes to the general issue of how to establish thresholds for trotting horses upon sportive examination. 100 randomly selected post competition serum and urine samples, respectively, were submitted to cortisol analysis by means of HPLC. Concentrations of the endogenous corticosteroid in serum and urine followed a log-normal distribution with mean values of 61 and 49 ng/ml, respectively. The probability was 1: 100,000 to exceed concentration limits of 230 (serum) and 394 ng/ml (urine). Designation of thresholds for cortisol has proven problematic and is discussed here.

An experimental investigation was performed to examine the influence of ACTH on the long-term results of muscle regeneration after nerve repair. Twenty albino-rabbits ("White Russians") served as the animal model. The epi-perineural neurorrhaphy of the fibular nerve was carried out under microscopic control with 11x0 sutures. A computer-supported light-microscopic analysis of representative muscle-fiber diameters was performed for detection of nerve regeneration on the effector muscle of the peroneal nerve, the anterior tibial muscle, after 3, 4, 5 1/2, 7, and 8 months. In addition, the nerves were examined by light microscopy using not only standard techniques but also surgical immunohistological staining techniques (APAAP). The acceleration of nerve regeneration already described in the literature was confirmed by our investigations. However, the results observed after eight months were similar, regardless of the ACTH dosage applied. Muscle regeneration was not influenced by the injection of ACTH. It therefore does not appear justifiable to clinically apply ACTH for improvement of nerve and muscle regeneration.

A survey is given on the regulation of the formation of corticoliberin and of pro-opiomelanocortin and of ACTH, respectively, and on the significance of these compounds. The formation of pro-opiomelanocortin is furthered by corticoliberin, vasopressin, oxytocin and angiotensin II. Receptors for the binding of corticoliberin appear in numerous parts of the central nervous system. In various diseases the content of corticoliberin in the plasma and in certain tissues is changed. The inhibition of the ACTH secretion by glucocorticosteroids takes place via a decrease of the formation of corticoliberin and by a reduction of the equipment of the corticotrophic cells with receptors for its binding. The secretion of corticoliberin and of ACTH, respectively, is increased by loads, by hypoglycaemia, by blood losses, by hypoxia and by infections. In the glucocorticosteroid receptors there are 2 types with different affinity to cortisol and corticosterone.

The temporal changes of aldosterone concentration and renin activity in plasma under the influence of stimulating and inhibiting factors were tested in two patients with Bartter's syndrome. There was a normal response to potassium and sodium administration, spironolactone, angiotensin II, ACTH and dexamethasone. Changes in plasma-aldosterone concentration, as measured at frequent intervals during angiotensin II infusion, suggest differential regulation of aldosterone synthesis by angiotensin II. In one patient the symptoms improved with administration of glucocorticoid derivatives.

The dynamic response of the adaptive closed-loop control system hypothalamus-anterior pituitary-adrenal cortex after application of short-time disturb pulses were examined experimentally in the pig. Blood sampling was performed biologically non-reactive by chronically implanted vascular catheters in the upper vena cava. A circadian biphase periodical dynamics characterizes the distrubance response of the adaptive control system, respectively, its direct and indirect parameters. After distrubance variables induced initial excess the plasma corticosteriods undershoot the basic level over a long period. Conversely, the dynamics of the eosinophils is determined through an initial eosinopenic phase and a subsequent typical overshoot. Periodical dynamic is absent in the steady state. The controller of the adaptive system does not show any spontaneous activity in the steady state without stress. The absence of an endogenic periodicity of the dependent parameters likewise gives evidence of an active oscillator. On the other hand, the controlling unit of the adaptive system constitutes a control response of circadian periodicty after activation by disturbance variables in pulse shape. The high damping of the control system terminates the transient state within 24 hours, and the corticosteriods and the eosinophils reach the steady state level. This control quality of the adaptive control system gains a high importance in the origination of the spontaneous circadian periodicity by corticosteriods and eosinophils and for the biological compensation of exogenous distrubance variables.

Peptide chemistry has reached a plateau on which more work is devoted to the improvement of known basic principles than to the development of really new methods. As a consequence, routine syntheses of peptides concentrate on few protecting groups and coupling procedures only. The recent progress in purification of peptides by liquid chromatography helped to promote this trend. Meanwhile, recombinant technology permits the synthesis of proteins and possibly of some lower peptides, too. It cannot compete, however, with chemical solid-phase synthesis of a newly discovered peptide with up to about 40 amino acids in speed but may take over the synthesis for large-scale production. Peptides containing modified or non-natural structures, which are often superior to the natural compounds as drugs, will remain subject of chemical synthesis, too. Present research focuses on the role of peptide and protein factors in the immune response and on structure and biological activities of neuropeptides.

The adrenocortical function after induction of anaesthesia using either etomidate, methohexital or midazolam was examined in 30 patients undergoing open heart surgery (ACVB). Midazolam and methohexital did not suppress the typical stress response assessed from the magnitude of the ACTH, cortisol and aldosterone levels. The ACTH-test was also normal. In contrast, induction of anaesthesia using etomidate led to a progressive fall in cortisol and aldosterone accompanied by an increase in ACTH. The ACTH-test resulted in only a minor increase in adrenocortical hormones. Thus an induction dose of etomidate, in contrast to methohexital and midazolam, markedly alters the normal function of the adrenal cortex. This side-effect of etomidate lasts for at least 4 hours but is no longer detectable after 24 hours.

The effects of turpentine oil, vaccines, pyrogens, corticotrophin, prednisolone, adrenaline and autologous haemoglobin on the haptoglobin content of plasma was investigated in cattle and pigs. In comparison with rabbits, relatively small doses of turpentine oil led to a considerable increase in haptoglobin, a 50% increase occurring within 4 to 6 days in pigs and only 1.5-2 days in cattle. Bacterial products also increased haptoglobin. It was confirmed that pigs react very rapidly (after 8 hours) to injection of corticotrophin, prednisolone or adrenaline with an increase in plasma haptoglobin. Following complete saturation of infused haemoglobin by haptoglobin, new haptoglobin was rapidly formed, so that the initial haptoglobin concentration was regained about 24 hours after infusion of haemoglobin.

The effect of the antiserotoninergic agent cyproheptadine (C) on the adrenal system was studied in male rats, the adrenocorticol function of which was assessed by analysis of the urinary excretion of free corticosterone. After a feeding period with 0.5--0.7 mg C/kg body weight/day for several months significant differences in the urinary excretion of free corticosterone were only found when the rats were exposed to systemic stress stimuli as cold (increase from 118.7 +/- 5.3 to 305.5 +/- 5.1 vs. 417.8 +/- 48.6 ng/d in the controls; p less than 0.001) and hunger (no increase of free corticosterone in treated animals as compared to an increase to 446.0 +/- 53.6 ng/d in the controls). In contrast to these findings no effect of C was seen when studying the neurotropic stress stimuli reserpine and ether. The same was true when measuring free corticosterone under basal conditions and after ACTH- or metyrapone stimulation. It is concluded that serotonin plays a major role as hypothalamic neurotransmitter in systemic but not in the studied neurotropic stress stimuli. The site of serotonin action does not comprise adrenal synthesis of steroids and the hypothalamic-pituitary-adrenal feedback system, as is shown by the ACTH- and metyrapone stimulation tests.

After long time application of homologous ACTH the morphokinesis of the adrenal cortex of the pig was investigated experimentally. Following results were obtained: 1. In view of the controls the absolute and relative weight of the adrenals is raised considerably. 2. The progressive transformation is followed by the disappearance of the zonal structure of the adrenal cortex, and the parenchyma get the picture of fasciculata cells generally. 3. Nearly exclusive the zona fasciculata consists of great, pale activated spongiocytes with 2 nucleoli frequently. Topochemically glycogen and the lipids are inconstant, however the histochemical activity of succinodehydrogenase, lactate dehydrogenase, acid and alkaline phosphatase are considerable raised in regard of the controls. 4. The zona fasciculata contains degenerated cells isolated only. Signs of extensive regressive changes are not present. 5. The zona glomerulosa is dissolving or eliminating respectively. The consequences for the synthesis of the adrenal steroid hormones are discussed. 6. A large, spongy subcapsular blastema with several cell layers and a rich capillary network develop between the fibrous capsula of the adrenal and the zona fasiculata. The fasciculata cells are the direct continuation of the subcapsular blastema. The blastema contains neither glycogen nor lipids and histochemical activities of the enzymes are absent, too. The significance of the subcapsular blastema for the morphological and functional adaptation of the adrenal cortex in stress are discussed. Under the conditions of the closed hypothalamo-hypophyseal-adrenal control system the new origin of cells (hyperplasia) is not significant for the morphokinetic adaptive reactions of the adrenal cortex. Rather the subcapsular blastema represents a reserve area which after the destruction of the endocrine parenchyma through specific pathogens the organism enabled to the regeneration of the adrenal cortex.

The basis of this investigation was the question of whether low plasma cortisol concentrations during epidural anaesthesia are caused by sympathetic denervation of the adrenals. In 6 otherwise healthy patients undergoing upper abdominal operation 15-20 ml 0.75% bupivacaine was given via epidural catheter which had been inserted thoracically. Ringer's lactate solution 1,000 ml was infused during the time of onset of anaesthesia. When segmental epidural anaesthesia had spread from T2/3 to T12/L1/2 0.01 U/kg of ACTH were given intravenously. 5, 10, 20, and 30 minutes thereafter plasma ACTH and cortisol concentrations were measured. The same experimental procedure was carried out in a control group without epidural anaesthesia. The patients in both groups were unpremedicated and unanaesthetized. Plasma ACTH levels rose from 100 pg/ml (basic values) to 500-600 pg/ml immediately after ACTH injection in both groups and then decreased logarithmically. The increase of plasma cortisol concentrations was significant 15 minutes after the ACTH peak and rose from 0.28-0.3 mumol/l (10-11 micrograms/dl) up to 0.7 mumol/l (25 micrograms/dl) in both groups. We can, therefore, rule out that thoracic epidural anaesthesia with 0.75% bupivacaine impairs ACTH stimulated cortisol secretion.

Exophthalmos has been induced in carp by injecting thyrotropin releasing hormone (TRH) (PYRO-glutamyl-histidyl-prolinamide) into the coelom. This effect was dose-dependent (dose range 5-750 mug). It was significantly potentiated by prior administration of beta-1 minus 24 coricotropin (Synacthen, Ciba) and inhibited by prednisclone. No significant increase was obtained with 2-phenylalanine-8-lysire-vasopressin (Octapressin, Sandoz). The results show that in the fish model, TRH exerts an exophthalmogenic effect by stimulating endogenous TSH, whereas in man this is not the case. They afford further evidence that the carp model does not reproduce the conditions which occur in ophthalmic Graves' disease.

Angiotensin was regarded as the major stimulus of aldosterone secretion until the late sixties, when the discussion about the regulation of aldosterone release has been renewed. The present study demonstrates the response of plasma renin activity, aldosterone in serum and electrolytes in serum and urine to ACTH (0.25 mg Synacthen i.v.), pretreatment with dexamethasone (2 mg Millicorten p.o.) and to combined administrations of furosemide (40 mg Lasix i.v.) + potassium (80 mmol Kalinor p.o.) and furosemide + propranolol (5 mg Dociton i.v.) in eight healthy volunteers. Plasma renin activity and aldosterone were measured by radioimmunoassay, electrolytes in serum and urine according to routine methods. ACTH increases aldosterone without influencing plasma renin activity. Pretreatment with dexamethasone decreases aldosterone and stimulates renin response to upright posture. Potassium delays the increase of plasma renin activity after furosemide and propranolol inhibits the furosemide-induced renin release, both without impairing aldosterone secretion. We conclude that the regulatory system of aldosterone production is far more complex than suggested by the concept of the renin-angiotensin-aldosterone-system.

No marked gluconeogenetic performance was recordable from nursed piglets aged, between one and five days, in response to ACTH nor glucocorticosteroid application. Store pigs, aged twelve weeks, however, exhibited glucose rises of 34 per cent one hour after injection or 55 per cent three hours from ACTH application. The point was made, in an attempt to elucidate the above findings, that in newborn piglets, few days after birth, the gluconeogenetic capacity is insufficient because of functional immaturity of the liver. The behaviours of several metabolites in the liver and muscles of store pigs were examined under differentiated model conditions to check up and verify that view.

Both medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are effective in the treatment of metastatic breast cancer. Although the dose-dependent mode of actions of MPA have been extensively clarified, there is still some uncertainty regarding the mode of actions and dosage of MA. Thirty-three patients with metastatic breast cancer were treated with various dosages of MA under a phase-II study. Eight patients were given 200 mg, 9 X 400 mg, 10 X 600 mg and 6 X 800 mg MA daily per os. The LH, FSH, TBI, T3, T4, TSH, ACTH, aldosterone, testosterone, prolactin and cortisol levels were determined regularly during treatment to enable the investigation of the pharmacodynamics of MA. A complete remission was achieved in two patients, a partial remission in seven patients and there was no change in eight patients (total responder rate 51.5%). The clinical and endocrine changes therefore suggest that the dose-dependent mode of actions of MPA and MA are identical. Equivalent dosages of MPA are 1000-1500 mg per os and of MA 160-200 mg. Furthermore, similar relationships between the endocrine changes and remission behaviour of MA and MPA have been observed. Persisting tumour remissions are inevitable under cortisol suppression and normal prolactin, aldosterone and ACTH levels.

ACTH affects behavior of rats. The results of the reported experiments suggest that ACTH effects on conditioned behavior are the result of an improved motivation or attention. The ACTH fragments, ACTH 4--10 and ACTH 4--9, have the behavioral effects of ACTH but are devoid of endocrine activities. The ACTH 4--9 analog H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) has behavioral activity after oral administration. ACTH-like-peptides restore the behavioral deficiencies of hypophysectomised rats and delay extinction of conditioned behavior of normal rats independent of the type of conditioning. So is extinction of pole jump avoidance and extinction of conditioned tast aversion delayed after Org 2766. Moreover ACTH-like peptides reduce the behavioral deficit in rats with amnesia even when the treatment is given two weeks after the induction of amnesia. In man the administration of a single dose of ACTH 4--10 on Org 2766 reduces the duration of lapses as well as the number of errors of volunteers in a continuous performance task. These and similar observations suggest that ACTH-like peptides may be of practical consequence for the therapy of patients with impairments of cognitive processes.

In plasma of newborn piglets 12.6 +/- 2.9 mug cortisol/100 ml was estimated radioimmunologically. During the first 24 hours of life the concentration decreases to 1/3 of the starting level. After application of 5 IU ACTH/kg body weight, there was in newborn as in 5-day-old piglets an increase in the concentration of cortisol, while an influence on the level of glucose in plasma could not be detected in 0-day-old animals.

Radio-immunological estimation of free cortisol in urine in a group of normal persons showed a median daily excretion of 42,5 +/- 22,8 mug (n = 31) using radio-loss-labelling, extraction, and thin layer chromatography. After simple extraction the median value was 54.1 +/- 15.3 mug/d (n = 10). Radioimmunological estimation in simple urine extract seems to be sufficient for routine clinical purposes. The estimation of free cortisol in urine permits a better differentiation between normal adrenal function and adrenal hyperactivity than the determination of 17-hydroxycorticosteroids (17-OHCS). This is shown by comparison of 1) the frequency distribution of the basal values of 17-OHCS and free cortisol in normal persons and in Cushing's disease, 2) the suppression effect of dexamethasone on 17-OHCS and free cortisol in Cushing patients, and 3) the stimulatory effect of ACTH on 17-OHCS and free cortisol in normal persons.

The influence of dexamethasone, ACTH and the combination of both on the glycogen content of the rat adrenal gland was studied. Dexamethasone induces a transient increase of the adrenal glycogen content in a time and dose-dependent manner. The application of ACTH has no effect on the glycogen content. Surprisingly, the increase of the glycogen content induced by dexamethasone is completely blocked by the simultaneous application of ACTH.

Infusion of fructose solution (25 g in 100 ml) in sugar rations of 0.5 g or 1.0 g per kilogram of body weight usually induced in calf temporary drop of glucose in the blood plasma. This was attributable to rise in insulin secretion and glucose conversion or insufficiently fast effectiveness of insulin antagonists (adrenaline, glucagon, glucocorticosteroids). Such glucose drop could not be prevented by administration of 50 mg of prednisolone four hours before fructose infusion and 25 IU of ACTH five hours before infusion. Glucose as well as free fatty acids in the blood plasma went up in response to injection of 2.5 microgram/kg body weight during hypoglycaemia. The action of adrenaline was found to depend on the insulin dose given before in cases of insulin-induced hypoglycaemia. Doses of 0.5 g fructose per kilogram of body weight were administered in nine experimental infusions. Average half-life recorded from the blood plasma was 21.3 +/- 3.4 minutes.

The examination carried out with thrombin marked by 131J resulted in a considerable increase of the thrombin clearance rate in healty male rats during the stress (caused by an immobilization lasting 30 minutes) and in an increase of thrombin deposits in the liver. A further increase of thrombin clearance occurred by the combination of immobilization and administration of ACTH. Contrary to ACTH the thrombin clearance is not stimulated in healthy animals by hydrocortisone. Thrombin clearance and thrombin deposits in the liver are lowered in adrenalectomized rats. In these animals the administration of ACTH does not result in an increase of thrombin clearance. The rate of thrombin clearance is normalized in adrenalectomized animals after administering hydrocortisone without as well as under conditions of stress. In adrenalectomized animals having received hydrocortisone as well as in healthy animals the administration of ACTH will results in an increase of thrombin clearance. From these experiments the conclusion can be drawn that ACTH will increase the intensity of thrombin clearance in stress and that hydrocortisone plays a transmitting part here.

The effects of prednisolone and ACTH on in vitro oxygen consumption and aerobic and anaerobic glycolysis of human placentas of early pregnancy were studied. Oxygen consumption and anaerobic glycolysis were significantly reduced by prednisolone, while ACTH resulted in a significant increase in aerobic glycolysis during the 2 hr experimental period.

DCS and ACTH causes an increasing cellular proliferation in the arterial wall of the rabbit. The combination of both shows only a small further increasing. The importance of these experiments is thought as an additional cause in the atherosclerotic vessel wall alteration.

(L)-SKF 12185, a reversible inhibitor of the enzyme 11 beta-hydroxylase, can, if radioiodinated, be used for the scintigraphic imaging of the adrenal cortex. An increased uptake of 131I-(L)-SKF 12185 was observed therein 2-3 hrs after ACTH stimulation. This effect can be explained by the steroid neogenesis induced by ACTH stimulation and the activation of the required enzymes connected therewith. The inhibitor attaches competitively with the relevant substrates to the free enzyme binding sites and produces an enhanced adrenal uptake. Thus ACTH stimulation increased the 3 hr uptake by 69% whereas the 24 hr uptake which, because of its relatively high adrenal/liver ratio, is more useful in the scintigraphic imaging of the adrenals, could not be improved significantly.

In rabbits, the simultaneous i.v. injection of corticotrophin (ACTH) and bacterial lipopolysaccharide or sodium nucleinate (NN), as well as ATCH application before and after administration of one of the two pyrogens, induces changes in the course of body temperature as compared with other animals injected only one of the pyrogens. Principal differences between the effect of a bacterial lipopolysaccharide and that of sodium nucleinate cannot be observed. At simultaneous pyrogen application, the administration of ACTH leads to a delayed occurrence of temperature increases. Prophylactic ACTH injection induces, if performed only 30 min before pyrogen application, a still greater delay of pyrogen-induced temperature increase, while pyrogens applied 2 h after administration of ACTH induce temperature increases almost immediately. If ACTH is administered after pyrogen application this will at first lead to a temperature reduction, to be followed by repeated increase of temperature so that as a rule temperature curves with two peaks develop. This is true irrespective of whether ACTH application is performed 30, 60, or 90 min after pyrogen administration. Orientation tests have shown that only a part of ACTH present in the test solution can be detected if the biological assay of ACTH is made using the method based on the determination of the ascorbic acid content in the suprarenal glands of prednisolone-treated rats and if one of the two pyrogens simultaneously is applied.