Hyperlipidaemia in Asthmatic Patients Receiving Long-term Steroid Therapy

Plasma lipids were measured in 100 female asthmatic patients receiving long-term steroid therapy. A significant increase in the incidence of endogenous hypertriglyceridaemia but not of hypercholesterolaemia was found. The hypertriglyceridaemia was not due to obesity or diabetes. Neither the dose of steroid, duration of therapy, nor the addition of corticotrophin gel or depot tetracosactrin influenced the prevalence of hypertriglyceridaemia.     

Prolonged Corticotrophic Action of a Synthetic Substituted α1-18 ACTH

The adrenocorticotrophic effects of a synthetic corticotrophin analogue, α^1-18 ACTH with D-serine¹, lysine¹⁷, and lysine amide¹⁸ substitutions has been studied. It is effective after both intramuscular and subcutaneous administration and compared with tetracosactrin depot (Synacthen depot, Cortrosyn depot) it has a similarly prolonged time course of action—about 24 hours after 0·5 mg and 30 hours after 1 mg. Unlike tetracosactrin depot, however, it is well absorbed when given intranasally and does not produce painful reactions at the site of injection. Its prolonged time course of action does not depend on a formulation designed to delay its release from the injection site but most probably on a decreased rate of degradation in the circulation.     

Hypothalamic-pituitary-adrenal Function in Patients Treated with Long-term Depot Tetracosactrin

Four patients treated with depot tetracosactrin for 10 to 18 months maintained normal hypothalamic-pituitary-adrenal function assessed by the nyctohemeral variation of plasma corticosteroids and by the responses of plasma corticosteroids to insulin-induced hypoglycaemia, lysine-vasopressin, and depot tetracosactrin. The pituitary component of the response was analysed by measuring plasma immunoreactive ACTH levels. Three patients showed a nyctohemeral ACTH rhythm and normal ACTH responses to insulin-induced hypoglycaemia. Consistently undetectable morning plasma ACTH levels were found in the fourth patient, who also showed an unusually delayed rise in both ACTH and corticosteroid levels in response to insulin-induced hypoglycaemia, though the peak values attained were normal.The lack of suppression of hypothalamic-pituitary-adrenal function together with the good clinical response in these four patients suggests that treatment with depot tetracosactrin should be considered when long-term corticosteroid therapy is required.     

Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.

Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.     

Assessment of Long-acting Synthetic Corticotrophin in Hypersensitive Asthmatics and Normal Subjects

The synthetic polypeptide depot-tetracosactrin (Synacthen-Depot) was given to nine steroid-treated asthmatic patients hypersensitive to animal corticotrophin. Eight had a satisfactory increase in plasma and urinary 17-hydroxycorticosteroids (17-OHCS). The remaining patient had been shown previously to have adrenal suppression. None of the patients developed allergic reactions to depot-tetracosactrin, and seven have been receiving regular injections of the polypeptide twice weekly for the past eight months.In 13 normal subjects intramuscular injections of 1 mg. and 0.5 mg. of depot-tetracosactrin and 40 units of corticotrophin-gel were equally potent in raising the plasma 17-OHCS, but depot-tetracosactrin had a significantly longer action than corticotrophin-gel.     

Effects of levodopa and dopamine on plasma 11-hydroxycorticosteroid concentrations in mice.

The effects of levodopa on the plasma concentration of 11-hydroxycorticosteroids and glucose were examined in mice. In fasted, nialamide treated mice, but not in fed mice, levodopa produced a significant decrease in the plasma concentration of 11-hydroxycorticosteroids. This was accompanied by a significant and marked decrease in the plasma glucose concentration. These effects of levodopa could be mimicked by relatively small doses of dopamine injected intracerebroventricularly but not intravenously. The integrity of the hypothalamic-pituitary adrenal axis in nialamide-treated mice was suggested by the elevation in plasma 11-hydroxycorticosteroids produced by fasting or by insulin induced hypoglycaemia. These results indicate that in the mouse, as in other species, levodopa can inhibit stress provoked increases in the secretion of 11-hydroxycorticosteroids.     

The plasmatic 11-hydroxy-corticosteroid response in the human to a synthetic octadecapeptide corticotrophin (C-41795-Ba).

The adrenal response as measured by the plasmatic changes in 11-hydroxy-corticosteroid (11-OHCS) concentration following the administration of a synthetic octadecapeptide (C-41795-Ba) was compared in 17 normal young males with that obtained with the commercially available tetracosactrin. C-41795-Ba polypeptide shows a higher potency than tetracosactrin. Its effects are longer lasting when administered intravenously which indicates a significant local inactivation of the polypeptide.     

Quantitative trait loci for individual adipose depot weights in C57BL/6ByJ x 129P3/J F2 mice

To understand how genotype influences fat patterning and obesity, we conducted an autosomal genome scan using male and female F₂ hybrids between the C57BL/6ByJ and 129P3/J parental mouse strains. Mice were studied in middle-adulthood and were fed a low-energy, low-fat diet during their lifetime. We measured the weight of the retroperitoneal adipose depot (near the kidney) and the gonadal adipose depot (near the epididymis in males and ovaries in females). An important feature of the analysis was the comparison of linkage results for absolute adipose depot weight and depot weight adjusted for body size, i.e., relative weight. We detected 67 suggestive linkages for six phenotypes, which fell into one of three categories: those specific to absolute but not relative depot weight (Chr 5, 11, and 14), those specific to relative but not absolute depot weight (Chr 9, 15, and 16), and those involving both (Chr 2 and 7). Some quantitative trait loci (QTLs) affected one adipose depot more than another: Retroperitoneal depot weight was linked to Chr 8, 11, 12, and 17, but the linkage effects for the gonadal depot were stronger for Chr 5, 7, and 9. Several linkages were specific to sex; for instance, the absolute weight of gonadal fat was linked to Chromosome 7 in male (LOD = 3.4) but not female mice (LOD = 0.2). Refining obesity as a phenotype may uncover clues about gene function that will assist in positional cloning efforts.     

Benign and Malignant Breast Disease in South Wales: A Study of Urinary Steroids

The levels of aetiocholanolone, androsterone, and 17-hydroxycorticosteroids were measured in women without known disease of the breast, in women with benign breast disease, and in women with primary and advanced breast cancer. Statistical analysis showed there was no difference in the excretion of urinary 17-hydroxycorticosteroids in the various groups of patients. Detailed analysis of the aetiocholanolone and androsterone levels, however, indicated that patients with advanced localized disease excreted significantly less of these 11-deoxy-17-oxosteroids than those in the other groups.     

Role of Vegetarianism,Smoking, and Hydroxocobalamin in Optic Neuritis

Only 20 patients with optic neuritis of unknown aetiology could be collected in Bombay over a period of two and a half years. Only six of them were smokers and only three (one a non-smoker) had bilateral centrocaecal scotomata similar to those found in tobacco amblyopia. In 11 untreated patients the serum vitamin B₁₂ and plasma thiocyanate levels were estimated and found to show no significant differences from those in normal control subjects. Treatment with hydroxocobalamin in the majority of cases and with cyanocobalamin, corticotrophin, or prednisolone in the rest showed equally good results; spontaneous improvement was seen in one case.No significant role could be assigned to smoking (cyanide) or to vegetarianism in the production of optic neuritis in these patients; nor was there any evidence of depletion of total (cyanide-extracted) B₁₂ or of an increase in the proportion of non-cyanide-extracted B₁₂ in the serum.     

Inhibition of neuronal nitric oxide synthase (n-cNOS) reverses the corticotrophin-induced behavioral effects in rats

The nitric oxide (NO) synthase inhibitor N^G-monomethyl-L-arginine (N-NMMA) and the competitive substrate for NO synthase L-arginine were used to determine the role of endogenous NO on the behavioral and neuroendocrine responsiveness following systemic corticotrophin in dexamethasone-suppressed rats. Corticotrophin (50-200 mU/kg, s.c.) dose-dependently decreased behavioral activity in the actimeter and produced significant anxiolytic and anti-risk activity in the plus-maze behavior test, without affecting systolic blood pressure. Rats given corticotrophin showed significant increased plasma corticosterone and reduced adrenal ascorbic acid level. These behavioral and adrenal responses of corticotrophin were dose dependently blocked by metyrapone (20 and 50 mg/kg, i.p.), an inhibitor of steroid 11-hydroxylase in adrenal and neural tissues that block steroidogenesis. Intracerebroventricular administration of L-NMMA (20 g/rat in 10 l) significantly prevented the behavioral hypoactivity and anxiolytic-like responses of corticotrophin without influencing the adrenal responsiveness. The effect of L-NMMA was completely reversed by preadministration of L-arginine (300 mg/kg, i.p.). These results suggest that neuronal nitric oxide pathway plays an important modulating role in the behavioral effects of corticotrophin by mechanisms other than those involving cardiovascular effects.     

Change in the dependence of lymphocyte reactivity to phytomitogens on endogenous hormonal factors in experimental bacterial lesion of the prostate]

The relationship between the blast lymphocyte transformation response (BLTR) to PHA P, Con A, PWM and 11-hydroxycorticosteroids (I) and the testosterone (II) levels in the blood plasma and the excretion of 17-ketosteroids with the urine were studied in 11 dogs with experimental urogenous prostatitis, provoked by Staphylococcus aureus, isolated from a patient with chronic prostatitis. Multiple correlation between the BLTR and hormonal factors was noted before the experiment. It was disturbed in a month and restored 2 months after the beginning of the experiment. Before the studies the relationships were mainly realized by direct correlation with 1 and 2 months after the experiment--due to the negative correlation with II. A homeostatic nature of the hormone lymphoid relationship with respect to 11-hydroxy-corticosteroids is suggested.     

Comparison of Corticotrophin and Corticosteroid Response to Lysine Vasopressin,Insulin, and Pyrogen in Man

Plasma corticotrophin (ACTH) and corticosteroid levels in response to lysine vasopressin (LVP), insulin hypoglycaemia, and pyrogen have been compared in seven subjects with normal pituitary adrenal function. Intramuscular vasopressin was a weak stimulus to corticotrophin release, peak values lying within the range 49 to 141 pg/ml. Insulin hypoglycaemia consistently caused a more noticeable increase, with peak levels between 114 and 364 pg/ml, while pyrogen was the most powerful, corticotrophin levels rising to between 209 and 1,725 pg/ml. Peak plasma corticosteroid levels showed less pronounced differences between the three tests, and correlated poorly with peak ACTH levels. Thus, relatively small acute changes in corticotrophin levels produce near-maximal adrenal stimulation. Under these conditions, plasma corticosteroid measurements do not accurately reflect circulating corticotrophin levels. These findings help to explain the physiological basis of several observations on the corticosteroid responses to these clinical test procedures.     

Endocrine Response to Substitution of Corticotrophin for Oral Prednisolone in Asthmatic Children

The hypothalamo-pituitary-adrenal axis has been assessed in 17 asthmatic children before and after long-term prednisolone therapy was changed to daily corticotrophin. In 14 of the 17 children the plasma corticosteroid concentration exceeded 15 μg/100 ml within five days of starting corticotrophin. No exacerbation of asthmatic symptoms occurred during conversion. The plasma corticosteroid response to insulin-induced hypoglycaemia was normal in four children about six weeks after conversion to corticotrophin, took up to 36 months to become normal in nine, and remained abnormal in one child throughout the period of the trial.     

Comparison of Effects of Long-term Corticotrophin and Corticosteroid Treatment on Responses of Plasma Growth Hormone,ACTH, and Corticosteroid to Hypoglycaemia

The development of the highly sensitive cytochemical bioassay for ACTH has permitted the measurement of plasma ACTH levels during the insulin hypoglycaemia test (I.H.T.) in patients treated with corticosteroids and corticotrophin. The ACTH, corticosteroid, and growth hormone (GH) responses in the I.H.T. were measured in three groups of 12 rheumatoid arthritis patients. One group was receiving long-term corticotrophin treatment, the second was undergoing long-term corticosteroid treatment, and the third had never received systemic hormone therapy. The increments in plasma ACTH, corticosteroids, and GH were diminished in the corticosteroid-treated group, as were increments in plasma GH and ACTH in the corticotrophin-treated group; but in this group the corticosteroid increment was normal. Examination of the area under the curve of the ACTH response showed that the total amount of ACTH secreted was normal though the rate of secretion was reduced. In the corticosteroid-treated group both rate and total secretion were diminished.     

Endocrine and metabolic mechanisms of the pathological syndrome due to antigens of homologous glial tissue in monkeys

Monkeys (Macaca mulatta) of both sexes repeatedly immunized with a complex of glial antigens of the homologous brain demonstrated abnormalities of hormonal functions after 1 to 5 weeks. These abnormalities were marked by a decrease in the total serum tyroxine (after 1 week) and a rise in the concentration of 11-hydroxycorticosteroids (11-OHCS) that occurred after 5 weeks. The changes in tyroxine level were more stable than those in the concentration of 11-OHCS. The immunized animals manifested changes in the disc electrophoregram of the serum. Application of stress resulted in a consistent elevation of the concentration of 11-OHCS and in temporary changes in the number and intensity of individual fractions of serum proteins. The fractional composition of serum proteins was different in control and experimental monkeys.     

Beclomethasone Dipropionate Steroid Aerosol in Treatment of Perennial Allergic Asthma in Children

Thirty-one chronic perennial asthmatics aged from 2½ to 16 years were treated with beclomethasone dipropionate pressurized aerosols for up to 20 months. Of these, 16 patients dependent on oral corticosteroid or corticotrophin for up to 11 years were successfully transferred to this treatment, with one exception. Steroid withdrawal symptoms were slight. Loss of weight, disappearance of Cushingoid features, and resumption of growth indicated lack of systemic side effects. Fifteen others inadequately controlled on bronchodilators or disodium cromoglycate, were also effectively treated, and no clinical evidence of adrenal suppression was noted.     

Adrenocortical suppression in workers manufacturing synthetic glucocorticoids.

A man who had worked for 16 years in the manufacture of a potent corticosteroid was found to be suffering from chronic adrenocortical insufficiency attributed to chronic absorption of the glucocorticoid. Eleven other symptom-free workers were therefore screened. Two of these workers, like the first patient, gave grossly abnormal responses to the Synacthen (tetracosactrin) test; one had been employed for only seven months. All 12 men had facial plethora, suggesting absorption of the drug in spite of their having adhered to the safety precautions. All workers manufacturing potent steroids should therfore be screened regularly by measurement of their plasma cortisol concentrations and should be moved regularly to processing other drugs.     

Hormonal regulation of anabolic processes and of protein utilization efficiency in the early postnatal period

The levels of thyroid, pituitary and steroid hormones-thyroxine, triiodothyronine and 11-hydroxycorticosteroids in the blood serum, somatotropin in the pituitary, and processes of protein assimilation were studied in rats in the early postnatal period. The highest endogenous production of thyroxine, triiodothyronine and somatotropin was detected in 15-day-old rats. The highest level of protein utilization was detected in 7 to 15-day-old rats, followed by the lowering of the utilization on changing over to definitive nutrition. Endogenous production of the anabolic hormones thyroxine, triiodothyronine and somatotropin was found to correlate with a high level of protein utilization in rats within the first days of life after birth.     

Effect of zinc deficiency and zinc supplementation on adrenals,plasma steroids and thymus in rats

Weanling rats were given diets deficient in or supplemented with zinc. Within a few weeks there were increases in the weight of the adrenal glands and in the concentration of cholesterol and 11-hydroxycorticosteroids in the adrenal glands of the zinc deficient animals. The decrease in cholesterol concentration due to ACTH administration was greater in zinc-deficient than in supplemented rats. After four weeks on the zinc-deficient diet rats had smaller thymus glands than zinc-supplemented rats but zinc-deficient diets had no such effect on adrenalectomised rats. The addition of 2 mg zinc/ml drinking water had no effect on adrenal weight or thymus weight but increased plasma 11-hydroxysteroids after 30 days. The possible connection between zinc intake and resistance to injury and disease is discussed.