Intact Adrenals Research Articles

THE SECRETION AND DISPOSITION OF CORTISOL DURING PREGNANCY

The following findings were obtained which bear on the mechanisms concerned in the rise of plasma free 17-hydroxycorticoid (17-OHCS) levels during pregnancy: 1) Cortisol accounted for approximately 90 per cent of the plasma free 17-OHCS in pregnant women during the third trimester. 2) No cortisol (F), cortisone (E), tetrahydrocortisol (THF) or tetrahydrocortisone (THE) were detected in the urine of 2 adrenalectomized pregnant patients maintained on 1 mg. of 9-alpha-fluorohydrocortisone daily during the third trimester. 3) When ACTH was administered intravenously to a woman with intact adrenals during pregnancy and the postpartum period, there was a greater response during pregnancy as determined by the excretion of F+E and the rise in the level of plasma free 17-OHCS, but no greater response as determined by the excretion of F+E+THF+THE. 4) In a normal woman followed throughout pregnancy there was a marked rise in plasma free 17-OHCS levels but little change in urinary total 17-OHCS excretion. 5) When cor...

The role of the adrenal cortex in the normal adaptation to dietary sodium deprivation.

During short periods of rigid dietary sodium deprivation, there was no significant change in the urinary output of total 17-hydroxycorticoids in a normal subject and in a patient with intact adrenals given a constant quantity of cortisone orally. The urinary excretion of cortisol and cortisone was also unaffected under these circumstances. The administration of a constant dose of prednisone or deoxycorticosterone to patients with Addison's disease did not permit normal adaptation to acute dietary sodium deprivation, although the latter was much more effective than the former. These observations tend to emphasize the physiologic importance of a rise in the urinary excretion of aldosterone in the adaptation to sodium restriction, and it would appear that the rise in urinary levels of aldosterone during a low sodium diet is a reflection of an increased secretion of this hormone rather than a result of alteration in its intermediary metabolism.

The secretion and disposition of cortisol during pregnancy.

The following findings were obtained which bear on the mechanisms concerned in the rise of plasma free 17-hydroxycorticoid (17-OHCS) levels during pregnancy: 1) Cortisol accounted for approximately 90 per cent of the plasma free 17-OHCS in pregnant women during the third trimester. 2) No cortisol (F), cortisone (E), tetrahydrocortisol (THF) or tetrahydrocortisone (THE) were detected in the urine of 2 adrenalectomized pregnant patients maintained on 1 mg. of 9-alpha-fluorohydrocortisone daily during the third trimester. 3) When ACTH was administered intravenously to a woman with intact adrenals during pregnancy and the postpartum period, there was a greater response during pregnancy as determined by the excretion of F+E and the rise in the level of plasma free 17-OHCS, but no greater response as determined by the excretion of F+E+THF+THE. 4) In a normal woman followed throughout pregnancy there was a marked rise in plasma free 17-OHCS levels but little change in urinary total 17-OHCS excretion. 5) When cor...

Dietary cholesterol and adrenal regulation of plasma lipids.

Adrenalectomized dogs maintained on desoxycorticosterone acetate manifest a progressive depletion of plasma phospholipid and cholesterol. Within a 4-week period a mean decrease of 60% is observed. The daily addition of cholesterol to the Purina chow diet prevented the hypolipemic response and resulted in significant elevation in the concentration of plasma cholesterol. The feeding of an identical amount of cholesterol to dogs with intact adrenals was not associated with any alteration in plasma lipid levels. The feeding of identical amounts of highly saturated fats or soya lecithin to adrenalectomized dogs resulted in the characteristic decline of plasma phospholipid and cholesterol. A significant contribution of the adrenal gland to the regulation of plasma lipid metabolism in normal and cholesterol-fed dogs is indicated.

Adrenal glands in the development of renal hypertension in rats.

The adrenal glands of the rat do not appear to be necessary for the development of experimental renal hypertension by kidney encapsulation. Male and female rats became hypertensive when both kidneys were encapsulated with latex envelopes whether they were adrenalectomized two weeks prior to or at the time of kidney encapsulation. The type of hypertension produced in adrenalectomized rats did not differ from that of rats with intact adrenals with regard to time course of development of the elevated blood pressure (6–8 weeks), maximal elevation attained (190–220 mm Hg), polydipsia and hypertrophied hearts.

Relation of number of transplants to total volume of regenerating adrenocortical tissue.

SummaryThe total volume of adrenocortical tissue regenerating in intramuscular autotransplants in rats during the first 2 weeks after operation is proportional to number of transplants growing. Thereafter, the total volume is about the same irrespective of the number of implants made or transplants regenerating, so the volumes per transplant are inversely proportional to the number of grafts. Average volume of regenerating tissue and cell depth increases with increasing age of transplant. At 90 days after operation the cell depth is like that of intact adrenal glands but the volume is less. Apparently transplants cannot deliver the amount of cortical secretion necessary to establish a pituitary-adrenal equilibrium until after 2 weeks of growth.

The relationship of estrogen and of pituitary hormones to the metabolic effects of progesterone.

WHEN progesterone is administered to men and women in a dosage approximating the quantity secreted during early pregnancy (50–100 mg. daily), it induces a mild to moderate acceleration of protein catabolism (1–4) and an increased excretion of urinary sodium and chloride (1, 2). The enhanced catabolism appears to be a metabolic effect of progesterone itself, but the salt-dissipating influence can be explained on the basis of an inhibition of salt-retaining adrenal corticoids at a renal level. In subjects with normal adrenals, the catabolic process seems less intense and the increase in the excretion of urinary sodium is distinctly smaller than the same effects induced in hormone-treated Addisonians. Furthermore, only in individuals with intact adrenal glands is the sodium loss promptly recovered after progesterone treatment is discontinued. Since the natriuresis and chloruresis induced by progesterone seem to be dependent upon a competitive reaction, the presence of adrenal hormones is required for this re...

The metabolic response to adrenalectomy and hypophysectomy

1. 1. Observations have been made upon the balance of sodium, potassium, chloride and nitrogen and the excretion of corticosteroids in the urine in three patients subjected to bilateral adrenalectomy and given constant doses of cortisone acetate, and in two patients undergoing hypophysectomy, only one of whom received cortisone acetate. 2. 2. The usual post-operative metabolic changes of sodium and chloride retention with loss of potassium and nitrogen in the urine occurred in all patients. In the three patients subjected to second stage adrenalectomy, the metabolic response was not associated with a rise in the urinary excretion of adrenocorticosteroids (acid-stable formaldehydogenic or 17-hydroxy-steroids). Increase in urinary corticosteroids occurred in both patients after hypophysectomy and in the one patient studied on whom a first stage adrenalectomy was performed. 3. 3. It is concluded that the metabolic responses observed after second stage adrenalectomy occurred in the absence of significant alterations in the rate of adrenocortical secretion. The observations we have made do not eliminate the possibility that trauma and surgical operation in patients with intact adrenal glands increase the secretory activity of the adrenal cortex. However the occurrence of alterations in electrolyte and nitrogen balance following surgical trauma may not be used as evidence that such an increase in secretion occurs. 4. 4. The role of the cortisone acetate given to the patients before and after removal of the adrenal glands in the metabolic response is discussed. Although the results are not inconsistent with the “permissive” action of the hormone as suggested by Ingle, the possibility that alterations in metabolism and the rate of excretion of the hormone result in an increase in the blood concentration of biologically effective hormone with consequent alterations in electrolyte and nitrogen balance cannot be excluded. Nevertheless, if such an alteration in the rate of disposal of biologically active hormone occurs for some days after the operation, it must do so without causing a rise in the urinary content of the measured steroid métabolites such as is normally found after operations not involving the adrenal glands. 5. 5. Four possible interpretations of the increase in corticosteroids in the urine after hypophysectomy are suggested but it is not possible to decide which of these explanations is correct.

Evaluation of adrenal cortical function by stimulation with corticotropin (ACTH).

Most tests previously employed to prove or disprove the presence of adrenal cortical insufficiency were, by their nature, indirect and depended on general metabolic or hematologic alterations which occur in the organism deficient in adrenal cortical hormones. Unfortunately, from a diagnostic point of view, the stress of nonspecific illnesses increases the demand for cortical hormone. False-positive water-loading tests and saltdeprivation tests are frequently seen in a variety of illnesses. Furthermore, the mere measure of the concentration of steroids in urine or blood frequently fails to differentiate those persons with adrenal insufficiency from those with intact adrenals. Apparently this is due to the considerable individual physiologic variations in excretion of steroid in health and in disease. To overcome this difficulty and still provide a direct and objective test of adrenal function, it is possible to combine the use of corticotropin (ACTH) with methods which measure the concentration of adrenal hormone. In

INFLUENCE OF ADRENAL CORTICAL HORMONES UPON THE LEVEL OF PLASMA AMINO ACIDS IN EVISCERATE RATS

INTRODUCTION After removal of the liver, ammo acids released from tissue proteins cannot be deaminated and therefore accumulate in the plasma. The rate of rise of the plasma amino acids may therefore be considered a rough indication of the net rate of protein breakdown. When adrenalectomized rats are eviscerated, the accumulation of plasma amino acids is depressed (Bondy, 1949; Ingle, Prestrud and Nezamis, 1948). In a previous communication it was claimed that the administration of large amounts of adrenal cortical extract to eviscerated rats with intact adrenals increased the rate of rise of plasma amino acids above control values within 4 hours (Bondy, 1949). Subsequent attempts to duplicate this experiment were unsuccessful. Further experiments were therefore carried out to determine whether adrenal cortical hormones can influence protein breakdown in the liverless animal, and to evaluate some of the factors concerned in the reaction. METHODS Two sets of experiments were carried out.

Circulatory effects of adrenocortical lack and excess observed in the hamster cheek pouch

The circulation in the everted, transillumined cheek pouch of adrenalectomized hamsters and the microscopic appearance of the small blood vessels remained essentially normal until twenty-four hours before death at five to seven days. The rate of blood flow then diminished and stasis developed. In terminal stages of adrenal insufficiency, the arterioles were frequently constricted. The threshold of the vascular smooth muscle to direct electrical stimulation with a microelectrode remained low as compared with normal values, but the threshold to topically applied nor-epinephrine increased slightly. An increased susceptibility to petechial formation from negative pressure occurred at one to three days after adrenalectomy, but an increased resistance developed terminally, paralleling the onset of vasoconstriction. Cortisone acetate (5 mg. daily doses) produced arterial vasoconstriction in the cheek pouch of normal hamsters with intact adrenal glands, persisting from an early period until death at fourteen to thirty days. The threshold of the vascular smooth muscle to the microelectrode test and also to the norepinephrine test was elevated. The persistent vasoconstriction may explain clinical findings such as the tendency for infection to occur. Furthermore, vasoconstriction may also explain the increased resistance to petechial formation induced by negative pressure. A significant finding may be the sticking of leukocytes to the endothelial lining of venules and the concomitant leukocytosis during prolonged cortisone treatment. DCA (1 mg. daily plus 1 per cent saline) produced no significant changes in the microscopic appearance of cheek pouch blood vessels until the period of severe weight loss prior to death. An increased vascular fragility persisted during DCA administration as indicated by the negative pressure test. Although vascular spasm was observed occasionally, DCA did not produce vasoconstriction comparable to that caused by cortisone.

A steroid metabolic study on adrenalectomized patients after administration of compounds E and F and Reichstein's substance S.

When steroid metabolic investigations are performed on patients with intact adrenals, the question always arises, how do administered steroids affect the secretion of the adrenals themselves? Hence, patients who have undergone total adrenalectomy are suitable subjects for the study of this problem. Despite the report of Laidlaw et al. (1952) that continued steroid excretion takes place after adrenalectomy, there is reason to believe that in adrenalectomized women and orchidectomized, adrenalectomized men without substitution therapy, the steroid excretion is of an order that cannot fundamentally affect the results in steroid metabolic studies. In some cases we have been able to demonstrate that as early as 48 hours after discontinuation of substitution therapy the 17-ketosteroid excretion is very small in these patients (Birke & Plantin, 1953). When it was reported by Cohen (1951) that the corticoids of the urine are conjugated to glucuronic acid and that a substantially greater yield is obtained

Effect of adreno-cortical extracts on bone marrow eosinophiles of mice.

The regulation of the numbers of blood lymphocytes seems to be under pituitary control and is mediated by way of the adrenal cortex (Dougherty and White, 1944). In human patients with intact adrenals under administration of ACTH there is a decrease in circulating eosino-philes, a decrease in lymphocytes, and an increase in neutrophiles (Forsham, 1948). Since the decrease in eosinophiles is approximately twice as great as that of lymphocytes, the eosinophiles are a more sensitive indication of adrenal cortical activity than the lymphocytes (Forsham, 1948). The work of Speirs and Meyer (1949) has established that stresses of various kinds will produce a marked decrease in the number of circulating eosinophiles in animals with intact adrenals and in adrenalectomized animals given adrenal cortical hormones. The response reaches a maximum at four hours after injection or stimulation, followed by a return to normal numbers of cells within eight to twelve hours.

Adrenalectomy in the Shay Rat

Summary 1.ACTH, cortisone (CA) or desoxycorticosterone (DCA) had no beneficial effect upon the extent or severity of the ulcers seen in the forestomach of the pylorus-ligated rat. 2.DCA and, to a lesser extent, CA produced small increases in gastric secretion in pylorus-ligated rats with intact adrenals. 3.Adrenalectomy profoundly lowered the volume of gastric secretion and almost completely prevented ulceration of the forestomach in pylorus-ligated rats. 4.The administration of normal saline, normal glucose solution, ACE, CA, and DCA partially restored the volume of gastric juice in adrenalectomized pylorus-ligated rats. 5.Partial restoration, with adequate therapy, of the normal rate of gastric secretion after adrenalectomy had as its corollary that increasing amounts of forestomach ulcerations were present.

Pituitary-adrenal relationship in fullterm and in premature infants, as evidenced by eosinophil response.

EXPOSURE of the organism to stress or the administration of a toxic substance results in the elaboration of adrenocorticotropic hormone (ACTH) by the pituitary, which in turn stimulates the adrenal cortex. This phenomenon was originally postulated by Selye (1) and demonstrated more clearly by Long (1947, (2)), Sayers and Sayers (1949, (3)) and others. One of the manifestations of increased adrenocortical secretion is a decline in circulating eosinophils (Dalton and Selye, 1937, (4); and Thorn et al., 1948, (5)). In a patient with intact adrenals, the administration of ACTH causes a pronounced decline in circulating eosinophils. In the primary hypoadrenal state, however, only the injection of one of the 11-oxygen corticosteroids (compounds E and F) will produce an identical response (Hills et al, 1949, (6)). The administration of epinephrine, acting as a nonspecific stress, results in a fall in circulating eosinophils in the presence of an intact pituitary-adrenal axis. If the integrity of this system is b...

Development of hypertension in the adrenalectomized nephritic rat maintained on NaCl.

In response to cytotoxic serum nephritis, bilaterally adrenalectomized rats develop hypertension as frequently as do animals with intact adrenals. In order for hypertension to appear among such adrenalectomized rats, it is necessary that a satisfactory state of nutrition be maintained over a period of weeks. In our laboratory, the difficulties encountered in fulfilling this provision have been considerable in spite of the employment of a high NaCl regimen. This experience has led us to wonder whether the conflicting results in the literature relating to the question of hypertension in adrenalectomized animals may not be due, in part, to similar difficulties.

Prolonged Survival of Adrenalectomized-Nephrectomized Rats on a Low Potassium Diet.

SummaryAdrenalectomized-nephrectomized rats fed a chow diet before operation have a high mortality rate. If the animals are prepared preoperatively for 3 days on a lowpotassium diet, the adrenalectomized animals survive longer than rats with intact adrenals. The rate of production of urea is normal immediately after adrenalectomy, and fails to accelerate in the manner characteristic of rats which intact adrenals subjected to starvation and uremia. The blood urea nitrogen level at death is lower in adrenalectomized than in control animals. Administration of adrenal ccrtical extract to adrenalectomized-nephrectomized rats tends to restore the survival time and terminal blood urea nitrogen level to control values.

THE EFFECT OF THYROXINE ON THE EXTENT OF REGENERATION IN THE ENUCLEATED ADRENAL GLAND OF THE RAT

It has previously been shown that regeneration of cortical tissue from the capsule of an enucleated adrenal gland occurs when the opposite gland is removed (1). The presence of one intact adrenal gland suppresses regeneration in the other enucleated gland. Likewise, regeneration of cortical tissue in an enucleated gland may be completely suppressed by the administration of cortin (1). Thus it seems clear that the physiologic requirement by the organism for cortical hormone is an important factor influencing the regeneration of the adrenal cortex. It is well known that the administration of thyroxine to the normal animal produces hyperplasia of the adrenal cortices. When thyroxine is administered to the adrenalectomized dog, the maintenance requirements for cortin are increased (3). Since thyroxine induces cortical hyperplasia in the adrenal glands of normal animals, will it increase the extent of cortical regeneration within enucleated adrenal glands?

Relation of Adrenal Cortex to Development of Scurvy.

It is well known that in scurvy (guinea pigs), marked changes develop in the adrenal. The cortex of this gland is rich in hexuronic acid which has been shown by King to be vitamin C. This vitamin, at least in the guinea pig, is not synthesized to any extent in the body and, therefore, its concentration in the adrenal cortex may be indicative of participation of the latter as an intermediary step in its utilization. If this is true, cortin may play some rôle in the process. To test this hypothesis 3 series of guinea pigs with different amounts of cortin were used. The animals in each group (9 or 10 animals to a group) were balanced for sex and weight and placed on a pre-experimental diet of vitamin C-free ration and lettuce ad libitum, for one week previous to the experiment. At the beginning of the experimental period, the lettuce was discontinued. All animals not injected with extract were injected with one cc. of isotonic NaCl solution twice daily so that they would be subjected to the same manipulation. Series I—Normal amount of cortin (intact adrenals). Group I—Basal diet. Group 2—Basal diet and 0.7 cc. of orange juice daily (one-half protective dose). Series II—Added cortin (by injection). Group 3—Basal diet and 1 cc. of cortin twice daily (40 gm. whole gland per cc). The guinea pigs on the control diet consistently lost weight from the beginning of the experiment which was carried out over a period of 28 days. This is not typical of a negative control series of vitamin C. One or both of 2 factors may have been responsible, the amount of vitamin C obtained from lettuce in the pre-experimental period may not have been optimal or the frequent injections, in animals made sensitive by vitamin C deficiency, may have influenced the appetite.