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Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section.

The effects of somatostatin on tolbutamide-stimulated insulin release were studied in 4 patients with insulin-producing tumors of the pancreas and in 6 normal subjects. In contrast to its effective inhibition of insulin release in normal subjects, somatostatin, without exception, failed to inhibit tolbutamide-induced insulin release in the patients with pancreatic beta-cell tumors. This differential effect of somatostatin may prove useful in the diagnosis of insulin-producing tumors of the pancreas.

To characterize further the mechanism by which somatostatin lowers plasma glucose levels in man, we studied its effect on glucagon-induced glycogenolysis in 6 normal subjects. Additionally, we examined the effect of somatostatin on glucagonand tolbutamide-stimulated insulin release. During infusion of somatostatin (250 μg iv bolus followed by a sustained infusion of 500 μg/hr), plasma glucose responses to glucagon (1 mg iv) exceeded those seen after glucagon administration alone. The resultant hyperglycemia (190–200 mg/100 ml) was unaffected by administration of tolbutamide (1 g iv) and persisted for 15 min after stopping the somatostatin infusion. Plasma insulin remained at basal levels throughout the infusion, despite administration of glucagon and tolbutamide (with coexistent hyperglycemia). Within 15 min after stopping the somatostatin infusion, plasma insulin rose abruptly and plasma glucose declined toward basal levels. These studies indicate that, in man: 1) the hypoglycemic effect of soma...

Through the use of a feedback-controlled dextrose infusion system, we obtained continuous monitoring of the blood glucose level in a patient undergoing surgery for multiple pancreatic beta-cell tumors. In addition, this device infused dextrose at variable rates to maintain a predetermined euglycemic level of 90 mg/dl. Before locating the source of excessive insulin production, the maximum dextrose infusion rate of 400 mg/min was required; but after extirpation of multiple insulinomas, the dextrose-infusion rate declined whereas the blood glucose level rose above the preselected level. These results emphasize the usefulness of a monitoring and infusion system not only in protecting the patient from the hazard of hypoglycemia under anesthesia but also as an aid in determining whether all insulin-secreting tumors have been removed.

Of 12 patients with Cushing’s disease who had successful selective microadenoma resection documented by clinical remission and reversal of hypercortisolism, 11 developed postoperative hypoadrenalism with deficient adrenal responsiveness to exogenous ACTH. In addition, of 11 patients tested with hypoglycemia, all had subnormal cortisol responses, and 10 had deficient ACTH responses. Pituitary-adrenal function then gradually returned to normal; at last testing, normal cortisol responses to ACTH stimulation and insulin hypoglycemia were present in 8 of 12 and 6 of 11 patients, respectively, and 9 of 11 had normal plasma ACTH responses to hypoglycemia. Two patients with persistent hypoadrenalism had had prior incomplete bilateral adrenalectomies. The ACTH and glucocorticoid deficiency was not caused by the surgical procedure or hydrocortisone replacement, since it resolved despite replacement therapy; further, adrenal insufficiency did not occur in 10 acromegalic patients who received the same operation and i...

In 6 normal subjects, L-dopa (500 mg PO) and apomorphine (0.6 mg sc) increased circulating growth hormone and suppressed prolactin levels in a parallel and quantitatively similar fashion, but only L-dopa induced a rise in plasma glucagon, glucose, and insulin levels. The failure of apomorphine to affect glucagon secretion, despite a substantial effect on growth hormone and prolactin, was also observed in insulin-dependent diabetics known to exhibit A-cell hyperresponsiveness to various stimuli. In view of the highly dissimilar molecular and pharmacologic characteristics of L-dopa and apomorphine, these data do not exclude a local dopaminergic effect of L-dopa at the pancreatic level, but strongly militate against a central dopaminergic pathway for glucagon stimulation.

Seventy patients with reactive hypoglycemia strictly defined by criteria which interpret the low blood glucose value in relationship to clinical and physiologic parameters, were studied to determine if abnormalities in insulin secretion could be demonstrated. These patients were separated into four groups: alimentary (N = 5), diabetic (N = 16), hormonal (N = 5), and idiopathic (N = 44). The findings in these patients were compared to normal control subjects and to weight- and disease-matched patient controls. All of the patients with hormonal and most patients with idiopathic reactive hypoglycemia (thirty-two of forty-four) demonstrated delayed insulin secretion regardless of the control group used for comparison. Diabetic reactive hypoglycemic patients exhibited delayed insulin secretion when compared to normal controls but not when compared to weight-matched diabetic controls. Excessive insulin secretion was consistently found only in the patients with the alimentary variety of reactive hypoglycemia. Using weight- and diseasematched control groups, no abnormalities in insulin secretion could be found to account for the hypoglycemia in the diabetic reactive hypoglycemic patients and some idiopathic reactive hypoglycemic (nine of forty-four) patients. These results help to explain the inconsistent findings of previous investigators and suggest that reactive hypoglycemia is a syndrome having multiple etiologies.

In an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p less than 0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p less than 0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments of alpha-amino nitrogen were not affected by phenformin. Thls, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling-particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.

After Cryohypophysectomy, fasting levels of growth hormone (GH) fell to less than 10 ng/ml in 38 (76 per cent) of 50 patients with acromegaly. Effects, including lowered serum insulin levels and improved glucose tolerance, were rapid and long-lasting. Optimal endocrine-metabolic results, defined as lowering of the GH level to 10 ng/ml or less and normal glucose tolerance (attained in 60 per cent of patients), were most often achieved when preoperative glucose tolerance was normal or mildly abnormal. Factors that favored optimal lowering of GH were preoperative GH level below 50 ng/ml and moderately, rather than greatly, enlarged sellae turcica. Factors that favored normal carbohydrate balance after treatment were postoperative fasting GH level of 10 ng/ml or less and preoperative symptom duration of 10 years or less. A family history of diabetes was not an important over-all factor in glucose intolerance. Although postoperative reduction in 24-hour urinary excretion of 17-hydroxycorticosteroids was associated with adequate GH reduction, adrenal reserve and thyroid function remained normal in most patients. In contrast to the prognostic significance of high GH levels, adrenal and thyroid function could not be related to eventual GH response or to carbohydrate metabolism.

In a pair of 19-year-old monozygotic twin girls, one developed insulin-dependent, ketosis-prone diabetes at the age of three and has required insulin for the past 16 years. Her identical twin has maintained normal oral and intravenous glucose tolerance with normal insulin release and glucagon suppression. An unequivocal hypertrophy of the muscle capillary basement membrane(1,800 ± 148 Å) was found in the diabetic twin, while a normal thickness of 1,149 ± 62 Å was present in her nondiabetic sister. Follow-up of the present subjects and data from other discordant identical twins who have reached adulthood could determine whether muscle capillary basement membrane hypertrophy is an independent marker of genetic diabetes in adults. Discordance of diabetic microangiopathy in a pair of monozygotic twins has important implications regarding the influence of heredity and environment on diabetic microangiopathy.

The present studies demonstrate that endogenous glucagon is hyperglycaemic, lipolytic and ketogenic in man, and that insulin deficiency is necessary, but is in itself not sufficient, to cause fulminant diabetic ketoacidosis. Furthermore, continuous elevation of endogenous glucagon secretion appears to be necessary for the maintenance and continued development of the characteristic metabolic consequences of insulin lack.

Nine normal subjects ingested 100 gm. glucose, fructose, and sucrose on separate days after an overnight fast. Plasma glucose, fructose, insulin, glucagon, growth hormone, and triglyceride levels were then measured over the following 5 hr. Plasma glucose and insulin peaks were both significantly lower after fructose ingestion as compared with glucose and sucrose. Plasma glucagon suppression was significantly less after fructose. Growth hormone showed a late stimulation after glucose and sucrose but did not rise after fructose intake. Triglyceride levels were significantly increased at 3 to 5 hr. after fructose ingestion.

We studied the contribution of alpha- and beta-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 mug/kg.min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the beta-adrenergic blocker, propranolol, nor the alpha-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82+/-9 to 128+/-14 pg/ml; P < 0.005) and serum insulin (from 7.5+/-1 to 13+/-1.5 muU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5+/-1 to 5.2+/-0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine. Whereas some metabolic and cardiovascular effects of dopamine are mediated through adrenergic mechanisms, these observations indicate that this is not the case for the effects of this catecholamine on glucagon, insulin, and prolactin secretion, and thus provide further support for the theory of a specific dopaminergic sensitivity of these hormonal systems in man.

To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.

SummaryPrevious findings in this laboratory that AVT inhibited the preovulatory surge of LH and subsequent ovulation prompted the present study demonstrating that AVT effects a marked suppression of the prolactin surge during proestrus, but does not affect the concurrent surge of FSH. Microgram amounts of AVT (administered from 1300 to 1600 hr on the afternoon of proestrus) suppressed the prolactin surge significantly, relative to saline-treated controls and comparable doses of antidiuretic hormone and oxytocin (P < 0.001); and prolonged administration with increased amounts of AVT (up to 16 μg over the period from 0900 through 1600 hr) had no effect on the FSH surge. These results support earlier suggestions that different mechanisms are involved in the cyclic release of LH and FSH and that the surge of FSH is minimally involved in ovulation in the cycling rat.These investigations were supported in part by the Levi J. and Mary Skaggs Foundation of Oakland, California. We are indebted to Alicia Sagasay an...

A special glucose infusion test was used to provide successive steplike increments of glucose stimulation in six normal-weight and seven obese subjects. This “staircase” method of glucose infusion demonstrates that insulin responds in “spike” fashion despite maintenance of a continuous, fixed, submaximal glucose stimulation. Further, the “spike” response recurs as the glucose concentration is stepped up. Obese subjects showed an exaggeration of both the first phase “spike” pattern and the more gradual second phase of insulin release. Mathematical analysis of early phase insulin release indicates that obese persons have greater total amounts of insulin available for release at all glucose concentrations than do normals, yet the proportion of totally available insulin released to a given glucose stimulus is not increased in obesity. These findings imply that the early phase, hyperinsulin response to glucose in obesity is due to a greater quantity of insulin available for release rather than to an increased sensitivity of the beta cell to glucose.

CS comprises a group of disorders characterized by hypercortisolism. The variety of causes--pituitary-dependent CS (CD), adrenal tumor, and the ectopic ACTH syndrome--necessitates a variety of therapies--surgical, radiotherapeutic, and medical. Once a specific diagnosis is made, specific therapy can be instituted. Although some controversy persists regarding treatment, particularly that of CD, for most patients it is straightforward. However, in our experience with more than 60 patients, therapeutic dilemmas can arise in a number of circumstances, e.g. the patient with the radiologically normal sella or recurrent CD after adrenalectomy. In addition, the treatment of such conditions as the large ACTH-producing pituitary tumor, Nelson's syndrome, the malignant ectopic ACTH syndrome, and adrenal carcinoma is not entirely satisfactory. Our approach to these problems is illustrated by seven cases, and we emphasize that the proper management of CS requires both correct diagnosis and the logical application of all available therapies.

We undertook trans-sphenoidal microsurgical pituitary exploration in 20 consecutive patients with Cushing's disease, eight of whom had normal sellar polytomography. Pituitary adenomas were selectively resected in 17 and histologically confirmed in 14. In one patient total hypophysectomy revealed a 1.5-mm basophilic adenoma, and in two patients vascular anomalies prevented sellar exploration. Hypercortisolism was corrected in 17 patients (i.e., in 16 of the 17 undergoing selective tumor removal and in the one with total hypophysectomy). Panhypopituitarism occurred only in this patient, and transient diabetes insipidus occurred in five. Most patients became glucocorticoid deficient and required replacement therapy. We conclude that pituitary tumors are present in the great majority of patient with Cushing's disease, even in the absence of demonstrable tomographic changes in the sella turcica, and that selective removal corrects hypercortisolism with little morbidity.

In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 mug/min), a beta adrenergic agonist, plasma glucagon rose from a mean (+/-SE) basal level of 104+/-10 to 171+/-15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 mug/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122+/-15 to 75+/-17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118+/-16 to 175+/-21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function.

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 ± 0.8 vs. 9.0 ± 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p < 0.01) to values (16.8 ± 1.2) that exceeded those of normal subjects by four hours (p < 0.01). These were similar to results found in the same subjects studied when their diabetes was in < optimal control (14.9 ± 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 ± 0.8; p < 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals. These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.

In four patients who required maintenance glucocorticoid therapy after bilateral adrenalectomy for Cushing's disease, we compared the effects of im injection and oral ingestion of cortisone acetate and hydrocortisone hemisuccinate. By the former route of administration, cortisone acetate was not effective in elevating plasma cortisol levels or in suppressing plasma adrenocorticotropin, although hydrocortisone was. When given by mouth, no significant difference was found between the two steroids. Therefore, in the treatment of acute adrenal insufficiency or in the maintenance of patients with chronic adrenal insufficiency and in their preparation for surgery or other stressful situations, we advise against im injection of cortisone acetate. Oral ingestion, however, is appropriate for maintenance.

The present experiments were undertaken to investigate the effect of alterations in extracellular Ca++ concentration on glucagon release from the isolated perfusedrat pancreas.In control studies using perfusate containing 5.0 mEq/1 Ca++,arginine (19.2 HIM) alone or withglucose (100 mg/100 ml) caused biphasic glucagon release. Insulin responses to arginine alone were monophasic whereas arginine plus glucose caused biphasic insulin release. During perfusion with Ca++-free medium, glucagon releasewas inhibited > 90% and insulin release was inhibited about 75%. Subsequent introduction of 5.0 mEq/1 Ca++ to medium during stimulation of previously Ca++-depleted pancreases promptly restored glucagon and insulin responses toward control levels. Thus, like other endocrine tissue, the pancreatic alpha-cell requires calcium for normal secretory function. (Endocrinology 94: 1381, 1974)

In developing what was to become the official method for assaying corticotropin (ACTH) preparations, Sayers, Sayers, and Woodbury (1948) found that more uniform results were obtained during their assays if the ACTH was administered intravenously rather than by extravascular routes. Thus, when ACTH came into clinical use the potencies of various clinical preparations were assayed in terms of their capacity, when administered intravenously to hypophysectomized rats, to cause depletion of adrenal ascorbic acid content. Most of the ACTH administered clinically, however, has been given by the intramuscular route. Soon after the introduction of ACTH into clinical medicine it was reported by Gordon, Kelsey, and Meyer (1951) that the available ACTH preparations were many times more potent, judged by clinical indices, when administered as prolonged intravenous infusions than when administered intramuscularly. It then became apparent from the studies of Forsham, Renold, and Frawley (1951)

HUMAN growth hormone (HGH) administered to children with hypopituitarism has an anabolic effect and increases the rate of linear growth without undue stimulation of bony maturation. 1,2 Short-term balance studies in individuals with intact pituitary function have demonstrated an anabolic effect, but attempts to stimulate growth have produced inconsistent results. 3,4 Although growth retardation due to hypopituitarism is relatively infrequent, a number of children have constitutional dwarfing of various other types, in whom an agent which can produce growth would be most useful. This is a report of our study of the effect of HGH (Li) on linear growth in two patients with gonadal dysgenesis. Procedure The HGH used in this study was prepared by the Li method 5 from pituitaries acquired by the Pituitary Bank of the University of California-San Francisco Medical Center.* The HGH, a dry powder, was dissolved in saline solution and passed through a Millipore filter

Plasma corticosteroids (11-OHCS) and serum immunoreactive growth hormone (IRGH) were measured in six normal subjects during an insulin tolerance test (ITT) and in four patients with normal endocrine function during the first hour of abdominal surgery. Three normal subjects were given a short dexamethasone suppression (1 mg every 6 h for five doses) followed by an ITT 2 h after the last dose. Three patients with normal endocrine function were treated identically, receiving the last dose 2 h before an operation. Five patients with bilateral adrenal hyperplasia (pituitary ACTH excess) had an ITT and were followed at surgery. During all ITTs the hypoglycaemia was adequate (blood glucose less than 40 mg/100 ml). All normal subjects responded adequately to the ITT (11-OHCS max: 26.8 ± 4.4 μg/100 ml, 2 sem; IRGH max: 35.6 ± 11.2 ng/ml), and surgery (11-OHCS max: 35.5 ± 1.7 μg/100 ml; IRGH max: 42.4 ± 12.4 ng/ml). The dexamethasone-suppressed subjects failed to show a rise in 11-OHCS during the ITT or at surgery, and the IRGH response was significantly lower compared with the non-suppressed subjects. All but one patient with Cushing's disease also failed to raise 11-OHCS levels during the ITT and at surgery; the rise in IRGH was blunted in both situations. The similarity in response to stress in (acutely) dexamethasone-suppressed normal subjects and those with Cushing's disease is striking. It suggests that feedback inhibition of increased ACTH secretion, rather than an intrinsic hypothalamic defect, may be the critical factor in the poor steroid response to a variety of stresses in Cushing's disease.

IN 1908, Babes and Jonescu observed that conditions of stress in man and laboratory animals were associated with the depletion of suprarenal lipid. Multiple intravenous injections of epinephrine produced a similar depletion, accompanied by adrenal hypertrophy in rabbits (1). Vogt later demonstrated that following the administration of epinephrine, cortical hormones could be detected in the adrenal venous blood of cats and dogs (2). Long and Fry (3) studied this response of the adrenal cortex to epinephrine, using the assay of Sayers (4) for adrenal corticotropic hormone (ACTH). They described a significant ACTH release in response to injected epinephrine in normal rats; on the other hand, hypophysectomized rats failed to show this response, in spite of the fact that their adrenal cortices were maintained with exogenous pituitary hormone injections. From these data Long postulated that the effect of epinephrine on the adrenal cortex was mediated by the pituitary. Vogt subsequently reported similar differen...

Measurement of unconjugated cortisol in the urine affords a reliable index of the biologically active fraction of circulating cortisol useful in the diagnosis of Cushing's syndrome. A simple and accurate technique using glass fiber chromatography was developed to determine unconjugated urinary cortisol. One hundred ml of urine was extracted with dichloromethane without previous hydrolysis, applied to glass fiber sheets and run in 1 or 2 different chromatographic systems for 20 min. Quantitation was performed by the Porter-Silber reaction, and values were corrected for losses by means of added tracer amounts of ortisol-4-C14. Mean recovery was 80.5%, and replicate determinations had an average deviation from the mean of 5.5%. Thirty-eight normal subjects studied with this technique had a mean value of urinary unconjugated cortisol of 71.4 μg/day, with arange of 0–181. Nine patients with Cushing's syndrome had values of 297 to 3,605 μg/day. In thyrotoxic and obese patients with elevated urinary 17-hydroxyco...

In a previous report (1) were described the results of experiments in which isotopic uric acid was injected intravenously into normal and gouty human male subjects. The purpose was to ascertain the magnitude of the "miscible pool," that quantity of uric acid present in the body capable of prompt mixing with the injected material, and the rate of its turnover. The results indicated that there are some 1200 mg. of miscible uric acid normally present, a finding in accord with that of Geren and associates (2), that between 50 and 75% of this is each day replaced by newly formed uric acid and that this latter quantity exceeds the quantity excreted daily in the urine, suggesting the occurrence of limited catabolism of uric acid in man. In the gouty subjects studied, the magnitude of this miscible pool exceeded the normal levels by as much as 15 fold. Indeed, so large was the quantity of promptly miscible uric acid as to indicate that at least a portion of this material must reside in the solid phase rather than in solution in body fluids.

AS EARLY as the end of the last century there were indications in the literature that adrenal cortical hormones were effective when given orally. Notable among these was a report by Osler in 1896 of a patient with Addison's disease who appeared to respond clinically to a glycerol extract of hog adrenal glands.1 In 1931 Britton and Silvette2 , 3 demonstrated conclusively that an orally administered adrenal extract could provide adequate substitution therapy in adrenalectomized cats. It was logical, then, that cortisone, once available in quantity, should be tried by a route that offers so many clinical advantages. The clinical effectiveness of . . .

A rapid oral metyrapone test (0.5 Gm. every hour for six doses) and a 4 p.m. plasma ACTH bioassay were performed in 20 consecutive patients with Cushing's syndrome. At surgery, 11 had adrenocortical hyperplasia, six had an adrenocortical adenoma, and three had an adrenocortical carcinoma. None had clinical findings of the ectopic ACTH syndrome and all have been followed at least two years postoperatively. All but one patient with hyperplasia doubled their urinary 17-hydroxycorticosteroids the day of the rapid oral metyrapone test; those with adrenocortical tumors showed no significant rise. Eight patients with hyperplasia had 4 p.m. ACTH measurements and all showed detectable plasma ACTH. Six of those with tumors also had a bioassay and in none was the ACTH detectable. The rapid oral metyrapone test and measurement of the plasma ACTH level are extremely useful in determining the cause of Cushing's syndrome, and considerably reduce the number of hospital days required.

DURING the past few years it has become increasingly evident that the adrenal cortical hormones exert a marked influence on a wide variety of metabolic processes in man. The over-all effects exerted by these hormones may be divided into three general groups: an electrolyte-regulating effect; the regulation of the rate of utilization of carbohydrate, protein and fat; and an androgenic and anabolic effect. Nature of Adrenal Cortical Activity Electrolyte-Regulating Effect of Adrenal Cortical Steroids This is characterized by urinary retention of sodium and chloride, increased excretion of potassium, increased plasma and extracellular fluid volume.1 It has also been shown that . . .

A simple method has been developed for clinically measuring plasma testosterone. Its sensitivity allows one to measure normal female levels of plasma, and the results are comparable to those obtained by double isotope derivative methods. This procedure requires paper chromatography of a methylene chloride extract of plasma and final determination by the competitive protein-binding technique, using salt precipitation of the bound fraction. By this method, the normal range for plasma testosterone was 26 to 108 mμg/100 ml in females and 273 to 1211 mμg/100 ml in males.

The radioimmunologic activity of ovine ACTH (αs-ACTH) and a C-terminal (αs22–39-ACTH) fraction of ovine ACTH before and after carboxypeptidase digestion was studied with 2 antiporcine and 2 antiovine ACTH sera. The amino acids released after carboxypeptidase digestion were measured. These were mainly the C-terminal phenylalanine and only traces of glutamic acid and leucine. With the 2 antiporcine ACTH sera, the immunologic activity of αs-ACTH and αs22–39-ACTH was almost completely abolished by carboxypeptidase treatment. The steroidogenic activity of ACTH was unchanged. This is a further example of the dissociation in immunologic and biologic activities of ACTH. With 2 antiovine ACTH sera, the results were different: carboxypeptidase treatment caused only a slight decrease in immunologic activity of αs-ACTH but a marked decrease in that of αs22–39-ACTH. It is concluded that the C-terminal phenylalanine is necessary for the binding of ACTH peptides with the antiporcine ACTH sera studied. While the...

Six patients with Cushing's syndrome were treated with aminoglutethimide in doses ranging from 1000 to 1500 mg./day. Two had adrenocortical adenomas, 1 carcinoma and 3 bilateral hyperplasia. The 3 with tumors responded with a marked decrease in cortisol secretion rates, urinary 17-hydroxycorticosteroids (17-OHCS), and 17-ketosteroids (17-KS) after the initial 2 days of treatment and showed no rebound for a further 8 days of therapy. This suppression was achieved with doses less than those recommended for maximal anti-convulsant therapy. In contrast, the 3 cases of bilateral hyperplasia showed incomplete suppression of steroid secretion even at higher dose levels. There were no unfavorable reactions to the drug. Aminoglutethimide is a promising agent for the control of excess steroid secretion in adrenocortical tumors.

INTRODUCTION In 1924 Evans (25) reported that the injection of anterior pituitary extract was followed by adrenal hypertrophy. Smith (61, 62) in 1926 demonstrated that hypophysectomy induced atrophy of the adrenal cortex and that implantation of living hypophyseal tissue was followed by restoration of the gland to normal. These classical experiments established without doubt the specific tropic influence of the anterior pituitary on adrenal cortical function. Isolation of the adrenocorticotropic principle from anterior pituitary gland extract was reported by Collip in 1933 (15). In 1940 a somewhat simpler mode of preparation was described by Bates et al. (8). Further purification of the adrenocorticotropic hormone was accomplished by Evans and his group in California and Long and Sayers and their collaborators in New Haven. The former group worked with sheep pituitaries; whereas the latter used hog pitiiitaries. In 1943 Li et al. (41), employing a salt fractionation method, and Sayers et al. (56), using i...