Grant W. Liddle

Results of Treatment in 108 Patients with Cushing's Syndrome

Abstract In 17 years, 108 patients with Cushings syndrome were treated at Vanderbilt University. Seventeen had adrenal adenoma, 10 adrenal carcinoma, 17 ectopic ACTH syndrome, and 64 Cushings disease. Surgery for adrenal adenoma was uniformly successful. Three carcinomas were surgically cured, and two patients had remissions; these two and another patient subsequently responded to o.p′DDD. Four cases were not amenable to therapy. No patient with ectopic ACTH syndrome was cured, but some responded metabolically to metyrapone. In Cushings disease, pituitary irradiation cured 10 of 51 patients and improved 13 without complications. All six unilateral adrenalectomies and two of five subtotal adrenalectomies were unsuccessful, but bilateral adrenalectomy (19 cases) was always curative. After o,p′DDD treatment serum cortisol levels returned to normal, without mineralocorticoid deficiency, in eight patients. Thus, except in patients with ectopic ACTH syndrome or adrenal carcinoma, appropriate treatment for Cu...

Role of the Sympathetic Nervous System in Regulating Renin and Aldosterone Production in Man

Several lines of evidence have been developed indicating that the sympathetic nervous system may play a role in mediating the renal and adrenocortical secretory responses to upright posture and sodium deprivation. Despite concurrent increases in arterial blood pressure, the plasma renin activity of normal subjects increased both in response to the infusion of catecholamines (norepinephrine: epinephrine, 10:1) and in response to stimulation of the sympathetic nervous system by cold. Aldosterone excretion was also increased by catecholamine infusion. In normal subjects the stimuli of upright posture and of sodium depletion both resulted in increases in urinary catecholamines, plasma renin activity, and urinary aldosterone. A patient with severe autonomic insufficiency did not experience normal elevations of urinary catecholamines, plasma renin activity, or urinary aldosterone in response to upright posture or sodium deprivation, despite a substantial fall in arterial blood pressure. When orthostatic hypotension was prevented by infusion of catecholamines, however, increases in plasma renin activity and in aldosterone excretion were observed. We suggest that both upright posture and sodium depletion lead to decreases in effective plasma volume and increases in sympathetic nervous system activity. This increase in sympathetic activity is then responsible for an increase in renal afferent arteriolar constriction, leading to an increase in renin secretion and, ultimately, an increase in aldosterone secretion.

Results of Treating Childhood Cushing's Disease with Pituitary Irradiation

To determine the usefulness of conventional pituitary irradiation in childhood Cushings disease, we reviewed the results of this treatment in 15 patients. Twelve were cured (mean plasma cortisol of less than 10 microgram per deciliter and 24-hour urinary 17-hydroxycorticosteroid excretion of less than 7 mg per gram of creatinine) within 18 months, and 10 of the 15 were cured within nine months. Three failures required bilateral adrenalectomy. Growth resumed in 12, with adult heights of 156 to 166 cm. Sexual development proceeded normally in all 15, with normal secondary sexual characteristics and sexual function, and demonstrated fertility in four married adults. Intellectual function appeared normal. Basal and stimulated hormone levels were normal, except for subnormal (5 ng per milliliter or less) growth hormone levels after hypoglycemia in one of 12 patients. There were no complications of therapy and no progressive pituitary enlargement or hyperpigmentation. Pituitary irradiation is safe and effective therapy for childhood Cushings disease.

Effects of glucagon on adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate in human plasma and urine

Glucagon, infused intravenously into fasting, well-hydrated, normal men in doses of 25-200 ng/kg per min, induced up to 30-fold increases in both plasma and urinary cyclic AMP. Cyclic GMP levels were unaffected by glucagon. Simultaneous cyclic AMP and inulin clearance studies demonstrated that the glucagon-induced increase in urinary cyclic AMP was entirely due to glomerular filtration of the elevated plasma levels of the nucleotide. The cyclic AMP response to glucagon was not mediated by parathyroid hormone or epinephrine, and trypsintreated glucagon was completely inactive. The perfused rat liver released cyclic AMP into the perfusate in response to glucagon, indicating that the liver is a possible source of the cyclic AMP entering the extracellular fluids in response to glucagon in vivo.

Dopamine Inhibits Angiotensin-Stimulated Aldosterone Biosynthesis in Bovine Adrenal Cells

The possibility that dopamine may play a role in the in vivo control of aldosterone production in man was suggested to us by reports from others; (a) that bromocriptine, a dopaminergic agonist, inhibits the aldosterone response to diuresis and to the infusion of angiotensin or ACTH; and (b) that metaclopramide, a dopamine blocking agent, causes elevations in plasma aldosterone levels. To determine whether such effects were direct or indirect, we examined the action of dopamine on aldosterone biosynthesis in isolated, bovine adrenal cells. Dopamine significantly inhibits the aldosterone response to angiotensin (P < 0.001), but does not influence basal aldosterone biosynthesis. It has previously been reported that angiotensin stimulates both the early and late phases of aldosterone biosynthesis. The present experiments demonstrated that the enhancing effect of angiotensin on the conversion of deoxycorticosterone to aldosterone (late phase of aldosterone biosynthesis) was almost completely inhibited by dopamine (P < 0.001). A significant inhibitory effect of dopamine (10 nM) was seen even when aldosterone biosynthesis was stimulated by a grossly supraphysiological concentration of angiotensin II (10 muM). However, these studies did not demonstrate any direct effect of dopamine on the early phase of aldosterone biosynthesis (cholesterol to pregnenolone) basally or when stimulated, or on the late phase of aldosterone biosynthesis under basal conditions. These in vitro studies suggest a direct inhibitory role for dopamine on the late phase of aldosterone biosynthesis, which may account for the in vivo inhibition of the aldosterone response to angiotensin in subjects treated with a dopaminergic agent.

In Vitro Stimulation of Renin Production by Epinephrine, Norepinephrine, and Cyclic AMP∗:

Summary The preparation of a dog renal cell suspension suitable for the study of renin production is described. This suspension was utilized to study the in vitro effects of agents that have previously been shown to affect renin production in vivo. Since production and destruction of renin could not be separately quantified, data were limited to “net production” of renin. Incubated controls had only slightly higher renin content than did the nonincubated controls, but the addition of epinephrine, norepinephrine or cyclic AMP caused striking increases in “net production” of renin. The effects of these agents on “net renin production” were abolished by cycloheximide, an inhibitor of protein synthesis. It is suggested that the reninstimulating effect of catecholamines in the intact animal might be due, at least in part, to a direct chemical action on the renal cells. Cyclic AMP may play a role as an intracellular mediator of the action of catecholamines.

Effect of Diazoxide on Plasma Renin Activity in Hypertensive Patients

Excerpt Suppression of renin production is a characteristic of primary aldosteronism; therefore, measurement of plasma renin activity has been proposed as a procedure for screening hypertensive pat...

Dual mechanism regulating adrenocortical function in man

Abstract Secretion of aldosterone and secretion of hydrocortisone by the human adrenal cortex appear to be regulated by distinctly different mechanisms, as shown by the following observations. 1.1. Sodium deprivation results in large increases in aldosterone output but does not appreciably affect 17-hydroxycorticoid output. 2.2. Certain diseases (congestive heart failure, cirrhosis and nephrosis) are characterized by an increase in aldosterone output without clinical or laboratory evidence of more general hyper-adrenocorticism. 3.3. Administration of ACTH results in relatively large increases in hydrocortisone (17-hydroxycorticoid) output but results in only comparatively small increases in aldosterone output. 4.4. Suppression of ACTH release by administration of cortisone or by damage to the pituitary reduces hydrocortisone secretion to minimal amounts but has relatively little effect on secretion of aldosterone. Thus it appears that the secretion of aldosterone is responsive to changes in water and electrolyte metabolism, whereas the secretion of hydrocortisone is regulated by production of ACTH.

Effects of Glucagon on Lipolysis and Ketogenesis in Normal and Diabetic Men

The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/ml. In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P=<0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.

CORRELATION OF PLASMA ACTH CONCENTRATION WITH ADRENOCORTICAL RESPONSE IN NORMAL HUMAN SUBJECTS, SURGICAL PATIENTS, AND PATIENTS WITH CUSHING'S DISEASE.

The role of ACTH in various clinical disorders has been difficult to ascertain because the available assay methods have lacked the sensitivity necessary for valid quantitation of the hormone in the plasma of normal subjects (1-4). Even the method of Lipscomb and Nelson (5), the most sensitive practical bioassay procedure now available, usually requires the injection of at least 0.05 mUof ACTHper rat, if responses are to be elicited that will be statistically significant without the use of a prohibitive number of animals. It is usually impractical to inject more than 5 ml of crude human plasma into a single rat. Therefore, in order to be accurately measurable by this procedure, the concentration of ACTH in the plasma must be at least 0.05 mUper 5 ml, or 1 mUper 100 ml. Numerous studies indicate that normal plasma levels of ACTHare well below this concentration. Byr the adrenal ascorbic acid depletion assay method, Sydnor, Sayers, Brown, and Tyler (1) were unable to detect ACTH in plasma of normal subjects, even after attempting to extract the hormone with oxvcellulose in preparation for the bioassay. These workers concluded that blood ACTH concentrations of normal human subjects were less than 0.5 mUper 100 ml. Using a similar procedure, Fujita (3) estimated the normal level of ACTHto be about 1 mUper L, i.e., 0.1 mUper 100 ml. Cooper and Nelson (6) were able to detect ACTH in the plasma of only 3 of 10 patients before surgery, by a method that they