Use of In-111 pentetreotide scintigraphy in the diagnosis of a midgut carcinoid causing Cushing's syndrome.

A 57-year-old man presented with clinical features of hypercortisolism and was diagnosed with ACTH-dependent Cushing's syndrome. Biochemical testing showed partial suppression of urinary free cortisol with high dose dexamethasone. Initial computed tomography (CT) of the chest and abdomen, and magnetic resonance imaging of the pituitary were negative. In-111 pentetreotide scintigraphy with single photon emission computerized tomography revealed two 'hot' lesions in the abdomen which were then confirmed by subsequent directed thin-slice abdominal CT and small bowel barium study. At surgery, two segments of ileum, adjoining mesentery and lymph nodes were resected. Histopathology was consistent with a malignant carcinoid tumor of the ileum which stained intensely for ACTH. Plasma ACTH, and serum and urinary cortisol normalized postoperatively. To our knowledge, this is the first reported case of ileal carcinoid tumor causing Cushing's syndrome with premortem diagnosis. Another unique feature of this case is that In-111 pentetreotide scan provided the decisive clue to localization of the tumor.

Hypocalcemia and skeletal disease as presenting features of celiac disease.

OBJECTIVE: To describe 15 patients examined for hypocalcemia, skeletal disease, or both in whom the diagnosis of celiac disease was subsequently made. DESIGN: Observational case series. PATIENTS: Fifteen patients (7 women and 8 men) were examined for hypocalcemia (n = 11), skeletal disease (n = 3), or both (n = 1). The diagnosis of celiac disease was subsequently made. The mean age of the patients was 62 years, and 11 patients were 60 years of age or older. RESULTS: Four patients had no gastrointestinal symptoms, 7 patients had mild or intermittent gastrointestinal symptoms, and 4 patients had persistent diarrhea. Ten patients had experienced weight loss. The serum total alkaline phosphatase level was elevated in 10 of 15 patients, the parathyroid hormone level was elevated in all patients, and the urinary calcium level was low in all 6 of the patients tested. The level of 25-hydroxyvitamin D was frankly low in 4 patients, marginal in 8 patients, and normal in 3 patients. Bone mineral density was reduced in all 8 patients in whom it was measured. CONCLUSIONS: Celiac disease should be considered in patients with unexplained metabolic bone disease or hypocalcemia, especially because gastrointestinal symptoms may be absent or mild. Advanced age does not exclude the diagnosis of celiac disease.

Effect of rapid intra-atrial saline infusion on atrial pressures and atrial natriuretic hormone secretion.

To evaluate the relationship between the right atrial pressure and atrial natriuretic hormone secretion, we studied 16 healthy males, ages 18-24, after five days on a low-salt diet (mean 24-h urinary sodium excretion: 17 +/- 3 mEq). After 90 min of equilibration to the supine position, a multilumen catheter was inserted into the right atrium, and 11 of isotonic saline was infused intra-atrially over 15 min through this catheter. Blood pressure, heart rate, and right atrial pressure were recorded just before (0 min), immediately after completion of the infusion (15 min), and every 15 min for 45 min thereafter. Two blood samples were drawn at each time point for atrial natriuretic hormone assay: one from the right atrium (central) and the other from a peripheral vein. Blood pressure did not change significantly during the entire study. Heart rate increased by 5 beats/min on average at 15 min (p < 0.005) and returned to baseline at 60 min. Good correlation occurred between central and peripheral atrial natriuretic hormone levels at times 0, 30, 45 and 60 min (r2 = 0.66, 0.45, 0.76 and 0.70, respectively; p < or = 0.02). An increase in right atrial pressure and an increase in central atrial natriuretic hormone levels correlated well at times 30, 45 and 60 min, but there was no such correlation between an increase in right atrial pressure and an increase in peripheral atrial natriuretic hormone levels at any time point. Similarly, a maximum increase in right atrial pressure correlated with a maximum increase in central atrial natriuretic hormone levels (r2 = 0.48; p < 0.02), but not with a maximum increase in peripheral levels of this hormone. We concluded that an increase in right atrial pressure caused by a rapid infusion of isotonic saline induces secretion of atrial natriuretic hormone in the right atrium. The observed discrepant course of change in central and peripheral atrial natriuretic hormone levels suggests the additional contribution of secretion beyond the level of the coronary sinus.

Vasopressin and atrial natriuretic hormone response to hypertonic saline during the follicular and luteal phases of the menstrual cycle.

We studied the hormonal responses to hypertonic saline during the follicular (days 2-9) and luteal (days 21-28) phases of the menstrual cycle in nine healthy young women, aged 19-25 years. On both study days, each woman was infused with 5% hypertonic saline for 1 h at the rate of 0.1 ml/kg/min. Serum progesterone and oestradiol concentrations confirmed the reported stage of the menstrual cycle. No difference in weight or haematocrit was observed between the two stages of the study for each woman. Baseline blood pressure, serum sodium, plasma osmolality, plasma vasopressin and thirst levels were almost identical for both stages, and changed to the same degree during infusion of hypertonic saline. Baseline atrial natriuretic hormone concentrations were higher during the follicular phase and became significantly higher than during the luteal phase following infusion of hypertonic saline. We concluded that the intravascular volume during the luteal phase may be effectively decreased in comparison to the follicular phase.

Effect of atrial natriuretic hormone on vasopressin and thirst response to osmotic stimulation in human subjects.

To evaluate the effect of systemically administered atrial natriuretic hormone (ANH) on osmotically induced secretion of arginine vasopressin (AVP) and thirst sensation, 11 healthy men, aged 18 to 28 years, were studied on four occasions. The intravenous infusions of placebo (P) or one of three doses of ser-tyr28 human ANH (0.6 [LD], 1.8 [MD], and 5.4 [HD] pmol/kg/min) were given in random order over 2 hours. During the second hour, subjects also received a 5% saline (HS) infusion (0.1 ml/kg/min). The baseline parameters were similar on each of the study days. Plasma ANH levels increased approximately twofold, eightfold, and 25-fold during LD, MD, and HD infusions, respectively. HS infusion caused increases in serum sodium level (5 to 7 mEq/L) and osmolality (14 to 15 mOsm/L) (p < 0.001). During HS infusion on P day, ANH levels almost doubled (p < 0.001). AVP levels remained stable during the first hour of ANH infusions. An addition of HS caused a significant increase in AVP levels (p < 0.001). The magnitude of this increase was similar on each of the study days. Similarly, thirst perception increased significantly (p < 0.01) and to the same extent during HS infusion on all study days. Both AVP levels and thirst showed a very good correlation with serum osmolality on each of the study days, and there were no significant differences between any of the slopes or intercepts. We conclude that short-term elevation of plasma ANH levels up to 25-fold affects neither the osmotically stimulated secretion of AVP nor thirst perception.

Effect of atrial natriuretic hormone on hypertonic saline-induced suppression of the renin-aldosterone system.

To evaluate the effect of physiologic doses of atrial natriuretic hormone (ANH) on hypertonic saline-induced renin-aldosterone system suppression, nine healthy subjects were studied three times: 1) on a low-salt (LS) diet with a 2 h placebo infusion; 2) on LS with 2 h infusion of human Ser-Tyr28 ANH (0.6 pmol/kg/min)(LS+ANH); and 3) on a high-salt (HS) diet with a 2 h placebo infusion. On each study day during the second hour of infusion, subjects also received 3% saline (0.1 mL/kg/min) infusion. Data from eight subjects were used for analysis because of a sampling error in one subject. During ANH infusion, plasma ANH levels increased about twofold and reached levels similar to ANH levels on HS. Serum sodium increased by 3-4 mEq/L, and serum osmolality increased by 7-8 mOsm/L during 3% saline infusion on all study days. ANH levels remained stable during 3% saline infusion. During the first hour of ANH infusion, plasma renin activity (PRA) decreased by about 24% and aldosterone levels by about 27%. Hypertonic saline caused further suppression of PRA and aldosterone. The extent of the suppression was similar under each condition, and the levels at the end of hypertonic saline infusion reached about 60% of the levels at the beginning of the saline infusion. We conclude that low-dose ANH infusion does not seem to have any major influence on PRA and aldosterone response to hypertonic saline.

Effect of atrial natriuretic hormone on metoclopramide-induced stimulation of aldosterone.

The effect of atrial natriuretic hormone (ANH) on metoclopramide-induced stimulation of aldosterone was studied in eight healthy young men after 3 days of controlled diet (150 mEq sodium, 100 mEq potassium). Baseline values were obtained after subjects had remained sitting for 1 hour. Subjects then received 2-hour infusions of placebo, dopamine (2 micrograms/kg/min), ANH (0.6 pmol/kg/min), and ANH plus dopamine. One hour after the beginning of each infusion, a 10 mg intravenous bolus of metoclopramide was given. Prolactin levels increased 10-fold after metoclopramide with placebo infusion, and about 50% of this stimulation was abolished by preinfusion with dopamine. ANH preinfusion did not suppress prolactin release. Urinary sodium excretion increased prominently during dopamine infusion. ANH at this dose had no effect on natriuresis. The dopamine dose given had almost no effect on metoclopramide-induced aldosterone secretion, whereas ANH infusions, which resulted in approximate doubling of plasma ANH levels, suppressed aldosterone. This study supports a role of ANH in aldosterone regulation, even at nonnatriuretic doses, and suggests that ANH is acting not only through the renin-angiotensin system but under certain conditions has significant physiologic action directly on glomerulosa cells.

Regulation of adrenal atrial natriuretic hormone receptor subtypes.

Regulation of atrial natriuretic hormone (ANH) receptor binding and aldosterone suppression was studied in isolated adrenal glomerulosa cells from rats fed a high-salt (HS) or low-salt (LS) diet for 3 days. In plasma of HS rats, aldosterone levels were 5 times lower and immunoreactive ANH two times higher than in LS rats. Competitive binding studies showed the same affinity for human atrial natriuretic hormone (hANH) in both pools of cells, but receptor density was 50% higher on LS cells. A linear ANH analog that binds to non-guanylate-cyclase-coupled receptors did not show increased binding to LS cells. Cyclic GMP production in response to hANH was identical in both groups. The aldosterone-inhibitory effect of hANH on both groups of basal and angiotensin II-stimulated cells was also identical. Thus a short-term high-salt diet causes decreased density of ANH receptors in glomerulosa cells without changing biological activity of ANH. These results suggest that dietary salt content changes the number of ANH receptors and that non-guanylate-cyclase-coupled receptors contain at least two classes of receptors.

Effect of varying potassium intake on atrial natriuretic hormone-induced suppression of aldosterone.

To further assess the mechanism of atrial natriuretic hormone (ANH) induced suppression of aldosterone, we infused 0.5 pmol/kg/min Ser-Tyr28 human ANH over 2 h under three dietary conditions: low salt (LS), low potassium (LK), and high potassium (HK). The diets were consumed for 3 days before each study day. After 3 days of LK diet, blood pressure was slightly higher than under the other conditions. Serum potassium on LK was significantly lower than on HK (3.8 +/- 0.1 v 4.3 +/- 0.2). The ANH infusion did not cause any changes in blood pressure or urinary sodium and potassium excretion. Urine volume increased with ANH infusion under all diet conditions. Plasma renin activity and plasma angiotensin II levels were significantly lower on LK than on LS or HK, probably reflecting sodium retention. Increase in plasma ANH levels of about 75% (well within normal range) suppressed all hormonal parameters on LS and HK diets, but had no significant effect on LK diet. The pattern of aldosterone changes closely followed the changes in the renin-angiotensin system. We conclude that under various physiologic conditions ANH suppresses aldosterone predominantly through suppression of renin.

Effect of hypoxic exercise on atrial natriuretic factor and aldosterone regulation.

To evaluate the possible physiologic role of atrial natriuretic factor (ANF) in the observed dissociation of aldosterone secretion from the renin-angiotensin system during hypoxic exercise, 12 untrained men, ages 18 to 24, were studied on two separate days for 30 min during hypoxic (16% O2) and normoxic (room air) exercise on a bicycle ergometer. Workloads were adjusted to produce individual heart rates that remained within 70 to 75% of their previously measured maximum. Hemoglobin saturation decreased during hypoxia from 98 +/- 0.1% to 90 +/- 0.4% (P less than .01). Plasma aldosterone levels increased significantly (P less than .01) under both breathing conditions, yet were on average 36% lower during hypoxia than during normoxia (P less than .001). Plasma ANF levels increased during exercise under both conditions (P less than .01), yet levels were 45% greater during hypoxia than during normoxia (P less than .001). Plasma renin activity, adrenocorticotropic hormone, cortisol, potassium, and systolic blood pressure increased during exercise on both study days (P less than .01, compared to basal level), and showed no difference between normoxic and hypoxic conditions. Plasma pH was slightly higher during hypoxic exercise (P less than .05, compared to normoxia). We conclude that acute hypoxemia is a potent enhancing stimulus for ANF release during dynamic exercise and that ANF is probably a contributing factor in the dissociation of aldosterone secretion from the renin-angiotensin system under these conditions.

The physiological role of atrial natriuretic hormone in the regulation of aldosterone and salt and water metabolism.

To investigate the mechanisms by which small changes in plasma levels of atrial natriuretic hormone (ANH) affect aldosterone, 10 normal young men were infused for 2 h with 0.6 pmol/kg.min human [Ser,Tyr28]ANH under 3 study conditions: 1) high salt diet (H), 2) low salt diet (L), and 3) low salt diet plus pretreatment with the angiotensin-converting enzyme inhibitor enalapril (LE). Baseline ANH levels were higher on H than on L or LE. A postural drop in ANH was observed when subjects went from standing to sitting. Plasma ANH levels increased during infusion by up to 4.5 pmol/L (H, 7.0 +/- 1.3 to 11.5 +/- 1.4; L, 4.3 +/- 0.6 to 8.7 +/- 1.1; LE, 4.2 +/- 0.5 to 8.6 +/- 1.5). At all time points, plasma ANH was well within the normal range. Plasma aldosterone did not change during H, decreased by about 60% for both low salt conditions, and remained suppressed at 1 h of recovery for L, but not for LE. This suggests that ANH can suppress aldosterone by both indirect and direct mechanisms, although the indirect mechanism appears to predominate. A prompt increase in urine flow was seen during ANH infusion and was sustained at 1 h of recovery, but little change was seen in urinary sodium or potassium excretion, heart rate, or blood pressure. The difference between the natriuretic and diuretic effects of ANH was seen under all conditions. These results support the hypothesis that within the normal physiological range, ANH is a regulator of salt and water metabolism in normal man.

Effect of hypoxia on atrial natriuretic factor and aldosterone regulation in humans.

To evaluate the possible physiological role of atrial natriuretic factor (ANF) on the observed dissociation of aldosterone from the renin-angiotensin system during acute hypoxia, 7 men, ages 18-27 yr, were studied on two separate days for 1 h under hypoxic (12% O2) and normoxic (room air) conditions. Subjects were on a low-salt diet (urinary sodium 67 +/- 13 meq/24 h) and suppressed with dexamethasone. Hemoglobin saturation decreased during hypoxemia to 68 +/- 1% (P less than 0.01), whereas heart rate increased from 65 +/- 3 to 89 +/- 5 beats/min (P less than 0.01). Plasma aldosterone levels decreased 43% from basal during hypoxemia (P less than 0.01), whereas ANF levels increased by 50% (P less than 0.05). Levels of both were unchanged during normoxemia. Plasma renin activity, angiotensin II, blood pressure, and pH did not change under either condition, and plasma cortisol levels were totally suppressed. These results indicate that acute hypoxemia is a potent stimulus for ANF release and that ANF is probably a major factor responsible for the dissociation of aldosterone from the renin-angiotensin system under these conditions.

Atrial natriuretic hormone and aldosterone regulation in salt-depleted state.

To evaluate the effect of very low-dose infusion of atrial natriuretic hormone (ANH) on aldosterone regulation, seven normal young men were infused for 2.5 h with 0.47 pmol.kg-1.min-1 of human [Ser-Tyr28]ANH or placebo. During the last 0.5 h 4 pmol.kg-1.min-1 of angiotensin II were also infused. ANH plasma levels increased from 3.46 +/- 0.25 to a maximum of 6.80 +/- 0.88 pmol/l, which is well within normal limits. Plasma aldosterone decreased almost 40%, from 40.7 +/- 5.7 to 25.9 +/- 4.9 ng/dl after 2 h. ANH infusion caused a slight decrease in blood pressure and slight increase in renal excretion of sodium and potassium. These results suggest that even small changes in ANH levels, within the normal range, have physiological significance, particularly in aldosterone regulation.

Steroid secretion by a virilizing lipoid cell ovarian tumor: origins of dehydroepiandrosterone sulfate.

A 78-year-old woman had a 3-year history of severe virilization caused by a lipoid cell ovarian tumor localized by pelvic ultrasound examination and NP-59 scan. Steroid secretion was evaluated by the following: 1) peripheral plasma levels before and after hormonal stimulation with ACTH or hCG, 2) venous catheterization and measurement of steroid levels in the left and right ovarian veins during surgery, 3) measurements of enzymatic activities in the tumor tissue compared with those in normal ovarian tissue, and 4) steroid secretion studies in vitro of the tumor tissue, surrounding tissue, and contralateral ovarian tissue. The tumor tissue secreted both delta 5 and delta 4 androgens, including dehydroepiandrosterone sulfate. Dehydroepiandrosterone sulfate was also secreted by the surrounding and contralateral ovarian tissue.

Medical treatment of low-renin aldosteronism.

Among the subsets of LRA, IHA and GSA should always be treated medically. APA and APC should be treated surgically if possible, with unilateral adrenalectomy. First-line treatment of IHA and for preoperative preparation of APA and APC patients is the aldosterone antagonist spironolactone. If this agent cannot be used because of side effects, sodium transport inhibitors are appropriate alternatives. Patients with IHA and APA can also be treated with calcium channel blockers, but only nifedipine has been tested in these conditions. IHA can probably also be treated with the converting enzyme inhibitor enalapril, but the experience with this agent is very limited. The same is true for steroidogenesis inhibitors, of which ketoconazole seems to be the most promising. GSA is usually treated with dexamethasone. Spironolactone and amiloride can be used as alternatives. The only proven auxiliary medication for treatment of APC is o,p'-DDD.

Atrial natriuretic hormone effect on renal function and aldosterone secretion in sodium depletion.

The effects of atrial natriuretic hormone (ANH) on aldosterone secretion and renal function have been well documented, but the physiological role of ANH is still unknown. To address this issue, eight normal men were infused for 4 h with low-dose (1.1 pmol.kg-1.min-1) human [Ser-Tyr28]ANH after 3 days of low-salt (LS) diet. The same subjects were also studied with placebo infusion on LS and high-salt (HS) diet. ANH infusion caused doubling of urine flow, a fourfold increase in urinary sodium excretion, and a slight increase in potassium excretion. Immunoreactive ANH levels increased from 3.1 +/- 0.5 to 21.0 +/- 1.9 pmol/l during ANH infusion. ANH infusion suppressed plasma renin activity (PRA) to one-third of the basal value, and plasma aldosterone was suppressed from 46.5 +/- 6.5 to 20.9 +/- 2.6 ng/dl. Low-dose ANH infusion caused a marked increase in urine flow and urinary sodium excretion and prominent suppression of PRA and plasma aldosterone in sodium-depleted subjects. These results suggest a physiological significance of ANH in regulation of kidney function and aldosterone secretion.

Effect of vasopressors on atrial natriuretic factor and hemodynamic function in humans.

To assess the effects of vasopressors on plasma levels of immunoreactive atrial natriuretic factor (ANF), 13 normal men were studied on two occasions. On the experimental day, subjects received sequential 15-minute intravenous infusions of angiotensin II in doses of 4, 8, and 16 pmol/kg/min. Following a 30-minute recovery period, subjects received sequential 15-minute infusions of phenylephrine in doses of 0.4 and 0.8 micrograms/kg/min. Right atrial pressure, mean pulmonary capillary wedge pressure, pulmonary artery pressure, mean systemic arterial pressure, and plasma levels of renin activity, aldosterone, angiotensin II, and immunoreactive ANF were obtained sequentially throughout the protocol. During the control day, vehicle was infused and plasma samples were obtained for hormone measurements. Infusion of angiotensin II and phenylephrine increased mean systemic arterial pressure in a stepwise fashion. Both right atrial pressure and pulmonary capillary wedge pressure increased significantly during both doses of phenylephrine, but only the highest dose of angiotensin II significantly increased atrial pressures. Plasma levels of immunoreactive ANF increased parallel with the changes in right atrial pressure and pulmonary capillary wedge pressure, with significant increases occurring only at the highest dose of both pressors. Angiotensin II and aldosterone levels increased and renin activity decreased during infusion of angiotensin II. There were no significant changes in plasma levels of immunoreactive ANF during the control day. These studies demonstrate that infusion of vasopressors increases plasma levels of ANF, but only when the vasopressor effect is associated with significant increases in right atrial and pulmonary capillary wedge pressures. Atrial stretch is the most likely mediator of the increase in plasma levels of immunoreactive ANF during vasoconstriction.