Ectopic secretion of neurohypophyseal peptides in patients with malignancy

A great deal of information has been accumulated on the synthesis and release of AVP, oxytocin, and their associated neurophysins under normal circumstances. In 1957, Schwartz and Bartter first described SIAD in patients with lung cancer and postulated that the clinical findings were the results of excessive vasopressin secretion. Tumors have been known since 1964 to produce vasopressin, and small cell (oat cell) carcinoma of the lung is by far the most frequent malignant cause of SIAD. The biosynthetic pathway for the synthesis of AVP and its associated neurophysin (and to a lesser extent, oxytocin and its neurophysin) is well described and is similar if not identical to the synthesis of these peptides in the hypothalamus. However, there is little reliable information on the control of peptide synthesis and release by these tumors. The clinical picture of SIAD is well described and occurs in 20% to 40% of patients with SCCL, although up to 88% of patients with extensive SCCL have elevated circulating levels of one or more neurohypophyseal peptides. This information has led to considerable interest in the use of these peptides as tumor markers for the diagnosis, evaluation, and assessment of therapy in these patients. With the recognition of the high incidence of secretion of neurohypophyseal peptides by SCCL, studies have been initiated to determine the value of radioactive vasopressin neurophysin antibodies in localizing tumors that synthesize these peptides. The studies provide potentially useful information in diagnosing and following patients with SCCL and also offer some promise that radiolabeled antineurophysins could eventually be used to treat these patients.     

Identification of vasopressin-like peptides in the plasma of a patient with the syndrome of inappropriate secretion of antidiuretic hormone and an oat cell carcinoma

In this study we have identified and characterized several vasopressin-like peptides in the plasma of a patient with the syndrome of inappropriate antidiuretic hormone secretion and oat cell carcinoma of the lung. Immunoreactive plasma vasopressin was measured after gel filtration (Sephadex G-25) or C-18 cartridge extraction using two different region-specific antisera: AS1 and AS2. Antiserum AS1 is more specifically directed towards the antigenic site of the hexapeptidic ring of arginine-vasopressin (AVP), whereas AS2 is more specifically directed towards the C-terminal region of AVP. Unexpectedly, the Sephadex G-25 gel filtration elution profile of the immunoreactive vasopressin was very heterogeneous, indicating the presence of several molecular species. After extraction of total AVP and AVP-like peptides of this plasma, an unusual AS1/AS2 ratio of immunoreactivity was observed, suggesting the presence of vasopressin-like peptides which differ from AVP in the C-terminus.     

Plasma vasopressin and human neurophysins in physiological and pathological states associated with changes in vasopressin secretion.

Using sensitive specific RIAs for vasopressin (AVP) and the two major human neurophysins, the relationship between AVP and the individual human neurophysins was investigated in man by measuring changes in plasma concentrations in physiological and pathological states known to be associated with changes in AVP secretion. Dehydration, water loading, and hemorrhage produced small but significant changes in plasma AVP concentrations without changes in the individual human neurophysins. In response to the stimulus of cigarette smoke inhalation, large parallel changes in plasma AVP and human neurophysin I (HNPI) levels were seen without change in plasma human neurophysin II (HNPII) levels. In the pathological states of diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion,the observations more strongly supported a specific association between AVP and NHPI. In eight patients with central diabetes insipidus, plasma AVP and HNPI levels were low or undetectable, while plasma HNPII levels were normal. There was a clear distinction of both plasma AVP and HNPI levels in patients with central diabetes insipidus and those in patients whti nephrogenic diabetes insipidus. In 14 patients with the syndrome of inappropriate antidiuretic hormone secretion due to causes other than ectopic AVP production from tumors, plasma AVP and HNPI levels were elevated or normal, while plasma HNPII levels were normal. There was a highly significant positive correlation (r = 0.99) between plasma AVP and HNPI levels in these patients, with a 1:1 molar ratio. These data suggest that the secretion of AVP and HNPI in man are functionally related, while the secretion of HNPII is independent of AVP secretion.     

Radioimmunoassay of plasma vasopressin in physiological and pathological states in man.

A radioimmunoassay method for the measurement of arginine-vasopressin (AVP) in human plasma has been developed which requires 5 ml of plasma and has a lower limit of detection of 1-8 pg/ml plasma. Arginine-vasopressin was found to be stable in whole blood for up to 1 h at room temperature and for at least 4 h at 4 degrees C, while in plasma stored at -20 degrees C no loss was seen over 10 days. Dehydration and rehydration in normal subjects produced appropriate changes in AVP concentration but there was considerable variability in the levels attained by individual subjects and no obvious correlation with plasma osmolality. No consistent increase in plasma AVP concentration was seen on change of posture from the recumbent to the upright position. Vigorous exercise produced a marked rise in plasma AVP concentrations in most subjects which could not be attributed simply to an increase in plasma osmolality. In fusion studies with Pitressin in normal subjects showed a mean half-life of 6-4 min with an overall plasma clearance rate of 8-5 ml/min/kg body weight and a mean volume of distribution of 5-33 l. In patients with a biochemical picture suggestive of inappropriate antidiuretic hormone secretion, markedly raised plasma AVP concentrations were found only in patients with bronchial carcinoma.     

Serum Neurophysins in familial central diabetes insipidus.

Antibovine neurophysin antibodies (anti-bNpI and/or anti-bNpII) are present in certain patients with familial central diabetes insipidus; these are exogenous origin, as they are not present in patients who have not received treatment with crude posterior pituitary extracts over the years preceding the analysis. Immunoreactive neurophysins were detectable in the blood of five patients with familial central diabetes insipidus, and in two of them, the levels increased after a short period of water restriction. There is marked polymorphism of these neurophysins from one serum to another: neurophysin I was consistently absent, while neurophysin II, accessory neurophysins, and other immunoreactive substances not present in normal sera were sometimes present in variable amounts. Immunoreactive AVP was undetectable in the urine of all patients, while immunoreactive OT was found in three of them; the latter substance could, however, be arginine vasotocin. Data are presented suggesting that the association between the biosynthesis of neurophysin I and AVP on the one hand, and neurophysin II and OT on the other hand is maintained in patients with isolated AVP deficiency on the basis of a congenital defect.     

Response of plasma vasopressin to ethanol in congestive heart failure

Plasma arginine vasopressin (AVP) levels are frequently increased in patients with congestive heart failure (CHF). Further, AVP does not respond normally to certain osmotic and nonosmotic manipulations in this condition. As a test of the central suppressibility of AVP in CHF, an oral ethanol challenge was given (0.7 ml/kg body weight) to 10 patients with CHF and 10 normal control subjects, and the response of AVP, osmolality, heart rate and blood pressure was measured over the next 2 hours. In the CHF group, AVP was 9.6 +/- 3.9 pg/ml (+/- standard deviation) at control and remained unchanged throughout the protocol. In the normal group, AVP was 6.9 +/- 2.9 pg/ml at control and declined significantly to 4.9 +/- 2.0 pg/ml at 20 minutes (p less than 0.05). Osmolality and blood ethanol changes were similar in the 2 groups, as were those in mean arterial pressure. The administration of ethanol therefore did not result in an acute decrease in plasma AVP in patients with CHF, but did so in normal subjects. Differences in the response of blood pressure and osmolality do not explain the abnormality; hence, a defect in the central control of AVP release may exist in CHF. This observation may have implications for the mechanisms involved in the generation or maintenance of elevated AVP levels in patients with this disease.     

Human neurophysins in carcinoma of the lung: relation to histology, disease stage, response rate, survival, and syndrome of inappropriate antidiuretic hormone secretion

At diagnosis, 65% of 103 patients with small cell carcinoma of the lung were found to have elevated plasma concentrations of vasopressin-associated human neurophysin (VP-HNP), oxytocin-associated human neurophysin (OT-HNP), or both, which were thought to be related to tumor secretion of these proteins. The remainder of patients were designated as nonsecretors (24%) or possible secretors (11%), depending upon plasma concentration of the neurophysins prior to therapy. There was a significantly higher percentage of secretors among patients with extensive disease (82%) than among those with limited disease (40%) (P = 0.001). However, within each stage group, there was no correlation between secretory status and response to therapy, survival, or histologic subtype. In addition, patients who initially were nonsecretors or possible secretors maintained this status throughout the course of disease remission and subsequent relapse. These findings suggest the possibility of biochemical differences between tumors which present as limited disease and those which present as extensive disease. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was infrequent in limited disease but was present in 33% of patients with extensive disease. SIADH was not seen without VP-HNP elevation; however, with extensive disease, 49% of patients with elevated VP-HNP had SIADH. In contrast, elevated plasma concentrations of the neurophysins were seen in only 19.6% of 56 patients with non-small cell carcinoma of the lung. The levels were in general lower than those in patients with small cell carcinoma and were seen at approximately equal frequencies in each major cellular subtype.     

Ectopic production of antidiuretic hormone (adh), adrenocorticotrophic hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) by an oat cell carcinoma of the lung.

A 61 year old woman presented with profound hyponatremia and markedly low serum osmolality. Urine osmolality was greater than the serum osmolality, an abnormality that was corrected by water restriction, suggesting inappropriate ADH secretion. Although there were no physical signs of Cushing's syndrome, her serum potassium level was low and markedly elevated levels of plasma and urine corticosteroids were not altered by the administration of large amounts of dexamethasone, suggesting the ectopic ACTH-MSH syndrome. Plasma levels of immunoreactive ACTH and beta-MSH were elevated. At autopsy, a metastastic oat cell carcinoma of the lung, not detected antemortem by chest roentgenograms and bronchoscopy, was found. Immunoreactive ADH, ACTH and beta-MSH were detected in the primary tumor and in metastases to the liver. beta-MSH was also detected in the spleen, in which metastases were observed. This is the first documented case of the simultaneous production of ADH, ACTH and beta-MSH by neoplastic tissue associated with clinical manifestations of the syndrome of inappropriate ADH secretion and the ectopic ACTH-MSH syndrome.     

Study of antidiuretic hormones (arginine vasopressin) in 24 cases of primary adrenal insufficiency

24 Addisonian patients were compared to 27 healthy subjects. Radioimmunoassay of plasma antidiuretic hormone showed higher concentrations of Arginine-vasopressin (AVP) in Addisonians than in normals, in spite of lower natremia and plasma osmolality. Statistical analysis showed a negative correlation between AVP and osmolality in Addisonian patients. On the other hand, no correlation was found between AVP and cortisol, or AVP and PRA. These results suggested an inadequate secretion of antidiuretic hormone in Addison disease. Under substitutive treatment, glucocorticoids alone didn't completely lower AVP concentration which was only normalized after administration of mineralocorticoids.     

Painful dysphagia from infiltrating oat cell carcinoma

Oat cell carcinoma of the lung is an aggressive malignancy with a propensity for widespread dissemination. Surprisingly, spread of this tumor to the esophagus from adjacent lung is unusual. Although submucosal involvement has been noted occasionally, overt mucosal ulceration, to our knowledge, has not been demonstrated previously. Two patients with oat cell carcinoma developed painful dysphagia and mucosal ulceration from tumor infiltration into the esophagus.     

Effect of administration of corticotropin-releasing hormone and glucocorticoid on arginine vasopressin response to osmotic stimulus in normal subjects and patients with hypocorticotropinism without overt diabetes insipidus

We examined the effect of CRH administration on the response of plasma arginine vasopressin (AVP) induced by an osmotic stimulus in six normal subjects and five patients with hypocorticotropinism without overt diabetes insipidus (four patients with Sheehan's syndrome and one with idiopathic pituitary dwarfism with ACTH deficiency). Hypertonic saline infusion (855 mmol/L saline solutions at a rate of 205 mumol/kg.min for 10 min) increased plasma AVP 5.7-fold (P less than 0.01) in normal subjects and 2.4-fold (P less than 0.05) in the patients. CRH administration significantly augmented the plasma AVP response to the osmotic stimulus in the normal subjects, but not in the patients with hypocorticotropinism. CRH administration alone did not influence plasma AVP. These findings suggest that a central CRH-related mechanism(s) was at least partly involved in the augmentation of AVP release. Based on the relatively low plasma AVP response to the osmotic stimulus in patients and their lower plasma AVP levels and higher plasma osmolality under basal conditions, we suggest that patients with hypocorticotropinism have partial diabetes insipidus, in which impairment of central CRH action might be, at least in part, involved. The response of plasma AVP to the osmotic stimulus was attenuated significantly when the patients were given cortisol. Since basal PRA, plasma aldosterone, plasma osmolality, hematocrit, body weight, mean blood pressure, and heart rate were similar with and without cortisol administration, this effect of cortisol may have been due to central suppression of the AVP response to the osmotic stimulus.     

A short water deprivation test incorporating urinary arginine vasopressin estimations for the investigation of posterior pituitary function in children

The value of a 7-h water deprivation test incorporating urinary osmolality and urinary arginine vasopressin (AVP) measurements was investigated in 20 children with suspected anterior or posterior pituitary dysfunction (group A) and 11 presenting with polyuria and polydipsia (group B). A control group of 16 healthy children was also studied. Urinary osmolalities in the control subjects after 7 h of water deprivation were 827-1136 mosmol/kg and urinary AVP 114-320 pmol/l. Of the group A patients, 5 had symptomatic diabetes insipidus with urinary osmolalities less than 300 mosmol/kg, and urinary AVP concentrations of less than 10 pmol/l, and 5 had normal urinary concentrating ability. The other 10 patients had varying degrees of partial diabetes insipidus (urinary AVP 6-53 pmol/l) although in 3 urinary concentrating ability was well maintained (osmolality 650-747 mosmol/kg). In group B, a diagnosis of compulsive water drinking was made in 9 patients, 1 had nephrogenic diabetes insipidus (urinary osmolality 68 mosmol/kg, AVP 782 pmol/l), and the final patient had transient diabetes insipidus. The test described was easy to perform and well tolerated even in young children. Using this test alone, it was possible to identify patients with partial defects of posterior pituitary function even when urinary concentrating ability was maintained, as well as those with complete cranial diabetes insipidus, nephrogenic diabetes insipidus, and compulsive water drinking.     

Arginine vasopressin and the renal response to water loading in congestive heart failure

Previous studies have shown on the basis of isolated comparisons that plasma arginine vasopressin (AVP) levels are inappropriately increased for a given serum osmolality in patients with CHF. To explore further the osmoregulation of AVP in this condition, the response of plasma AVP to a 15- to 20-ml/kg oral water load was compared in 26 patients with CHF and 14 normal subjects. In the normal subjects, serum osmolality decreased from 289 +/- 5.0 to 282 +/- 5.0 mOsm/kg (p less than 0.001) and AVP from 3.6 +/- 1.1 to 2.1 +/- 0.78 pg/ml (p less than 0.001). In the patients with CHF, osmolality decreased from 289 +/- 7.0 to to 281 +/- 7.0 mOsm/kg and AVP from 7.1 +/- 3.6 to 5.8 +/- 3.4 pg/ml (p less than 0.001). As a percentage of the control value, the decrease in AVP was much greater in the normal group, 41 +/- 15% vs 18 +/- 10% (p less than 0.001). Urinary osmolality levels were measured before and after water loading in 11 patients and in 7 normal subjects. Normal subjects diluted from 812 +/- 130 to 133 +/- 26 mOsm/kg (p less than 0.001) and CHF patients from 599 +/- 218 to 253 +/- 170 mOsm/kg, a statistically significant (p less than 0.01) but smaller (p less than 0.05) level of suppression. There were, however, 2 distinct groups within the CHF population: one in which urine osmolality was appropriately decreased (from 594 +/- 269 to 144 +/- 37 mOsm/kg, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion

This study explored whether atrial natriuretic hormone (ANH) might be involved in the escape from salt and water retention that occurs in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Sixteen patients with low serum Na+ concentrations [123 +/- 1 (+/- SE) mmol/L] were studied. Each patient excreted urine that was hyperosmolar (mean, 391 +/- 4 mosmol/kg) in relation to serum osmolality (mean, 258 +/- 4 mosmol/kg). Sodium excretion (81 +/- 20 mmol/L) also was inappropriate to the low serum Na+ level. The probable causes of SIADH were head trauma (4), pneumonia (5), lung cancer (3), and chlorpropamide therapy (4). In the nontumor patients, plasma and/or urinary vasopressin (AVP) concentrations were in the normal range, but inappropriate for serum osmolality. Urinary AVP values of 50 pg/mL or more (greater than 46 pmol/L) were found in the three tumor patients. The mean plasma ANH concentration was 6-fold higher than that in normal subjects [296 +/- 51 vs. 51 +/- 13 pg/mL (100 +/- 20 vs. 17 +/- 4 pmol/L); P less than 0.01]. Six SIADH patients were studied again after brief (1-3 days) water restriction. Although serum osmolality increased in each, their plasma AVP concentrations decreased very little, and urinary AVP excretion and plasma ANH did not change. These results indicate that plasma ANH levels are markedly increased in patients with SIADH. Their increased ANH secretion may antagonize water retention resulting from the inappropriate AVP secretion.     

Osmoregulation of vasopressin secretion in patients with the syndrome of inappropriate antidiuresis associated with central nervous system disorders.

To clarify the characteristics of vasopressin (AVP) secretion in patients with the syndrome of inappropriate antidiuresis (SIAD) related to central nervous system disorders, we examined the response of AVP secretion to osmotic stimulus by hypertonic saline infusion and analyzed the possible causative factors in six patients with SIAD associated with head trauma or cerebral infarction. Hyponatremia developed after head trauma in four patients and cerebral infarction in two patients. In all patients the clinical state and laboratory findings fulfilled the criteria for SIAD, which was supported by either nonsuppressible plasma AVP levels or effectiveness of treatments with water restriction, demeclocycline, nonpeptide V2 AVP antagonist or diphenylhydantoin. Although patterns of plasma AVP response to the osmotic stimulus varied, plasma AVP concentrations neither increased nor decreased to undetectable levels with a rise in plasma osmolality. In one patient, plasma AVP levels responded to increasing plasma osmolality when plasma osmolality normalized; in which the threshold and the sensitivity of osmostat were normal. In two other patients, AVP secretion responded to plasma osmolality after the treatment. The changes in AVP secretion were not due to nonosmotic stimuli for AVP release. In conclusion, this study shows that patients with SIAD and central nervous system disorders may have persistent AVP secretion with a loss of hypotonic suppression such as found in patients with adrenal insufficiency or depletional hyponatremia in central nervous system disorders, indicating that careful evaluation is necessary to determine the relationship between persistent AVP secretion and the pathogenesis of hyponatremic disorders.     

Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism

In six patients with pseudohypoparathyroidism (PHP) who were deficient in guanine nucleotide-binding stimulatory protein (Ns) activity, the response to endogenous arginine vasopressin (AVP) was tested during water deprivation. Hourly plasma osmolality (Posm), urinary osmolality (Uosm), and urinary AVP (UAVP) values were compared to those in normal subjects. The Uosm vs. Posm and the UAVP vs. Uosm relationships of the patients were all within the normal range. Four patients with Ns-deficient PHP were subjected to maintained water loads and infused with AVP at three different rates for 1 h each to assess their responses to exogenous AVP. Urinary volume and osmolality values from the final 30 min of each infusion rate were measured. All volume values except 1 were within 1.6 SD of normal, and all osmolality values except 1 were within 1.1 SD of normal. In conclusion, these studies indicate that these six patients with Ns-deficient PHP are not resistant to the antidiuretic (cAMP-mediated) action of endogenous or exogenous AVP, in contrast to the previously documented resistance of patients with Ns-deficient PHP to the actions of PTH, TSH, glucagon, and gonadotropins.     

Spontaneous remission of cranial diabetes insipidus due to concomitant development of ADH-producing lung cancer--an autopsied case

The very rare occurrence of an ADH-producing small cell carcinoma of the lung in a 52 year old male patient with cranial diabetes insipidus since childhood is described. In this case diabetes insipidus disappeared concomitantly with development of lung cancer and re-appeared with shrinkage of the lung tumour by radiation therapy. Further progressive expansion of the primary and metastatic tumours induced the syndrome of inappropriate ADH secretion once again (SIADH). This deterioration in the clinical course was reflected in the plasma levels of ADH and neurophysins. The existence of vasopressin in the tumour tissue was also demonstrated by means of an immunohistochemical staining technique combined with anti-vasopressin serum.     

Disturbance of osmoregulated thirst and vasopressin secretion in thyrotoxicosis

OBJECTIVE: To assess the effect of untreated thyrotoxicosis on osmoregulated thirst sensation and AVP secretion. DESIGN: Measurements were made at 30-minute intervals while untreated thyrotoxic patients were given sodium chloride 855 mmol/l intravenously for 2 hours followed by water drinking ad libitum for 2 hours. The protocol was repeated when the patients were euthyroid. PATIENTS: Eight newly diagnosed thyrotoxic patients were studied. MEASUREMENTS: Thirst sensation (visual analogue scale), plasma osmolality, AVP and plasma renin activity were measured. RESULTS: Prior to osmotic stimulation and after plasma osmolality had been returned to normal by drinking water, thirst sensation was increased in the thyrotoxic state. Plasma AVP showed an exaggerated response to hypertonic saline in the patients when they were thyrotoxic. Increasing plasma osmolality produced a linear increase in thirst sensation and log linear increase in plasma AVP. However, in the thyrotoxic state both these relations were altered. The apparent osmolar thresholds for onset of thirst sensation and AVP release were similar (281 and 280 mosm/kg respectively) and were reduced similarly in the thyrotoxic state (269 and 274 mosm/kg respectively). CONCLUSIONS: The osmostat mechanisms which regulate thirst sensation and AVP release are reset in the thyrotoxic state. The responses of thirst sensation and of plasma AVP to increasing plasma osmolality are altered similarly, suggesting that thyrotoxicosis affects both homeostatic functions by a common mechanism.     

Plasmatic arginine vasopressin levels in total and partial diabetes insipidus

Plasma arginine vasopressin (AVP) was measured in 24 patients with polyuria exceeding 3.5 l/day diagnosed as severe or partial diabetes insipidus according to the dehydration test. All patients with severe diabetes insipidus diagnosed by the dehydration test had very low or undetectable basal AVP values and always subnormal plasma osmolality. Patients with partial diabetes insipidus diagnosed by the dehydration test had a wide range of AVP and osmolality values. The stimulation test performed on these patients was able to differentiate patients with primary polydipsia from patients with partial diabetes insipidus. The measurement of basal plasma AVP is capable of diagnosing all patients with severe diabetes insipidus; when we combine the stimulation test with the measurement of AVP, we can differentiate partial diabetes insipidus from other forms of polyuria.     

Plasma arginine-8-vasopressin responses to osmotic or histamine stimulation contribute to the differential diagnosis of central diabetes insipidus

The arginine-8-vasopressin (AVP) responses to osmotic and histamine stimuli were evaluated in 21 patients with central diabetes insipidus (CDI) and compared to those of 10 healthy controls. Plasma AVP was measured by radioimmunoassay. Following the infusion of 2.5% saline, the AVP responses of CDI patients fell into two distinct groups: CDI I gave no response at all, while CDI II responded subnormally. Histamine increased the plasma AVP level significantly in healthy volunteers. Patients with CDI II gave subnormal AVP responses to histamine. The AVP reactions of the patients with CDI I fell into two subgroups: CDI I/A had undetectable plasma AVP, while histamine evoked AVP release in CDI I/B. Histamine trial did not lead to any change in plasma osmolality. The authors conclude that patients with CDI II suffer from a partial CDI, while those with CDI I/A represent a complete form of the disease. The remainder (CDI I/B) presumably have an osmoreceptor failure. Osmotic and non-osmotic stimulation may provide a useful tool in the differential diagnosis of CDI.