A case of hyponatremia in panhypopituitarism caused by the primary empty sella syndrome

A 64-year-old woman was admitted for evaluation of hyponatremia. She was maintained on hypertonic saline administration. Without this therapy, the serum Na concentration decreased progressively to 127 mEq/L and the plasma osmolality to 254 mOsm/Kg H2O, on Day 3. At that time, the concentration of antidiuretic hormone (ADH) was as high as 3.5 pg/ml. A skull radiogram revealed an enlarged sella turcica. Computed tomography (CT) revealed a low density in the sella, and magnetic resonance imaging revealed equal intensity of the sella turcica and the cerebrospinal fluid. A diagnosis of empty sella syndrome was made by metrizamide cisternography in conjunction with CT scanning. A diagnosis of panhypopituitarism was made by endocrine function tests. 123I-thyroidal uptake was 6% when her serum TSH was 10.9 microU/ml, suggesting that she might also have primary hypothyroidism. When this patient was given glucocorticoid before levothyroxine replacement, her serum Na concentration rose up to about 140 mEq/L and a normal relationship between her plasma ADH level (2.4 pg/ml) and plasma osmolality (281 mOsm/kg H2O) was restored. Therefore, it was suggested that ADH hypersecretion induced by the glucocorticoid deficiency might in part contribute to the development of hyponatremia. This is the case of primary empty syndrome associated with panhypopituitarism, in whom initial symptom was caused by hyponatremia.     

A case of syndrome of inappropriate secretion of antidiuretic hormone associated with diabetes mellitus.

A 46-year-old man, presenting with headache, nausea, and lassitude, was diagnosed as having diabetes mellitus and hyponatremia, and admitted to Tohoku University Hospital. Insulin treatment improved the hyperglycemia but aggravated hyponatremia, which was proved to be elicited by the inappropriate secretion of antidiuretic hormone (SIADH). An acute water load failed to suppress ADH release in the supine posture but slightly increased plasma atrial natriuretic peptide (ANP). On the other hand, plasma ADH markedly increased in response to an upright posture, accompanied by a fall in blood pressure and a rise in heart rate. After treatment with droxidopa "a sympathomimetic drug", ambulatory blood pressure gradually increased and hyponatremia disappeared. However, blood pressure and ADH responses to upright posture were not improved by treatment with the drug. Moreover, plasma ADH was still not sufficiently suppressed by acute water loading in the supine position, but plasma ANP markedly increased, thereby resulting in urinary dilution and natriuresis. These results suggest that exaggerated ADH release (SIADH) was brought about by the baroreceptor reflex stimulated by the postural hypotension, and also by the impaired osmoregulation associated with diabetic neuropathy, and that droxidopa improved cardiovascular function and increased ANP release with resultant urinary dilution and natriuresis in spite of slightly increased ADH release.     

May primary empty sella turcica be a cause of isolated ACTH deficiency? A case report and the review of related literature

Isolated ACTH deficiency is an uncommon cause of secondary adrenocortical insufficiency and accompaniment with primary empty sella has been reported in several cases. We present a case of isolated ACTH deficiency associated with empty sella. A sixty-two year old woman was admitted to our endocrine clinic with complaints of weakness, fatigue, weight loss, nausea, vomiting, and lack of appetite for about one month. Physical examination indicated orthostatic hypotension and epigastric tenderness. Laboratory investigations revealed hypoglycemia, hyponatremia and anemia, in addition low plasma cortisole and ACTH levels. Serum cortisole responses to short and prolonged ACTH stimulation were tested and partial and accurate responses were obtained, respectively. Plasma ACTH and serum cortisole levels failed to respond after intravenous injection of human corticotropin releasing hormone. Other hypophysial hormone levels were within the normal reference ranges. Although cranial and abdominal computerized tomography images were evaluated as normal, cranial magnetic resonance imaging of the pituitary gland revealed 'primary empty sella turcica'. Replacement therapy with methylprednisolon resulted in the improvement of hypoglycemia, hyponatremia and clinical symptoms. Based on these results, the patient was diagnosed as isolated ACTH deficiency and was scheduled for follow up by our outpatient clinic. Our report is consistent with other reports pointing out that primary empty sella may be responsible for pathogenesis of isolated ACTH deficiency.     

Inverse correlation between urinary 17-hydroxycorticosteroid (17-OHCS) excretion and thyrotropin-releasing hormone (TRH)-induced thyrotropin (TSH) response in disorders of adrenocorticotropic hormone (ACTH) and adrenal secretion

A TRH test was performed in patients with Cushing's syndrome and isolated ACTH deficiency, and serum TSH was measured. A TRH-induced TSH showed low response in patients with Cushing's syndrome but showed excessive response in patients with isolated ACTH deficiency. However, in both diseases TRH-induced TSH response showed a tendency to normalize after the treatment. Urinary 17-OHCS excretion was measured in patients with Cushing's syndrome and isolated ACTH deficiency before and after the treatment. There was a definite inverse correlation between ;the logarithm for urinary 17-OHCS excretion and the peak TSH response to TRH. These results suggested that glucocorticoids regulate not only ACTH but also TSH secretion.     

Circulating antidiuretic hormone in the X-irradiated rat

Male rats exposed to 500 R of whole-body x-irradiation were allowed food and water ad libitum and housed in metabolism cages; water and food intake and urinary and fecal excretion were recorded daily. Urine output increased 200% during the first 24 hours after irradiation. No significant changes occurred in daily sodium, potassium, urea, or total solute excretion, although calcium excretion approximately doubled after irradiation. The marked increase in free water excretion implicates antidiuretic hormone (ADH) in this phenomenon. Application of a sensitive bioassay for ADH permitted measurement of plasma ADH concentrations in undisturbed, unanesthetized rats before and after irradiation. ADH levels were lower and frequently not detectable 24 hours after exposure. High ADH levels, however, could be provoked in irradiated rats by hemorrhage, indicating that the receptor cells and secretory ability of the posterior pituitary remained intact. Furthermore, irradiated rats responded normally to small intravenous injections (4 to 8 microU) of exogenous ADH. Rats with congenital diabetes insipidus given daily injections of Pitressin showed no postirradiation diuresis. Lastly, increased urinary calcium excretion may result from hypercalcemia which is known to induce diuresis through calcium-vasopressin antagonism. These results further suggest that the diuretic response is due to decreased circulating ADH.     

Effects of corticotropin releasing factor and growth hormone releasing factor on pituitary hormone secretion in patients with congenital thyrotropin deficiency. Abnormal response of growth hormone to corticotropin releasing factor

Blood concentrations of anterior pituitary hormones, ACTH, GH, TSH, PRL, LH, and FSH were determined in corticotropin releasing factor (CRF) test (synthetic ovine CRF 1.0 microgram per kg body weight) and growth hormone releasing factor (GRF) test (synthetic human pancreatic GRF-44 100 micrograms) in 2 female sibling patients with congenital isolated TSH deficiency, in their mother, in 2 patients with congenital primary hypothyroidism and in 8 normal controls. The patients with isolated TSH deficiency showed normally increased plasma ACTH and serum GH after CRF and GRF, respectively, and also showed an abnormal GH response to CRF. The serum GH showed a rapid increase to maximum levels (12.9 ng/ml) within 30 to 60 min followed by decrease. The possibility of secretion of abnormal GH could be excluded by the fact that on serum dilution, GH value gave a linear plot passing through zero. In addition, serum PRL, LH and FSH levels after CRF administration in case 1 and PRL after GRF in case 2 were also slightly increased but these responses were marginal. The mother of the patients, patients with congenital primary hypothyroidism, and normal healthy controls showed normal responses of pituitary hormones throughout the experiment. Data from the present study and a previous report show that abnormal GH response to the hypothalamic hormones (CRF, TRH and LHRH) may be observed in patients with congenital isolated TSH deficiency.     

Human corticotropin-releasing hormone test in normal subjects and patients with hypothalamic, pituitary or adrenocortical disorders

Human corticotropin-releasing hormone (hCRH) test was performed in 57 normal volunteers and 102 patients with hypothalamic, pituitary and adrenocortical diseases. Intravenous bolus injection of synthetic hCRH, 100 micrograms for adults or 1.5 micrograms/kg for children, increased plasma ACTH and cortisol levels in about 90% of normal subjects. In 47 patients with Cushing's disease, plasma ACTH tended to show an exaggerated response to hCRH and peak ACTH was the most frequent abnormal component among the several reaction parameters. Poor responders among normal subjects and patients with Cushing's disease had significantly higher plasma cortisol levels before CRH administration. Patients with hypothalamic hypopituitarism showed exaggerated response, whereas patients with primary pituitary lesion, isolated ACTH deficiency or adrenal Cushing's syndrome showed no ACTH response. These differences in the response of patients suggest the value of the hCRH test in their differential diagnosis.     

Role of substance P in water homeostasis.

The effect of the naturally occurring peptide substance P on release of antidiuretic hormone (ADH) was studied in anesthetized dogs. Intravenous infusions of substance P in doses of 0.5, 5.0, and 50 ng/kg/min increased plasma concentrations of ADH in a dose-related fashion. At the two low doses, this increase occured in the absence of changes in urine volume, sodium excretion, free water clearance, and urinary cyclic AMP excretion. In addition, when substance P was administered in a concentration of 0.5 ng/kg/min, plasma levels of ADH were increased even though blood pressure did not change, suggesting that substance P may release antidiuretic hormone by a direct mechanism. Intrarenal infusions at a rate of 0.5 and 5 ng/kg/min caused dose-related decreases in free water clearance and significant increases in urinary cyclic AMP excretion. These data suggest that substabce P may play an important role in the regulation of water balance.     

Insulin hypoglycemia test and releasing hormone (corticotropin-releasing hormone and growth hormone-releasing hormone) stimulation in patients with pituitary failure of different origin

To investigate the efficacy of endocrine evaluation in diagnosing and localizing the cause of anterior pituitary failure, 17 patients with suprasellar space-occupying lesions, 4 patients with intrasellar tumors, 8 patients with no detectable anatomical lesion, 1 patient with posttraumatic failure and 1 patient with septooptical dysplasia were investigated. Endocrine evaluation consisted of measuring adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) levels during insulin hypoglycemia test (IHT) and after administration of corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH). In addition, basal prolactin levels, gonadal and thyroid function were evaluated. The results showed that 4 of 17 patients with suprasellar tumors had normal ACTH and GH responses during IHT and after releasing hormone (RH) administration. Five of these patients had a normal ACTH or cortisol rise but no GH response during IHT. All 5 had a normal ACTH and 3 had normal GH rise after RH. Seven patients with suprasellar tumors had no ACTH or GH response during IHT, but all had an ACTH response to CRH. Only 3 of this group had a GH response to GRH. There was one exception of a patient who showed a GH and ACTH rise during IHT but only a blunted ACTH and no GH rise after RH administration. Four patients with pituitary failure and no demonstrable lesion had an ACTH rise after CRH but no GH rise after GRH, whereas in 3 patients with isolated ACTH deficiency no ACTH rise after CRH was seen. In 4 patients with nonsecreting pituitary tumors normal ACTH responses to IHT and CRH were seen, whereas GH rose during IHT only in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluid conservation in athletes: responses to water intake, supine posture, and immersion

The roles of antidiuretic hormone (ADH) and aldosterone in the elicited diuretic responses of trained and untrained men to seated, supine, and head-out water immersed conditions were studied. Volunteers were comprised of groups of six untrained individuals, six trained swimmers, and six trained runners. Each subject underwent three protocols, six hours in a seated position, supine position, or immersion (35 degrees C water). The last two protocols were preceded and followed by 1 h of seated position. After 10 h of fasting, 0.5% body wt of water was drunk. One hour later the trained groups had higher urine osmolalities (P less than 0.05) and urinary excretion rates of ADH (P less than 0.05) and lower urine flow rates (P less than 0.05) than untrained subjects. Throughout the sitting protocol, urinary ADH was also higher in both trained groups (P less than 0.05). Both supine posture and immersion resulted in significant decreases in urinary ADH in the untrained subjects (P less than 0.05) but no changes wer noted in swimmers and only during the second hour of immersion in the runners (P less than 0.05). The natriuresis and kaliuresis were greater during immersion than in the supine position but plasma renin activity, measured only in trained groups, and plasma aldosterone, measured in the untrained group, were decreased similarly with both protocols. The increases in urinary sodium excretion and urine flow rate were lower in trained than untrained subjects during the supine and immersion protocols (P less than 0.05). The data are compatible with an increased osmotic but decreased volume sensitivity of ADH control in trained men.     

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.     

Significant increase in plasma immunoreactive atrial natriuretic polypeptide concentration during head-out water immersion

To investigate the physiological regulatory mechanism of human atrial natriuretic polypeptide (hANP) secretion, plasma hANP was measured by a direct radioimmunoassay during head-out total body water immersion (WI) in normal men. Five healthy men were immersed in water for 1 hr. Urine volume and Na excretion were significantly increased during WI. Plasma hANP increased significantly during WI peaking at 30 min. and returned toward the baseline after WI. Plasma renin activity and norepinephrine were suppressed occasionally during WI. Plasma ADH did not change throughout the study period. Maximal increments in plasma hANP correllated with that in urine output or urinary Na excretion during WI. These data suggest that acute central hypervolemia caused by WI increases hANP secretion and that this increase may participate in the diuretic response to WI.     

Measurement of thyroid stimulating hormone (TSH) in human urine

Using a highly sensitive and specific immunoradiometric assay kit for human TSH, we measured TSH concentrations in unprocessed urines in normal subjects, in patients with primary hypothyroidism, and patients with renal disease. In five of ten normal subjects TSH was detectable in urine samples (less than 20-69 microU/day). In five patients with hypothyroidism, the urinary TSH excretion was increased. In seven out of ten patients with nephrotic syndrome, eight out of nine patients with chronic renal failure and two patients with tubular dysfunction, the urinary TSH excretion was increased. The urinary TSH excretion correlated significantly with both urinary protein excretion and urinary beta 2-microglobulin excretion. These results suggest that the renal handling of TSH involves both glomerular filtration and tubular re-absorption, and that urinary TSH excretion is increased when serum TSH is increased and either glomerular or tubular function is impaired.     

Urinary excretion of aquaporin-2 and inappropriate secretion of vasopressin in hyponatremic patients after cerebral infarction.

Aquaporin-2, a water-channel protein, is known to increase water permeability due to vasopressin binding to V2 receptors at the renal collecting duct and is excreted into the urine. It is still unclear whether a hyponatremic state is caused by vasopressin-dependent aquaporin-2 in patients clinically diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone. To determine this, we measured urinary aquaporin-2 and vasopressin by radioimmunoassay in normonatremic or hyponatremic patients after cerebral infarction and in healthy controls. In the normonatremia group, urinary aquaporin-2 and plasma AVP levels were higher than in controls. In the hyponatremia group, plasma AVP was relatively high despite low plasma osmolality in each patient. However, urinary aquaporin-2 in hyponatremia was significantly increased when compared with the other two groups. In conclusion, AQP-2 increment does not directly reflect non-osmotic AVP secretion in a hyponatremic state. This result indicates that the urinary excretion of AQP-2 is not only AVP-dependent in hyponatremic states.     

Cardiorenal-endocrine responses to head-out immersion at night

Cardiorenal-endocrine responses to 3-h head-out immersion (HOI) (water temperature = 34.5 +/- 0.5 degrees C) were studied during day (0900-1400 h) and night (2300-0400 h) in six hydropenic male human subjects. Although HOI induced a reversible increase in urine flow in all subjects, the response was faster and greater in magnitude during the day compared with night (P less than 0.05). Na excretion and osmolal clearance (Cosm) also followed the identical response pattern as urine flow, and in fact, the HOI-induced diuresis was entirely accounted for by the increased Cosm. Endogenous creatinine clearance was not different between the day and the night and remained unchanged during HOI. Both plasma renin activity and aldosterone concentration and urinary aldosterone excretion were nearly twofold greater during the day compared with night before HOI but decreased to the same level during HOI in both daytime and the nighttime series (P less than 0.05). There was no correlation between the Na excretion rate and renin-aldosterone levels either before or during HOI. Plasma antidiuretic hormone (ADH) level was comparable between day and night before HOI and decreased to a similar level during HOI in both daytime and nighttime series (P less than 0.05 for nighttime HOI). Cardiac output increased from 3.3 1/min before HOI to 5-6 1/min during HOI without showing any significant circadian difference. Hematocrit, hemoglobin, and plasma concentrations remained unchanged under all conditions. It is concluded that the renal response to HOI is subject to nocturnal inhibition, which cannot be attributed to circadian differences in the degree of HOI-induced central blood pooling, renin-aldosterone, or ADH responses.     

Antidiuretic Effect of Eel ANP Infused at Physiological Doses in Conscious, Seawater-Adapted Eels, Anguilla japonica

Atrial natriuretic peptide (ANP) is known as a potent natriuretic/diuretic hormone in vertebrates. However, eel ANP infused at doses that did not alter arterial blood pressure (0.3-3.0 pmol/kg/min) decreased urine volume and increased urinary Na concentration in seawater (SW)-adapted eels but not in freshwater (FW)-adapted eels. The renal effects were dose-dependent and disappeared after infusate was switched back to a vehicle (0.9% NaCl). Urinary Na excretion (volume x Na concentration) did not change during ANP infusion. ANP infusion increased plasma ANP concentration, but the increase at the highest dose was still within those observed endogenously after injection of hypertonic saline. Urinary Mg and Ca concentrations increased during ANP infusion in SW eels, but urinary Ca excretion decreased in FW eels. Plasma Na concentration profoundly decreased during ANP infusion only in SW eels, suggesting that ANP stimulates Na extrusion via non-renal routes. These results indicate that ANP is a hormone which specifically extrudes Na ions and thereby promotes SW adaptation in the eel. This is in sharp contrast with mammals where ANP is a volume regulating hormone that extrudes both Na and water.     

A case of partial hypopituitarism with empty sella following normal course of pregnancy and delivery

A 28 year-old woman was admitted to Jichi Medical School Hospital because of amenorrhea, cold intolerance, easy fatigability and body weight loss. She was pregnant at the age of 26 years. She delivered a 3230 g healthy girl at full term without any complications. However, she did not have any lactation or recurrence of menstruation after the delivery. Serum cortisol was 0.7 micrograms/dl, and plasma adrenocorticotropic hormone (ACTH) was less than 10 pg/ml. Both hormones failed to increase in response to insulin-induced hypoglycemia or exogenous arginine vasopressin. However, serum cortisol and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were significantly increased by the repeated administration of ACTH. Serum prolactin was 2.2 ng/ml and the level did not rise after the administration of thyrotropin releasing hormone (TRH). Responses of release of adenohypophysial hormones including gonadotropins, growth hormone and thyroid stimulating hormone (TSH) were normal. Serological studies showed an antibody to the pituitary gland which was demonstrated by an indirect immunofluorescence technique. Plain skull X-ray film and brain computerized tomography revealed an empty sella of the normal size. These results indicate the presence of partial deficiency of ACTH and prolactin, and that autoimmune disorders may be involved in the pathogenesis of her hypopituitarism.     

Influence of antidiuretic hormone on intrarenal blood flow distribution in diabetes insipidus dogs and rats.

The distribution of labeled microspheres within the renal cortex was used to evaluate the influence of physiological amounts of antidiuretic hormone on intrarenal blood flow distribution in hypophysectomized dogs and in rats with hereditary diabetes insipidus. In both species, intravenous infusions of ADH caused a significant decrease in the ratio of inner to outer cortical blood flow. The change in blood flow distribution observed in the hypophysectomized dog with ADH was primarily a consequence of a decrease in inner cortical blood flow. No consistent changes in outer cortical blood flow were found. Also in the dog, glomerular filtration rates and electrolyte excretion rates (Na and K) increased following ADH. In contrast, ADH infusion into Brattleboro rats caused no change in glomerular filtration or excretion of Na and K.     

Urinary 5-ene-steroid excretion in non-classical congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency (NC-3BHSD)

The diagnosis of non-classical 3 beta-hydroxysteroid dehydrogenase deficiency (NC-3BHSD) is made either on the basis of significantly elevated serum levels of basal and post-ACTH 5-ene-steroids or by the presence of elevated urinary 5-ene-steroid metabolites. There has been only one report to date describing a single patient where the diagnosis was based on both serum and urinary 5-ene-steroid levels. We, therefore, measured both serum 5-ene-steroid responses to ACTH 1-24 (by RIA) and urinary 5-ene-steroid metabolites (GC-MS) in 42 hirsute premenopausal women. While the serum 5-ene-steroid profile was consistent with NC-3BHSD in 5 women, only 2 of them had increased excretion of 5-ene-steroid metabolites. Elevated 5-ene-steroid excretion was also observed in several patients with normal serum 5-ene-steroids. Detection of NC-3BHSD by either elevated serum 5-ene-steroids or increased urinary excretion of their metabolites in isolation may not therefore be reliable.     

Ability of corticotropin releasing hormone to stimulate cortisol secretion independent from pituitary adrenocorticotropin

Cortisol secretion by the adrenal cortex is thought to depend upon a preceding release of pituitary ACTH. This concept ignores a large number of observations suggesting important extrapituitary influences on adrenocortical function. The present study was designed to demonstrate the contribution of these extrapituitary mechanisms in the release of cortisol induced by human corticotropin releasing hormone (hCRH) in man. In patients with proven deficiency in pituitary ACTH the functional atrophy of the adrenals had been restored by pretreatment with long-acting ACTH. Fifty-eight hours after the second and last injection of ACTH a CRH test was performed (100 micrograms hCRH intravenously). Administration of hCRH induced a small but significant increase in plasma cortisol. Surprisingly, this rise was preceded by an increase in plasma ACTH similar to the ACTH response observed in the control group. It appeared that hCRH is able to stimulate cortisol release in the absence of pituitary ACTH, presumably by stimulating extrapituitary sources of ACTH.