Abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma.

OBJECTIVE: In this study we aimed to establish the frequency of postoperative diabetes insipidus and the incidence and characteristics of abnormalities of thirst in a cohort of patients with craniopharyngioma, in whom neurosurgery had been performed. DESIGN: Diabetes insipidus was determined by either standard criteria for diagnosis in the immediate postoperative period, or by water deprivation test, in all craniopharyngioma and pituitary tumour patients who underwent surgery in Beaumont Hospital between the years 1986 and 1998. Osmoregulated thirst and vasopressin release were studied during a 2-h infusion of hypertonic (5%) saline followed by a 30-min period of free access to water. PATIENTS: Data on the incidence of postoperative diabetes insipidus was collected in 26 patients with craniopharyngioma and 154 patients with pituitary adenomata. We recruited 16 healthy control patients, 16 patients with cranial diabetes insipidus following pituitary tumour surgery and 16 patients with cranial diabetes insipidus following craniopharyngioma resection for the hypertonic saline infusion study. RESULTS: Twenty-five patients out of 26 (96%) patients developed diabetes insipidus after surgery for craniopharyngioma, a much higher incidence than after surgery for suprasellar (26/88, 30%, P < 0.001) or intrasellar pituitary tumours (9/66, 14%, P < 0.001). Hypertonic saline infusion identified abnormal thirst responses in five of the 16 craniopharygioma patients studied; all of the pituitary tumour patients had a normal thirst response. Three of the craniopharyngioma patients had adipsic diabetes insipidus whilst two had polydipsic diabetes insipidus. CONCLUSION: This study demonstrates following surgery for craniopharyngioma there is a high incidence of cranial diabetes insipidus and a significant incidence of abnormal thirst responses to osmotic stimuli.

Downward resetting of the osmotic threshold for thirst in patients with SIADH.

The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by euvolemic hyponatremia. Patients with SIADH continue to drink normal amounts of fluid, despite plasma osmolalities well below the physiological osmotic threshold for onset of thirst. The regulation of thirst has not been previously studied in SIADH. We studied the characteristics of osmotically stimulated thirst and arginine vasopressin (AVP) secretion in eight subjects with SIADH and eight healthy controls and the nonosmotic suppression of thirst and AVP during drinking in the same subjects. Subjects underwent a 2-h infusion of hypertonic (855 mmol/l) NaCl solution, followed by 30 min of free access to water. Thirst rose significantly in both SIADH (1.5 +/- 0.6 to 8.0 +/- 1.2 cm, P < 0.0001) and controls (1.8 +/- 0.8 to 8.4 +/- 1.5 cm, P < 0.0001), but the osmotic threshold for thirst was lower in SIADH (264 +/- 5.5 vs. 285.9 +/- 2.8 mosmol/kgH(2)O, P < 0.0001). SIADH subjects drank volumes of water similar to controls after cessation of the infusion (948.8 +/- 207.6 vs. 1,091 +/- 184 ml, P = 0.23). The act of drinking suppressed thirst in both SIADH and controls but did not suppress plasma AVP concentrations in SIADH compared with controls (P = 0.007). We conclude that there is downward resetting of the osmotic threshold for thirst in SIADH but that thirst responds to osmotic stimulation and is suppressed by drinking around the lowered set point. In addition, we demonstrated that drinking does not completely suppress plasma AVP in SIADH.

Tests of posterior pituitary function.

The posterior pituitary hormone vasopressin is one of the principal endocrine regulators of fluid and electrolyte balance. Tests of posterior pituitary function are based on the physiology and pathophysiology of vasopressin, and involve studies that aim at defining the production and action of the hormone in response to fixed stimuli with reference to standard normal ranges.

The role of arginine vasopressin in human labour: functional studies, fetal production and localisation of V1a receptor mRNA.

OBJECTIVE: To investigate labour-associated changes in: 1. the myometrial contractile response to arginine vasopressin compared with oxytocin in vitro 2. fetal production of arginine vasopressin and 3. myometrial vasopressin V1a receptor mRNA. DESIGN: The contractile response to vasopressin (compared with oxytocin) was investigated in paired myometrial strips in vitro. Blood was taken from the umbilical artery and vein at delivery and arginine vasopressin measured by radio-immunoassay. V1a receptor mRNA was determined by in situ hybridisation. RESULTS: Myometrium was more sensitive to arginine vasopressin than oxytocin (P<0.05 for frequency, amplitude and activity integral in paired strips) after, but not before labour. There was a marked umbilical arteriovenous difference in arginine vasopressin concentration at delivery suggesting fetal production which was not influenced by labour. Myometrial vasopressin V1a receptor mRNA was not increased after the onset of labour. CONCLUSIONS: The human uterus is extremely sensitive to arginine vasopressin in vitro. Arginine vasopressin is produced by the fetus but fetal formation is not increased during labour.

Altered osmotic thresholds for arginine vasopressin secretion and thirst during superovulation and in the ovarian hyperstimulation syndrome (OHSS): relevance to the pathophysiology of OHSS.

OBJECTIVE: To test the hypothesis that decreases in and maintenance of a new steady state in plasma osmolality and sodium level in ovarian hyperstimulation syndrome (OHSS) are due to altered osmoregulation of arginine vasopressin secretion and thirst. DESIGN: Prospective study. SETTING: IVF-ET program in a university-based assisted reproductive treatment center. PATIENT(S): Eight women undergoing superovulation for IVF-ET and five women with normal menstrual cycles. INTERVENTION(S): Two-hour infusion of 5% saline on day 3 or 4 after hCG administration in patients undergoing IVF or in the early luteal phase in controls. A 5% saline infusion test was done on day 10 after hCG administration in one patient with OHSS and one patient without OHSS, both of whom were undergoing IVF. MAIN OUTCOME MEASURE(S): Comparison of changes in thresholds for thirst and plasma vasopressin to plasma osmolality. Changes in urine osmolality, plasma electrolytes, hemoglobin level, and hematocrit were assessed at baseline and during infusion of 5% saline. RESULT(S): The sensitivity of the changes in arginine vasopressin secretion and thirst after 5% saline infusion was similar in IVF patients on day 3 or 4 after hCG and controls. However, the osmotic threshold was significantly lower by 6 mOsm/kg in IVF patients. By day 10 after hCG, the lower osmotic thresholds for arginine vasopressin secretion and thirst persisted in OHSS, although the sensitivity to arginine vasopressin secretion was markedly reduced. CONCLUSION(S): The osmotic thresholds for arginine vasopressin secretion and thirst are reset to lower plasma osmolality during superovulation for IVF-ET. This new lower body tonicity is maintained until at least day 10 after hCG in OHSS. Decreases in plasma osmolality and plasma sodium levels in OHSS are due to altered osmoregulation rather than electrolyte losses; correction of apparent "electrolyte imbalance" in OHSS is therefore inappropriate.

Renal resistance to vasopressin in poorly controlled type 1 diabetes mellitus.

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P<0.001) rise in urine osmolality in controls (67.6+/-10.7 to 720+/-31.1 mosmol/kg, P<0.001) than in IDDM patients (64.3+/-21.6 to 516.7+/-89.3 mosmol/kg, P<0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8+/-105.6 fmol/mg creatinine) than in IDDM (462.0+/-94.9 fmol/mg creatinine, P = 0. 003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A(Ic) (r = -0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A(Ic) >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8+/-49.0; A, 640.0+/-137.2 mosmol/kg, P<0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 +/-69 to 375+/-280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.

Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison's disease.

Although autoimmune Addison's disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964de113) in United Kingdom subjects with APS1, by using the restriction enzymes Bst7II and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.

The effect of labour and maternal oxytocin infusion on fetal plasma oxytocin concentration.

It is not known whether human labour is associated with increased fetal oxytocin production or transfer of oxytocin across the placenta. Previous reports are contradictory, due in part, to the influence of maternal analgesia on fetal production. We determined plasma oxytocin concentration in the umbilical artery and vein of women after vaginal delivery and after caesarean section with general anaesthesia before or after the onset of labour. The results demonstrate that fetal production of oxytocin is not influenced by general anaesthesia, thus enabling comparison of labour and nonlabour samples at caesarean section. Labour was not associated with an increase in fetal oxytocin production. Oxytocin was also measured in the umbilical artery and vein during maternal oxytocin infusion to assess placental transfer. The results do not support transfer of oxytocin across the placenta in women.

Exaggerated cardiovascular response to anaesthesia--a case for investigation.

We present a case of a 40-year-old woman who developed major cardiovascular complications during anaesthesia for an elective clipping of a cerebral arteriovenous malformation. Postoperative investigation confirmed the diagnosis of an adrenal phaeochromocytoma. In retrospect, it became apparent that she had experienced a series of potentially life-threatening events over a 20-year period all of which are known complications of phaeochromocytoma. This case highlights the importance of investigating young patients who have unexpected and unexplained cardiovascular events during anaesthesia and surgery.

Exaggerated vasopressin secretion and attenuated osmoregulated thirst in human survivors of hyperosmolar coma.

AIMS/HYPOTHESIS: To test the hypothesis that subnormal thirst sensation could contribute to the development of the hypernatraemia characteristic of hyperosmolar coma, we studied osmoregulation in survivors of hyperosmolar coma. METHODS: Eight survivors of hyperosmolar coma, eight control subjects with Type II (non-insulin-dependent) diabetes mellitus and eight healthy control subjects underwent water deprivation during which measurements of thirst, plasma osmolality and vasopressin were taken. RESULTS: Water deprivation caused greater peak plasma osmolality in the hyperosmolar coma group (301.7 +/- 2.7 mmol/kg) than in Type II diabetic (294.3 +/- 3.2 mmol/kg, p < 0.01) or control group (296.9 +/- 3.0 mmol/kg, p < 0.01) and a greater increase in plasma vasopressin concentration (hyperosmolar coma, 5.8 +/- 1.3 pmol/l, Type II diabetes, 1.8 +/- 1.3 pmol/l, p < 0.001, control subjects, 2.2 +/- 1.8 pmol/l, p < 0.001). Thirst ratings were lower following water deprivation in the hyperosmolar coma group (3.5 +/- 0.8 cm) than in Type II diabetes (7.7 +/- 1.6 cm, p < 0.001) or control subjects (7.4 +/- 1.3 cm, p <0.001), and the hyperosmolar group patients drank less in 30 min following water deprivation (401 +/- 105 ml) than Type II diabetic (856 +/- 218 ml, p < 0.001) or control subjects (789 +/- 213 ml, p < 0.001). CONCLUSION/INTERPRETATION: Survivors of hyperosmolar coma have subnormal osmoregulated thirst and fluid intake, which might contribute to the hypernatraemic dehydration typical of the condition.

A review of water balance in ageing in health and disease.

The elderly are at increased risk of changes in body water and sodium, often accompanying comorbid disease states, which are associated with increased mortality. The clinical assessment of the hydration status of an elderly patient is difficult and the elderly care physician relies on both the clinical picture and laboratory investigation. Although still contentious, research suggests that the elderly may appreciate thirst less readily. However, healthy elderly may be able to produce an enhanced vasopressin response to osmotic stimulation compared to their younger counterparts, possibly in response to reduced renal function. The changes in these systems, when combined with coincident disease, place elderly patients at risk of water imbalance and electrolyte disturbance.

Does positive pressure ventilation increase arginine vasopressin in preterm neonates?

AIM: To examine the effect of intermittent positive pressure ventilation (IPPV) on plasma arginine vasopressin concentration (pAVP) in preterm neonates. METHODS: Thirty five neonates were classified, at the time of blood sampling, into three groups: unstable ventilated; stable ventilated; and stable non-ventilated. A modification of an extraction method for pAVP was developed for use in studies on very small babies, and sampling methods were compared. RESULTS: The pAVP (median, range) was similar in the ventilated (1.85 pmol/l, 0.5 to 3.4) and non-ventilated (2.0, 0.5 to 2.6) stable babies, but was significantly higher (5.7, 1.1 to 25) in the unstable group. There was an inverse correlation between systolic blood pressure and pAVP concentration. CONCLUSIONS: This study shows that in preterm neonates pAVP concentration is affected by the clinical condition and blood pressure, but not by treatment with IPPV.

Central-peripheral temperature difference, blood pressure, and arginine vasopressin in preterm neonates undergoing volume expansion.

AIM: To examine the effect of intravascular volume expansion for the treatment of hypovolaemia in sick preterm neonates. METHODS: An intravenous infusion of 20 ml per kg of 4.5% albumin was given to 14 preterm neonates. The effects on systolic blood pressure, central peripheral temperature difference (c-pT), and plasma arginine vasopressin concentration (pAVP) were measured. RESULTS: Thirteen babies showed a rise in systolic blood pressure. The six babies with the highest initial values of pAVP and c-pT showed a fall in both of these after infusion. The babies with lower initial pAVP (below 4 pmol/l) showed either a rise (two) or no change (six) after albumin infusion. There was a significant correlation between c-pT and log pAVP before (r2 = 0.61; p < 0.05) and after infusion (r2 = 0.45; p < 0.05). CONCLUSIONS: Plasma AVP concentration is related to c-pT in unwell preterm newborns. This study suggests that clinical assessment of hypovolaemia in preterm newborns is poor and could be improved by using c-pT.

Hypothalamic adipsic syndrome: diagnosis and management.

Patients with hypothalamic adipsic syndrome, especially in conjunction with diabetes insipidus, pose management difficulties. They are at risk of both under- and over-hydration. We present 4 patients with hypothalamic adipsic syndromes, due to different causes, illustrating the practical difficulties encountered in this condition. The principles of management, with a sliding scale of water intake related to changes in daily body weight, are discussed.

Atrial natriuretic peptide in preeclampsia: metabolic clearance, sodium excretion and renal hemodynamics.

To further elucidate the role of atrial natriuretic peptide (ANP) in preeclampsia, its metabolic clearance (MCRANP) was determined concomitantly with its effects on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF). Ten untreated preeclamptic primigravidae (PET) were studied at 29-37 wk gestation and again 4 mo postpartum (PP). Basal plasma concentration of ANP was significantly increased in PET compared with PP (14.8 +/- 1.9 vs. 4.1 +/- 0.5 pmol/l, respectively; P < 0.0001). MCRANP in PET and PP was 5.0 +/- 0.8 and 4.9 +/- 0.5 l/min [not significant (NS)], respectively. In PET, infusion of ANP produced (basal vs. ANP) a natriuresis (UNa 0.14 +/- 0.02 vs. 0.28 +/- 0.04 mmol/min, P < 0.001) and an increase in GFR (97 +/- 7 vs. 106 +/- 8 ml/min, P < 0.05), with ERPF unchanged (609 +/- 24 vs. 634 +/- 29 ml/min, NS). In PP, ANP infusion also produced a natriuresis (UNa 0.20 +/- 0.02 vs. 0.25 +/- 0.02 mmol/min, P = 0.01), no significant change in GFR (109 +/- 7 vs. 102 +/- 4 ml/min), and a significant reduction in ERPF (514 +/- 22 vs. 409 +/- 18 ml/min, P < 0.0001). Analysis of variance demonstrated a greater natriuretic effect of ANP in PET compared with PP (P < 0.05), similarly a significant difference in the effect of ANP on ERPF (P < 0.01) and GFR (P < 0.05) was seen but not on filtration fraction (P = 0.35).

Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression.

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

Persistent nephrogenic diabetes insipidus following lithium therapy.

We report the case of a patient who developed severe hypernatraemic dehydration following a head injury. Ten years previously he had been diagnosed to have lithium-induced nephrogenic diabetes insipidus, and lithium therapy had been discontinued. He remained thirsty and polyuric despite cessation of lithium and investigations on admission showed him to have normal osmoregulated thirst and vasopressin secretion, with clear evidence of nephrogenic diabetes insipidus. Lithium induced nephrogenic diabetes insipidus is considered to be reversible on cessation of therapy but polyuria persisted in this patient for ten years after lithium was stopped. We discuss the possible renal mechanisms and the implications for management of patients with lithium-induced nephrogenic diabetes insipidus.