Two Cases of Hypopituitarism Caused by Intrasellar Aneurysm.

Giant internal carotid artery aneurysms sometimes extend into the sellar region, which rarely but occasionally results in hypopituitarism due to the compression of the normal pituitary gland or hypothalamus. Hyponatremia is a known complication of hypopituitarism. We herein report two cases of hypopituitarism caused by intrasellar aneurysm of different origins, resulting in hyponatremia. Untreated hypopituitarism may lead to lethargy, coma, cardiac arrhythmia, and death. Therefore, we must be alert for the occurrence of giant intrasellar aneurysm, as it causes hypopituitarism. The prompt diagnosis and treatment of hypopituitarism are necessary to prevent this fatal outcome.

Evaluation of the (1-24) adrenocorticotropin stimulation test for the diagnosis of primary aldosteronism.

OBJECTIVE: The purpose of this study was to investigate the diagnostic power of the adrenocorticotropin (ACTH) stimulation test in patients with primary aldosteronism (PA) and those with aldosterone-producing adenoma (APA). DESIGN: This study was based on a retrospective database analysis. SUBJECTS AND METHODS: We assessed 158 hypertensive patients with a high plasma aldosterone-to-renin ratio (ARR) including 97 with at least one positive confirmatory test result who did not undergo surgery and comprised a "possible PA" group, 19 with negative results in all tests who were the "non-PA" group, and 41 diagnosed with APA following surgery who were the APA group. The "confirmed PA group" included APA patients and patients from the possible PA group showing both high ARR and hypokalemia. One case was diagnosed as a metastasis. RESULTS: Receiver-operating characteristic (ROC) analysis showed that the diagnostic accuracy of ACTH test was not very effective in differentiating between APA patients and possible PA and non-PA patients. The optimal cut-off value of maximal plasma aldosterone concentration for differentiating between patient in the confirmed PA group and other patients showed moderate accuracy. CONCLUSIONS: The ACTH test may not be useful as a screening or confirmatory test, but the test may be useful for differentiating between patients with confirmed PA and the rest of the cohort. The positive finding of the ACTH test may at least support a higher likelihood of lateralizing on adrenal venous sampling.

Evaluation of plasma, salivary, and urinary cortisol levels for diagnosis of Cushing's syndrome.

As a screening test for Cushing's syndrome, the evaluation of late-night cortisol levels is indispensable. We evaluated the usefulness and accuracy of plasma, urinary, and salivary cortisol levels measured late at night for the diagnosis of Cushing's syndrome. High cortisol levels (> 5 microg/dL) during the night are indicative of Cushing's syndrome, although night plasma cortisol levels are not readily reproducible because of the stressful situation. There was no correlation between plasma and urinary cortisol levels late at night, and late-night urinary cortisol levels provided weak information for the diagnosis of Cushing's syndrome. By contrast, late-night plasma and salivary cortisol levels showed a positive correlation, and salivary cortisol sampling was found to be useful for the diagnosis of Cushing's syndrome, because more than 0.4 microg/dL of late-night salivary cortisol levels gave a sensitivity of 86% and a specificity of 100% in our hospital. This method is also useful for the diagnosis of early or mild stage Cushing's syndrome, so-called subclinical Cushing's syndrome. Inherent differences between assays make it difficult to define optimal diagnostic criteria. However, the relative levels of salivary cortisol ratio, which is presented as a relative level, compared with the mean levels of healthy subjects in each institute, is useful for the screening of Cushing's syndrome as the cut-off level of 1.5 shows both high sensitivity and specificity in subclinical and overt Cushing's syndrome. Late-night salivary cortisol measurement is therefore a primary method of choice in the screening of patients suspected of having Cushing's syndrome.

Analysis of hydrogen peroxide in an aqueous extract of cigarette smoke and effect of pH on the yield.

An analysis of hydrogen peroxide in an aqueous extract of cigarette smoke, which contains many redox-active compounds, requires a method with high selectivity. An aqueous extract of the particulate phase of cigarette smoke was analyzed by HPLC with an electrochemical detector (ECD). Samples were prepared by collecting the particulate phase of the cigarette smoke on a glass fiber filter and extracting it with a phosphate buffer. The obtained solution was purified by using a Waters Oasis MCX cation-exchange cartridge, and then analyzed by an HPLC-ECD system with a Shodex KS-801 mixed-mode resin column. Pre-injecting hydrogen peroxide at a high concentration into the HPLC instrument stabilized the analytical results. The recovery of hydrogen peroxide by using an extract of the particulate phase of the cigarette smoke was more than 80%. An increase in the amount of hydrogen peroxide was observed during extraction with the phosphate buffer at higher pH values. In contrast, extraction with phosphoric acid did not increase the amount of hydrogen peroxide during extraction.

Diagnostic usefulness of the growth hormone-releasing peptide-2 test as a substitute for the insulin tolerance test in hypopituitarism.

Adrenal insufficiency can result from primary disorder of the adrenal gland or occurs secondarily due to deficiency in adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). To prevent adrenal crisis, it is thus important to test the remaining function of the adrenal gland. Tests for the function of the hypothalamic-pituitary-adrenal (HPA) axis are also useful for examining localization of disease causing adrenal insufficiency. Generally, the insulin tolerance test (ITT) is useful for examining the HPA axis in both hypothalamic and pituitary diseases; however, ITT has a number of disadvantages. The growth hormone-releasing peptide (GHRP)-2 test may be a useful tool for diagnosing secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage. In the present study, we examined the diagnostic usefulness of the GHRP-2 test as a substitute for ITT in hypopituitarism. We showed that patients with significant ACTH response to ITT also had significant response to the GHRP-2 test, while patients with no significant ACTH response to ITT also had no significant response to the GHRP-2 test. These data suggest that the GHRP-2 test may be a useful diagnostic tool for secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage.

Diagnosis of a case of ectopic parathyroid adenoma on the early image of 99mTc-MIBI scintigram.

We report the case of a 64-year-old woman who had a severe hypercalcemia. Serum calcium, intact parathyroid hormone (PTH), 1alpha, 25 (OH)(2 )vitamin D(3) levels were all elevated, and serum phosphorus level was decreased, which were all consistent with primary hyperparathyroidism (PHPT). (201)Tl/(99m)Tc subtraction scintigraphy failed to detect any abnormal accumulation in the neck and chest, while (99m)Tc-MIBI scintigraphy demonstrated the focal accumulation of increased radiotracer uptake in the mediastinum only on the early image, but not on the delayed image. Neck and chest computerized tomography scanning showed a small nodule at the retrosternal region, and a selective venous sampling study of the intact PTH suggested PTH production from the nodule. Together with the observation of the early image of (99m)Tc-MIBI scintigraphy, it was diagnosed that the patient had an ectopic parathyroid adenoma. Video-assisted thoracic surgery was performed. A 15-mm diameter mass, visualized by an intravenous infusion of methylene blue, was excited. The histopathology was consistent with the parathyroid adenoma. The adenoma was composed of mainly chief cells and rarely oxyphil cells. The absence of oxyphil cells would explain the lack of (99m)Tc-MIBI retention on late-phase imaging in our case. Even without uptake on the delayed image of (99m)Tc-MIBI scintigram, the early image was available for the localization of an ectopic parathyroid adenoma.

Differential regulation of CREB and ERK phosphorylation through corticotropin-releasing factor receptors type 1 and 2 in AtT-20 and A7r5 cells.

The corticotropin-releasing factor (CRF) family of peptides generally exerts its biological actions by binding to two major subtypes of CRF receptors: CRF receptor type 1 (CRF1 receptor) and CRF receptor type 2 (CRF2 receptor). In this study, we investigated the mechanism by which three ligands altered phosphorylation of CREB and ERK 1/2, using AtT-20 cells (expressing CRF1 receptor) and A7r5 cells (expressing CRF2 receptor). Incubation with 100 nM of CRF, urocortin 1 (UCN 1), or UCN 2 increased CREB phosphorylation. The protein kinase A pathway was involved in the CRF- or UCN-mediated increase in CREB phosphorylation in both cell lines. Bisindolylmaleimide partially inhibited the CRF-mediated increase in CREB phosphorylation, but only in AtT-20 cells, suggesting that the protein kinase C pathway is involved in regulation of CREB phosphorylation via CRF1 receptor but not CRF2 receptor. CRF increased ERK phosphorylation in AtT-20 cells, whereas the UCNs decreased it in A7r5 cells. Bisindolylmaleimide partially inhibited the UCN-mediated decrease in ERK phosphorylation in A7r5 cells, suggesting that the protein kinase C pathway is partially involved in CRF2 receptor signal transduction. In AtT-20 cells, the mitogen-activated protein kinase kinase pathway regulated ERK phosphorylation following CRF1 receptor activation. These findings suggest differential regulation of CREB and ERK 1/2 phosphorylation through CRF receptors.

[Acute infectious diseases in occupied Japan].

Japan's health statistics system, considered among the best in the world today, continually complies and organizes information about various infectious diseases. However, systematic surveillance was not conducted by the Ministry of Health and Welfare between World War II and the postwar period, creating a gap in health data. In contrast, the GHQ/SCAP/PHW. which was closely involved in health and medical reform during the Occupation, thoroughly investigated the health conditions of the Japanese people during this period. This article describes the trends in acute infectious diseases in Occupied Japan by using statistical records listed in the appendices of the "Weekly Bulletin", an official document of the GHQ/SCAP that is currently kept in the National Diet Library Modern Japanese Political History Materials Room.

Urocortin induces interleukin-6 gene expression via cyclooxygenase-2 activity in aortic smooth muscle cells.

Corticotropin-releasing factor (CRF) plays a central role in controlling stress-related activity of the hypothalamic-pituitary-adrenal axis. Four CRF-related peptides have been found in mammals: CRF and urocortins (Ucns) 1-3. Ucns bound to CRF(2beta) receptors have a physiological role in the cardiovascular system. We previously found that both Ucn1 and -2 induced accumulation of intracellular cAMP via CRF(2beta) receptor binding and significantly increased IL-6 secretion by A7r5 aortic smooth muscle cells. In the present study, we investigated Ucn effects on IL-6 gene expression and IL-6 synthesis in A7r5 aortic smooth muscle cells. Ucn1 and -2 stimulated IL-6 gene transcription and IL-6 secretion via CRF(2) receptors. Indomethacin, a cyclooxygenase (COX) inhibitor, suppressed IL-6 gene transcription and IL-6 secretion by Ucn1 or -2. NS-398, a COX-2 inhibitor, suppressed IL-6 induction to the same extent as indomethacin. These results suggest that the COX-2 pathway is involved downstream in regulation of Ucn-increased IL-6 gene expression and IL-6 secretion. In addition, COX-2 expression levels were increased at 6 h with the combination of Ucn1 and IL-1, compared with single peptide activation. Ucn1 showed a potent stimulatory effect on IL-6 output, whereas IL-1 alone had no significant effects. However, when Ucn1 was simultaneously used with IL-1, it markedly potentiated the increments in IL-6 output and promoter activity produced by Ucn1. Taken together, these findings indicate that the COX-2 pathway plays a major role in increasing IL-6 levels stimulated by Ucn and IL-1 in A7r5 cells.

G protein-coupled receptor kinase 2 involvement in desensitization of corticotropin-releasing factor (CRF) receptor type 1 by CRF in murine corticotrophs.

Hypothalamic CRF stimulates synthesis and secretion of ACTH via CRF receptor type 1 (CRFR1) in the anterior pituitary gland. After agonist-activated stimulation of receptor signaling, CRFR1 is down-regulated and desensitized. Generally, it is thought that G protein-coupled receptors may be desensitized by G protein-coupled receptor kinases (GRKs). However, the role of GRKs in corticotropic cells has not been determined. In this study we focused on involvement of GRKs in desensitization of CRFR1 by CRF in corticotropic cells. We found that GRK2 (but not GRK3) mRNA and protein were expressed in rat anterior pituitary cells and AtT-20 cells (a line of mouse corticotroph tumor cells). To determine the role of GRK2 in CRF-induced desensitization of CRFR1 in mouse corticotrophs, AtT-20 cells were transfected with a dominant-negative mutant GRK2 construct. CRF desensitized the cAMP-dependent response by CRFR1. Desensitization of CRFR1 by CRF was significantly less in AtT-20 cells transfected with the dominant-negative mutant GRK2 construct compared with desensitization in control (an empty vector-transfected) AtT-20 cells. Furthermore, pretreatment with a protein kinase A inhibitor also partially blocked desensitization of CRFR1 by CRF. These results suggest that GRK2 is involved in CRF-induced desensitization of CRFR1 in AtT-20 cells, and the protein kinase A pathway may also have an important role in desensitization of CRFR1 by CRF seen in corticotropic cells.

Differential regulation of corticotropin-releasing factor receptor type 1 (CRF1 receptor) mRNA via protein kinase A and mitogen-activated protein kinase pathways in rat anterior pituitary cells.

Corticotropin-releasing factor (CRF) receptor type 1 (CRF(1) receptor) mRNA levels are down-regulated by CRF via the cyclic AMP-protein kinase A (PKA) pathway. In this study, we focused on the involvement of both the mitogen-activated protein (MAP) kinase pathway and PKA in this regulation. Real-time PCR (RT-PCR) revealed that a MAP kinase, extracellular signal-regulated kinases 1/2, pathway was also involved in the down-regulation of CRF(1) receptor mRNA levels by CRF in the rat anterior pituitary (AP). Down-regulation of CRF(1) receptor mRNA levels was caused by a post-transcriptional system such as mRNA degradation, as incubation with CRF significantly decreased the half-life of CRF(1) receptor mRNA. Furthermore, pre-treatment with a PKA inhibitor completely blocked CRF-induced CRF(1) receptor mRNA destabilization, while pre-treatment with an extracellular signal-regulated kinases 1/2 inhibitor had no inhibitory effect. These results suggested that in the rat AP, down-regulation of CRF(1) receptor mRNA levels is caused by mRNA degradation via PKA, but not by the MAP kinase pathway.

Usefulness of the thyrotropin-releasing hormone test in pre-clinical acromegaly.

Acromegaly is caused primarily by pituitary growth hormone (GH)-secreting tumors. It is usually recognized because of characteristic manifestations, and diagnosed clinically. However, there exists a mild stage of acromegaly, which poses a diagnostic problem due to the absence of typical clinical manifestations. Here we present four patients with pre-clinical acromegaly, who showed minimal acromegaloid features with elevated levels of insulin-like growth factor-I. Basal GH levels were within normal levels in 3 of 4 cases, while insulin-like growth factor-I levels were elevated above normal in all cases. Plasma GH levels were elevated in response to thyrotropin-releasing hormone (TRH) in all cases, indicating a diagnostic value of the TRH stimulation test. In contrast, an oral glucose tolerance test was not useful for the diagnosis, because of the low GH levels (less than 1 ng/ml) and/or secondary to diabetes mellitus. In response to a dopamine agonist, GH levels were increased in the two cases, whereas GH levels were decreased or remained unchanged in the other two cases. We therefore suggest that the TRH stimulation test would be helpful to examine the presence of pre-clinical acromegaly. Diagnosis of the early stages of acromegaly is important to prevent progression to overt acromegaly.

A case of pseudoaldosteronism, accompanied with hypocalcemia and exaggerated ACTH response.

Glycyrrhizic acid (GA) inhibits the activity of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney, with the resulting increase in intrarenal cortisol concentration leading to hypertension and suppression of the renin-aldosterone system. In this paper we describe an interesting case of pseudoaldosteronism, associated with hypocalcemia and an exaggerated ACTH response. A 72-year-old woman was referred to our department for further evaluation of hypokalemia and hypocalcemia. The patient had been taking GA (150 mg/day) for the previous year for treatment of liver damage. Plasma renin activity and aldosterone concentration were both within lower normal limits. Urinary excretion of potassium and calcium was within the upper limit of the normal range and increased with administration of supplements. Plasma ACTH levels increased markedly in response to an intravenous injection of CRH. Cessation of GA and the potassium and calcium supplements on admission, led to a gradual normalization of serum potassium and calcium levels and blood pressure. The hypocalcaemia in our patient was related to decreased tubular reabsorption of calcium as a consequence of renal corticoid excess. It is possible that an increase in the number of CRH receptors in the pituitary following GA treatment caused the exaggerated ACTH response in association with pseudoaldosteronism. The existence of hypocalcemia and an exaggerated ACTH response should be observed carefully when managing pseudoaldosteronism.

A case of preclinical Cushing's disease, accompanied with thyroid papillary carcinoma and adrenal incidentaloma.

A 75-year-old woman had tumors in her pituitary, thyroid and left adrenal gland. Plasma ACTH and cortisol levels were both mildly elevated. Both plasma ACTH and cortisol concentrations were partially suppressed by 1 mg of overnight dexamethasone suppression test, while both were inhibited with a dosage of 8 mg dexamethasone. Plasma ACTH and cortisol levels were increased in response to human CRH and desmopressin. Together with the observation of pituitary microadenoma, the patient had a pituitary ACTH-producing tumor. The patient, however, had no typical Cushingoid features, hypertension, or impaired glucose tolerance, suggesting that the tumor had an autonomic ACTH secretion that was insufficient for expressing clinical symptoms, the so-called preclinical Cushing's disease. A case of preclinical Cushing's disease is extremely rare. Further, the patient had thyroid papillary carcinoma and non-functioning adrenal tumor. Molecular genetic analysis demonstrated a polymorphism of the menin gene in the patient. Even without Cushingoid features in pituitary incidentaloma, we concluded that the elevated ACTH and cortisol levels should be followed up by CRH, desmopressin and dexamethasone suppression tests. This patient with preclinical Cushing's disease would be observed whether the physical conditions in the patient develop to overt Cushing's disease.

Hypoglycemia associated with big insulin-like growth factor II produced during development of malignant fibrous histiocytoma.

We describe a rare case of hypoglycemia associated with a high molecular weight form of insulin-like growth factor II (big IGF-II) produced during the development of malignant fibrous histiocytoma (MFH). A 66-year-old man was referred to our department for further evaluation of hypoglycemia. At the age of 59, he had been diagnosed as having a MFH in the retroperitoneum, and underwent incomplete resection of the tumor. He had no symptoms of hypoglycemia at that time. Within the last few years, he developed symptoms of hypoglycemia in the early morning. Computerized tomography scans of the abdomen showed multiple tumors around the peritoneum and the liver. Serum insulin levels were decreased although no other hormonal deficiencies were observed. Serum IGF-II levels were elevated as a result of big IGF-II production. Taken together, these results indicated that hypoglycemia in this patient was associated with the production of big IGF-II by the MFH. The most effective therapeutic modality in patients with non-islet cell tumor hypoglycemia is resection of the tumor. In our case, as complete resection was impossible, dexamethasone and glucagon were administered and proved to be effective for preventing hypoglycemia.