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A 57-year-old woman was admitted to our hospital with occipital headache and nausea. She had severe hypertension (192/122mmHg), hypokalemia (2.8mEq/l) and fasting hyperglycemia (127 mg/dl). Further examination revealed elevated plasma ACTH (124pg/ml) and cortisol (26.5 mu g/dl) with a lack of diurnal rhythm. Plasma ACTH or cortisol did not increase by injection of corticotropin releasing hormone (CRH). Rapid ACTH test resulted in an exaggerated response of plasma cortisol. Abdominal MRI scan showed a left adrenal tumor. Since the bilateral adrenal venous blood sampling revealed a significant increase of cortisol on the left, left adrenalectomy was performed. Histological examination of the resected adrenal gland revealed marked cortical hyperplasia. Postoperative investigations revealed that despite a small dose of steroid replacement for only 20 days, plasma ACTH level was decreased for a period of 6 months. Both plasma ACTH and cortisol increased by a CRH injection 38 days after surgery. CRH test during bilateral inferior petrosal sinus sampling indicated that this patient had no functioning pituitary tumor. Although the exact mechanism of high plasma ACTH level in this case was unknown, these findings suggest that any substance secreted from primary adrenal nodular hyperplasia adrenal nodular hyperplasia may stimulate pituitary ACTH production. This is a very rare case of Cushing's syndrome due to unilateral primary adrenal nodular hyperplasia with elevated plasma ACTH.

We encountered a patient with siolated ACTH deficiency accompanying dementia. A 69-year old man was admitted because of abdominal pain. A decrease of serum Na level (114mEq/l) due to increased urinary Na excretion suggested the existence of adrenal insufficiency. While serum cortisol and urinary 17-OHCS, 17-KS excretions were reduced, plasma ACTH level remained below the normal range. Since daily ACTH injections increased both serum cortisol level and urinary 17-OHCS excretion, the patient was diagnosed as having isolated ACTH deficiency. The severity of dementia was measured by using the Hasegawa Dementia Scale. Both cerebral blood flow and metabolism, assessed with Positron Emission Computed Tomography (PET), decreased even after the start of 20mg/day cortril administration. An increase of the cortril supplement dose to 30mg/day attenuated the reduction of cerebral blood flow with the improvement of dementia from score point "1" to "27" (Hasegawa scale). The present case raised the possibility that loss of glucocorticoid may involve the development of dementia, resulting from decreased cerebral blood flow and metabolism.

Thyroxine-binding globulin (TBG), a major thyroid hormone-binding protein, is denatured by heat and subsequently loses its binding activity. This study aimed to investigate changes in the function of thyroid hormone-binding proteins utilizing a method of heat treatment. The first aim of this study was to examine how the relationship between thyroid hormones and binding proteins changes with heat treatment at 56 degrees C in serum from normal subjects. When approximately half of the native TBG was denatured by heat, the mean percentage of T4 bound to thyroxine-binding prealbumin (TBPA), measured by a single immunoprecipitation method, was increased from 15.3% to 25.7% and the percentage of T4 bound to albumin was increased from 4.7% to 7.5%. Serum free T4 concentration were increased to 166.0 +/- 17.1% (Mean +/- SD) from the basal value. By heating at 58 degrees C, T4 bound to TBPA was denatured, but T4 bound to albumin showed a significant increase, and serum free T4 concentrations were increased to 396.0 +/- 62.1%. Because T4 binding ratios of TBPA and albumin were increased after TBG denaturation, free hormone concentrations did not increase very greatly. The second aim of this study was to examine the properties of TBG in patients with non familial partial deficiency of TBG (NFPD-TBG). When the serum sample of NFPD-TBG was heated, the half time of NFPD-TBG was 14.1 +/- 5.5 min, which was significantly shorter than that of normal TBG (45.1 +/- 7.0 min, P < 0.001). Isoelectric focusing (IEF) of NFPD-TBG showed that the pIs were not different from those of normal TBG. When serum from NFPD-TBG was mixed with normal serum, the half time was still shorter than the normal serum samples. The data suggest that the molecular structure of NFPD-TBG is not abnormal, but a certain factor which alters the heat stability of TBG exists in the serum from NFPD-TBG.

Adrenal tumors showing no clinical manifestations (incidentaloma) are frequently encountered during imaging analysis upon routine examinations. These tumors are sometimes associated with hypertension and/or diabetes mellitus (DM). We have examined six cases of incidentalomas with these symptoms in this study. All patients underwent endocrinological evaluation by measuring plasma cortisol and aldosterone levels to assess adrenocortical function. The levels of urinary 17-hydroxysteroids, 17-ketosteroids and catecholamines were also measured. Imaging analysis were performed by using 131I-adosterol scintigraphy, computed tomography and magnetic resonance imaging. Whereas one case was diagnosed as having an adrenal adenoma without the examination of a surgical specimen, other cases underwent surgical removal of the tumor, and final diagnoses were made by pathohistological examination of the tumors. Three cases were diagnosed as having adrenocortical adenomas (one was functioning and others were non-functioning) and one case was diagnosed as having a functional adrenocortical carcinoma. Adenomas were found to produce either non-functional steroids or a small amount of functional steroid hormones. The adenoma patients all suffered hypertension, whereas one of the adenoma patients and the carcinoma patient showed signs of DM. By contrast, of the six cases, one case was diagnosed as having an adrenal cyst, and one case was diagnosed with myelolipoma. Although these two cases suffered DM and hypertension, respectively, it seemed to be unlikely that these clinical symptoms were caused by the adrenal disease. Thus, the present analysis of the six incidentaloma patients suggests that once an adrenal incidentaloma patient with hypertension and/or DM is found, both endocrinological and imaging examinations are necessary to determine the indication of surgical treatment. This analysis supports the present consensus that non-functional adenomas whose sizes are 3cm or less and whose sizes do not change at any reevaluation period, as well as adrenal cysts and myelolipoma should not be surgically removed.

A case with primary triple cancers including thyroid cancer is reported. A 57-year old woman complaining of laryngeal discomfort was found to have an firm elastic lump on the right anterior neck. On 123I scan, the nodule in the right thyroid lobe accumulated considerable amounts of radioiodine as a warm nodule, while the remainder of the gland showed decreased uptake. Thyroid hormone levels remained within normal ranges. Cytological findings obtained by fine-needle aspiration biopsy showed papillary carcinoma. Right lobectomy was performed. The histological examinations revealed papillary carcinoma embedded within adenomatous thyroid tissue. It is probable that the surrounding adenomatous tissue accumulated radioiodine, since the warm nodule on 123I scan was larger than the size of the carcinoma. Examinations of the gastrointestinal tract revealed the presence of poorly differentiated adenocarcinoma in the stomach and well differentiated adenocarcinoma (carcinoma in adenoma) in the rectum. Expressions of ras p21 and p53 were examined immunohistochemically in these carcinoma tissues. The ras p21 product was clearly detected in not only the thyroid carcinoma but in a part of the surrounding adenomatous regions as well. Both ras p21 and p53 proteins were observed in the rectal cancer tissue. In contrast, these oncoproteins were not found in the gastric cancer tissue. In this case ras oncogene activation may be an early event in the tumorigenic process of the thyroid and rectum. However, different genetic alterations seem to occur during the development of these three carcinomas.

TZP-4238, a new steroidal antiandrogen, is an orally active drug in rats and dogs. The effects of TZP-4238 on the androgen receptor and androgen content were examined in comparison with other antiandrogens in rats. The prostate DHT levels decreased markedly within 4-8 hr after a single oral administration of TZP-4238 8mg/kg. The prostatic testosterone concentrations fell below the detection limit (5pg/g of tissue) at 4-12 hr after the initiation of treatment. The plasma testosterone level also fell to 60% of the control level after 4-8 hr and then returned to the normal range. Eight percent of DHT present in normal prostatic tissue was located in the nuclear fraction. TZP-4238 reduced the concentration of DHT in nuclei to 50% of the normal level. The concentration of the plasma drug which induced a 50% decrease in the prostatic DHT, the IC50, was about 10ng/ml, while the IC50 value for plasma testosterone was 30-50ng/ml. After oral administration of 15-OH TZP-4238, the main metabolite, the level of plasma testosterone was significantly elevated above the control level. The androgen receptor level was markedly reduced at 24 hr following castration and returned to the normal range within 5 hr of a single injection of testosterone. TZP-4238 reduced the nuclear androgen receptor level to 60% at 24 hr after a single oral dose and then, the receptor content returned to its original level. Both 15-OH TZP-4238 and cyproterone acetate also reduced the androgen receptor and DHT contents to 50%. A series of in vivo studies demonstrated that TZP-4238 inhibited the uptake of testosterone and the decrease of DHT and testosterone, and decreased the nuclear androgen receptor in the rat prostate.

The application of the microdialysis technique for the analysis of neuropeptide release was described. The recoveries of neuropeptides are affected by the nature of the dialysis membrane, the sort of perfusion method, the internal diameter and length of the outlet tube, and the flow rate of the perfusate. The studies on the mechanism of neuropeptide release using brain microdialysis were summarized. Brain microdialysis technique allows the direct and dynamic analysis of neuropeptide release and provides a useful tool for studying the mechanism of the central regulation of the release of neuropeptides.

We studied the adrenosuppressive effect of antiandrogen TZP-4238 and its metabolites. The binding affinity for the corticosteroid receptor using rat hepatic cytosol was in the order 11-OH TZP-4238 > 11, 15-(OH)2 TZP-4238 >> TZP-4238 > or = 15-OH TZP-4238 > 11-keto TZP-4238. Male beagle dogs aged 1-6 years were randomly divided into TZP-4238 (0.05, 0.5mg/kg) treatment groups and CMA (0.5mg/kg) treatment group. Each group was administered the drug per os every day for 8 weeks. Plasma cortisol, TZP-4238 and its metabolite levels were measured by on-line coupling of liquid chromatography with thermospray or atmospheric pressure ionization mass spectrometry using selective ion monitoring (LC-MS/SIM). LC-MS/SIM provided a sensitive and reliable method of unequivocal confirmation of the presence of steroidal drugs in the plasma. The plasma cortisol level was lowered below 1 ng/ml at 1 week after oral administration of TZP-4238 at 0.5mg/kg or CMA at 0.5mg/kg. The decline continued throughout the treatment for 8 weeks. Upon termination of administration, the cortisol level returned to the normal level (6ng/ml) by 4 weeks. However in the group given 0.05mg/kg TZP-4238, the cortisol level remained within the normal range. To analyze the cortisol decreasing mechanism, we administered TZP-4238 at 0.5mg/kg for 7 days to one beagle dog. When the plasma 11-OH TZP-4238 level was increased, the cortisol level decreased time dependently and the concentration of plasma 11-OH TZP-4238 which induced 50% inhibition was 2ng/ml. The decrease in the plasma cortisol level was highly correlated to the extent of the increase of the plasma 11-OH TZP-4238 (r2 = 0.840). We conclude that the adrenosuppressive effect of antiandrogen TZP-4238 is not due to TZP-4238 itself but its metabolite 11-OH TZP-4238.

We have carried out a follow-up study on iodine-induced goiter to clarify whether or not iodine could be a factor in the progression as well as the promotion of thyroid autoimmunity. We selected 143 women of child-bearing age without any previous thyroid disorders who had received hysterosalpingography (H.S.G.). 45 Sex and age-matched healthy subjects were chosen as controls. Serum nonhormonal iodine (S.N.I.) levels, frequency of goiter and antimicrosomal antibody (MCHA) in all the Lipiodol-cases were significantly higher than those in the controls (p < 0.001, < 0.01 and < 0.01), respectively. When the subjects were divided into 9 groups according to the duration of each 5 months after H.S.G., serum TSH and S.N.I. levels, incidence of goiter and MCHA in the initial group were significantly higher than those in the other groups (p < 0.05). The S.N.I. levels became normalized in 30 months after H.S.G. and the goiters disappeared in almost the same duration, while the incidence of higher MCHA titers declined gradually but significantly around 40 months after H.S.G. compared with that in the first 5 months after H.S.G. (p < 0.05). The frequency of goiter and MCHA in 44 cases after a 6-39 month follow-up decreased significantly compared to that in the initial group (p < 0.05). Therefore, we tried an individual longitudinal follow-up study on MCHA titer in 12 cases for 35-103 months, resulting in a significant reduction or negativeness of the titer in 6 cases. Likewise, MCHA titers in all cases decreased significantly (p < 0.05) on later evaluation. The present data suggest that iodine in Lipiodol administered via the vagina will act not only as the promoting factor, but as an aggravating agent for thyroid autoimmunity.