Recent progress in the studies of epitope analysis of the TSH-R against TSH-R Ab was reviewed extensively. Using both site-directed mutagenesis and synthetic TSH-R peptide, binding and/or action sites of TSH-R Ab have been known to be multiple and discontinuous, but the significance of two unique and TSH-R specific regions has been implicated. Further, the possible existence of heterogeneity among stimulatory TSH-R Ab has also been indicated.
As for immunogenetic factors related to autoimmune thyroid diseases, studies on HLA analysis, TSH-R specific T lymphocyte analysis and V_H analysis of TSH-R Ab were discussed. Of note was the negative association of HLA-DP w2 antigen in Japanese patients with Graves' disease and hypothyroidism due to blocking TSH-R Ab, and we proposed a new concept of autoimmune TSH receptor disease within autoimmune thyroid disease and emphasized possible critical roles of HLA-DP. Recent evidence of restricted usage of the Ig V_H gene in cloned B lymphocytes from Graves' patients producing TSH-R Ab has also been presented.

View full abstract

A 46-year-old man was admitted because of hypotension and consciousness disturbance. He was a patient with hemophilia B, and diagnosed as having an AIDS- related complex 2 years prior to admission. On admission he had severe hyponatremia. Hormonal studies revealed that he had Addison's disease. Serum cytomegalovirus (CMV) antibody titers were high, and a CMV antigen was detected in his urine, which suggested CMV adrenalitis caused by an active CMV infection. After the administration of hydrocortisone and ganciclovir, his general clinical condition and biochemical test results were back to normal. However, the adrenal dysfunction was irreversible, despite the treatment with ganciclovir. With an increase in the number of AIDS patients, we have to consider adrenal insufficiency due to a CMV infection in patients with AIDS.

View full abstract

The purpose of the present study is to investigate by a computed tomography (CT) thyroid CT number (Hounsfield units; H.U.) in chronic thyroiditis (CH).
The correlation of the CT value with the concentration of KI solution in the test tube of thyroid phantom for thyroid scintigram was linear. No significant correlation between thyroid CT number and the urinary iodine concentration was also observed in 36 patients with CH. A mean thyroid CT number (±SD) of 81±24 H.U. in 155 patients with CH was significantly (P<0.001) lower than 125±18 H.U. in 95 normal subjects. The patients with CH could be arbitrarily divided into 3 groups according to the decrease in their thyroid CT number: normal (N) group (_??_88 H.U.), moderately decreased (MD) group (70-87 H.U.) and the greately decreased (GD) group (<70 H.U.). There was a significant difference in the thyroid volume among 21.2±9.1cm³ in the N group, 32.2±18.1 in the MD group (P<0.05 vs. N group) and 43.6±23.3 in the GD group (P<0.01 vs. N and MD group). The mean serum TSH concentration of 38.95±54.61μU/ml in the SD group was significantly (P<0.01) higher than either 4.11±3.64 in the MD group or 2.00±1.43 in the N group. The serum TSH level in the MD group differed significantly (P<0.05) from that of the N group.
Hypothyroidism characterized by low serum FT₄ (<0.8ng/dl) and very high serum TSH was observed in none in the N group, in 2 (7.1%) of 28 cases in the MD group and in 16 (33.3%) of 48 cases in the GD group. And latent hypothyroidism characterized by an increase in serum TSH levels (_??_5μU/ml) and normal concentrations of thyroid hormones was found in 2 (5.1%) of 39 cases in the N group, 5 (17.9%) in the MD group and 16 (33.3%) of the GD group. There was a significant (P<0.005) difference in multiple chi-square analysis in the comparison between the GD group and the N group or MD group. The frequency of higher titers of antimicrosomal Ab and antithyroglobulin Ab seemed to be correlated with the amount of decrease in the thyroid CT number. In conclusion, there was a significant correlation between the thyroid CT number and the severity of chronic thyroiditis.

View full abstract

The purpose of the present study was to investigate by a computed tomography (CT) the Hounsfield unit (H.U.) of the thyroid in hyperthyroid and euthyroid Graves' disease and destructive thyrotoxicosis.
The mean thyroid CT number in 95 controls was 122±18 H.U. (±SD) and did not change significantly with advancing age. The mean thyroid CT number (±SD) of 85±22 H.U. in 60 patients with hyperthyroid Graves' disease was significantly (P <0.001) lower than either in normal controls or 116± 22 H.U. in 11 patients with euthyroid Graves' disease (P<0.001). Comparison of thyroid hormones and TSH receptor Ab values of untreated patients with a normal and an abnormally low thyroid CT number showed that serum total and free T₃ were significantly (P <0.05) higher in the latter group than in the former group. With respect to the effect of methimazol (MMI) on the thyroid CT number, in the untreated 10 patients with a low thyroid CT number, the initial mean CT number was 65±11 H.U. and increased significantly (P<0.05) to 76± 14 H.U. after treatment with MMI. In contrast, in 6 patients with a normal thyroid CT number prior to therapy, the initial mean thyroid CT number was 102±11 H.U. and fell significantly (P<0.05) to 84±16 H.U. after treatment with MMI.
The thyroid CT number in destructive thyrotoxicosis is markedly decreased to less than 70 H.U. and the mean values of 57±7 H.U. in 6 patients with silent thyroiditis and of 61±5 H.U. in 7 with subacute thyroiditis differ significantly (P<0.001) from Graves' disease. In conclusion, the thyroid CT number is significantly reduced in hyperthyroid Graves' disease, normal in euthyroid Graves' disease and markedly decreased in destructive thyrotoxicosis. The high T₃ value seemed to play an important role in the pathogenesis of a decline in the thyroid CT number in Graves' disease. An antithyroid drug therapy caused two different changes in the thyroid CT number, depending on whether the thyroid CT number prior to therapy was normal or low.

View full abstract

One infant and a cousin with incomplete androgen insensitivity syndrome were reported. The familial pedigree showed that the disorder was inherited in three generations in X-linked recessive fashion. An androgen binding study of cultured genital skin fibroblast from patients showed normal maximum binding capacity and a normal apparent dissociation constant. Heat stability assay showed binding decreased to less than 30% at 41°C compared with the amount at 30°C, indicating that the androgen receptor was thermolabile.

View full abstract

We studied the changes in serum sodium (Na) and potassium (K) levels in seventeen patients in diabetic ketoacidosis and nine patients in non-ketotic hyperosmolar coma, who had marked hyperglycemia (707.4±75.6mg/dl, mean±SEM) and dehydration. The disorder characterized two types of alteration. The one group was hyponatremia with hyperkalemia in 17 patients in diabetic ketoacidosis (132.9±2.0 and 5.7±0.2mEq/l), and 4 patients in non-ketotic hyperosmolar coma (125.8 ±4.3 and 5.2±0.5mEq/l). The other was hypernatremia (162.5±1.8mEq/l) with hypokalemia (3.4± 0.2mEq/l) in 5 patients in non-ketotic hyperosmolar coma. Intensive therapy with insulin and fluid administration improved the diabetic hyperglycemia and associated abnormalities. The vectors showing the normalization of serum Na and K levels was in quite opposite directions between the patients with hyponatremia with hyperkalemia and those with hypernatremia with hypokalemia. The amounts of loss of circulatory blood volume exceeded 20% in three groups of patients, a loss greater in the hypernatremic patients than in the hyponatremic ones. These results indicate that serious body water depletion produces hypernatremia instead of hyponatremia in patients in diabetic coma. The disorder may be caused by the altered distribution of electrolytes between the intra- and extra-cellular spaces.

View full abstract

Adrenal autotransplantation after bilateral total adrenalectomy has been utilized to eliminate the need for replacement therapy and to prevent the late occurrence of Nelson's syndrome in some patients with Cushing's disease. It is possible to follow these cases up closely today, owing to the highly developed hormonal evaluation and imaging techniques. In this study, two patients who under-went bilateral total adrenalectomy and cortex autotransplantation are presented. The autografts were found functional and the patients had not required any steroid replacement therapy.

View full abstract

To examine whether physical exercise is beneficial in preventing postmenopausal osteoporosis, we measured bone mineral density (BMD) in three distinct groups of healthy postmenopausal Japanese women aged 49-61 yrs: 11 volleyball players (V) and 5 joggers (J), and 9 controls (C) who had not been participating in regular physical activity. BMD was measured at the lumbar spine (L₂-L₄) and proximal femur using dual energy X-ray absorptiometry, and at the radius using single X-ray photon absorptiometry. Serum levels of estradiol (E₂), parathyroid hormone (PTH) and calcitonin were also measured by radioimmunoassay. Osteocalcin was determined by enzyme immunoassay. BMD in the lumbar spine was greater in the V and J groups than in the C group (P<0.01). The J group had a significantly lower PTH level than the C group. In contrast to eight- bearing bones, we found no significant differences in BMD at the radius among the three groups. BMD at the distal radius was negatively correlated with years after menopause in both the V group and the J group significantly. These results indicate that regular physical exercise has a positive effect on the maintenance of bone mineral in postmenopausal women and that the protective action is localized in skeletal sites used predominantly for the sport without opposing the negative regulation caused by estrogen deficiency in systemic bones.

View full abstract

To explore the direct effect of estradiol-17β on pig luteal cells and its ability to counteract a gonadotropic stimulus, luteal cells were incubated in vitro in the presence of estradiol alone, human chorionic gonadotrophin (hCG) alone or estradiol combined with hCG. Luteal cells were collected at three different stages of the luteal phase (0-3 days after ovulation, early; 8-10 days after ovulation, mid; and 14-16 days after ovulation, late). Estradiol alone did not exert any effect on progesterone production by any of the 3 types of luteal cells.
Progesterone production by cells in the mid-luteal phase was enhanced by hCG in a dose dependent manner. High doses of estradiol combined with hCG significantly diminished production of progesterone by cells collected during the early luteal phase. The strongest inhibitory effect of estradiol on hCG stimulated progesterone production was observed in cultures of luteal cells in the midluteal phase. In contrast, 100ng of estradiol and the 10 and 100ng/ml concentrations of hCG increased progesterone secretion over basal control values in cultured luteal cells in the late luteal phase. Differences in the production of progesterone in response to estradiol at different stage of the luteal phase suggest that different cellular mechanisms must be triggered in each luteal phase investigated. These data support a physiological role for estrogen in the regulation of the pig corpus luteum during its life span in the non-fertile cycle.

View full abstract

Body composition was assessed by bioelectrical impedance analysis (BIA) in 100 Japanese normal adults, 9 patients with acromegaly and 11 patients with growth hormone (GH) deficiency. Body weight (BW) was greater in normal males than in normal females. Percent body fat (BF/BW) was greater in females than in males and was increased with age in both sexes. Percent total body water (TBW/BW) was less in females than in males. Although percent extracellular water (ECW/BW) was not different between both sexes, the ECW/TBW ratio was greater in females than in males. Percent body cell mass (BCM/BW) was lower in females than in males. The patients with acromegaly had a lower percent BF but a higher percent TBW, percent ECW and ECW/TBW ratio than normal subjects, while the patients with GH deficiency had a higher percent BF and ECW/TBW ratio, but lower percent TBW. Percent body cell mass (BCM/BW) was higher in acromegaly and lower in GH deficiency than in normals. There was a negative correlation (r=-0.62) between plasma IGF-I levels and percent BF, whereas a positive correlation (r=0.51) was found between the plasma IGF-I level and percent BCM. It is suggested, therefore, that body composition is affected by sex and age in normals, and by GH secretion in patients with pituitary dysfunction. Plasma IGF-I levels may be one of the factors responsible for alterations in body composition.

View full abstract

The gene encoding Proinsulin Kyoto has been isolated and characterized by DNA sequencing, indicating that the molecular basis of the disorder is a G-T point mutation in the insulin gene which creates a Hind III site. In addition, in the 3'-untranslated region of the mutant insulin gene, a Pst I site negative, α type allele was found, and in the normal gene, a Pst I site positive, β type allele was found. In order to clarify the frequency of the mutation and to determine whether this mutation is associated with diabetes mellitus or not, we have investigated Hind III polymorphism in 91 normal Japanese subjects and patients with IDDM and NIDDM. No cases with the Proinsulin Kyoto gene were found among the subjects examined. Secondly, to determine whether this α type allele is associated with DM in Japanese, we investigated Pst I polymorphism in the same subjects. The frequencies of the α type and β type alleles were 92% and 8%, respectively. No significant difference in genotypic frequency was found among normal, NIDDM, and IDDM. We conclude that the Proinsulin Kyoto gene is not a common cause of DM and the occurrence of the α type insulin gene in Japanese diabetes is more frequent than in other races, so this Pst I polymorphism is not a marker for diabetes mellitus in Japanese.

View full abstract

Effects of vanadate on liver 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (6PF-2-K/F-2, 6-P₂ase) mRNA and protein inductions were examined in streptozotocin (STZ)-induced diabetic rats. In diabetic rats at one week after STZ (60mg/kg body weight), the liver 6PF-2-K activity was decreased to 22% of the control. The enzyme protein was also decreased to 31% of the control, but the reduction in mRNA was not significant. Treatment of diabetes with vanadate (10mg/kg BW, i.v., every 8h), as well as insulin (10u/kg BW, s.c., every 8h), increased the 6PF-2-K activity and theenzyme protein content, though it was not completely restored to the control level. 68% of the control was the figure for enzyme activity and 65% of the control for protein content after 24-h of treatment. On the other hand, vanadate, like insulin, increased enzyme mRNA content to a higher level than the control (140% of the control). The present results indicate that vanadate, like insulin, modulates the liver 6PF-2-K/Fru-2, 6-P₂ase gene expression, and stimulated protein induction contribu tes to the regulation of its enzyme activity, resulting in amelioration of the deranged carbohydrate metabolism in the diabetic state.

View full abstract

The cytologic localization and cellular levels of myc oncoprotein in the human ovary during follicular growth, regression and atresia were examined by the avidin/biotin immunoperoxidase method with a specific antibody to myc oncoprotein. In primordial follicles, only the oocyte showed intense immunostaining for myc protein, whereas the granulosa cells were negative for the staining. In preantral follicles, both the oocyte and granulosa cells were moderately immunostained for myc protein.In antral and preovulatory follicles, there was no appreciable staining for myc protein in the granulosa or theca cells, while myc protein staining in the oocyte persisted with less intensity. It is of interest that myc protein expression in granulosa cells was apparent only during the preantral follicle stage. Corpora lutea during the early and mid luteal phase were negative for myc protein staining, whereas in regressing corpora lutea during the late luteal phase, peripheral theca lutein cells adjacent to the central core of scar tissue were immunostained for myc protein. Corpora albicans showed no staining for myc protein. In atretic follicles, granulosa cells and theca interna cells demonstrated positive staining for myc protein. Ovarian stromal cells were negative for the immunostaining throughout the menstrual cycle. This demonstrates that myc protein is expressed in a stage-limited manner in the human ovary during follicular growth and regression. The abundant expression of myc protein in the oocyte at the primordial and preantral follicle stages and in the granulosa cells at the preantral follicle stage suggests a role for myc expression in the initial growth of the oocyte as well as in the autonomous growth of granulosa cells during the preantral stage seemingly independent of gonadotropic stimulation. Furthermore, notable expression of myc protein in the granulosa cells and theca interna cells of atretic follicles and in the peripheral theca lutein cells of regressing corpora lutea implies the possible participation of myc expression in remodelling the ovarian local tissue following atresia and luteolysis in the human ovary.

View full abstract

Lymphocytic adenohypophysitis is an autoimmune disorder of the anterior pituitary gland which usually occurs in a woman in the postpartum period. It has been considered that lymphocytic hypophysitis is confined to the adenohypophysis sparing the neurohypophysis, and that diabetes insipidus is not a clinical feature of the disorder. Here we report the case of a 50-year-old woman with lymphocytic hypophysitis which presented with diabetes insipidus. MRI indicated homogenous swelling of the whole pituitary gland, loss of the normal high intensity of the posterior pituitary, and thickening of the pituitary stalk. A biopsied specimen of the pituitary revealed diffuse lymphocytic infiltration. The diabetes insipidus was controlled by the administration of DDAVP. The anterior pituitary function was not greatly damaged, and no hormonal replacement therapy was necessary. We suggest that this case represents a variant of lymphocytic adenohypophysitis and/or lymphocytic infundibulo-neurohypophysitis, in which the chronic inflammatory process involves the infundibulum, adenohypophysis and neurohypophysis.

View full abstract

To assess whether atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) participate in impaired water excretion in patients with hypothyroid states (HS), an oral acute water loading (WL) test (20ml/kg•BW/45min) was performed before and after L-thyroxine (T₄) treatment in 5 hypothyroid patients. Plasma ANP, AVP, osmolality (Posm), total protein and renal water excretion were simultaneously determined, and these data were compared to the data from five normal subjects (NS). The impaired water excretion rate in HS was entirely improved in the euthyroid states (ES) after T₄ therapy for at least 7 months. Plasma ANP in HS was lower than that in NS (5.9±0.9 vs. 16.5±3.6 pmol/L, P<0.05), but increased after T₄ treatment (21.2±5.7pmol/L, P<0.05). Plasma AVP in HS (1.6± 0.5pmol/L) showed a tendency to be lower than those in ES and NS (2.9±0.4 and 2.9±0.7pmol/L), but did not respond to a fall in Posm after WL, unlike ES and NS. Significant positive correlation were noticed between Posm and plasma AVP in ES and NS, but not in HS. These results suggest that not only the impaired release and/or metabolisms of AVP and ANP, but also derangement of renal water and electrolytes handling might induce attenuation of C_H2O formation in hypothyroid states.

View full abstract

We studied the steroidogenetic action and concomitant subcellular redistribution of protein kinase C (PKC) in cortisol hypersecreting adrenal adenoma cells obtained from two patients withCushing's syndrome. Isolated adenoma cells were treated with 10^-9M and 10^-6 M 12-O-tetradecanoyl phorbol-13-acetate (TPA) or 10^-6M ACTH. Treatment of the isolated adenoma cells with TPA resulted in cortisol secretion equivalent to that with ACTH-treatment. Immunoblot analysis of PKC during treatment with ACTH or TPA showed that PKCβ translocated from cytosol to membrane. A small amount of PKCα, but not membrane-associated PKCα, was detectable in the cytosolic fraction. It appeared that TPA-induced cortisol secretion mimicked ACTH-induced cortisol secretion, and that PKCβ translocated from cytosol to membrane on stimulation by both ACTH and TPA. We suggested that ACTH-induced cortisol secretion in human cortisol hypersecreting adrenal adenoma is mediated by PKCβ activation.

View full abstract