A novel pituitary protein “7B2” was secreted by GH₁ cells. The secretion of 7B2 was increased in the presence of human GRF in a dose-responsive manner. In contrast, a somatostatin analog, SMS 201-995, revealed the inhibitory effects on the basal- and GRF-induced secretion of 7B2 at the concentration of 10^-7M. These findings suggest that 7B2 is a secretory protein of rat GH₁ cells under certain conditions.

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The metal content of diaphragm, gastrocnemius, ventricle, and bladder muscles in genetically obese diabetic KK-CA^y and alloxan-diabetic ddY mice was compared with that in prediabetic KK-CA^y and normal ddY mice, because the muscles of the diabetic KK-CA^y mice had morphological abnormalities, such as atrophy, disappearance of Z-band, disturbed myofibrils and swollen sarcoplasmic reticulum. The amounts of calcium (Ca) in gastrocnemius, ventricle and bladder muscles from the prediabetic KK-CA^y mice were significantly 7.7, 98.3, and 36.9% greater, respectively, than those in normal ddY mice. In contrast, the magnesium (Mg) content of the diaphragm, the gastrocnemius, and the ventricle in the prediabetic mice was 8.6, 7.4, and 4.3% lower, respectively, than in the ddY mice. The iron (Fe) content of the diaphragm, gastrocnemius, and ventricle muscles in the prediabetic mice was 29.2, 43.6, and 44.6% greater, respectively, than in the ddY mice. The Ca content in the gastrocnemius muscles of the diabetic KK-CA^y mice and the alloxan-diabetic mice was 19.8 and 11.7% higher, respectively, than in the prediabetic and normal mice. The Ca content of the ventricle muscle was increased only in the alloxan-mice. The gastrocnemius Mg was also 9.0 and 5.5% greater in the KK-CA^y and the alloxan-mice. The Fe content of the diaphragm and the gastrocnemius muscles from the KK-CA^y mice was 27.3 and 23.2% greater, respectively, than in the prediabetic mice. The zinc (Zn) content of the gastrocnemius and the bladder was 16.4 and 18.0% higher, but the ventricle Zn was 13.4% lower, respectively, than in the prediabetic control. The changes in metal content induced by the diabetic state may be related to the morphological abnormalities.

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We examined effects of sodium valproate, a gamma amino butyric acid (GABA)-transminase inhibitor, on the secretion of immunoreactive (IR)-ACTH and IR-β-endorphin/LPH from cultured rat anterior pituitary cells to determine whether sodium valproate has a direct action on the secretion of ACTH and its related peptides from the cultured rat anterior pituitary gland. During the 3 h incubation, the basal secretion of IR-ACTH and IR-β-endorphin/LPH decreased to 50.8% and 58.3%, respectively, of the control concentration after adding 10^-7M sodium valproate into the incubation media and to 67.7% and 69.3%, respectively, of the control levels with 10^-8M sodium valproate. However, sodium valproate at a concentration of 10^-8M or 10^-9M did not affect the basal concentration of IR-ACTH and IR-β-endorphin/LPH. Sodium valproate at a concentration of 10-7 M significantly attenuated the stimulated release of IR-ACTH and IR-β-endorphin/LPH by 10^-9 or 10^-10M of ovine corticotrophin releasing factor. These results indicate that sodium valproate could directly effect rat anterior pituitary cells to suppress both basal and stimulated release of proopiomelanocortin derived peptides and this supports the hypothesis that sodium valproate has a direct effect at the pituitary corticortroph in reducing plasma ACTH.

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A 40 year-old man was admitted to our hospital for detailed examination of hypokalemia (2.7mEq/l). His blood pressure was normal. Metabolic alkalosis, ACTH dependent hyperaldosteronism (18ng/dl) and over-response to synthetic ACTH were observed. Plasma renin activity, on the other hand, was within the normal range (1.7ng/ml/hr). Serum potassium was normalized to 4.1mEq/l and the responsiveness of the renin-angiotensin-aldosterone system was recovered after the administration of dexamethasone. These results led us to suggest that this case might be normotensive glucocorticoid-suppressible hyperaldotseronism. The etiology which was not associated with hypertension and low plasma renin activity has not been clarified but may be related to the shortness of duration of this disease. Our case was also afflicted with mild hypercortisolemia and excessive excretion of urinary 17-hydroxycorticosteroid and 17-ketosteroid which was suppressed by the administration of dexamethasone (2mg/day). These findings may be related to hypersensitivity of the fascicullar zone of the adrenal gland to ACTH.

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Neonatal polycythemia is a perinatal complication in infants of diabetic mothers. The cord CBC (complete blood counts), serum iron, transferrin and ferritin concentrations were studied in newborn infants of 9 GDM (gestational diabetes), 21 NIDDM (noninsulin-dependent diabetes mellitus), and 8 IDDM (insulin-dependent diabetes mellitus) mothers.
The RBC (red blood cell) count, Hb (hemoglobin) and Het (hematocrit) of these infants were higher than control infants. There was no difference between the serum iron concentration of the infants of each group diabetic mothers and the infants in the control group, but the transferrin concentration was significantly higher and the ferritin was significantly lower in the infants of diabetic mothers than in those of control mothers. There was a significant negative correlation between transferrin and ferritin (r=-0.491 p<0.001). Erythropoiesis is considered to be enhanced in the fetuses of diabetic mothers, and the iron needed for erythropoiesis is reportedly transported from the mother to the fetus according to the demands of the fetus, but the iron storage was shown to be reduced in the fetuses of diabetic mothers.

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The effect of a diabetic state in the diabetic KK-CA^y mouse on calcium activated neutral proteinase (CANP) of hind-limb skeletal muscles was investigated. In the diabetic state, there was an increased sensitivity to activation of CANP by calcium (Ca). In addition, there was an enhancement of maximal activity of the enzyme. The effect was induced by secondary modification of the diabetic state, but not genetical factors. Several lines of evidence suggest that the CANP is responsible for 92 K dalton protein in diabetic skeletal muscles. Among the evidence are the following: a) The 92 K band in the diabetic muscles was lower than in the prediabetic mouse and restored by the addition of 2mM EDTA and 2mM EGTA, b) The band was reduced by increasing the Ca content and neutral pH in the non-diabetic normal muscles. c) E-64-C, a CANP inhibitor, restored the 92K component reduced by the diabetic state. Since the band in denervated muscles was not changed by the Ca chelating agents, the reduction of the band in the diabetic muscles is related with musclotrophic factors, not diabetic neuropathy. These results suggest that diabetic amyotrophy may be regarded as a phenomenon linked to an increase in intracellular Ca ions and an increase in CANP activity.

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The urinary volume (U.V.), Na excretion (U_NaV) and K excretion (U_KV) have been reported to show a circadian rhythm in man, but the mechanism of this rhythm has not been made clear. To investigate how atrial natriuretic peptide (ANP) and endogenous digitalis-like substance (DLS) participate in the circadian change in urinary electrolyte, the circadian changes in ANP and DLS (digoxin-like immunoactivity: DLI, Na-K-ATPase inhibitor: ATPI, ouabain binding inhibitor to Na-K-ATPase: OBI) were evaluated in 5 normal man. ANP, DLI and OBI showed no significant correlation with urinary electrolyte excretion, but there was a significant positive correlation between plasma ATPI and urinary Na excretion. From these results it is suggested that circulating Na-K-ATPase inhibitor (plasma ATPI) may be involved in the regulation of the circadian rhythm of urinary Na excretion.

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To elucidate the origin and regulatory mechanism of deoxycorticosterone (DOC) and deoxycorticosterone sulfate during fetal life, the levels of serum DOC, DOC sulfate, progesterone, cortisol, corticosterone and 18-hydroxydeoxycorticosterone (180H-DOC) were determined in the fraction separated on high performance liquid chromatogram (HPLC) by radioimmunoassay (RIA) using the serum from normal newborn. Elimination curves both of serum DOC and DOC sulfate showed two phases: rapidly decressing and slowly decreaseing ones. Both serum DOC and DOC sulfate correlated with progesterone (r=0.340, p<0.01; r=0.737, p<0.01, respectively). They also correlated with cortisol (DOC, r=0.467, p<0.01; DOC sulfate, r=0.549, p<0.01, respectively). Serum DOC reached normal adult levels by 16 hrs after birth. However serum DOC sulfate concentration was maintained high throughout the entire early neonatal period. On the contrary, the changes in serum cortisol, corticosterone and 180H-DOC showed a peak surge in the initial phase after delivery. Both serum corticosterone and 180H-DOC correlated with cortisol (r=0.518, p<0.01; r=0.410, p<0.01, respectively).
These findings suggest that, in the fetus, serum DOC and DOC sulfate are mainly produced at extraadrenal sites isolated from normal mineralocorticoids synthesis and after birth they begin to be formed at adrenal glands.

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Subacute thyroiditis is generally thought to be a self-limited inflammatory disease of the thyroid gland. This paper describes serial observations on the clinical course of a typical patient with subacute thyroiditis. This patient showed specific features of destructive thyrotoxicosis with increases in the serum levels of acute phase reactants and in the erythrocyte sedimentation rate. She also showed signs of liver dysfunction [slightly increased alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), and leucine aminopeptidase (LAP)], slight anemia, glucose intolerance, increased pancreatic enzymes, splenomegaly, and an increase in peripheral Leu 7 positive (NK/K) cells. These abnormalities all improved with recovery from disease. These findings indicate that in this patient with subacute thyroiditis inflammation is not limited to the thyroid gland but also involves the liver, pancreas and spleen. Thus the subacute thyroiditis in this patient may be a systemic multi-organ disease.

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To elucidate the relationship between the mother's TSH-receptor antibody activities and the status of thyroid dysfunction in their offspring, blood was taken from 5 mothers with chronic thyroiditis with potent thyrotropin (TSH)-receptor blocking activity, and the potency of TBII and TSBAb activity was assayed more quantitatively. In those mothers whose infants suffered from neonatal hypothyroidism, the 50% inhibition of binding of labeled TSH to its receptors was obtained at more than 30 to 50-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 30-fold dilution. Similarly, in those mother whose infants suffered from neonatal hypothyroidism, the 50% inhibition of TSHinduced c AMP accumulation was obtained at approximately 400 to 3000-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 50-fold dilution. On the other hand TBII activity was much less potent in serum from patients with Graves' disease. These results suggested that the titration of serum with dilution to obtain 50% inhibition of labelled TSH binding to its receptor may be the simplest way to predict thyroid dysfunction of the newborn infants born to mothers with chronic thyroiditis.

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The levels of 6 circulating tumor markers were evaluated in a total of 131 female subjects with altered thyroid states; 36 normal subjects, 46 hyperthyroid patients with Graves' disease, and 49 primary hypothyroid patients.
The mean CEA concentration was observed to be significantly higher (p<0.02) in hypothyroid patients than in normal and hyperthyroid patients (1.1±0.1ng/ml, 0.8±0.1ng/ml and 0.8±0.1ng/ml, respectively). Similarily, the mean serum CA 125 concentration in hypothyroid patients was higher (p<0.02) than in normal and hyperthyroid patients (13.0±2.6 U/ml, 7.6±1.1 U/ml and 5.5±0.8 U/ml, respectively), and the mean serum CA 15-3 concentration in hypothyroid patients was significantly higher than in normal subjects (p<0.01) and hyperthyroid patients (p<0.001)(16.2±0.9 U/ml, 13.9±0.6 U/ml and 10.6±0.5 U/ml, respectively). No statistical difference was found in mean CA 19-9 in the three subject groups. AFP in the hypothyroid patients (3.6±0.3ng/ml) was significantly higher (p<0.05) than in normal subjects (2.6±0.2ng/ml) and hyperthyroid patients (1.7±0.2ng/ml)(p<0.01). On the other hand, serum ferritin was low in the hypothyroid patients (65.9 8.0ng/ml) and significantly increased (69.1±9.0ng/ml)(p<0.02) with the normalization of thyroid function. In hyperthyroidism, serum ferritin (70.2±7.0 ng/ml) was significantly higher than in the hypothyroid patients (p<0.01).
A significant inverse correlation was found between AFP, CEA, CA 15-3, and CA 125 with T₃, T₄, FT₃ and FT₄. There was a significant positive correlation between ferritin and FT₃ and FT₄ in hyperthyroid patients. Further, the same positive correlation was observed in all subjects. Our data suggest that when patients are suffering from hyper-or hypothyroidism, caution should be taken when reading the tumor marker concentration.

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The steroid, 19-hydroxyandrost-4-ene-3, 17-dione (19-hydroxyandrostenedione, 19-OH-A-dione) has been known to enhance the mineralocorticoid action of aldosterone. To investigate the age-related change in the plasma 19-OH-Adione concentration, plasma 19-OH-A-dione, androst-4-ene-3, 17-dione (A-dione), aldosterone and cortisol of 38 non-hypertensive healthy subjects (18 young men and 20 aged men) measured by specific radioimmunoassays. The basal plasma 19-OH-A-dione and A-dione concentration in aged men was significantly lower than in young men (P<0.01). Moreover, there was found to be a positive correlation between plasma 19-OH-A-dione and A-dione (P<0.01). On the other hand, plasma aldosterone and cortisol in aged men showed a tendency to decrease, but no statistical significance compared to young men was observed. This study demonstrated that there was an apparent age-related decrease not only in plasma A-dione, but also in plasma 19-OH-A-dione, an amplifier of aldosterone action.

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In an attempt to clarify the pathophysiological role of endothelin (ET), a novel vasoconstrictor peptide, we administered this peptide into the medium of isolated perfused rat kidney (IPK). ET increased renal vascular resistance by 53%, and reduced inulin clearance by 29% in IPK at a higher concentration of 500 PM. However, fractional excretion of sodium and urine flow rate were increased by 160% and 109%, respectively. These findings suggest that ET modulates the tubular sodium reabsorption as well as the renal hemodynamics.

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Human placental trophoblasts contain 3, 5, 3'-triiodo-L-thyronine (T₃) nuclear receptors not only at term but all throughout pregnancy. We determined which of the trophoblast, cytotrophoblast (C-cell) or syncytiotrophoblasts (S-cell) respond to thyroid hormone, and whether the T₃ binding capacity changes with placental aging. Nuclear protein of mononuclear cells purified from term chorionic tissue by enzymatic digestion and Percoll gradient centrifugation had an apparent association constant (Ka) of 5.2× 10⁹M^-1 and a binding capacity of 445 fmol T₃/mg DNA, 8 times greater than that of term trophoblasts. Primary harvested mononuclear cells reacted against neither anti-hCG-β nor and-hPL antibodies, although some of them reacted immunocytochemically against anti-hCG-α antibody. These cells aggregated with each other and transformed into multinuclear cells in culture after 96 hrs of incubation, showing that these primary harvested cells were C cells that had morphologically transformed into S cells. The transformed cells secreted hCG and hPL and immunocytochemically stained for these makers, suggesting that the C cells had functionally transformed into S cells. Nuclear binding of T₃ in trophoblastic tissue is present not only at tuna but throughout pregnancy. Although each nuclei had a similar Ka value, the binding capacity decreased towards term. These findings suggest that nuclear T₃ receptors of placental trophoblast change with placental aging and this change is mainly due to the change in the C/S cell ratio. We concluded that the cytotrophoblast is an active target cell of thyroid hormone.

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The role of substance P (SP) in the control of thyroid stimulating hormone (TSH) release and the influence of gonadal steroid were investigated. Intravenous administration of SP failed to alter plasma levels of TSH in ovariectomized (OVX) rats, whereas SP induced a significant increase in plasma TSH in estradiol benzoate-primed (Eb-primed) OVX rats (P<0.001). Further, intravenously administered SP did not affect the plasma TSH concentration in normal male rats, but significantly increased it in Eb-primed castrated male rats (P<0.01). These data suggest possible roles for SP at the level of the hypothalamus and/or the pituitary gland in stimulating TSH secretion under the influence of estrogen.

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A 55-year-old man was admitted to our hospital with an anterior neck tumor, hoarseness, and dysphagia that had continued for a few weeks. He was diagnosed as anaplastic thyroid cancer by fine-needle aspiration cytology. He was treated by external radiation and chemotherapy, but left hemothorax developed and he died of respiratory failure on the 76th day in hospital. On admission, the levels of serum free triiodothyronine (FT3), free thyroxine (FT4), and TSH were 12.8pg/ml, 4.2ng/dl, and 0μU/ml, respectively. The simultaneous thyroidal I-131 uptake rate was 1.2% at 24 hours. The levels of free thyroid hormones fell gradually without antithyroid drugs to result in hypothyroidism (FT3 0.8pg/ml, FT4 0 ng/dl, and TSH 36μU/ml). The rapid growth of anaplastic thyroid cancer seemed to be responsible for destructive thyrotoxicosis followed by hypothyroidism in this patient.

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Unique association of hypothyrotropinemia with euthyroidism was described in 2 children of short stature. Both had a history of intrauterine growth retardation (IUGR), but showed an appropriate growth rate after infancy (5 cm/y). Growth hormone secretion after provocation tests was normal, whereas TSH response to TRH was absent. With a highly sensitive TSH radioimmunoassay (RIA) and a specific RIA for TSH-α-subunit, both responded to a high dose of TRH stimulation. Serum thyroid hormones were within the normal range, while prolactin response to TRH was exaggerated. Exogenous thyroxine (T4) supplement in case 1 did not improve his growth rate, indicating absence of hypothyroidism. Case 2 was treated with stanozolol, which accelerated his growth velocity to 8 cm/y. During the treatment, serum T4 gradually decreased to 50% of the initial level, but blunted TSH response to TRH remained unchanged. These results indicate that their thyrotrophs are resistant to TRH stimulation and the pituitary setpoint of TSH release is unusually high. The exact mechanism involved in maintaining euthyroidism despite hypothyrotropinemia remains to be elucidated, but a common history of IUGR appears to play a role in producing this pituitary-thyroid state.

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