Testosterone binding protein from rat liver cytosol, which had been incubated with [³H] testosterone followed by treatment with dextran-coated charcoal, was analyzed by DEAE-cellulose and phosphocellulose chromatography. On DEAE-cellulose chromatography, two distinct peaks of radioactivity were eluted at 0.07M and 0.19M KCI, both sedimented in 4S regions. Phosphocellulose chromatography resulted in a broad peak at 0.08M KCl, with a shoulder at 0.04M KCl, both sedimented at 4S. These findings indicated that testosterone binding protein consists of two types of components each with 4S.

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In order to investigate the mechanisms of increased plasma inactive renin in diabetics with diabetic microvascular complications, changes in active and inactive renin with the progress of diabetes mellitus were studied, and effects of standing on inactive renin release and the relationship between plasma inactive renin and serum trypsin or protease inhibitors were also studied. Inactive renin increased with the aggravation of diabetes mellitus, but active renin didn't show significant changes with the aggravation of diabetes mellitus. Active renin was significantly increased both in the healthy subjects and in the diabetic patients when they were in an upright position, but no significant change was observed in inactive renin. Serum trypsin in diabetics with retinopathy and nephropathy was lower than that in those with no clinical sign of microangiopathy, but the correlation between plasma inactive renin and serum trypsin was not significant. There was a significant correlation between plasma inactive renin and serum α2-globulin (r=0.52, p<0.01). Although plasma inactive renin was not significantly correlated with serum α1-antitrypsin, there was a significant correlationbetween plasma inactive renin and serum α2-macroglobulin (r=0.61, p<0.01).
These results show that the increased levels of plasma inactive renin observed with the development of diabetic microangiopathy are probably related to the altered plasma protein metabolism observed in patients with diabetes mellitus. However, it is not clear whether this altered protein metabolism is related to the conversion from inactive to active renin.

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The levels of unconjugated estradiol (E₂), estriol (E₃) and total (conjugated plus unconjugated) E₃ in maternal vein serum during labor, cord vein serum, and cord artery serum were measured in normal singleton and twin pregnanceis with appropriate for dates babies (AFD) and with light for dates babies (LFD). The mean level of total E₃ in the maternal vein serum in singleton pregnancy was significantly lower in the LFD group than in the AFD group, but no differences were seen in the mean levels of unconjugated E₂ or E₃ between the groups. The concentration of unconjugated E₂ in the maternal vein serum was significantly higher in the twin group with a large placenta than in the singleton group with a small placenta, while the concentration of total E₃ in the case of twin pregnancy with LFD was lower than that in singleton pregnancy with AFD but not significantly. No difference in the concentration of total E₃ was observed between the cord vein serum and cord artery serum. The present data suggest that the total E₃ level in maternal vein serum may be used in evaluating fetal states such as intrauterine growth retardation.

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We treated a hypertensive patient with recurrent pheochromocytoma (paraganglioma) associated with glucagonoma. No clinical symptom of glucagonoma was found and it could be detected only by a slight elevation of plasma immunoreactive glucagon (IRG) while the extirpated pancreatic tumor contained much IRG. This case could not be classified as either multiple endocrine neoplasia (MEN) type I or type II.

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To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T₃ and rT₃ were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT₃, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T₄. In contrast, serum 3, 5-T₂ concentrations in hyperthyroid patients (mean±SE: 4.0±0.5ng/dl) were not significantly different from those in controls (3.9±0.4ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T₂ levels in the hypothyroid patients (3.8±0.6ng/dl) were also within the normal range and showed no significant change following the T₄ replacement therapy. However, serum 3, 5-T₂ as wellas 3, 3'-T₂ concentrations rose significantly with a marked rise in serum T₃ following T₃ administration, 75μg/day for 7days, in Graves' patients in euthyroid state. These results indicate that serum concentrations of 3, 3'-T₂ and 3', 5'-T₂ well reflect the thyroid function states, but that serum 3, 5-T₂ concentrations change little in altered thyroid function states, although it is monodeiodinated from T3 in vivo.

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The effects of various osmotic agents on the release of oxytocin were examined in a superfusion system. Oxytocin was released significantly from the rat pituitary by superfusion with medium of an osmolality of 350mOsm/kg H₂O adjusted with NaCl, regardless of the presence of the rat hypothalamus. Media adjusted to an osmolality of 350 mOsm/kg H₂O with sucrose, glucose, urea or mannitol had no effect on oxytocin release from the hypothalamo-pituitary complex. Medium containing excess Na₂SO₄ induced significant release of oxytocin from the pituitary without the hypothalamus. The administration of tetraethlyammonium chloride had no oxytocin secretion. These data suggest that oxytocin release from the pituitary is influenced by the level of sodium ion rather than the osmotic pressure.

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Nuclear binding abilities of 3 glucocorticoids, dexamethasone (Dex), prednisolone (Pred) and corticosterone (Cort), which exhibited different biopotencies were comparedin vitro. Cytosols labelled with ³H-Dex, ³H-Pred and ³H-Cort from the rat liver prepared by incubation at 0°C for 16hr were bound to isolated liver nuclei in rates of approximately 25%, 9% and 1% of added radioactivity, respectively. Nuclear binding rates observed were correlated with biopotencies of these steroids. Time course studies of the cytosol binding revealed that the difference in the nuclear binding ability of these ligands was attributable, at least in part, to the metabolic transformation of ligands during the incubation period. A significant portion of ³H-Pred and ³H-Cort was transformed to polar metabolite (s) even under the incubation conditions at 0°C. Kd's of the cytosol binding to ³H-Dex which was metabolically stable were decreased with the length of incubation time, significantly lower Kd being observed in the cytosol incubated for 16hr than in those incubated for 2 and 6hr. Kd's and the number of maximum binding sites were erratic when the ligands received biotransformation during the course of incubation. Transformed ³H-Pred and ³H-Cort during the incubation still exhibited features of the protein bound state. Besides biotransformation of ligands, structure related difference in the nuclear binding ability of these glucocorticoids was also observed. These observations suggest that metabolic susceptibility as well as structure related ability of the nuclear binding may contribute to the biopotency of glucocorticoids.

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The effect of testosterone treatment on the cytosolic androgen receptor in an androgen-dependent tumor (Shionogi Carcinoma 115, SC 115) and its sublines of altered hormone-dependency (CS 1, less androgen-dependent, and CS 2, androgenindependent) was examined. In all tumors examined a single, high-affinity binding to ³H-R 1881 was detected in cytosols. The size of the maximum binding sites was in the order SC 115, CS 1 and CS 2. Inhibition experiments revealed that the binding to ³H-R 1881 in cytosols of these tumors was attributable to the androgen receptor. The amount of the androgen receptor in cytosols was decreased at 1hr after testosterone injection, then replenished gradually towards the pretreatment level. Depletion of the androgen receptor was dependent on the dose of testosterone administered. Multiple injections of testosterone depressed the replenishment of the receptor. Treatment with actinomycin D or cycloheximide did not alter the dynamics of the androgen receptor. Therefore, it was concluded that the depletion and replenishment of the androgen receptor in cytosols of the tumors were caused by receptor recycling. Because a similar pattern of depletion and replenishment of the androgen receptor was also observed in the less androgen-dependent and-independent tumors, the growth of tumors was felt to be unrelated to the receptor dynamics.

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order to corroborate the regulatory role of Ca⁺⁺-calmodulin system in the steroidogenic response to adrenocorticotropic hormone (ACTH), the effects of calmodulin inhibitors (chlorpromazine, trifluoperazine, and W-7) on cortisol production and cellular cholesterol ester hydrolysis induced by ACTH in bovine adrenocortical cells were examined.
Three calmodulin inhibitors diminished not only the cholesterol ester hydrolysis and cortisol production induced by ACTH in the presence of Ca++, but also inhibited the Ca⁺⁺-induced hydrolysis and cortisol production in the absence of ACTH. Neither cortisol production in crude mitochondrial fraction nor the ACTH-induced Ca⁺⁺-influx was affected by chlorpromazine.
These results indicate that Ca++-calmodulin system plays a significant regulatory role in the supply of free cholesterol to the adrenal mitochondria in the steroidogenic response to ACTH.

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The administration of estrogens for gonadal dysgenesis is sometimes associated with the development of endometrial neoplasms. An approach which minimizes the inadvertent side effects while still providing the desired therapeutic effects may be to imitate the hormonal milieu of the normal menstruating woman. Oral administration of estradiol will not necessarily accomplish this, because of the intestinal conversion of estradiol to estrone. That problem can be overcome by the vaginal administration of estrogenes.

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Monodeiodination of T₄ to T₃ and rT₃ in the intact cells of dog renal tubuli and glomeruli was investigated. The tubuli and glomeruli were obtained by a sieve method. T₄ (2μg/ml) was incubated in Tris-HCl buffer, pH 7.5, with renal cells (180μμ protein/ml) and 5mM DTT for 1h at 37°C and the T₃ and rT₃ generated during incubation were measured by specific radioimmunoassays. In order of decreasing activity, dog renal cortical tubuli, cortical homogenate, glomeruli and medullary tubuli were capable of converting T₄ to T₃. Net rT₃ production from T₄ in cortical tubuli was also greater than that in cortical homogenate. The conversion of T₄ to T₃ and also to rT₃ in cortical tubuli was enzymatic in nature, since the reactions showed dependence on time and protein concentration; instability to heating; temperature and pH optimum. The production of T₃ and rT₃ from T₄ was maximum at pH 6.5 and at pH 9.5, respectively, indicating that two different enzymic systems, a 5-and a 5'-monodeiodinase, might be involved in the deiodination of the tyrosyl and the phenolic ring of T₄ in dog kidney.

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In order to investigate the degree of pituitary reserve of TSH secretion and the fluctuation of thyroid function in children with chronic lymphocytic thyroiditis, TSH response to TRH was examined in 42 patients, and the thyroid function was carefully followed up in two patients retrospectively and in four prospectively.
Increased basal TSH levels were revealed in seven patients (16.8%), and an exaggerated response of TSH to TRH loading in 15 (35.8%). We retrospectively observed spontaneous recovery of thyroid function in two cases. In one of them, two episodes of a transient decrease in thyroid function over a period of several years were noted. Prospectively, low normal T4, elevated TSH and normal T3 were detected in two cases at the first visit. Thereafter, TSH levels decreased to the normal range and the exaggerated response of TSH to TRH became normal. In two other cases, typical transient hypothyroidism occurred during the observation period. These fluctuations lasted for only a few months, and concomitant changes in the size of the thyroid gland were observed. No signs or symptoms suggesting viral infection were noted during the study period. Nor were changes in titers of thyroid auto-antibodies detected.
These results show that the secretion of TSH is exaggerated and the thyroid function is decreased in adolescents with chronic lymphocytic thyroiditis, but the thyroid function may fluctuate from euthyroid to hypothyroid within a short period. The causes of these changes, especially of the transient hypothyroidism remain to be clarified.

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The responses of TSH and PRL to intravenous doses of 500μg of TRH were investigated in 26 patients with primary hyperparathyroidism. Fourteen patients (54%) showed low responses of TSH with peak values of less than 5μU/ml (Group A). Twelve patients showed normal responses of TSH to TRH (Group B). Among the 26, 12 cases belonging to Group A and eight in Group B were reexamined after the correction of serum calcium level by parathyroidectomy. After successful treatment, the responses of TSH to TRH in six of the 12 patients in Group A returned to normal, whereas those in the remaining six were unchanged. The responses in the eight patients in Group B after surgery were not changed when compared to those before treatment. The basal values of PRL and the responses of PRL to TRH were normal in all patients and did not change after treatment.
We showed that patients with primary hyperparathyroidism have a high incidence (54%) of suppressed TSH response to TRH. Hypercalcemia was obviously one of the causative factors in inducing this abnormality in six patients. However, persistently suppressed responses of TSH to TRH were observed in the other six patients in Group A even after the correction of the serum calcium level by surgery. This finding suggests a primary failure of the TSH-regulatory mechanism in some cases of primary hyperparathyroidism.

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A glucagon-like substance named biliary IRG²⁰⁰⁰ whose molecular weight is approximately 2, 000 was isolated by gel filtration from rabbit bile. This substance showed a strong crossreactivity as equivalent to 25.7±5.1ng/ml of porcine glucagon in RIA with antiserum 30K specificity.
Biliary IRG²⁰⁰⁰ brought about a significant increase and delayed the response of blood glucose level in coexistence with porcine glucagon, though it has no appreciable effect on the glucose level when administered singly to the mouse intraperitoneally. The response with the coexistence of these materials was far greater than when porcine glucagon was given alone.
In Mortimore's type rat liver perfusion, a significant rise in glucose concentration in effluent was also observed when a mixture of biliary IRG²⁰⁰⁰ and porcine glucagon was perfused. The rate of ¹²⁵I-glucagon degradation was found delayed in the presence of biliary IRG²⁰⁰⁰ when examined in the rat.
Thus the increase and delayed response of glucose level in coexistence of porcine glucagon with biliary IRG²⁰⁰⁰ may be explained by a suppressive effect of glucagon degradation due to biliary IRG²⁰⁰⁰.

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Of 9 patients with chronic hepatitis treated with intravenous administration of 40 to 200mg/day of glycyrrhizin, 3 diabetic patients receiving concomitant insulin developed hypokalemia, sodium retention and suppression of both plasma aldosterone concentration and plasma renin activity after the administration for 3 to 6days. In the remanining 6 patients (5 nondiabetic and 1 diabetic) receiving no insulin, the administration over the long term (18 to 266days) never caused these abnormalites.
The development of hypokalemia and sodium retention in the patients was not associated with increased urinary excretion of potassium, indicating a different condition from pseudoaldosteronism caused by the desoxycorticosterone-like action of glycyrrhizin. These findings suggest that insulin which is known to have hypok alemic, antinatriuretic and antikaliuretic activity, as well as glycyrrhizin plays an important pathogenetic role in the observed electrolyte disturbance, and suppression of both renin and aldosterone.

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We studied the relationship among the status of the human oocytes, the E₂ concentration in the antral fluid and the follicular size in the different phases of the menstrual cycle, in order to determine the microenvironment of the follicles with healthy or degenerative oocytes in the human ovary. In the follicular phase of the menstrual cycle, follicles which contained a healthy but not degenerative oocyte had a significantly higher level of 17β-estradiol (E₂). In the late follicular phase, the larger follicles (≥13mm, in diameter) had only healthy oocytes. It seems that the follicle containing a degenerative oocyte does not develop physiologically until maturation of the preovulatory folllicle.
In the luteal phase, there were no relationships among the status of the oocyte, E₂ concentration in the antral fluid and the follicular size. However, the E₂ levels of the antral follicles with healthy oocytes in an ovary with corpus luteum were significantly lower than those in the contralateral ovary. The results suggest that the corpus luteum may exert an influence on the adjacent follicles.

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The culture for 7days in medium with 5.5mM glucose and 1mM 2-deoxy-Dglucose enhanced the glucose sensitivity of neonatal rat B cells, and even stimulated their growth in vitro. Also, 2-deoxy-D-glucose supplementation maintained insulin release evoked by leucine and 2-ketoisocaproate from B cells at day 7 at levels several times higher than at day 1. The effect of leucine was greatly augmented by glutamine, whereas that of the 2-keto acid remained almost unchanged irrespective of the presence of glutamine. These results suggest an increase in oxidative catabolism of medium nutrients in B cells grown in medium with 2-deoxy-D-glucose for 7days, and such metabolic changes may promote the growth of B cells in vitro.

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We describe the results of metabolic studies in a 17-year-old woman with diabetes mellitus which was the initial manifestation of idiopathic chronic calcifying pancreatitis (CCP). These studies were done on 2 occasions, 5months and 5years after the onset of diabetes, when her diabetes could be managed by glibenclamide and insulin, respectively.
Five months after the onset of diabetes, oral glucose produced a small increase in insulin and a paradoxical rise in both glucagon immunoreactivity (GI) and growth hormone (GH). By contrast, arginine-stimulated responses of the three hormones were normal. No increase in GI and a blunted rise in GH resulted from an insulininduced decrease in blood glucose.
Five years later, when CCP was demonstrated by roentogenologic examinations and tests of pancreatic exocrine function, oral glucose was followed by a flat and depressed response of C-peptide immunoreactivity and a markedly elevated response of gut glucagon-like-immunoreactivity (gut GLI). There were delayed and extremely low responses of pancreatic polypeptide to a test meal, irrespective whether or not her diabetes required treatment with insulin.
These results demonstrate that CCP can cause diabetes in adolescenes, as it does in adults, and that the adolescent woman described here had impaired responses of PP and gut GLI as well as insulin, GI and GH, especially to changes in blood glucose levels.

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