The effect of caerulein on insulin response to graded amounts of glucose from the isolated perfused rat pancreas was investigated in the presence or absence of an amino acids mixture. Caerulein at a concentration of 0.1ng/ml which is a submaximal concentration for an effect on exocrine pancreatic secretion potentiated insulin responses to glucose concentrations less than 200mg/dl, but produced no further increase when added to a glucose stimulus over a 200mg/dl. However, in the presence of amino acids the insulin response to 200mg/dl glucose was significantly potentiated by the stimulation of 0.1ng/ml caerulein. The effectiveness of caerulein as an insulinotropic agent depended on the glucose concentration only when amino acids were present. These results indicate that caerulein, at a concentration which stimulate pancreatic exocrine secretion, has a synergistic effect on insulin response to glucose and amino acids and therefore raises the possibility that endogenously released CCK may contribute to the entero-insular axis.

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Total serum calcium (Ca), ionic calcium (Ca⁺⁺), phosphorus, magnesium, total protein, immunoreactive parathyroid hormone (iPTH), calcitonin (iCT) and prolactin (iPRL) were measured in 30 paired samples of cord and maternal blood obtained at term delivery. In the cord blood, the concentrations of Ca, Ca⁺⁺, phosphorus, magnesium, albumin, iCT and iPRL were all higher, and the concentrations of total protein and iPTH lower than in the maternal blood. The calcium binding capacity of albumin assessed with the equation (Ca-Ca⁺⁺)/albumin, was similar at a given concentration of Ca in both the maternal and fetal circulations. There was a significant positive correlation between cord Ca⁺⁺ and maternal Ca or Ca++, and a significant negative correlation between Ca⁺⁺ and iPRL in cord blood. These data suggest that there is an active system transporting calcium from mother to fetus through the placenta, and PRL is the only one of the three hormones which was correlated with ionic calcium values in the fetus. The negative relationship between Ca⁺⁺ and iPRL in the cord blood suggests an inhibitory effect of the relative hypercalcemia on PRL serection in the fetus.

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The effect of acetylcholine (ACh) on corticoidogenesis in primary cultured bovine adrenocortical cells was examined. One hour exposure to 10^-3M ACh resulted in a stimulative effect on corticoidogenesis in the freshly isolated cells, and the effect of ACh grew intense during primary culture and reached the maximum on, day 2. ACh showed the effect at a higher concentration than 10^-6M. Thus the primary 2-day cultured cells were used. The corticoidogenic effect of ACh was inhibited by atropine but not by hexamethonium The effect of ACh was dose dependent, and the extracellular Ca++ was obligatory in inducing the effect. These results suggest that the corticoidogenic effect of ACh may be due to an increase in Ca⁺⁺-influx via muscarinic receptor in adrenocortical cells.

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The effects of bombesin and gastrin releasing peptide (GRP) on the release of catecholamine were investigated by using isolated rat adrenal gland. Bombesin and GRP stimulated an epinephrine (E) release with dose-dependency. A half maximal effect of bombesin was observed at 1.2×10^-9 M, and a maximal release of E occurred at 1×10^-6 M of bombesin. The stimulatory effect of GRP on the E release was very similar to that of bombesin. Although both these peptides also stimulated a norepinephrine (NE) release, a significant effect was detected at concentrations of bombesin and GRP above 1×10^-7 M. Nicotin and pilocarpine stimulated both E and NE releases dose dependently, but the effect of pilocarpine on E and NE release was 1/100 or less potent than that of nicotin. Bombesin-induced catecholamine releases were not inhibited by hexamethonium or atropine that fully impeded the stimulatory effects of nicotine or pilocarpine. In addition, bombesin had additive effects on the nicotine- or pilocarpine-induced E and NE releases. These data strongly suggest that bombesin. or GRP plays a physiological role as one of the important regulators in catecholamine secretion in the adrenal gland.

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Results of measurement of urinary steroid metabolite profile using gas chromatographic analysis in eight patients with adrenocortical tumors, i. e. 3 adenomas with Cushing's Syndrome, one adenoma with virilization, one adenoma without clinical manifestations, one carcinoma with Cushing's syndrome and virilization, one carcinoma with Cushing's syndrome and feminization, and one carcinoma without endocrinological symptoms, are reported. A unique pattern dominated by 5β and 11β-hydroxy steroid metabolites was confirmed in five patients with Cushing's syndrome consisting of three cases with adenomas and two with carcinomas. Excessive 3α, 17α, 21-trihydroxy-5β-pregnan-20-one (tetrahydro-11-deoxycortisol, THS) and Δ⁵-pregnene-3β, 11α, 20α-triol (Δ⁵-pregnenetriol) values were found in all three carcinomas including a nonfunctional carcinoma. These findings would strongly suggest the tumor to be a carcinoma, although excessive excretion of THS and Δ⁵-pregnenetriol was detected in one patient with a large adenoma associated with virilization. One patient with carcinoma was responsive to ACTH stimulation while the remainder show almost no response to exogenous ACTH. Urinary steroid profiling using gas chromatographic analysis, especially the values for THS and 5-pregnenetriol, appears to be a useful method to use in detecting these steroid metabolic characteristics in patients with adrenocortical carcinoma.

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Hyporesponsiveness of GH to insulin-induced hypoglycemia has previously been reported in hyperthyroid patients. In order to clarify the GH secretion in thyrotoxic patients, sleep-related increases in the serum GH concentration were investigated.
Eight thyrotoxic females ranging in age from 7 to 15 were treated with PTU. Blood samples for measurement of GH were drawn every 15 minutes during the first few hours of sleep before and during the treatment lasting about three months. The mean maximum serum GH level before the treatment was 10.0±5.5ng/ml (mean±SD); this rose to 23.2±14.6ng/ml (P<0.02) during the treatment. The maximum value of more than 10ng/ml was detected in only 3 out of the 8 patients before treatment. On the other hand, serum GH levels during PTU administration rose to above 10ng/ml in all patients except one. It was revealed that sleep-related elevations of GH occurred early in sleep and in close association with a slow-wave EEG pattern.
The results show that sleep-related GH release is low in the hyperthyroid state, but becomes significantly elevated during PTU administration. However, even in the hyperthyroid state, the sleep-related secretion of GH is closely correlated with the slow-wave sleep stage as in the euthyroid condition.

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TRH (10 and 1000μg/kg body weight (BW)) was injected ip into pregnant rats daily from day 0 to 20 of pregnancy, and the pituitary-thyroid axis of their pups (Mat-TRH rats) was examined on days 0, 4, 10, 21 and 90 after birth. The pituitary TSH content of male Mat-TRH rats was significantly lower on day 4, and higher on day 10 than that of control rats. The serum TSH was significantly higher on day 10 (except female 10μg/kg group).
An exaggerated TSH response to exogenous TRH (10μg/kg BW; ip) was observed on day 10 (males, 1000μg/kg group). The serum T⁴ level of female Mat-TRH rats was low on day 4 (1000μg/kg group), and higher on day 10. On days 21 and 90, the levels of pituitary TSH, serum TSH and T₄ in Mat-TRH rats were similar to those in controls, but the TSH response to TRH was still exaggerated (1000μg/kg group).
No significant difference between control and TRH-treated mothers was seen on days 10 and 90 postpartum except for a decreased pituitary TSH content on day 10 in the 1000μg/kg group. It is concluded that repeated administration of TRH to pregnant rats shows an effect on the pituitary-thyroid axis function of their progeny in later life.

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Analysis of urinary metabolites of [1, 2-³H]-aldosterone and [1, 2-³H]-3α, 5β-tetrahydroaldosterone was performed in male rabbits. The preliminary separaration of urinary metabolites was carried out by submitting these metabolites to countercurrent distribution. Further separation of each fraction thus obtained was achieved by means of DEAE-Sephadex A-25 column chromatography. The separated peak was then hydrolyzed with the enzyme and the free steroid released was identified on the basis of the mobilities of the steroid and its derivatives on paper chromatography.
After the injection of [1, 2-³H]-aldosterone, a major urinary metabolite was characterized as monosulphate of 3α, 5β-tetrahydroaldosterone. In addition, a small amount of the monoglucosiduronate fraction was found in the urine. 3α, 5β-tetrahydroaldosterone and 3α, 5β-tetrahydroaldosterone were detected as aglycones in this fraction. After the injection of [1, 2-³H]-3α, 5β-tetrahydroaldosterone, a similar pattern of urinary radiometabolites was observed.
The close similarity between the profile of urinary metabolites of [1, 2-³H]-aldosterone and that of [1, 2-³H]-3α, 5β-tetrahydroaldosterone suggests that the conversion of aldosterone to 3α, 5β-tetrahydroaldosterone is needed before the conjugation processes take place.

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The effect of dexamethasone on the release of ACTH, GH, PRL, LH and TSH was studied in monolayer cultures of rat pituitary cells in 4-hour incubation. With or without the addition of rat hypothalamic extract, the release of GH was significantly inhibited by dexamethasone at concentrations higher than 10^-9 M, although less remarkably than that of ACTH. Intracellular ACTH and GH were unchanged. PRL, LH and TSH were not affected. These results indicate that dexamethasone, when exerted for 4 hours, suppressed the release of GH as well as ACTH, at least in part, at the pituitary level.

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Two rabbits (TG-1, TG-2) were immunized with human thyroglobulin (HTg) and bled serially. Antisera were obtained at different times after the first immunization and kept separately and studied. In both rabbits production of anti-HTg, and anti-thyroid hormone antibodies such as anti-thyroxine (T4) and anti-triiodothyronine (T3) antibodies was observed. Binding parameters of anti-HTg antibodies with HTg, T4, and T3 were calculated in two selected antisera (70-day and 249-day). The Scatchard's plots of these antibodies were all curvelinear and were analyzed in two components: one, higher binding constant (Kal) and smaller binding capacity (Cap1) and the other, lower binding constant (Ka2) and larger binding capacity (Cap2). Kal values of anti-HTg, anti-T4, and anti-T3 antibodies in sera from TG-1 obtained from 70-day and 249-day bleeding were 1.1×10¹⁰M^-1, 6.0×10⁹ M^-1. 7.9×10⁸M^-1 and 1.7×10¹⁰M-1, 6.5 × 10⁹M^-1, 1.0 × 10⁹M^-1, respectively. Those from TG-2 were 1.7×10¹⁰M^-1, 1.8×10⁹M^-1, 6.4 × 10⁸M^-1 and 2.0×10¹⁰M^-1, 3.1×10⁹M^-1, 1.6×10⁹M^-1, respectively.
The significance of the production of anti-HTg and anti-thyroid hormone antibodies in rabbits immunized with HTg in relation to the antigenic structure of HTg molecule was discussed.

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Plasma growth hormone (GH) and somatomedin C responses to single and repeated administrations of synthetic human growth hormone releasing factor (hGRF-44) were studied in 29 patients with GH deficiency. hGRF-44 administered by single iv bolus (10μg/kg), repeated iv boluses (50 or 100μEg, once a day), repeated iv infusions (2.5μg/min for 90min, once a day), and/or repeated im injections (100μg, twice a day) for three to six consecutive days.
Ten of 16 patients had plasma GH responses to a single iv bolus injection, i.e., their plasma GH increased above 5ng/ml or twice the basal level. However none of them showed a plasma somatomedin C increase. To repeated iv bolus injections and repeated iv infusions of hGRF-44, 7 of 17 patients showed plasma GH responses, however in none of 7 patients did somatomedin C increase. Plasma somatomedin C did not increase after repeated im administrations of hGRF-44 for 5 days. Plasma somatomedin C increase was observed in two patients, from 0.32 to 0.54U/ml and from 0.16 to 0.46U/ml, in response to repeated iv boluses and repeated iv infusions, respectively.
These results suggest that hGRF-44 stimulates plasma GH secretion in some patients with GH deficiency, however the increases are not enough to stimulate somatomedin generation.

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The effects of bovine thyrotropin (TSH) on DNA synthesis and cyclic AMP production were studied in porcine thyroid follicles using suspension culture. During the early 72 hours incubation, the time-dependent uptake of [³H] thymidine by the follicles was obserbed. In the presence of 10mU/ml TSH, the uptake of [³H] thymidine was significantly depressed at 72hours incubation. TSH inhibition of [3H] thymidine incorporation was related to its concentration and the 50% inhibition was observed by using 1.0mU/ml TSH.
Under the same conditions, cyclic AMP production was stimulated by TSH and the stimulation was observed to be related to TSH concentration. In these experiments, the incubation time was 30min. Dibutyryl cyclic AMP, an analogue of cyclic AMP, inhibited the [3H] thymidine uptake at 72hours incubation.
From these results, it is suggested that TSH inhibits DNA synthesis, and that the inhibition may be mediated by cyclic AMP that is produced by TSH stimulation.

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Arginine-vasopressin and oxytocin in various portions of rat brain were determined by radioimmunoassays. The hormones were extracted from tissue samples into 0.1N HCl and then purified partially with acetone-petroleum ether extraction. The non-equilibration method was used for the assays. In this method recovery rates of arginine-vasopressin and oxytocin were 73.0±4.4% and 75.0±3.8%, respectively. Sensitivities of the assays were 1pg of argininevasopressin and 0.75pg (0.3μU) of oxytocin per assay tube.
The higher concentrations of arginine-vasopressin and oxytocin were confirmed in the hypothalamo-neurohypophyseal system, where these hormones are synthesized, transported and stored. Relatively high concentrations of these hormones, especially oxytocin, were detected in spinal cord. Amygdala, hippocampus, limbic forebrain and pineal body contained a certain amount of arginine-vasopressin (2-20pg/mg protein). Oxytocin (1-7pg/mg protein) was also detected in amygdala, pons and medulla oblongata, pineal body and midbrain. The low concentrations of these hormones were also found in cerebral coretex and cerebellum.

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A congenital hypothyroidism complicated by ventricular septal defects which was treated with L-triiodothyronine (L-T₃) alone from 1 5/12 to 25 years, is described.
The patient's growth and development was satisfactory and without side effects. It suggests that L-T₃ may be a safe drug for long term treatment of congenital hypothyroidism.

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The role of extracellular calcium in hormone-induced glycogenolysis was examined in a rat liver perfusion system by manipulating the perfusate calcium concentration and by using calcium antagonistic drugs.
When the perfusate contained 1mM CaCl₂, 5μM phenylephrine, 20nM vasopressin, and 10nM angiotensin II caused a persistent increase in glucose output and phosphorylase activity as well as a transient increase in ⁴⁵Ca efflux from ⁴⁵Ca preloaded liver. Verapamil hydrochloride (20-100μM) inhibited the activation of glucose output by these hormones in a dose-dependent manner. This inhibitory effect was also associated with the inhibition of hormone-induced activation of phosphorylase and ⁴⁵Ca efflux. In the absence of CaCl₂ in the perfusate, the glycogenolytic effect of phenylephrine and its inhibition by verapamil were obtained equally as in the presence of CaCl₂. However, the effects of vasopressin and angiotensin II were markedly attenuated and were not inhibited any further by verapamil. The substitution of diltiazem hydrochloride for verapamil produced essentially identical results. Cyclic AMP concentrations in the tissue did not change under any of these test conditions.
The results indicate that the glycogenolytic effect of α-adrenergic agonists depends on intracellular calcium but those of vasopressin and angiotensin II on extracellular calcium, and support the concept that calcium antagonistic drugs inhibit the glycogenolytic effects of calcium-dependent hormones at least by inhibiting the mobilization of calcium ion from cellular pools.

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Six patients with Cushing's disease and three with Cushing's syndrome due to an adrenal adenoma were monitored after their adenomectomy with the corticotropin-releasing hormone test to evaluate the progress of recovery of their pituitary adrenal function. Before surgery the patients with Cushing's disease showed either high, normal or low responses of plasma ACTH and cortisol to 100μg synthetic ovine corticotropin-releasing hormone (CRH) administered intravenously, whereas all three patients with Cushing's syndrome due to an adrenal adenoma showed no response of plasma ACTH or cortisol to CRH.
One or two months after surgery, the patients who had Cushing's disease had low levels of basal plasma ACTH and cortisol and their responses to CRH were extremely low. However, the same patients were tested later, it was found that their responses to CRH gradually increased and reached normal ranges approximately within one year after tumor removal, which coincided with the overall improvement in their clinical signs and symptoms due to adrenal insufficiency.
In contrast, the recovery of the pituitary adrenal function in patients who had Cushing's syndrome due to an adrenal adenoma was not complete even one year after surgery.
Thus the corticotropin-releasing factor test is a useful criteria to evaluate the recovery of the pituitary adrenal function in these patients after surgery, since the responses of plasma ACTH and cortisol to the administered CRH are parallel with the improvements in clinical signs and symptoms due to adrenal insufficiency in patients with Cushing's disease.

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The effects of microelectrophoretic applications of neurotransmitter substances and their antagonists on the activity of paraventricular oxytocinergic neurones were studied in urethane anesthetized lactating rats. Oxytocinergic neurones were identified by their antidromic response to the stimulation of the neurohypophysis and by their characteristic high frequency discharge of action potentials approximately 15-20 s before reflex milk ejection. Acetylcholine (ACh) excited the majority (75%) of paraventricular oxytocinergic neurones, and none of the cells was inhibited in its activity by ACh. In about half of the oxytocinergic cells, atropine and hexamethonium reduced the number of action potentials during the burst discharge preceding reflex milk ejection. Noradrenaline (NE), dopamine (DA) and serotonin (5-HT) reduced the activity of most (75-100%) of oxytocinergic neurones, and none of the cells was excited by these catecholamines. These results suggest that paraventricular oxytocinergic neurones receive excitatory cholinergic inputs and inhibitory noradrenergic, dopaminergic and serotonergic inputs.

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In order to investigate the changes in testicular volumes (TV) and salivary testosterone concentrations (ST) in normal male infants aged from birth to one year, TV in 158 and ST in 61 infants were measured cross-sectionally during this period. ST of normal male adolescents in Tanner's pubic hair stage from P2 to P5 (n=20) were also measured as the control. To clarify the relationship between remarkable height increase and testosterone (T) during early male infancy, longitudinal follow-up of 10 male infants (4 from birth to 4 months, 6 from birth to 7 months) were also carried out by simultaneous measurement of ST and crown-heel length. Maximum TV (ml) was observed at 1-4 months (1.7±0.6)(mean±SD) and was significantly higher than the values at birth (0.5± 0.1, P<0.01) and at 6-12 months of age (1.4±0.4, P<0.01). Maximum ST (ng/dl) was also observed at 1-4 months, with the mean value being 3.4±1.5, which was significantly higher than 1.9±0.8 at 6-12 months (P<0.01). The ST at four month was not significantly different from that at Tanner's pubic hair stage P2. The longitudinal study showed that the rise in ST was concomitant with the maximum increase in crown-heel length at 1-4 months. The fluctuations in ST and height increase were also apparently synchronous during the first year.

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The binding nature of mibolerone in cytosols and nuclear extracts from hypertrophic human prostate was examined in comparison with that of R 1881. The binding of mibolerone in the cytosol and nuclear extract was single and of high affinity when evaluated by the method of Scatchard (1949). Binding of mibolerone with testosterone-binding globulin was not detected. The sedimentation coefficients of the binder for mibolerone in the cytosol and nuclear extract were 10.6S and 3.6S, respectively.
When triamcinolone acetonide was induced in the binding medium, inhibition of mibolerone binding in the cytosol by testosterone and dihydrotestosterone was potentiated and this may imply that the binding observed in the presence of triamcinolone acetonide was responsible for the binding of the androgen roceptor. In the nuclear extract, the binding was attributable mainly to the androgen receptor irrespective of the presence or absence of triamcinolone acetonide. These properties of the binding observed in the hypertrophic human prostate were almost same as those of the binding with R 1881. Although maximum binding sites measured using mibolerone were correlated with those using R 1881 in the cytosols as well as in the nuclear extracts, the values obtained with mibolerone were slightly greater than those with R 1881.
Thus, mibolerone seems to be a suitable ligand for measuring the androgen receptor, but when compared with R 1881 no special merits in using mibolerone were detected.

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Serum luteinizing hormone (LH) and prolactin (PRL) concentrations were measured in young (3-4 month old) and middle-aged (10-12 month old) intact female rats on proestrus, in ovariectomized rats after two estrogen injections (estradiol benzoate; EB, 10μg/100g body weight, s. c.) or after preoptic stimulation in EB-primed ovariectomized rats. Only animals showing regular 4-day estrous cycles were selected for the experiment. The magnitude of proestrous LH surge was significantly smaller in middle-aged than in young rats. Two BE injections, at noon on Days 0 and 3, in ovariectomized middle-aged rats failed to induce surges in LH secretion on Day 4 whereas the same treatment produced LH surges in ovariectomized young rats. The preoptic electrochemical stimulation (50μA for 60 sec) produced a prompt rise in serum LH levels in ovariectomized EB-primed young but not in middle aged rats. The preoptic stimulation with a larger current (200μA) induced LH secretin in middle-aged rats. In none of these situations serum PRL concentrations were different between young and middle-age rats. These results suggest differential aging rates in the preoptic mechanisms governing LH and PRL secretion in the rat. The function of the preoptic ovulatory center in responding to the estrogen positive feedback action and inducing LH secretion may become impaired and independent of the PRL control mechanism, even before the regular estrous cycle terminates.

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Serial modifications of Bottenstein and Sato' serum-free hormone-supplemented medium resulted in a new promising medium (1: 1 mixture of L15 and MCDB 104 containing several supplements) for culturing neonatal rat brain cells. This medium favored the morphological and biochemical differentiation of the neurons, i ncluding particular types of cholinergic and cholinoceptive neurons, obtained enzymatically from the septum, preoptic area, and hypothalamus. On the other hand, the growth of non-neuronal cells was markedly suppressed in this medium. Therefore, their effects on the neurons are minimized in this culture. Effects of triiodothyronine (T₃) and estradiol (E₂) on the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), synthetic and degradative enzymes for acetylcholine, respectively, were examined in this culture. The optimal concentrations of T₃ and E₂ for AChE activity were around 1nM and 10pM, respectively. However, E₂ appeared to be somewhat inhibitory at higher concentrations. Although the activity of ChAT was maximum around 10pM of E₂, the ChAT activity increased as the concentration of T₃ wasi ncreased to 100nM.

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In the present study, we used an explant culture system of the human decidual tissues involving a new sampling method for investigating the productivity of immunoreactive prolactin (IR-PRL) for a 5 day period in labored and nonlabored deliveries. The maximal release of IR-PRL in the incubation medium for each 24 hour interval was achieved from the 2nd to the 3rd day of culture in both groups, which was 145.2±14.0ng/ml/10mg w.w.(mean± s.e.; n=7) in the labor group and 101.5±16.3ng/ml/10 mg w.w.(mean±s.e.; n=4) in the nonlabor group. The release of IR-PRL in both groups was not significantly different for the first 3 days. However, the amount of IR-PRL released in the nonlabor group was 50 to 70% of that of the labor group. The tissue content of IR-PRL in both groups ranged between 3.0 and 5.0ng/ml/10mg w.w. From these results, it was concluded that 1) our explant culture system for the human decidual tissues produced considerably more IR-PRL than those previously reported and 2) productivity of IR-PRL was lower in nonlabored delivery than in labored delivery and 3) since the tissue content of IR-PRL for each 24 hour interval was very small, it should be strongly emphasized that the production and release of IR-PRL takes place simultaneously in the human decidual tissues.

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A case of Graves' disease with high serum thyroxine (T4) and low triiodothyronine (T3) levels which was therefore initially diagnosed as a T4-thyrotoxicosis is reported.
Examination of the serum from the patient showed the presence of unusual protein which bound T3. It was later confirmed as IgG class anti-T3 antibodies. In addition to treatment with methylmercaptoimidazole (MMI), the patient was treated with prednisolone for 30 days (total amount 500mg). Titers of and-T3 antibodies in the sera were unchanged before and after prednisolone treatment.
Our present case indicates that it is clinically important to bear the presence of autoantibodies in mind to account for a possible error in measuring T3 and T4 by radioimmunoassay (RIA). In the case that RIA determination gives an unexpectedly high or low T3 and/or T4 value, the presence of autoantibodies to them should be considered and a test for them is recommended.

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A 26-yr-old female with primary hypothyroidism due to potent blocking type thyrotropin binding inhibitor immunoglobulins (TBII) was advised of the high risk of bearing a baby with neonatal transient hypothyroidism. This prediction proved valid and her baby was found to be hypothyroid with a potent TBII.
By expressing the baby's TBII as the absolute concentration, we found an almost linear regression of TBII and the half-life was calculated as 18.0 days. The TBII became undetectable by the 6th month and thyroid medicatio was stopped, however the baby remained euthyroid with subsequent normal physical and mental development.

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