Dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the serum of normal subjects and in patients with various endocrine diseases and hypertension by the modifying photometric assay method described by T. Nagatsu.
The mean serum DBH activity in 22 hyperthyroidism (mean ±s.e. = 10.2 ±1.1 I.U.), 6 primary aldosteronism (11.3 ±2.0), 11 Cushing syndrome (19.3 ±2.5), 13 essential hypertension (14.5 ±2.1) and 7 renovascular hypertension (20.0 ±6.4) was lower than in 52 normal subjects (28.1 ±1.7), while the serum DBH activity in 20 hypothyroidism (37.4 ±4.1), 3 pheochromocytoma (83.0 ±3.5) and 3 adrenal insufficiency (54.3 ±18.5) was higher than in normal subjects.
Serum DBH activity was negatively correlated with T₃-resin sponge uptake and T₄ levels in normal subjects and those thyroid disorders. Serum DBH activity increased after treatment with methimazole in 14 cases of hyperthyroidism, while it decreased after treatment with thyroxine in 6 cases of hypothyroidism. No diurnal variations were observed on the serum DBH activity in 13 normal subjects, 11 subjects with Cushing syndrome and 2 patients with adrenal insufficiency, while the serum DBH activity at 0 : 00, 6 : 00, 12 : 00 and 18 : 00 was negatively correlated with serum cortisol levels. Serum DBH activity increased after adrenalectomy in 11 patients with Cushing syndrome. The administration of DOCA resulted in a decrease of serum DBH activity in a patient with Addison's disease. Serum DBH activity was negatively correlated with the ratio of measured blood volume to predicted blood volume in 20 patients with these diseases.
The serum DBH activity in patients with increased circulating blood volume, such as in hyperthyroidism and primary aldosteronism, was lower than in normal subjects, while patients with decreased circulating blood volume, such as in hypothyroidism and adrenal insufficiency, showed higher serum DBH activity than normal subjects. These results indicate that serum DBH activity, is closely related to circulating blood volume. It is suggested that the serum DBH activity in these diseases represents sympathetic nerve activity responding to changes in the circulating blood volume.

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In order to clarify the correlation between serum levels of thyroid hormone and prolactin response to the thyrotropin-releasing hormone (TRH), untreated hyperthyroidism with diffuse goiter, euthyroid hyperthyroidism with PTU and primary hypothyroidism were employed. Group A (n=7) was untreated hyperthyroidism with mean values of 15.6 ± 0.5μg/ 100ml (T₄) and 467.7 ± 80.4ng/100ml (T₃); Group B (n=5) was PTU treated hyperthyroidism in euthyroid state within 6 months, with 9.3 ± 0.6μg/100ml (T₄) and 174.0 ± 16.1ng/ 100ml (T₃); Group C (n=10) consisted of subjects similar to those in group B with 1-2 yrs of euthyroidism, with 8.7 ± 1.4μg/100ml (T₄) and 146.2 ± 19.1ng/100ml (T₃); Group D consisted of subjects similar to those in groups B and C with a euthyroid state over 2 yrs, with 9.0 ± 0.5μg/100ml (T₄) and 122.8 ± 7.1ng/100ml (T₃) (n=13); Group E (n=8) was primary hypothyroidism before any treatment with 3.3 ± 0.4μg/100ml (T₄) and 51.0 ± 6.6 ng/100ml (T₃). Serum values of the thyroid hormones (T₄ and T₃) fell from group A to group E, and in each group, thyroid hormone levels in serum were considered to be in a relatively constant range over a long term.
Serum levels of TSH, PRL and T₃ were determined following a 500μg TRH injection in all groups. Although dissociation between PRL and TSH responses to the TRH provocation was seen in some groups, it seemed that both responses were inversely augmented according to the decrease of serum thyroid hormone levels. Therefore, statistical analyses were performed to elucidate the correlation between the levels of T₄, T₃ and the maximum level of PRL to the TRH injection. These results clearly indicated that maximum PRL response was in a hyperbola correlation with both thyroid hormones (T₃ and T₄).

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We described before measurement of plasma oxytocin levels by a specific and sensitive radioimmunoassay method.
Plasma oxytocin concentrations, measured in 111 pregnant patients, were 6.1 ± 1.9 pg/ml in the first trimester (0-16 weeks), 14.7 ± 7.3pg/ml in the second trimester (17-28 weeks), 28.4 ± 14.5pg/ml in the third trimester (29 weeks -), 29.8 ± 7.1pg/ml in the first stage of labor and 33.1 ± 12.1pg/ml in the third stage of labor, respectively. The levels increased during pregnancy and labor and decreased to 18.7 ± 9.0pg/ml on the second day and to 4.3 ± 2.7pg/ml on the seventh day after labor. The levels increased from 3.7 ± 1.7 pg/ml to 6.2 ± 3.7pg/ml during lactation.
In 42 women, 24 labors at term were induced by the intravenous administration of prostaglandin F_2α. The plasma oxytocin levels were increased from 18.3 ± 9.6pg/ml to 24.4 ± 9.3pg/ml in cases of successful induction delivery and from 12.3 ± 3.2pg/ml to 19.7 ± 12.0pg/ml in unsuccessful cases by a 90 minute infusion of prostaglandin F_2α.
The correlation coefficient (r) between the elevated levels of plasma oxytocin and the administered doses during the 90 minute infusion of prostaglandin F_2α was 0.4355 (P<0.05).
From the results described above, it may be assumed that oxytocin plays an important role in spontaneous labor.

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Numerous reports concerning the mechanism by which pituitary gonadotropin and prolactin are released by prostaglandins (μg) have been made since the experimental work of Orczyk & Behrman et al (1972). Nonetheless, it is still uncertain whether the location of this effect is in the hypothalamus, higher centers or in the pituitary gland.
In this paper, we report an investigation of the effects of μgE₂ on the vaginal smear in rats and observation of central nervous system changes based upon the recording of multiple unit activity (MUA). Furthermore, we have measured the effects of μgE₂ on these locations by determining the amounts of gonadotropin and prolactin in the blood and the pituitary gland.
Experiment I. First we observed the changes in the vaginal smear following a single subcutaneous injection of 10μg, 100μg or 500μg of μgE₂ in the DI period of mature, female Wistar strain rats undergoing normal 4 day (reproductive) cycles. Almost no changes were seen in the groups injected with 10μg or 100μg of μgE₂, but in the 500μg group, all animals showed disorder. From these results, we concluded that the 500μg μgE₂ subcutaneous injection had some sort of effect upon the rat's endocrine environment.
Experiment II. MUA recording electrodes were stereotaxically placed following the brain atlas of Albe-Fessard et al (1966) under the administration of Nembutal (anesthesia). After more than 2 weeks following the stereotaxy and after ascertaining that the normal reproductive cycle had recurred at least twice, 500μg of μgE₂ was administered in a single dose at 2 P.M. during the DI period, and the changes in the MUA of the medial preoptic area (MPO) and the medial amygdala (m-AMYG) were observed. A remarkable decrease in the level of activity at both locations was seen approximately 10 minutes after the μgE₂ administration, and this low level was maintained for approximately 60 minutes. These results were clearly due to the effects of the μgE₂ administration and indicate distinct changes in the electrical activity of the MPO and m-AMYG.
Experiment III. The rats having been castrated, 3 to 5 weeks later 500μg or 1000μg of μgE₂ was subcutaneously injected in a single dose following pretreatment with 100μg of estradiol benzoate and 10mg of progesterone. Blood samples were obtained by decapitation from both groups 10, 30 and 60 minutes later, and simultaneously the adenohypophysis was excised. Radioimmunoassay was performed using the method of Monroe et al (1968). Blood LH was found to have increased significantly 10 minutes after the administration of 500μg of μgE₂, returning to a resting level after 30 to 60 minutes. Significant changes in FSH levels were not found in either the blood or the pituitary. Blood prolactin increased significantly 10 minutes after the administration of a large dose of μgE₂ (1000μg) and showed a significantly high level after 30 minutes. By contrast, pituitary prolactin decreased significantly 10 minutes after the administration of 1000μg of μgE₂ and returned to a resting level after 30 to 60 minutes.
From the above experiments, it is apparent that there are notable similarities between the MUA rhythm patterns of the MPO and m-AMYG and the pattern of changes of LH and prolactin in the blood and pituitary following μgE₂ administration. It has been previously suggested that the release mechanism of gonadotropin and prolactin by μgE₂ works by way of LHRH, PIF and PRF. From the results we have obtained in this experiment, it is indicated that gonadotropin and prolactin secretions are enhanced by the action of LHRH, PIF and PRF on the higher nerve centers, the medial preoptic area and the medial amygdala.

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Ninety-one autopsy cases without overt thyroid disease were studied histologically and compared with serum anti-thyroid antibodies in relation to their histological findings.
The thyroid was divided into 16-20 serial slices 4-5mm thick. Each slice was sectioned into a 2.5μ thickness for microscopic observation, and the sections were stained with hematoxylin-and-eosin.
The following results were obtained :
Blood samples were obtained from the right atrium of the heart of each of the autopsy cases. The serum was then separated by centrifugation and stored at - 20°C until the assay. Anti-thyroglobulin and thyroid-microsomal antibodies were measured by the tanned red cell hemagglutination technique, using commercially available kits (Thyroid test and Microsome test, Fujizoki Pharmaceutical Co. Ltd., Tokyo). A serial four-fold dilution of an original 1 : 20 or more was regarded as positive.
The following results were obtained :
1) Of the 91 autopsy cases, 16 cases had lymphocytic infiltration in their thyroids. The incidence of cases with lymphocytic infiltration of the thyroid was two times as high in the females as it was in the males.
2) 16 cases had anti-thyroid antibodies (12 with MCHA, 2 with TGHA, 2 with MCHA and TGHA).
3) 13 of the 16 cases with lymphocytic infiltration had antithyroid antibodies; thus the correlation between lymphocytic infiltration and positive antibodies was highly significant at P<0.001.
4) Changes in follicular epithelium were more frequently observed among the cases with lymphocytic infiltration of moderate degree than among those of slight degree. Titer of antibodies was higher in cases with a moderate infiltration than it was in those with a slight infiltration.
5) Of the 91 cases examined, 40 cases had histological findings such as lymphocytic infiltration, benign tumor (adenoma) and metastatic as well as primary cancer, including 10 (11.0%) of small carcinoma (sclerosing carcinoma).
6) Some conditions (such as diabetes mellitus, cirrhosis of the liver etc.) which were regarded as common complications of Hashimoto's thyroiditis were not often found among the cases with lymphocytic infiltration.
From these results it was suggested that the cases having positive serum antithyroid antibodies and lymphocytic infiltration of their thyroids were subclinical types of auto-immune thyroiditis.

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Angiotensin II analogue (AIIA), 1-sarcosine, 8-isoleucine angiotensin II (Sar¹, Ile⁸-AII), was given in a graded dose to patients with adrenal hypofunction of various etiologies, and the blood pressure response to AIIA was observed to investigate the role of the renin-angiotensin system for the maintenance of blood pressure in the state of adrenal insufficiency.
An agonistic pressor response to AIIA was observed in the control subjects without adrenal hypofunction. In contrast with this, patients with Addison's disease showed a blood pressure fall to AIIA. When the test was repeated on the same patients after hydrocortisone replacement, these patients showed a neutral or pressor response.
Three patients with adrenalectomy and hydrocortisone replacement showed a pressor response to AIIA in a supine position. When these patients were tilted, fall in blood pressure to AIIA was observed in two of them who had been on a regular diet, whereas one patient who had been on a high sodium diet showed no fall in blood pressure with this procedure.
We concluded that the renin-angiotensin system plays an important role in the maintenance of normal or subnormal blood pressure in Addison's disease and in the postural change of adrenalectomized patients on hydrocortisone and regular salt intake. The response of blood pressure to AIIA may be a clue for the diagnosis of Addison's disease and the evaluation of the adequacy of replacement therapy with regard to these patients.

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A large dose of hydrocortisone has a protective effect in hemorrhagic and endotoxin shock. In recent years there has been considerable discussion suggesting that the release of catecholamines. may be the first step in the chain of events in shock. On the other hand, a large dose of hydrocortisone may inhibit the release of catecholamines, and this effect of hydrocortisone may be attributed to the inhibition of a calcium ion influx across the cell membrane.
The present experiments were performed in order to determine whether acetylcholine- and histamine-induced catecholamine release is effected by hydrocortisone and calcium ion in bovine adrenal medullary slices or not. The results were as follows :
1. Acetylcholine or histamine increased catecholamine release from the adrenal medullary slices.
2. The stimulatory effect of acetylcholine or histamine was inhibited by the addition of hydrocortisone.
3. The inhibitory effect of hydrocortisone was proportionally reversed by the increasing amount of added calcium ion in the media.
From the above results, it is suggested that hydrocortisone inhibits catecholamine release from the adrenal medullary slices and that the effect of hydrocortisone is due to a blocking of the transfer of calcium ion into the cells.

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The general radioimmunoassay (RIA) currently employed for the determination of serum HPL requires a special apparatus and a complicated technique. Therefore, in order to simplify the assay we tried to develop a new method using single radial immunodiffusion (SRID).
Basic examinations were made to establish a simplified HPL assay method by SRID. The optimal conditions finally decided for SRID were as follows : the thickness of the agar plate, 1.5mm; the diameter of the well, 3mm; the amount of antigen added, 10μl; antibody concentration, 1.0% for the measurement range from 1.0μg/ml to 16μg/ml and 0.5% for the measurement range from 0.25μg/ml to 1.0pg/ml.
Under these conditions serum HPL was detectable after the 9th week of gestation, and antigen was measurable over 0.25μg/ml. Serum HPL values measured by RIA and SRID from the 9th to the 42nd week of gestation in 138 normal pregnant women were identical, and the correlation was highly significant (r=0.842, p<0.001)
This SRID method was as reliable and sensitive as the RIA and made it easier than the RIA to measure the serum HPL of pregnant women. Therefore, with regard to placental function its clinical application should prove to be certainly beneficial.

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This study was performed to examine the oncogenic action of streptozotocin on the endocrine pancreas in male Wistar rats and to clarify physiologic responses in the course of and after the tumor induction. In addition, induced tumors were examined histologically and measurements of pancreatic hormones in tumors were done using radioimmunoassay.
Young male Wistar rats were injected intravenously with 65mg/kg of streptozotocin alone, or with streptozotocin, 65mg/kg, preceded by 15 min. by a single intraperitoneal injection of nicotinamide, 500mg/kg, or of picolinamide, 250mg/kg. The administration of streptozotocin alone resulted in gross intolerance to glucose with flat and depressed plasma insulin response, whereas the diabetogenic action of the nitrosourea compound was partially prevented by pretreatment with nicotinamide or picolinamide. Although those animals pretreated with nicotinamide or picolinamide did not show any signs of overt diabetes, slightly abnormal glucose tolerance was found one week after treatment.
Serial oral glucose tolerance tests in rats treated with streptozotocin and nicotinamide showed that the elevation of blood glucose levels after glucose loading was depressed significantly 7 months after treatment. Plasma insulin responses were distinctly elevated 9 months following treatment. The mean insulinogenic index increased from 0.34 at one week after treatment to 1.01 at the 5th month and was 1.65 and 2.87 at 7 and 9 months following treatment, respectively. These results suggest that islet cell tumors had already been induced within 7 months. Induced neoplasms were capable of secreting large amounts of insulin 9 months following the injection.
Nine to 26 months after the various treatment schedules, 110 pancreatic islet cell tumors were induced in 11 out of 19 (58%), in 25 out of 30 (83%), and in 13 out of 16 rats (81%) treated with streptozotocin alone, or with streptozotocin and nicotinamide or picolinamide. Blood glucose levels - less than 100mg/100ml even after glucose load -were low, and plasma insulin levels rose markedly following glucose load in tumor-bearing rats. Thus, insulinogenic responses were much greater as compared to those of tumor-free rats. No significant difference was observed among the rats with tumors induced by streptozotocin alone, or by streptozotocin with nicotinamide or picolinamide with regard to their blood glucose and plasma insulin responses to an oral glucose load. These findings suggest that pancreatic islet cell tumors induced by streptozotocin with and without nicotinamide or picolinamide are insulin-secreting, and that streptozotocin itself has oncogenic effects on the rat endocrine pancreas.
While pancreatic tissue from tumor-free rats contained 14 U/g wet weight of insulin, mean insulin concentrations in islet cell tumors amounted to 401 U/g wet weight, indicating that insulin-secreting tumors induced by streptozotocin have large stores of insulin. In addition, pancreatic glucagon was demonstrated immunochemically in some tumors, suggesting that these neoplasms consisted of at least more than one type of pancreatic endocrine cell.
Pancreatic islet cell tumors measuring up to 0.9cm were round, well-delineated, and were frequently observed in the splenic segment. They had a thin fibrous capsule and their cells stained, in general, with aldehyde-fuchsin. Ultrastructurally, most tumors examined consisted of granulated B cells, although the number of secretory granules appeared to be less than that of non-neoplastic B cells. The units of rough-surfaced endoplasmic reticulum appeared prominent. Cells whose secretory granules were similar to those of pancreatic A cells were encountered, while those characteristics of D cells were not encountered in the tumors examined.
Neither macroscopic nor microscopic abnormalities were observed in livers of tumor-bearing rats.

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