Electron microscopic studies were made on the morphological changes of mitochondria of the adrenal cortex of young and mature rats under various experimental conditions : administration of ACTH, DOCA, chorionic gonadotrophin and KC1 with accompanying decrease in Na/K ratio, removal of hypophysis, etc. Correlation between the ultrastructure of the adrenal cortex and its function was sought.
1) Mitochondria can be classified into two types according to the structure of the internal membrane : type I with the internal membrane possessing crista-like or filament-like structure and type II with the internal membrane of honeycomb-like structure. The former is mainly found in the zona glomerulosa and the latter in the zona fasciculata and reticularis. As the rat matures or as hyperfunction of the adrenal cortex develops, the type I mitochondria become more complex in structure with the protruding structure of the internal membrane forming a fine network. The type 1 mitochondria are transformed into type II. When hyperfunction of the adrenal cortex persists, the limiting membrane of mitochondria breaks and the internal structures of mitochondria come into contact with the endoplasmic reticulum surrounding the mitochondria.
2) The structure of mitochondria in the zona glomerulosa is altered when either the Na/K ratio is lowered or DOCA is administered. A similar change can be observed with the adminisiration of ACTH or by hypophysectomy. The function of the zona glomerulosa, therefore, seems to be under the influence of the alteration of the Na/K ratio as well as the function of the hypophysis, though to a lesser extent.
3) With the administration of chorionic gonadotrophin, a tubular structure appears in the type II mitochondria in the inner layer of the zona fasciculata and in the outer layer of the zona reticularis. This structure, after six weeks administration of chorionic gonadotrophin, changes into a vacuolar structure.
These changes in the mitochondria differ from those seen after the administration of ACTH, e.g., disappearance of the fine structure in the internal membrane of the type II mitochondria in the outer layer of the zona fasciculata and opening of the limiting membrane.

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The regulation of pituitary-thyroidal function through the central nervous system has been the subject of many studies, most of them dealing with the hypothalamus. The limbic system has been known to play an important role in autonomic nervous regulation, and recent studies at several laboratories have revealed that this part of the brain has an intimate relation to corticotropic and gonadotropic secretion.
The effect of electrical stimulation of the posterior orbital surface on pituitary-adrenocortical function has been reported from our laboratory.
With respect to the secretion of TSH, however, a definite relationship has not been established. Yamada and Greer reported that bilateral destruction of amygdaloid nuclear complex had little effect on PTU induced goitrogenic action. In this paper the effect of electrical stimulation of the limbic system on the pituitary-thyroidal function in dogs is reported.
Stimulation of the amygdaloid nuclear complex, the posterior orbital surface and the hippocamp formation was induced in morphine anesthetized dogs which had been previously labelled with I¹³¹.
In each of four cases in which the posterior orbital surface and the amygdaloid nuclear complex were stimulated, there was no significant increase in the concentration of PBI¹³¹ and inorganic I¹³¹ in the thyroid venous blood.
In 10 cases in which the hippocampal formation was stimulated, a definite increase in both of organic and inorganic I¹³¹ in the thyroid venous blood was observed with no significant change in the thyroid venous blood flow. Significant increase in the TSH content of the jugular vein blood, assayed in 4 animals by McKenzie's method, occurred in all cases within 30 minutes. Hypophysectomy prevented the response of the thyroid to hippocampal stimulation.

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Part 1. The metabolic effects of thyroxine analogues in the hypothyroid subjects ; A dissociation of various effects of analogues.
L-thyroxine, L-triiodothyronine, D-triiodothyronine and four compounds of triiodothyroformic acid group were administrated in increasing doses to hypothyroid patients, and one gouty patient was administrated D-triiodothyronine or triiodothyropropionic acid.1. The administration of L-thyroxine and L-triiodothyronine to myxedematous patients did not result in a marked dissociation in the decrease in serum cholesterol level and the increase basal metabolic rate.
2. In elevating the basal metabolic rate, D-triiodothyronine is approximately from 17 to 33 percent as active as L-thyroxine, acetyl triiodothyroformic acid is only from 0.1 to 0.4 percent as active as L-thyroxine, and each effect of triiodothyroformic acid, amide of triiodothyroformic acid and its methyl ester are less than from 0.1 to 0.2 percent, from 0.5 to 1.0 percent and from 0.1 to 0.2 percent of L-thyroxine.
3. It seemed that D-triiodothyronine and triiodothyroformic acid group were more effective in reducing the serum cholesterol than in increasing the basal metabolic rate. It is interesting to note that this dissociation was marked in triiodothyroformic acid group.
4. The administration of acetyl triiodothyroformic acid on hypothyroid subjects resulted in a decrease of serum uric acid and in an increase of urinary excretion of uric acid, and produced a negative phosphorus balance. In one gouty patient, a decrease of serum uric acid and an increase of urinary excretion of uric acid were observed over three months by the administration of D-triiodothyronine or triiodothyropropionic acid.
5. The rate of disappearance of triiodothyroformic acid group from the blood of hypothyroid patients was observed as half time of protein bound iodine after the cessation of chronic administration. The half time of protein bound iodine were 2.9 days for triiodothyroformic acid, 2.0 and 2.4 days for acetyl triiodothyroformic acid, 8.8 days for its amide and 4.5 days for methyl ester.
Part 2. The hypocholesterolemic effect of D-thyroxine and acetyl triiodothyroformic acid on euthyroid hypercholesterolemic patients.
D-thyroxine or acetyl triiodothyroformic acid were administrated to the ten euthyroid hypercholesterolemic patients respectively.
1. The administration of 4 mg. daily of D-thyroxine to ten euthyroid subjects produced a little elevation of basal metabolic rate. It seemed that the administration of less than 4 mg. daily of D-thyroxine failed to sustain the decreased serum cholesterol level in one or two weeks.
2. In administering 4 mg. daily of D-thyroxine, the elevation of protein bound iodine level was slight but thyroidal radioiodine uptake was markedly inhibited.
3. The administration ranging from 25 to 60 mg. daily of acetyl triiodothyroformic acid in ten euthyroid hypercholesterolemic patients produced rapid reduction of serum lipids without significant elevation of basal metabolic rate. In spite of the increase of doses, it seemed to return gradually to its pre-treatment value.
4. The administration of relatively large doses, as much as 60 mg. daily of acetyl triiodothyroformic acid from the beginning was able to produce the reduction in serum cholesterol level without significant elevation of basal metabolic rate continuously for more than three months. At present, therefore, it seems that acetyl triiodothyroformic acid is the most potent hypocholesterolemic agents among thyroxine analogues.
5. A high protein bound iodine and marked inhibition of thyroidal radioiodine uptake were observed by the administration of acetyl triiodothyroformic acid.

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It has been well established that catecholamine excretion in urine increases after insulin administration ; and the reduction of blood sugar below the normal range is considered to be the stimulant of catecholamine secretion. However, the hypoglycemic syndrome is occasionally encountered under insulin treatment of diabetics even when the blood sugar remains within normal range, and it is reasonably assumed that there is an increased discharge of catecholamine under such a condition. In this report, the relation between blood sugar variation and the excretion of catecholamine was analysed in normal subjects and patients with various severities of diabetes mellitus. The mechanism of increasement of catecholamine excretion was also investigated. The results were as follows :
1) The folds of increment in catecholamine excretion after the intravenous administration of insulin of 0.1 unit/kg to normal or diabetic subjects is significantly well correlated with the value represented as the following equation ;
(blood sugar before administration) / (minimum blood sugar value) (blood sugar before administration) x (minutes from adm. to minimum)
2) The transient increase of urinary catecholamine metabolites such as Metanephrine or Vanillylmandelic acid is observed in the early period of the treatment of diabetics with insulin or antidiabetic sulfonylurea.
3) The data was obtained in animal experiments, suggesting that the adaptation of the central nervous system to hypoglycemic state is the cause of the increased excretion of catecholamine observed in diabetics when the blood sugar remains within normal range after insulin administration.

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1) Fecal excretion of thyroxine increased greatly when young rats were fed powdered cellulose, barium sulfate or clay, added to the basal diet and then injected with I¹³¹-thyroxine.
2) A significant decrease in the thyroidal uptake of I¹³¹ occurred in 4 days. After 2 months on these diets, marked decreases in the weights of the thyroid glands and in I¹³¹ uptake, as well as degenerative atrophy of the thyroid glands were noted in the histologic picture. No changes were noted in other endocrine glands.
3) The inhibitory effects on the thyroid of the cellulose diet increased in a cold environment, and decreased in a warm environment. No inhibitory effect was noted in adult rats. The inhibitory effects appear to be based on thyroid hormone deficiency.
4) The inhibitory effects on the thyroid could not be observed when PTU or iodide was added to the cellulose diet. The inhibitory effects on the thyroid were noted when cellulose was added to a low iodine diet.
5) The formation of goiter occurred when excess iodide was added to the cellulose diet in a warm environment.
6) No significant difference in the rate of body weight increase was observed between the cellulose and control groups during the first 2 months, but after.2 months a decrease in the rate of body weight was noted in the cellulose groups as compared to the control groups.
7) After 2 months of cellulose diet an increase in thyroxine degradation rate was determined from the results of I¹³¹ excretion rate in urine and I¹³¹ distribution in the body after I¹³¹-thyroxine administration.
8) A decrease in the PBI and an increase in the T₃-erythrocyte uptake was noted after 2 months of cellulose diet ; after 6 months we noted a decrease in both.
9) The classic feed-back theory states that the activity of the centers regulating thyroidal function is controlled by the level of circulating thyroid hormone. This theory makes it difficult to explain our data and so we have theorized that the activity of the centers regulating thyroidal function is controlled by the degradation rate of thyroid hormone in peripheral tissues.

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The long-acting thyroid stimulator (L.A.T.S.) was distinguished from the thyrotropin by its prolonged action to release I¹³¹ from the thyroid in an assay for TSH. However, it is still questionable whether or not L.A.T.S. has really long-acting activity to stimulate the thyroid function. In this study the following experiments were carried out to clarify this problem. Hyperthyroid serum containing a high concentration of L.A.T.S. was injected intravenously to the mice every day for nine days and the thyroidal function was examined on the fourth day after the final injection. As controls, thyrotropin, normal human serum or saline solution were injected to mice in the same manner. In the first experiment thyroxine was not given to the mice, but in the second experiment thyroxine was injected subcutaneously six times every other day from the first injection of L.A.T.S. and control materials to supress the secretion of thyrotropin. The activity of TSH was measured by the Noguchi modification of McKenzie's method and the thyroidal function was examined by I¹³¹ uptake rate, conversion ratio and PBI¹³¹ (% dose per liter) at 24 hours after injection of I¹³¹. The metabolic course of iodine in the thyroid gland was observed by paper chromatography, and the histologicol changes studied by autopy.
The results are shown in Table 1, 2 and Fig. 1. The thyroidal function of mice receiving the injection of L.A.T.S. was more strongly activated than that of control animals when the feed-back mechanism of thyroid-pituitary was supressed by thyroxine injection. However, in the first experiment (in which mice did not receive thyroxine) there was not a significant difference in the thyroidal function between the mice which were injected with L.A.T.S. or control meterials because the level of TSH in the circulating blood was controlled by the endgenous thyrotropin secretion even though L.A.T.S. has prolonged activity. The histologic structure of the thyroid in mice which receivid L.A.T.S. and thyroxine was significantly different from that of control animals : acinal cell height increased and its plasma was clear just as commonly observed at the part of papillary proliferation of acinal cells in hyperthyroidism. However, when thyroxine was not given these specific findings were not observed.

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