The recent progress in the field of investigation of hypothalamic pituitary adrenal system is remarkable, and many reports concerning the experimental and clinical use of preparations of adrenocortical inhibitors have been published. The most widely accepted of these prreparations is SU-4885 (Metopirone, or Metyrapon.) It has the unique property of selectively inhibiting 11-β hydroxylation inthe biosynthesis of the three main corticosteroids : Cortisol, Corticosterone, & Aldosterone.
The present study was undertaken to clarify the relationship between plasma ACTH activity and Plsama 17-0HCS after oral administration of SU-4885 Materials & Methods
Eleven patients were studied. None of them had received exgenous steroid previously. Cardiovascular hepatic, and renal studies were estivated to be within normal limits in all of them. Daily 24-hour specimens of urine were collected (6 : 00 A.M. to 6 : 00 A.M.) throughout a week, analyzed for urinary 17-0HCS by the method of Peterson modified Glenn-Nelson's. SU-4885 was administered orally in a dose of 750 mg. every 4 hours 5 times. (6 A.M., 10 A.M., 2PM., 4P.M., 6P.M., 10P.M.).
No side-effects were observed during such admininistration. Blood samples were collected during every SU-4885 administration period, and Plasma 17-0HCS was measured by Rudd's method. Estimation of plasma ACTH activity was performed using the method of Arimura modified Lipscomb-Nelson's Results & Discussion
Minimum effective concentration of plasma ACTH-activity measured by Arimura's method was 0, 7 mU/d1 in human blood. Plasma ACTH-Activity at 6 : 00 A.M. starting SU-4885 administration was detectable, (0.7 to 0.9 mU/dl) in 7 patients and non-dettecable in 4 patients. Plasma 17-OHCS measured simultaneously was 8.6 to 13.7, e μg / dl. in blood. As 10 : 00 A.M., plasma ACTH activity was detectable (1.0 to 1.6 mU/dl.) in all patients and plasma 17-0HCS was slightly decreased in 8 patients, stationary in one, and slightly inereased in 2 (range 7.7 to 12.0 μg dl.). The decrease might suggest that the deppression of steroid-biosynthesis by SU-4885 had occurred transiently.
Plasma ACTH activity at 2 : 00 P.M. was 1 : 2 to 1.5 mU/dl., 1.2 to 1.7 mU/dl at 6 : 00 P.M., and 1.0 to 1.6 mU/dl. at 10 : 00 P.M.
Plasma 17-0HCS levels had gradually increased : 14.9 to 23.0 μg/dl. at 2 : 00 P.M., 20.1 to 26.6 μg/dl. at 6 : 00 P.M. and 25.1 to 32.5 μg/dl. at 10 : 00 P.M.
Pituitary ACTH discharge or secretion following the administration of SU-4885 is presumably caused through negative feedback mechanism triggered by the decrease in the level of plasma cortisol and another mechanism might exist in pitultary ACTH discharge or secretion following surgical intervention.
As corollaries to this postulate, it is inferred that SU-4885-test is useful diagnostic adjunct for estimation of pituitary reserve, but it does not necessarily demonstrate pituitary adrenocortical response following surgical intervention.

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The deiodination of thyroxine has been studied with radioactive iodinated thyroxine. The labeling of 3, 5 positions of the molecule is so difficult that only commercially available radiothyroxine is labeled with ¹³¹I at its 3', 5' positions. Therefore, the metabolism of iodines of 3, 5 positions remains to be clarified.
The present study was designed to prepare the doubly labeled thyroxine by mixing individually prepared 3', 5'-¹²⁵I-thyroxine and 3, 5-¹³¹I-thyroxine and to investigate its metabolism.
3, '5'-¹²⁵I-thyroxine was prepared by a new exchange labeling method. In this procedure, Na¹²⁵I was oxidized to ¹²⁵I₂ by HCl and H₂O₂ in a small test tube. The resultant ¹²⁵I₂ was extracted with ethyl ether followed by adding thyroxine in 50% ethanol buffered solution (pH 5.0), in which the exchange reaction took place. The yield was approximately 75%. The specific activity of the labeled thyroxine was 1 mCi/mg.
The same method of labeling was also applied successfully to the preparation of 3, 5-¹³¹I-diiodotyrosine which was a starting material of 3, 5-¹³¹I-thyroxine.
3, 5-¹³¹I-thyroxine was chemically synthesized employing the micro scale coupling reaction of Shiba & Cahnmann with DIHPPA and 3, 5-¹³¹I-diiodotyrosine. The product was purified by paperchromatography. The specific activity of the labeled product was 600-800μCi/mg.
Both labeled thyroxines were identified by paperchromatography in three different solvents, high voltage paperelectrophoresis and multiple recrystalizations.
The radioactivity of ¹²⁵I and ¹³¹I was separately measured by a well-type scintillation counter with two γ-ray spectrometers which were set for γ-ray photopeaks of ¹²⁵I and ¹³¹I, respectively.
The deiodination of the doubly labeled radio-thyroxine in homogenates and slices of rat tissues (liver, kindey, muscle, hypophysis and brain) was examined. In all cases the deiodination of 3', 5' positions were more rapid than those of 3, 5 positions.
Significant deiodinations of 3, 5 positions, as well as 3', 5' positions, occurred by exposing to ultra violet of a sterilamp but both deiodinations were inhibited when 5×10^-5M thio-uracil, 50% propylene glycohol or 50% human serum were added.
After intravenous administration of the doubly labeled radiothyroxine to rats, urinary excretion of ¹²⁵I was almost parallel with that of ¹³¹I. Paperelectrophoresis proved that 90-95% of the radioactivity was inorganic iodine. Bile was cellected continuously by a biliary fistula. ¹³¹I appeared in bile a little more than¹²⁵I and ¹²⁵I/¹³¹I ratio was 0.86.Paperelectrophoresis proved that 93-97% of the radioactivity was organic iodide.
Iodide compounds in the butanol extract were analyzed with two dimensional paper-chromatography. To simplify the identification, a method of determing the ratio of numbers of indine atoms of 3', 5'positions and those of 3, 5 positions from the ratio of ¹²⁵I and ¹³¹I of the spot on the paper was devised. With this method, the existence of the glucuronide of reverse triiodothyronine in bile suggested by Flock et al. was confirmed.

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Studies were made on the effects of administration of dehydroepiandrosterone (DHA) and cortisol (COL) on the weight of body, bone and muscle, and several organs in noraml and adrenalectomized female rats. As a preliminary experiment DHA was given to several groups of normal and ovariectomized female albino rats for about 2 weeks, and the body weight gain and weight of organs were determined. An Occasional and relativelyslight increase of body weight gain was observed as the result of DHA treatment in these groups.
In the second series of experiments, female Wistar strain rats (litter-sisters) were divided into six gorups. Bilaterally total adrenalectomy was performed in 5 groups under ether anesthesia, and one per cent saline and food were supplied ad libitum. Of these adrenalectomized groups, three groups were given daily injections of desoxycorticosterone acetate (DOC) and treated with either DHA, or COL, or the combination of DHA and COL. The remaining there groups served as controls, i.e. adrenalectomized control groups treated with or without DOC, and a non-adrenalectomized normal control group.
Body weight was daily measured. Animals were killed by exanguination under ether anesthesia, and autopsy was performed. The liver, kidney, heart, brain preputial gland and other organs were removed and weighed. After the removal of the intestinal organs, the skin and fat were removed from the muscles. The skeleton with muscles and the skin with fat were weighed, respectively, and then dried at 100°C for 48 hrs, and weithed again. Results obtained were as follows;
(1) The body weight gain was found on the average to be 41.4 67.2, 51.6, 53.6, 18.2, and 44.8g for the groups treated with (1) DOC alone, (2) DOC + DHA, (4) DOC + DHA + COL, (5) with no steroid, and (6) for non-adrenalectomized rats, respectively. Wet and dried weights of the skeleton with muscles were 89.6 (27.0), 98.8 (30.2) 90.6 (27.8), 94.4 (29.3), 65, 2 (20.1), and 91.8 (28.6) g for the groups, respectively (Figure in parentheses means dried weight of the tissue.). Administration of DHA to adrenalectomized female rats did induce an increase in body weight and in weight of both wet and dried carcasses.
(2) Absolute weitht of the liver and the weight ratio of the liver to body were found to be 8.64 (5.47), 11.06 (6.37), 8.84 (5.50), 11.25 (6.65), 5.30 (4.16), and 9.56 g) (5.89g%) for the groups described, respectively (The weithg ratio is in parentheses.). Hypertrophy of the liver is greatest in DHA- and DHA-COL-treated groups.
(3) The weight of the kidney was higher in the DHA-treated group than in controls. No significant weight gain of the heart and brain was observed.
(4) The weights of preputial glands with or without contents were 80 (59), 135 (88), 92 (64), 169 (107), 62 (43), and 108 (78) mg for the groups, respectively (Figure in parentheses means the weight without contents.). DHA induced a remarkable hypertrophy of the preputial gland and an increase of the contents. It would seem that COL acts on the hypertrophy of the tissue synergistically with DHA in adrenalectomized animal.
(5) The myotrophic activity of DHA on the m. levator ani of castrated male rat was observed to be about 37.4% of that of testosterone propionate (TP), and DHA has about 1.7% of the activity of TP on the rat accessory sex organ.
(6) Effects of DHA on growth, on protein metabolism in the liver, and on sexual behavior in the female were discussed.

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Urinary excretion of aldosterone was measured (since 1963) by the modified method. of Neher & ¥'Vettstein, in 10 patients with myasthenia gravis including 2 cases of fulminant form, 4 cases of generalized form and 4 cases of ocular form.
The normal range of aldosterone values was 2.2 to 11.2 μg/day (average : 5.5±2.2 μg/day) in 8 healthy adults, and the total recovery was 55.0 to 59.3% (average : 57.7%) with the addition of 30 μg of d-aldosterone free in 900 c.c. of boiled urine, and the average value of paper blank was 0.025±0.002.
A slight to moderate increase of urinary excretion of aldosterone was observed during the period “with” extremity weakness in 6 patients of fulminant form or generalized form, and then the value decreased to normal limits during the period “without” extremity weakness in 4 cases of 6 patients, whose muscle weakness was diminished by anticholinesterase therapy. In 4 cases of ocular form, however, aldosterone excretion was constantly within normal range.
The increase of sodium to potassium ratio in urine was also observed during the period “without” muscle weakness. No significant difference between both periods in the urinary excretion of 17-ketosteroids, 17-hydroxycorticosteroids and catecholamines was observed.
Transient hyperaldosteronuria, occuring during the period “with” extremity weakness in myasthenia gravis, might be explained by the following findings; 1) the abnormality in neuromuscular transmission with changes of intracellular electrolytes, wihch was considered to be one of the etiologic factors of myasthenia, 2) the occurence of clinically obvious muscle weakness with slight changes of mineralocortiocid activity, 3) the effectiveness of aldosterone antagonists and KCL tablets in this disease, notwithstanding normal electrolytes in serum, 4) the decrease of intracellular potassium caused by aldosterone, if potas-sium depletion was to occur in muscle tissue, 5) the inhibitory effect of aldosterone on acetylcholine in vitro.
The significance of the relation of the demonstrated hyperaldosteronuria, which may be secondary, in myasthenia gravis (of fulminant or generalized form), to the basic disorder in this desease is not yet apparent.

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In order to study the hypothalamo-pituitary adrenocortical response to stress stimuli, an increase of plasma 11-OHCS during insulin induced hypoglycemia was determined by De Moor's method and the result was compared with that of metopirone test in 4 control subjects and 69 patients with miscellaneous endocrine diseases.
(1) 2 cases out of 13 patients with pituitary chromophobe adenoma and 3 cases out of 23 patients with operated chromophobe adenoma showed no response to hypoglycemia. And also in craniopharyngiomas, one case among 5 patients before operation and one among 5 post operated patients failed to respond to hypoglycemia. Therefore, the pituitary adrenocortical response in insulin induced hypoglycemia was not affected unless hypothalamo-pituitary system was impared severely, while metopirone test was most sensitive for the detection of defects in ACTH secretion throughout the hypothalamo-pituitary system and was very effective to detect even slight disturbances in pituitary ACTH reserve, though it represents only one aspect of the reserve. Therefore, it is suggested that this “insulin stress” test may be taken as a true measure of total ACTH reserve.
(2) In 5 acromegalies, 2 cases associated with moderate hyperthyroidism and treated with ¹³¹I did not respond either to hypoglycemic stress or to metopirone. And in 5 thyrotoxic patients including 2 cases with a aromegaly previously described, only those 2 cases showed no response. Accordingly, coexistence of both the disease seemed to cause the failure of response to hypoglycemia.
(3) 5 cases among 6 patients with Cushing's syndrome showed no response to insulin induced hypoglycemia and one case poorly responded. And this effect was independent of the initial value of plasma 11-OHCS. As 3 cases with adrenal hyperplasia had nor-mal or subnormal response to Metopirone, this absent response to hypoglycemia may be due to the inability of hypothalamo-pituitary system to synthesize and secrete endogenous ACTH immediately in emergency. On the other hand, 3 cases with adrenal adenoma did not respond either to Metopirone or to hypolgycemia. This mechadism is perhaps referred to the inhibitory effect of endogenous corticosteroids from adenoma for hypothalmo-pituitary system to secrete endogenous ACTH.
(4) This “insulin stress” test is easy to perform and almost free from hazardous trouble. And consequently, it is very effective to detect the disturbances of total pituitary ACTH reserve. Protection from stressful stimuli and prophylactic administration of corticosteroids are recommended for the patients who have no response or disturbed response to insulin induced hypoglycemia.

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n the patients with cervical cancer undergoing extensive panhysterectomy, the effects of anabolic steroid on the protein metabolism following operation were observed. Thirty cases treated in our clinic were studied in this investigation. The intake and output of nitrogen were estimated exactly for 14 days after operation. Furthermore, protein patterns, nitrogen, creatinine and electrolytes in serum were measured pre- and postoperatively. The results were as follows :
1) Methenolone enanthate (ME) given on the first day after operation reduced the extent of the post-operative negative nitrogen balance significantly. Also, the shortening of catabolic phase compared with the control group was observed.
2) Amino acids preparation given for 3 days after operation did not cause any significance in the decrease nitrogen output or in the increase of nitrogen balance. This suggested that most of the amino acid preparations that were given were excreted without utilization ofprotein metabolism.
3) The group given ME plus amino acids preparation at the early postoperative period also indicated a significant decrease of nitrogen excretion and a significant increase of nitrogen balance. It seemed that anabolic steroid accelerated metabolic utilization of given amino acid preparations.
4) Higher doses of anabolic agents (ME + Methenolne acetate) given preoperatively were more effective in the decrease of nitrogen excretion and in the increase of nitrogen balance than that of other groups.
5) Administration of anabolic steroid and/or amino acid preparations did not cause in the serum protein patterns, serum creatinine and serum electrolytes followin operation.
6) Changes in NPN, amino-N and urea-N suggested that these steroids had anabolic effect on the protein metabolism.
7) Recovery of body weight was maintained by the administration of anabolic steroid. Water and sodium retention were not observed through the postoperative period in all groups.
8) No clinical side effects were observed in all cases administered with anabolic steroid.
From these results, the author concluded that the administration of anabolic steroid in preoperative or early postoperative period was effective on the protein metabolism following extensive panhysterectomy in the patients with cervical cancer.

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This part dealt with the study of the effects of anabolic steroid on the protein metabolism in the patients with cervical cancer treated by radiation therapy. Twenty cases as anabolic steroid group and 15 cases as control group were used in this investigation. All cases received 3200-4000 rad of telecobalt and 6000mg of Radium in total doses. The anabolic steroid (AS) group was given Methenolone enanthate 100mg per week or 19-Nortestosterone furylpropionate 25mg per 3 days from the beginning of the radiation course. The daily intake and output of nitrogen were estimated exactly before and during radiation therapy. Moreover, protein patterns, nitrogen, electrolytes in serum and body weight were measured at the same time.
The results were as follows :
1) Before the radiation therapy, well nourished patients with cervical cancer (more than 60g of protein intake per day) showed positive nitrogen balance of 3-7g/day.
2) ⁶⁰Co irradiation caused a decrease in the intake of nitrogen and a drop in the nitrogen balance. Therefore, in some patients of the control group, slight negative nitrogen balance occurred soon after starting the telecobalt therapy.
3) In the AS group the decreasing rate of nitrogen intake was much less than that in the control group. The alteration of nitrogen balance compared with that in pre-radiation period was minimum.
4) Thereafter, on proceeding with telecobalt therapy, the nitrogen intake and the nitrogen balance approached, slightly and slowly, the pre-radiation levels.
5) In Radium therapy following⁶⁰Co irradiation, the intake of nitrogen decreased again and the nitrogen balance remarkably tended to be lower in the control group.
6) In the AS group the extent of nitrogen balance was much more than that in the control group during all courses of telecobalt and Radium therapy.
7) Body weight in the control group showed about 5% decrease at the end of radiation therapy, but in the AS group it increased slightly and gradually.
8) Slight decrease in the total protein and albumin was observed during radiation therapy in the control group. The AS group did not show any significant change.
9) Serum amino-N and urea-N in the AS group were both lower than those in the control group through radiation therapy.
10) Changes in concentration of serum sodium and chloride were not remarkably obserbed, but in potassium, the AS group showed a slightly lower level than the control group.
The author concluded that anabolic steroid was useful for the protection of catabolism in the patients with cervical cancer during radiation therapy.

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