Organic exposure to various forms of stress creates a mechanism of adjustment to maintain the changes of internal environment to the minimum and to secure a rapid resumption which comes into operation for the homeostatic adaptation. The autonomic nervous system does seem to play a major role in such a mechanism. It is of our interest to assess the reaction of the organism through urinaty excretion of catecholamines during an induced disturbance of the equilibrium of the autonomic nervous system.
When adrenaline was loaded in patients with various diseases, urinary excretion of adrenaline increased by approximately 2% of the administered dose, while noradrenaline administration resulted in the urinary excretion of 1.3% of the administered noradrenaline. In each case, no significant correlation was noted between such increases in urinary excretion and renal function tested by PSP excretion or liver funotion by BSP retention. Urinary excretion of catecholamine appeared not to be affected by the hepatic and renal dysfunction, but to reflect blood catecholamine level approximately.
Urinary excretion of noradrenaline had decreased after adreanline loading. A significant correlation was seen between the absolute value of the decrease in urinary excretion of noradrenaline and urinary noradrenaline excretion before adrenaline administration (r=0.90), probably indicating a compensation mechanism of the adrenaline action for the sympathetic discharge.
A positive correlation was found between the increase in urinary excretion of noradrenaline upon noradrenaline administration and the level of urinary excretion of noradrenaline of control period (r=0.71). Urinary excertion of adrenaline also increased upon noradrenaline administration, showing a positive correlation with adrenaline excretion before noradrenaline administration (r =0.75).
Such increase in urinary excretion of adrenaline and decrease in urinary excretion of noradrenaline upon adrenaline administration as well as inverase in urinary excretion of both adrenaline and noradrenaline upon noradrenaline administration were also seen in experiments in rabbits. Noradrenaline loading in reserpinized rabbits also resulted in increases in urinary excretion of adrenaline and noradrenaline to the same extent as in control rabbits receiving noradrenaline alone. Increase in urinary excretion of adrenaline upon noradrenaline administration probably indicates the synthesis of adrenaline in vivo from the administered noradrenaline.
In order to see what happens to the catecholamine secretion, the parasympathomimetic agent such as pilocarpine or neostigmine was administered into the patients with thyrotoxicosis and atrial septal defect as well as the normal subjects, because urinary excretion of catecholamine has been found to increase in these patients. The urinary excretion of catecholamine increased remarkably in thyrotoxicosis but less significantly in atrial septal defect and normal subjects, while the administration of atropine, parasympatholytic agents, caused a decrease in urinary excretion of catecholamine proportional to its previous urinary level. Administration of neostigmine in rabbits caused a significant increase in urinary excretion of catecholamine. However, pretreatment with hexamethonium bromide resulted in an inhibition of the effect of neostigmine administration. From these results, it was presumed that the increase in urinary excretion of catecholamine upon administration of the parasympathomimetic agent is based upon the excitation of the sympathetic nervous system.

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Organic exposure to various forms of stress creates a mechanism of adjustment to maintain the changes of internal environment to the minimum and to secure a rapid resumption which comes into operation for the homeostatic adaptation. The autonomic nervous system does seem to play a major role in such a mechanism. It is of our interest to assess the reaction of the organism through urinary excretion of catecholamines during an induced disturbance of the equilibrium of the autonomic nervous system.
When adrenaline was loaded in patients with various diseases, urinary excretion of adrenaline increased by approximately 2% of the administered dose, while noradrenaline administration resulted in the urinary excretion of 1.3% of the administered noradrenaline. In each case, no significant correlation was noted between such increases in urinary excretion and renal function tested by PSP excretion or liver function by BSP retention. Urinary excretion of catecholamine appeared not to be affected by the hepatic and renal dysfunction, but to reflect blood catecholamine level approximately.
Urinary excretion of noradrenaline had decreased after adreanaline loading. A significant correlation was seen between the absolute value of the decrease in urinary excretion of noradrenaline and urinary noradrenaline excretion before adrenaline administration (r=0.90), probably indicating a compensation mechanism of the adrenaline action for the sympathetic discharge.
A positive correlation was found between the increase in urinary excretion of noradrenaline upon noradrenaline administration and the level of urinary excretion of noradrenaline of control period (r=0.71). Urinary excertion of adrenaline also increased upon noradrenaline administration, showing a positive correlation with adrenaline excretion before noradrenaline administration (r =0.75).
Such increase in urinary excretion of adrenaline and decrease in urinary excretion of noradrenaline upon adrenaline administration as well as inverase in urinary excretion of both adrenaline and noradrenaline upon noradrenaline administration were also seen in experiments in rabbits. Noradrenaline loading in reserpinized rabbits also resulted in increases in urinary excretion of adrenaline and noradrenaline to the same extent as in control rabbits receiving noradrenaline alone. Increase in urinary excretion of adrenaline upon noradrenaline administration probably indicates the synthesis of adrenaline in vivo from the administered noradrenaline.
In order to see what happens to the catecholamine secretion, the parasympathomimetic agent such as pilocarpine or neostigmine was administered into the patients with thyrotoxicosis and atrial septal defect as well as the normal subjects, because urinary excretion of catecholamine has been found to increase in these patients. The urinary excretion of catecholamine increased remarkably in thyrotoxicosis but less significantly in atrial septal defect and normal subjects, while the administration of atropine, parasympatholytic agents, caused a decrease in urinary excretion of catecholamine proportional to its previous urinary level. Administration of neostigmine in rabbits caused a significant increase in urinary excretion of catecholamine. However, pretreatment with hexamethonium bromide resulted in an inhibition of the effect of neostigmine administration. From these results, it was presumed that the increase in urinary excretion of catecholamine upon administration of the parasympathomimetic agent is based upon the excitation of the sympathe-tic nervous system.

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Recently, many synthetic progestine were reported to be useful for clinical purposes And many of these drugs are effective in both oral and subcutaneous administration, Progesterone, which is natural progestin, however, is inactive when administered orally, The inactivation of orally administered progesterone has been supposed to be due to the ring A reduction of progesterone in the liver. But the metabolism of orally administered progesterone has not yet been well analyzed.
In this experiment, metabolism of peogestserone was studied in three groups of Clauberg rabbits.
1. 3H-Progesterone was administered subcutaneously.
2. 3H-Progesterone was administered orally.
3. 3H-Progesterone subcutaneously and 14C-progesterone orally were administered.
After extraction of free steroid with chloroform (free fraction), the urine was hydorlyzed with β-glucuronidase and extracted with chloroform (glucuronide fraction). The urine was further hydrolyzed with HCl on the boiling water bath and extracted with chloroform (sulfate fraction). These chloroform extracts were washed with NaOH and water, and evaporated. The extracts were combined and the combined extract was adsorbed on alumina with benzene and eluted stepwise with different concentrations of methanol in benzene. Each 10 ml effluent was collected and the radioactivity was counted.
In this experiment the following results were obtained.
1. No marked difference in the distribution of excreted radioactivities in each of free, glucuronide and sulfate fraction bitween Group 1 and 2 was observed.
2. In Group 3, similar 3H/14C ratio was observed in each of free, glucuronide and sulfate fraction.
3. Column chromatography revealed three radioactive peaks. The elution pattern of radioactivities from the column in Group 1 was similar to that in Group 2.
4. In Group 3, no marked difference in the 3H/14C ratio of the three radioactive peaks was observed.
5. One of the urinary metabolite was identified as 20c&-hydroxypregn-4-ene-3-one by paper chromatography, acetylation, deacetylation, chromic acid oxidation and recrystalization.
6. 20α-hydroxypregn-4-ene-3-one was excreted in urine as glucuronide and the radioactivities were counted as 3-4% of the administered doses.
7. In Group 3, urinary excretion of 14C was faster than that of 3H.
8. Experiment with blood, after administration of radioactive progeaterone, revealed that the ratio of radioactivities incorporated into free fraction to the conjugated fraction was 23 times greater in Group 1 than in Group 2.
These results indicate that, in the Clauberg rabbit, the glucuronidation of C-20 reduced matabolite of progesterone, in addition to the ring A reduction, plays a significant role in the inactivation of progesterone in vivo.

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ACTH was assayed by the measurement of corticosterone in the adrenal venous plasma after the intravenous administration of test materials into the hypophysectomized rats whose right adrenal glands had been extirpated one week before. This method gave linearity of response to log doses of ACTH ranging from 0.03 to 1.0 milliunits (mU), with precision index (λ) of 0.32, enabling to detect 0.6 mU per 100 ml of plasma ACTH when a dose of 5 ml of plasma was injected.
1) Plasma from 5 normal subjects was found to contain ACTH in levels less than 0.6 mU per 100 ml. The oxycellulose technic was applied to extract ACTH from about 100 ml blood from 5 normal subjects in preparation for a biological assay, which revealed a mean ACTH level of 0.04 mU per 100 ml of blood. (96% fiducial range, 0.023-0.063 mU/100 ml of blood.) Four patients with Cushing's syndrome due to adrenal cortical hyperplasia and 2 patients with the same syndrome due to adrenal cortical adenoma failed to show elevated plasma ACTH levels. Similarly, no ACTH was detected in 7 patients with abnormal pigmentation and 9 of 10 patients with hyperthyroidism. Seven patients with adrenogenital syndrome had elevated ACTH levels ranging from 0.6 to 5.7 mU per 100 ml of plasma (mean±standard error (S.E.), 1.6±0.8 mU/100 ml of plasma.) In 10 patients with Addison's disease, plasma ACTH ranged from 0.9 to 93.8 mU per 100 ml (mean±S.E., 13.8±9.5 mU/100 ml of plasma.)
2) The elevated level of ACTH found in patients with adrenogenital syndrome and Addison's disease was significantly reduced by the oral administration of glucocorticoids, whereas aldosterone and desoxycorticosterone had no significant suppresive effect. One of the anabolic steroids, i.e. 2-hydroxymethylene-17α-methyl dihydrotestosterone (HMD), and testosterone had no effect on plasma ACTH levels, either.

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Plasma ACTH was determined by a modification of the method of Lipscomb and Nelson (femoral method) but, in some cases, test materials were injected into the aorta (aortic method).
1) After the oral administration of SU-4885, 3.0 g. per one day, plasma ACTH rose to a mean±standard error (S.E.), 1.6±0.4 mU/100 ml, ranging from 0.6 to 4.0 mU per 100 ml. in 9 endocrinologically normal subjects. In 5 patients after long-term steroid treatments plasma ACTH was not detectable except in one case. All 5 patients with anorexia nervosa had distinctly elevated ACTH levels after the administration of SU-4885. Two of 5 patients with anorexia nervosa showed more than normal rises both in plasma ACTH and in urinary 17-OHCS excretion. In 2 patients with Cushing's syndrome due to adrenal cortical hyperplasia no detectable ACTH in plasma was found, whereas one patient with Cushing's syndrome due to adrenal cortical adenoma had an elevated ACTH level after the administration of SU-4885, who showed good response to ACTH. However, no ACTH was detected in one unilaterally adrenalectomized patient for a adrenal cortical adenoma, even 2 years after an operation. Elevated ACTH levels were also noted in one patient with liver cirrhosis and one patient with Laurence-Moon-Biedle's syndrome. Generally, the elevated plasma ACTH levels were associated with high values of urinary 17-OHCS excretion, although there were several exceptional cases.
2) In 8 of 13 patients undergoing a major operation, such as laparotomy or thoracotomy, plasmas obtained one hour after the incision were found to have elevated ACTH levels ranging from 0.6 to 19.1 mU per 100 ml of plasma, which returned toward nondetectable levels within 24 hours postoperatively with the exception of one case. It was noted that increases in plasma ACTH occurred coincident with elevations in plasma cortisol when both were measured simultaneously in 6 cases. Plasma from two schizophrenic patients receiving electroconvulsive therapy was found to contain elevated ACTH levels.
3) The normal diurnal rhythm of plasma ACTH, that is, the rise in the early morning and the decline in the evening was noted in normal subjects, whereas it was absent in patients with Cushing's syndrome due to adrenal cortical hyperplasia. On the other hand, 4 patients : wiht adrenogenital syndrome and 10 patients with Addison's disease maintained the diurnal variation, showing greater differences than normal subjects between plasma ACTH levels in the early morning and those in the evening.

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After 2 I.U. of ACTH preparations (Organon) being quickly administered intravenously into 3 patients without renal, hepatic and metabolic dysfunctions (normal subjects), 3 patients with hyperthyroidism, 3 patients with hypothyroidism, 2 patients with hepatic diseases and 2 patients with uremia, blood samples were withdrawn 2, 5, 10, 20 and 30 minutes after the end of ACTH administration. Plasma ACTH was measured by a ra-dioimmunoassay using salt-precipitation technique, after having been extracted with the acid-alcohol method. In some of the cases, plasma ACTH was estimated by a modification of the method of Lipscomb and Nelson at a couple of time-points after the ACTH injection. The mean immunological half-life of exogenous ACTH in blood was about 14 minutes in normal subjects, about 33 min. in uremic patients, about 31 min. in patients with hypothyroidism, about 16 min. and 14 min. in patients with hyperthyroidism and hepatic disease, respectively. Therefore, there seemed to be a tendency that immunological half-lives of ACTH were longer in patients with hypothyroidism and uremia than in other cases. In most of the cases, the immunological half-life was longer than the biological one, especially in patients with thyroid disorders. When the biological ACTH level was compared with the immunological one, the former was noticed to be several to 20 times higher than the latter in value. The difference became more remarkable, as time elapsed after the end of ACTH administration.
These data suggest that there remained in the blood stream fragments of ACTH which had lost biological activities but still retained immunological activities.

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