Research preceding clinical use of drugs aims at the best possible prediction of the effects in man. In the case of anabolic steroids the predictive value of the levator ani assay appears to be satisfactory, and the precision of the figures obtained to be high. Experimental data are presented demonstrating that the results found in the same test with the same substances may be very different depending on the criterium used and the route and frequency of administration.

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For the determination of pregnanediol and pregnanetriol in urine two hydrolytic procedures have been applied :
(1) The enzymatic method involved treatment of the urine with β-glucuronidase and extraction with chloroform to give what is termed as the glucuronide fraction.
(2) Continuous extraction with chloroform at pH 0.7 was carried out to give what is termed as the sulfate fraction.
The principal results of our investigations are summarized as follows :
(a) Pregnanediol is excreted to a variable and often quantitatively important extent as a conjugate which may be hydrolyzed under conditions known to cleave sulfates.
(b) Pregnanetriol may be satisfactorily estimated after treatment of urine with β-glucuronidase alone.

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The genetic, morophologic, and metabolic features of hereditary obese-hyperglycemic mice, strain C 57 BL/6 J-ob mice, have been well described by Dr. Jean Mayer et al.
The present investigations were carried out in vitro for the purpose of extending the past finding. The results obtained are as follows :
1) Serum insulin-like activity of young OH mice increased markedly, but in older OH mice it decreased, more or less, lower than the level in their controls.
2) Glucose output by liver slice of OH mice was similar to those of their control mice when expressed per wet gram of liver. But the total liver function of adult OH mice was concluded to be approximately twice that of their control mice.
3) Epididymal adipose tissue from OH mice utilized less glucose than that of their control mice already in young age and the similar inclination was also found in older age. This was true in the absence of added insulin and in the presence of various doses of insulin. However, the sensitivity to insulin did not appear to be grossly disturbed.
4) Glucose uptake by diaphragm from young OH mice was at normal level, but decreased glucose uptake was found when old OH mice were used. The sensitivity to insulin was normal.
5) Release of NEFA from liver slice and diaphragm of young OH mice waf similar to those of their control mice, but decreased NEFA release was found when old OH mice were used.
6). Release of NEFA from epididymal adipose tissue of young OH mice was smaller than that obserbed in epididymal adipose tissue obtained from their control mice, but in fed status NEFA release from epididymal adipose tissue of OH mice was significantly greater than that of their control mice.
7) When the mice were exposed to cold at 4-5°C for 6-8 hours, release of NEFA from epididymal adipose tissue of OH mice was significantly lower than that observed in their control mice.

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Studies were made on the nature of blood composition, glucose output by liver slice, glucose uptake by isolated diaphragm and epidiymal adipose tissue and NEFA release from various tissues. Effects of insulin on glucose uptake by isolated tissue were also tested. Swiss albino mice were used as controls.
The results obtained are as follow :
1) Blood sugar level, serum cholesterol level, serum total fatty acid level and serum NEFA level increased with age.
2) Serum insulin-like activity of young mice was normal, but increased markedly in older mice.
3) Liver glucose output and liver glucose-6-phosphatase activity per wet gram of liver showed the same values with those of their control mice and of NZO mice, but the glucose-6-phosphatase activity in fasted NZO mice was significantly higher than that of their control mice. The liver phosphorylase activity per wet gram of liver was much greater than that of control mice. The total liver function of adult NZO mice was concluded to be approximately twice that of their control mice. This presumption is only due to the fact that NZO mice have livers weighing about two times that of their control mice.
4) Glucose uptake by diaphragm and epididymal adipose tissue from young mice were similar to those of their control mice, but decreased glucose uptake by diaphragm and epididymal adipose tissue were found in older mice.
5) Rate of NEFA release from liver slice and diaphragm behaved in va very similar manner with that of control mice. Release of NEFA from epididymal adipose tissue of young NZO mice was also similar to that of their of control mice, but the small reduction of NEFA release was shown when old NZO mice were used.

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The effects of some hormones upon NEFA release from liver slice, diaphragm and epididymal adipose tissue were investigated. Each tissue of the Hereditary Obese-hyperglycemic Mice (C 57/6J-ob, OH) and New Zealand Obese Mice (NZO) were incubated with hormones in the medium of Krebs-Ringer Bicarbonate buffer containing 3% bovine albumin and 5% Ediol (Emultion of 50% coconut oil).
The results obtained are as follow :
1) Effects of epinephrine and norepinephrine on NEFA release from liver slice and diaphragm were similar to those of their control mice.
2) Epididymal adipose tissue from OH mice exhibited an impairment in its ability to release NEFA when incubated with epinephrine, norepinephrine and ACTH. The inhibitory action of insulin and glucose on NEFA release was also less marked in epididymal adipose tissue from OH mice than in their control mice. However, this abnormality was not found in tissue from NZO mice.
Decrease sensitivity to those hormones on NEFA release from OH mice in vitro may be one of the metabolic abnormalities in this type of hyperglycemic obesity.

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The changes of androgen output in the spermatic vein blood of anesthetized dogs were analyzed by gas chromatography following FSH and LH (HCG) administration. A definite increase of testosterone and DHEA was seen following LH administration. No significant increase of androst-4-ene-3, 17-dione was demonstrated, contrary to our expectation.
³H-testosterone as well as H³-DHEA was also isolated from the spermatic vein blood following the infusion of 7-³H-pregnenolone through the spermatic artery in the LH treated dog.The ¹⁴C incorporation into DHEA, pregnenolone, testosterone and 17α-OH-pregnenolone from the spermatic vein blood was significantly higher when compared to those into progesterone and 17α-OH-progesterone following the infusion of 4-¹⁴C-cholesterol through the spermatic artery in the LH treated dog.
These findings support the view that DHEA is a important intermediate in the biosynthesis of testicular testosterone in vivo, at least in the presence of abundant LH.

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The tracer doses of tritiated aldosterone and tritiated or carbon-14 cortisol were injected intravenously in 10 cases with liver cirrhosis, 2 cases with acute hepatitis, a case with chronic hepatitis, 4 cases with hyperthyroidism, 3 cases with hypothyroidism and a case with cancer of the prostate. Daily secretion rate, mean plasma concentration, speed of metabolism, metabolic clearance rate, volume of distribution space and miscible pool of aldosterone and cortisol were calculated in these patients using two compartmental models of human body, discribed by Tait et al. Urinary metabolites of these radioactive steroid hormones were also estimated.
1) In all patients with liver cirrhosis, the delayed metabolism of cortisol and aldosterone was shown. Increased daily secretion rate, mean plasma concentration and miscible pool were found in most but not all patients with liver cirrhosis. The secretion rate of cortisol decreased in all cases with lirver cirrhosis. There were some changes in the metabolism of aldosterone and cortisol in patients with liver cirrhosis compared with normal subjects. Increased urinary excretion of free fraction of cortisol and aldosterone, and 3-oxo-conjugate of aldosterone and elevated tetrahydrocortisol/ tetrahydrocortisone ratio were found, while glucuronide fractions of these hormones in urine were decreased in patients with liver cirrhosis. These results suggest that there is decreased conversion to metabolites conjugated with grucuronic acid and reduced reaction of 11, β-hydroxylation in patients with liver cirrhosis.
2) In acute hepatitis, slightly delayed metabolism of cortisol and aldosterone was observed, but in chronic hepatitis, no significant changes in metabolism of these hormones compared with that in normal control, were obtained.
3) In hyperthyroidism, the speed of metabolism of cortisol was higher than normal controls. However, these values for aldosterone were slightly elevated. Urinary free fraction of cortisol was reduced, but metabolites conjugated with glucuronic acid were increased. The ratio of tetrahydrocortisol/tetrahydrocortisone in urine was decreased.
4) In hypothyroidism, the daily secretion rate of cortisol and aldosterone was decreased, but mean plasma concentration of these hormones was within normal range or slightly elevated, while metabolic clearance rate or speed of metabolism of these hormones was markedly decreased. Urinary free faction of these hormones was increased. Tetrahydrocortisol/tetrahydrocortisone ratio in urine was elevated. These results suggest that thyroid hormone accelarates the metabolism of these steroid hormones, and that it may play some role in the activation of 11 β-hydroxysteroid dehydrogenase in liver.
5) On the administration of estrogens, delayed metabolism of cortisol and aldosterone was observed. Mean plasma concentration of these steroid hormones was markedly elevated.

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For decades it has been postulated that hormonal inbalance is a major factor in tumorigenesis in the target organ. The regression of breast cancer induced by oophorectomy has been attributed to the removal of ovarian hormones in which estrogens play a important role. It is also known that the adrenal cortex secrete an amount of estrogen. These findings led to the conclusion that oophorectomy and adrenalectomy should be recommended for advanced breast cancer in man. In addition, there are extensive experimental data suggesting that pituitary hormones also lead to mammary tumors.
Recently, it has been established that adrenalectomy and oophorectomy, or hypophysectomy can induce prolonged regression of advanced breast cancer in 50 percent of patients. About 50 patients with advanced breast cancer received bilateral total adrenalectomy and oophorectomy in our clinic, 50 per-cent of these patients had remissions during more than 1 month and 40 per cent during more than 6 months. The average period of remission was 13.4 months. This operative procedure was effective because the mean survival time of remitted patients was 20.3 months compared with 2.3 months in non-remitted patients. Nearly half of the patients thus treated were benefited however, the rest had no remission.
If the effectiveness of this procedure could be predicted for each patient, unncessary major surgery would be avoided for those patients who obtained no remission. Moreover, even among remitted patients who had a relapse after one year or so, the exact mechanism of the relapse remains obscure.
The purpose of this paper is to put forward a working hypothesis in the hope that further investigation may lead to an anticipation of the effectiveness of surgery and an understanding of the exact mechanism of relapse. Several anterior pituitary functions before and after bilateral total adrenalectomy and oophorectomy were studied.
Urinary excretion of prolactin was determined by pigeon crop-sac method, urinary excretion of gonadotrophin was determined by chemical assay and bio-assay (mouse uterine weight method), serum sulfation factor was determined by ALMQVIST's method, and blood ACTH activity was estimated by adrenal ascorbic acid depletion method in hypophysectomized rat.
The summary of results was as followed :
1) No increase of excretion of prolactin, gonadotrophin and growth hormone was observed in patients with breast cancer.
2) No excess excretion of ACTH was observed in the adrectomized and oophorectomized patients with advanced breast cancer when they were maintained with adequate administration of steroid. No increase of excretion of prolactin, gonadotrophin and growth hormone was also observed in these patients.
3) There was no correlation between efficiency of surgery and the urinary excretion of prolactin and gonadotrophin. Therefore, it was impossible to anticipate the response of adrenalectomy and oophorectomy.
4) No increase of excretion of prolactin, gonadotrophin and ACTH was observed in the relapsed patients who previously had remissions after adrenalectomy and oophorectomy. It may be concluded that there are some other factors influencing the relapse besides pituitary hormones.

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1) The administration of anabolic steroid causes aggravation of glucose tolerance, especially in daily aggravation in alloxanized subdiabetic rat.
2) Anabolic steroid results in a decrease in ILA of the peripheral blood suggesting the probale cause in the liver and prolongation of ILA response on intravenous glucose injection is hardly considered to be derived from the pancreas.
3) Treatment with anabolic steroid suppressed the glucose uptake of the animal fat tissue and the action of extrinsic insulin.
4) The liver hexokinase activity was not influenced by the anabolic steroid.
It is concluded that the action of diabetogenicity of anabolic steroid is considered to be toward the liver and the fat tissue rather than toward the pancreas.

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