Further studies were made in 4-day cyclic rats on the action of exogenous progesterone in advancing the release of LH from the pituitary, evidenced by the earlier increase in ovarian progesterone secretion than the spontaneous preovulatory increase in secretion of this steroid. It was found that 1) exogenous progesterone injected subcutaneously during the period from 03.00 to 13.00 hr of proestrus increased the rate of ovarian progesterone secretion at 16.00 hr on that day, one hr earlier than the time of the spontaneous increase corresponding to the onset of LH release, maximal increase being induced by progesterone given at 11.00 hr, injections at 01.00 or 15.00 hr failed to increase the secretion; 2) a linear dose-response relationship between the secretory rate of progesterone and the log-dose of progesterone injected at 11.00 hr was obtained in the dosage range of 0.05 to 5 mg per rat; 3) advanced increase in progesterone secretion caused by an adequate amount of progesterone was seen around 14.00 hr at the earliest, regardless of the time of progesterone injection, i.e. the advancement of LH release by exogenous progesterone never exceeded 3 hr; 4) desoxycorticosterone (DOC), norethisterone and medroxyprogesterone acetate (MAP) exerted a similar effect but corticosterone and medroxyprogesterone did not; 5) the progesterone secretory rate at 16.00 or 19.00 hr in rats sufficiently primed with progesterone was almost double the maximal value obtained at the peak of LH release in intact rats, and such a “supersecretion” of progesterone was not obtained by an LH preparation, even when given in excess; 6) 20α-hydroxypregn-4-en-3-one (20α-OH-P) secretion was not always parallel with progesterone secretion under the various conditions described above; and 7) treatment with 5 mg of progesterone, medroxyprogesterone, corticosterone or DOC increased the ovarian secretory rate of 20α-OH-P but either smaller doses of progesterone, or the treatment before 05.00 hr on the day of proestrus, appeared to depress the secretion of this steroid.
From these results, it is suggested that exogenous progesterone not only acts on the neural process regulating the ovulating hormone release from the pituitary but also affects the ovary to increase its responsiveness to pituitary gonadotropins, and thus advances the release of ovulating hormone and causes the supersecretion of progesterone at the preovulatory state. It is further suggested that exogenous progesterone and synthetic progestins directly or indirectly affect the ovarian production of 20α-OH-P.

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Biliary bile acid composition and secretory rate, as well as cholesterol concentra tions in plasma, liver and bile, were investigated in rats given estradiol for 3 days and for 3 weeks, a 2% cholesterol supplemented diet for 4 to 8 weeks, and 1-thyroxine for a week, in order to ascertain the relations between cholesterol concentrations in tissues and bile acid production.
Biliary samples collected from control rats during the first 2 hrs. period of can nulation contained 11 mg bile acid per ml of biliary samples on an average, consisting of 69% cholic acid, 7% hyodeoxycholic acid, 6% deoxycholic acid, 6%α-muricholic acid, 5% chenodeoxycholic acid, 3% unidentified acid and minor percentages of lithocholic acid, two other unidentified acids, 7-oxo-lithocholic acids. A 3-day treatment with estradiol caused a decrease in plasma cholesterol and an increase in liver cholesterol, but a 3-week treatment with this steroid significantly increased the plasma cholesterol level. Either acute or chronic estradiol treatment caused an increase in chenodeoxycholic acid and its further converted bile acids in the bile. When rats were fed the cholesterol diet for several weeks, increases in chenodeoxycholic, hyodeoxycholic, α-muricholic and lithocholic acids with a concomitant decrease in cholic acid were observed, and this was accompa nied with a slight increase of cholesterol in the liver (30%) and plasma (10%). Both liver and plasma cholesterol levels were markedly elevated by giving cholesterol and sodium cholate simultaneously. 1-Thyroxine treatment caused no change in plasma cholesterol level but increased chenodeoxycholic acid formation to provide a biliary bile acid com position similar to that of the rats treated with estradiol or cholesterol diet
These data suggest that the treatment with either estradiol or cholesterol diet, as well as the treatment with 1-thyroxine, increases chenodeoxycholic acid formation. The increase of chenodeoxycholic acid formation appears to be related to an increase in the liver cholesterol level but not to the change in the plasma cholesterol level. A defence mechanism for alimentary hypercholesterolemia in the rat was discussed on the basis of chenodeoxycholic acid formation.

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A chemical method for the determination of catecholamine (CA) by pipsylation, reaction with p-iodobenzenesulfonyl chloride, was used to study CA release from the rat adrenal medulla or adrenal in vitro, and to estimate CA concentration in the rat adrenal medulla.
Removal of the rat pituitary gland caused a decrease of adrenal medulla weight within 7 days after hypophysectomy, and the decrease of medulla weight was accompanied with an elevation of CA concentration in medulla.
Corticosterone stimulated to increase CA release from adrenal medulla in vitro, but adrenocorticotropic hormone did not have a significant effect on CA release from adrenal medulla in vitro.

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LATS activity was neutralized by pretreatment of mice with anti-IgG in vivo. Simultaneous injection of epsilon-amino caproic acid and hydrocortisone does not inhibit LATS action. Human thyroid-microsomal fractions neutralize LATS activity and TSH activity. The decrease in activity of LATS and TSH caused by thyroid microsomes correlates positively. Calf thyroid microsomes are much less active than human thyroid microsomes in absorbing LATS activity. Deoxycholate and sonification solubilize the LATS neutralizing activity. No visible precipitate formed between these solubilized fraction and LATS-IgG, using the Ouchterlony agar diffusion method. LATS did not differ from TSH in heat stability, and partially heat denatured LATS still had a long acting type response. Dissociation of a small rapidly acting molecule from LATS could not be obtained in high molar NaCI solution. LATS-IgG fragments digested by proteolytic enzymes (papain, pepsin, trypsin, and ficin) had a prolonged response like LATS. However, these fragments, in the presence of cysteine, either gave the same response after 2 hr and 8 hr, or gave a short acting response like TSH. The thyroid stimulating active site of the LATS active gamma globulin may be situated in Fab or Fab fragments having the antibody combining site. LATS did not stimulate the chicken thyroid, although TSH had this action. The proteolytic fractions of LATS-IgG also did not stimulate the chicken thyroid. No increase of gammaglobulin and/or IgG was found in some sera with a high LATS activity. Binding of LATS-IgG to mouse or human thyroid could not be visualized using the Coon's immunofluorescent method. These data support the concept that LATS is an IgG having a high specific activity of thyroid stimulating action.

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The effect of ubiquinone (Co Q₇) was investigated in vitro on the biosynthesis of aldosterone from progesterone-4-¹⁴C and corticosterone-1, 2-³H using quartered rat adrenals. When progesterone was incubated with the adrenal tissue, the following metabolites could be obtained: 11-desoxycorticosterone, 11 β-hydroxyprogesterone, corticosterone, 18-hydroxycorticosterone and aldostei one. Ubiquinone inhibited the pi oduction of 18-hydroxycorticosterone and aldosterone with the resultant accumulation of corticosterone. This inhibitory effect of ubiquinone on the formation of aldosterone was more clearly observed when corticosterone was used as the substrate.
These results suggest that ubiquinone inhibits the activity of 18-hydroxylase in the adrenal, resulting in the reduction of aldosterone biosynthesis.

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In order to elucidate the facilitation of ovulatory release of luteinizing hormone (LH) and subsequent ovulation, subcutaneous injection or intrahypothalamic implantation of progesterone was carried out on the morning of proestrus in 4-day cyclic rats. By injecting progesterone on the morning or early afternoon of proestrus, an approximate 3 hr advancement of ovulatory release of LH was demonstrated by confirming the occurrence of ovulation on the next morning after timed hypophysectomy performed on the afternoon of proestrus. Ovulation also occurred about 3 hr earlier in the estrous morning when progesterone had been given on the morning of proestrus. The minimum effective dose of progesterone to facilitate LH-release was somewhere between 0.1 and 0.625mg per rat. Facilitation of LH-release by steroid administration on the morning of proestrus is not entirely specific for progesterone. Norethisterone, medroxyprogesterone acetate, and desoxycorticosterone (DOC) also induced the advanced release of LH. Facilitation of ovulatory release of LH was induced also in the rats having progesterone crystals implanted in the median eminence-arcuate region of the hypothalamus on the morning of proestrus. These results indicate that a neural timing factor regulating the onset of LHrelease in proestrus is labile to a certain extent, and that it operates about 3 hr in advance when it is exposed to progesterone given on the morning of proestrus, and that the appearance of facilitatory action of progesterone depends on the pre-existing estrogen level in the circulating blood.

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Several factors which affect the sensitivity of calcitonin bioassay were investigated. As to the assay animals, Sprague-Dawley and Holtzman rats were more sensitive than Wistar rats. In mice, C3H III strain gave better response to calcitonin than CF 1 and ddN strains. In each strain, younger rats were more sensitive than older ones. It was also demonstrated that the longer was the period of low calcium diet, the more remarkable was the response of the Wistar rats to calcitonin. In Wistar rats, phosphate in drinking water improved the sensitivity of the assay and intravenous administration of calcitonin produced steeper dose-response curve than subcutaneous administration.
When 3 to 4-week-old Sprague-Dawley rats were utilized, the hypocalcemic acitivity was detected in 25 to 66 mg of wet weight of human thyroid glands, while 5-week-old Sprague-Dawley rats were not so sensitive as to be able to detect hypocalcemic activity in 100mg of wet weight of human thyroid glands.
Two-week-old Holtzman rats were so sensitive that we detected hypocalcemic activity in 1mg of wet weight of a metastatic lymph node of the medullary thyroid carcinoma.

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Chemical analyses of protein, pentose, hexose and sialic acid in the crude human urinary extracts prepared from the non-acidified urine (NA), the supernatant of the acidified urine (SA) and the precipitate of the acidified urine (PPT) revealed a high content of sialic acids in Samples NA and PPT, both of which exert an inhibitory effect on human chorionic gonadotropin, compared with Sample SA which does not show inhibition.
A role of sialic acids in inhibition was, therefore, studied by the ovulation test and the ovarian ascorbic acid depletion assay. No differences were found in the inhibitory effect between Sample NA and hydrolyzed NA, and between Sample PPT and hydrolyzed PPT. The dialysate of the hydrolyzed NA or PPT did not show any inhibitory activity. The evidence suggests that the activity of a gonadotropin inhibitor is not accounted for by the presence of sialic acid.

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³H-leucine uptake of hypothalamic nuclei of female castrated rats at various early ages before puberty was estimated by autoradiography. In rats castrated on the 1st, 3rd, 5th and 10th day of life, leucine uptake in cell bodies of neurons of the preoptic area (POA), nucleus supraopticus (NSO), nucleus paraventricularis (NPV), nucleus ventromedialis (NVM) and nucleus arcuatus (NA) showed no significant change 14 days after castration, as compared with the uptake in normal rats. When castration was performed on the 20th and 30th day of life, leucine uptake of the POA, NVM and NA was significantly enhanced 14 days after castration, but uptake of NSO and NPV slightly decreased. From these findings it is suggested that hypothalamo-pituitary-gonadal system matures at the age of about 20 days, and also, that POA, NVM and NA are concerned with the regulation of gonadotropic function of the anterior pituitary.

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Treatment of the rats with actinomycin D or actidione for 48 hr prior to sacrificing animals resulted in a significant reduction of DNA synthesis and the activity of DNA polymerase in testosterone-stimulated ventral prostate on the 4th day after testosterone administration. Under the same treatment of inhibitors, increase of the rate of 5α-reduction of testosterone on the 4th day after testosterone treatment was lower than that in the from the animals treated with testosterone alone. However, some elevation of the of 5α-reduction was observed between the 2nd and 4th day after testosterone treatment, regardless of the administration of actinomycin D or actidione. Treatment of mitomycin C did not make a significant difference in the increase of the rate of 5α-reduction DNA polymerase activity.
It was concluded that the mode of increase of rate of 5α-reduction was different from that of DNA polymerase activity on the 4th day after testosterone treatment, and that some part of elevation of the rate of 5α-reduction was independent of the treatment of metabolic inhibitors.

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