The purpose of this study is to examine the effect of LH-RH on LH release in the baboon. Fifteen female baboons having the normal menstrual cycle were used for this study. One hundred μg of synthetic LH-RH was injected subcutaneously in both the early follicular phase and the early luteal phase. For control purposes, 1 ml of saline was injected subcutaneously in the luteal phase. Blood samples were collected by femoral vein puncture with light anesthesia under prearranged schedule and were assayed for LH-RH, LH, estrogen and progestin. The plasma level of LH-RH reached a maximum within 4 minutes after s.c. injection of 100 μg LH-RH, decreased sharply at first, and then slowly later. Fast and slow disappearance components (t1/2 = 4.7 min., 37.1 min. respectively) were observed. In the baboon given LH-RH during the luteal phase, peaks in plasma levels of LH were observed within 30 minutes and within 90 to 150 minutes after injection. A lesser pituitary response to LH-RH for LH release occurred during the follicular phase. The first peak of LH was well-correlated with the peak of plasma LH-RH, but the later elevations of LH (observed within 90 to 150 minutes after LH-RH injection) were not necessarily related to the plasma level of immunoassayable LH-RH. Elevation of plasma levels of estrogen and progestin was observed within 45 minutes after LH-RH injection. In saline control, the plasma level of LH was not elevated; however, plasma levels of estrogen and progestin were increased within 45 minutes after saline injection. Later elevation of plasma LH observed between 90 and 150 minutes after LH-RH injection may be due to administered LH-RH in cooperation with elevated levels of plasma estrogen and progestin. To pursue this problem, injections of estrogen and/or progesterone were performed during the early follicular phase. Injection of 600 μg of estrodiol benzoate (EB) for 3 days caused an elevation of plasma level of LH and enhanced pituitary LH responsiveness to LH-RH for LH release; however, injection of 100 μg EB for 3 days showed less effect on LH release. Injection of 10 mg of progesterone for 3 days also caused an elevation of plasma level of LH and enhanced the pituitary responsiveness to LH-RH for LH release. Injection of both 600 μg EB and 10 mg progesterone for 3 days did not elevated plasma level of LH and showed no significant effect of LH-RH on LH release as compared to control. These results suggest that elevated levels of circulating estrogen and progestin may determine LH release and exposure of the pituitary to LH-RH is necessary for LH release. In dose and time schedule used in this study, it is inferred that estrogen and progesterone may exert their direct effect to hypothalamus on endogenous LH-RH secretion and also may exert their effect on pituitary gonadotrophs to change the sensitivity to LH-RH, i.e. these steroid hormones may be major factors in the control of gonadotropin release in the baboon.

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The effects of food deprivation on circadian periodicity of plasma corticosterone levels were studied in adult male rats kept under regular light-dark alternation (light : 7 AM -7 PM). Blood samples were obtained by tail vein sampling method. Plasma levels of corticosterone determined by this method were comparable to those obtained by decapitation both in the morning and evening. Twenty-four hour patterns of plasma corticosterone levels determined at 4 hour intervals using these two different methods were also essentially similar, indicating that the tail vein sampling method is reliable and useful for the study on adrenocortical rhythm.
A restriction of feeding time between 10 AM and 6 PM for 2 weeks resulted in a phase shift of the circadian rhythm of plasma corticosterone levels. A peak appeared at 8 AM and the value was significantly higher than that at 6 PM. These findings confirmed the facts reported by Johnson and Levine, and Krieger. Overt circadian periodicity of plasma corticosterone levels persisted in rats fasted for three days. However, after the 5th day of food deprivation, the circadian rhythm was abolished and a flat 24 hour pattern of higher levels was observed.
These results indicated that the feeding pattern plays an important role in establishing of circadian rhythm of adrenocortical activity.

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These studies were undertaken to clarify the physiological role of thyrotropin releasing hormone (TRH) in regulation of the hypothalamic pituitary thyroid axis. Synthetic TRH was administered both acutely as a single intravenous dose of 500 micro-grams (TRH IV) and chronically (TRH p.o.), in the form of repetitive oral doses (10 mg b.i.d. for 4 days) to 21 normal, 26 hypothyroid, and 14 hyperthyroid subjects. Serial determinations were made of the serum levels of thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) after TRH IV nd TRH p.o. and changes in thyroidal untake of radioiodine were assessed after TRH p.o. In normal subjects, serum TSH and T3 rose in response to TRH IV but there was no significant change in the serum T4 levels.
The peak levels of serum TSH (TSH PL) ranged from 7.0 to 30.0 microunits per ml and serum T3 levels (T3 PL) from 126.2 to 197.4 ng/dl. After the first TRH p.o. dose, serum TSH levels rose (TSH PL : 7.0 - 34.0 microunits per ml) but the TSH increment decreased in response to subsequent doses of TRH. Nevertheless, both the mean serum T3 and T4 levels increased progressively in response to TRH p.o. reaching their peak levels on the 4th day (Mean T3 PL : 185.1 ± 4.0 ng/dl with a range of 152.8 to 216.8; Mean T4 PL : 11.7 ± 0.8 micrograms/dl with a range of 8.4 to 13.4). The mean 24-hour ¹³¹I uptake also increased by 19.9 ± 1.2% D over baseline with a range 9.1 to 30.7. After intramuscular TSH, the mean increment in a 24-hour ¹³¹I uptake was 13.2 ± 1.0% D with a range of 5.6 to 20.8%.
In all 26 patients with hypothyroidism, serum T3 and T4 failed to increase in response to TRH IV. Based on the TSH PL after TRH IV and the criteria of Pittman, the patients could be provisionally divided into primary hypothyroidism (13 patients whose TSH PL ranged from 52.5 to 500 microunits per ml), secondary or pituitary hypothyroidism (8 patients whose TSH PL varied from undetectable to 4.1 microunits/ml) and tertiary or hypothalamic hypothyroidism (5 patients whose TSH PL was from 8.8 to 30.4 microunits/ ml). The same patients were then restudied after TRH PO. Those classified as having primary hypothyroidism demonstrated no alterations in serum T3 and T4 levels or in the thyroidal uptake of ¹³¹I despite striking elevations in serum TSH reaching peak levels of 220 to 500 microunits/ml. Six of the eight patients tentatively classified as having secondary hypothyroidism on the basis of their response to TRH IV also failed to respond to TRH p.o. as evidenced by an absence of minimal serum TSH increase (TSH PL : U.D. -4.6 microunits/ml) and no change in the 24-hour thyroidal uptake of ¹³¹I (the change in uptake was from -1.9 to -0.6%) or serum T3 and T4 levels (T3 PL 12.5 to 130 ng/dl, T4 PL 2.0 to 7.6 micrograms per dl). In 2 of these 8 patients, however, TRH p.o. was followed by normal thyroidal responses despite an absence of minimal increase in TSH (TSH PL : 4.6 to 6.9 microunits/ml). In these subjects, 24-hour thyroidal uptake of ¹³¹I increased 17.6 to 24.5% T3 PL varied from 160 to 190 ng/dl and T4 PL from 9.0 to 9.6 micrograms/dl. In 4 of the 5 patients with tertiary or hypothalamic hypothyroidism, both ¹³¹I uptake and serum TSH rose (the change in the 24-hour ¹³¹I uptake was from 31.2 to 59.9%; TSH PL from 8.0 to 29.5 microunits/ml), although serum T3 and T4 remained in the normal range (T3 PL 120-140 ng/dl; T4 PL 4.8-6.6 micrograms/dl). In the 5th patient, ¹³¹I uptake, serum TSH, T3 and T4, all rose in response to TRH p.o. (the change in the 24-hour uptake of ¹³¹I was 20.7%, TSH PL 15.0 microunits/ml, T3 PL 180 ng/dl, T4 PL 13.0 micrograms/di). In primary hypothyroidism, thyroidal response to IM TSH remained subnormal after TRH p.o. but in secondary and tertiary hypothyroidism, the response was virtually restored to normal.

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In order to study the mechanism of gonadal dysfunction in patients with abnormal thyroid function, the pituitary luteinizing hormone (LH) response to 200μg of luteinizing hormone-releasing hormone (LH-RH) was investigated in 20 untreated and 18 treated hyperthyroid patients and in 21 untreated and 8 treated hypothyroid patients in addition to 29 matched control subjects.
Serum LH levels were measured by double-antibody radioimmunoassay technique with HLH kit Daiichi.
In untreated hyperthyroid men, the slightly elevated mean basal level and the exaggerated mean response to LH-RH of LH were observed, and in treated hyperthyroid men, both values were found to be similar to those of matched control men. Furthermore, in these patients, the maximal increments and the net increments of responses to LH-RH of LH were correlated with serum thyroxine levels and Thyopac-3 values.
In most untreated and treated hyperthyroid premenopausal women with and without menstrual disturbances, the basal levels and the responses to LH-RH of LH were similar to those of matched control premenopausal women.
In untreated hyperthyroid postmenopausal women, the mean basal level of LH was elevated, although the mean LH response to LH-RH was similar to that of matched control postmenopausal women, and in treated hyperthyroid postmenopausal women, the mean basal level and the mean response to LH-RH of LH were similar to those of matched control postmenopausal women. Furthermore, in these patients, the basal levels were correlated with serum thyroxine levels.
In untreated and treated hypothyroid men, the mean basal level and the mean response to LH-RH of LH were similar to those of untreated and treated hyperthyroid postmenopausal women.
In most untreated and treated hypothyroid premenopausal women with and without menstrual disturbances, the basal levels were observed to be inconsistent, and the LH responses to LH-RH were similar to those of matched control premenopausal women.
In untreated and treated hypothyroid postmenopausal women, the mean basal level and the mean response to LH-RH of LH were similar to those of matched control postmenopausal women.
These data indicate that the ability of the pituitary to secrete LH in patients with abnormal thyroid function was augmented in hyper-and hypothyroid men, and augmented in hyper-, but normal in hypothyroid postmenopausal women. Therefore, it is concluded that the cause of gonadal dysfunction at least in the premenopausal women with abnormal thyroid function lies not inside but outside the pituitary gland.

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Concanavalin A (Con A) was tested for its ability to affect thyroid activation induced by the thyroid stimulators in mouse thyroid tissues.
Con A was found to have the biphasic stimulatory and inhibitory effects on thyrotropin (TSH) -induced cyclic AMP formation and endocytosis, a step in thyroid hormone secretion, in mouse thyroid tissues. Low concentrations of Con A potentiated TSH-stimulated cyclic AMP formation and endocytosis. In contrast, high concentrations of Con A markedly inhibited TSH stimulations. These effects were reversed by the addition of methyl-alpha-D-glucoside to the second preincubation medium (without Con A) prior to TSH. A high concentration of Con A alone did not depress the basal levels of cyclic AMP or basal glucose oxidation in thyroid tissues. A high concentration of Con A also inhibited cyclic AMP formation induced by prostaglandin E₂ and the long-acting thyroid stimulator (LATS).
Binding of ¹²⁵I-labeled Con A to thyroid tissues increased with time up to 7 5 min and was very slowly reversible after attainment of equilibrium. Binding was directly proportional to tissue weight. Scatchard plot analysis on the binding of ¹²⁵I-labeled Con A to thyroid tissues indicated a positive cooperativity which seemed to be well correlated to the biphasic effects.

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The existence of substances in corn germ, which induce a positive response in pigeon crop test, has been previously reported by Okamoto and Takahashi in 1974. Following this first experiment, one of these substances was identified as ferulic acid by purification. In the present experiment FSH, LH and prolactin levels in the serum and the pituitary tissue of castrated male rats and EP (estradiol benzoate and progesterone) treated male rats were determined by radioimmunoassay at 5 to 180 min. after intravenous injection with 1 mg of ferulic acid. It was noted that FSH release only was promoted significantly at 5 min. after the injection, whereas LH and prolactin releases were inhibited at 5 to 10 min. after the injection. A rebound effect was noted in LH and prolactin releases after the injection.

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In order to investigate plasma prolactin and thyroid-stimulating-hormone (TSH) concentration and pituitary reserve of these two hormones in patients with breast cancer, following examinations were carried out.
Plasma prolactin concentration was measured before and 15, 30, 60, 90 minutes after the 500μg of thyrotropin-releasing-hormone (TRH) i.v. injection in 22 patients with breast cancer and 4 patients with benign breast disease. All patients did not take any hormonal therapy and any medication inducing prolactin secretion. Ten healthy females were also tested as controls. Plasma prolactin concentration was estimated by a double antibody radioimmunoassay (RIA) technique using hPRL RIA kit provided by NIAMDD. The basal prolactin concentration in patients with breast cancer was 18.6±2.1 ng/ml (Mean ± SEM), and it was slightly higher than the control group (14.7±2.2 ng/ml), but not statistically significant. In 6 out of 22 patients with breast cancer, high plasma prolactin concentrations more than 25 ng/ml were observed.
The maximal plasma prolactin concentration following the TRH injection was obtained at 15-30 minutes after TRH in most patients with breast cancer. The maximal value was 87.4 ± 9.2 ng/ml, and it was near the upper limit of normal range of prolactin response, and not significantly higher than the maximal value in the control group (59.7 ±5.7 ng/ml). In 7 patients with breast cancer, the maximal prolactin values more than 100 ng/ml were obtained after TRH injection.
There was no statistically significant difference between early breast cancer group (TNM : stage I & II, N=14) and advanced breast cancer group (TNM : stage III & IV, N=6) in both the plasma prolactin concentration and the pituitary prolactin reserve. Also there was no significant difference between premenopausal patients (N=8) and postmenepausal patients (N=12) in the plasma prolactin concentration and the pituitary prolactin reserve.
We observed the puzzling phenomenon that both the basal plasma prolactin concentration and the pituitary prolactin reserve in patients after radical mastectomy (N=7) were greater than those in patients who had not undergone any operation (N=15). This difference between these two groups were not statistically significant, but the prolactin reserve in patients after radical mastectomy was significantly greater than in control group (p<0.01).
The basal plasma prolactin value and the maximal value after TRH injection in 4 patients with benign breast disease were 44.2 ± 14.5 ng/ml and 116.0 ± 30.9 ng/ml respectively. Both of these values were significantly higher than those in the control group (p<0.01, p<0.05). In 2 patients with mastopathy, abnormally high plasma prolactin levels more than 50 ng/ml were obtained, and in one patient of these two, abnormally great prolactin reserve was observed (more than 200 ng/ml of plasma prolactin after TRH).
Plasma TSH concentration was measured before and 15, 30, 60, 90 minutes after 500 μg of TRH i.v. injection in 19 patients with breast cancer and 12 healthy control subjects. Plasma TSH concentration was estimated by the double antibody radioimmunoassay technique using the commercial kit provided by Daiichi Radioisotope Labs. (Tokyo).
The basal plasma TSH level and the maximal TSH level after the TRH injection were 3.5 ± 0.5μU/ml and 21.7 ± 3.3 μU/ml, respectively, in patients with breast cancer. Both of these values did not differ from those in the control group (basal plasma TSH level : 5.8 ± 0.6 μU/ml, maximal TSH level after TRH : 20.1 ± 1.3μU/ml).
From these results, following possibilities were indicated. (1) Breast cancer is able to develop under the circumstances with normal plasma prolactin concentration. But in about one third patients,

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