To clarify the mechanism of an increased response of diabetic D-cells to arginine, we studied the changes in responsiveness of pancreatic D-cell to this agent with the passage of time after the onset of diabetes and the effect of chronic insulin substitution on the altered D-cell function utilizing the perfused pancreas of streptozotocin diabetic rats. The magnitude of somatostatin (SRIF) response to arginine (10mM) was progressively increased with the duration of diabetes. The integrated response of SRIF during a 20min period of an arginine infusion one week after the injection of streptozotocin was not different from that in the normals, but it was increased by 240% at 8 weeks and by 390% at 15 weeks. The exaggerated pancreatic SRIF release observed in 8 week diabetic rats was partially ameliorated with the daily insulin replacement (15.0±1.0units/kg of B.W.). This was accompanied by a partial recovery from growth failure. The integrated amount of SRIF secreted during an arginine-stimulated period (20 min) was inversely correlated with an increase in body weight during an 8 week period (r=-0.741, p<0.001). From these results, it might be concluded that the alteration in diabetic D-cell function may be related to the metabolic and hormonal abnormalities of diabetes, rather than insulin deficiency itself.

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The results of clinical endocrine and metabolic studies on a 57-year-old female with surgically and autopsy verified glucagonoma syndrome were presented. All of the clinical manifestations of glucagonoma syndrome so far reported in the literature were noted but there was no evidence indicating the presence of multiple endocrine adenomatosis. The plasma IRG level was always more than 20 times above the normal, and the IRG response to insulin and tolbutamide injection was abnormal and the results of the other endocrinological studies revealed less remarkable features, if any. The surgically removed metastatic tumor of the liver contained an enormous amount of IRG and an appreciable amount of IRI, indicating that the elevated plasma IRG was mainly of tumor origin. These results clearly indicate that in glucagonoma there is some abnormality in glucagon release from the tumor. In addition to these findings, hypocalcemia, cardiac left ventricular hypertrophy and gastrointestinal dysfunction reportedly due to hyperglucagonemia were also seen in this patient.

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We have demonstrated the sex difference with respect to the dopaminergic modulation of serum TSH secretion in patients with primary hypothyroidism.
Ten patients, 4 men and 6 women, with hypothyroidism were given 10 mg of Domperidone (Domp) iv, a very potent and specific dopamine receptor blocking agent, which could not readily cross the blood brain barrier.
There was a significant rise in the TSH level after Domp iv in female patients with primary hvnothvroidism. from basal values at zero time of 74.4±33.8 (m±SE)μU/ml to 171.2 ±94.9 at 30min (P<0.001), 159.6±100. at 60min (P<0.001).In contrast, no significant change in serum TSH values after Domp iv occurred in male patients with primary hypothyroidism, from basal values at zero time of 181.1±39.9 μU/ml to 171.4±31.1 at 30 min, 180.7±33.2 at 60 min and 172.7±31.0 at 90 min. After thyroid hormone therapy, max Δ TSH values and the change from basal to peak values were significantly related to basal TSH values in female patients with primary hypothyroidism (r=+0.93, p<0.001), while max Δ TSH in male patients was inversely related to basal TSH values within the limited concentrations (r=-0.78, p<0.02).
It was conjectured from our results that maximum TSH responses to intravenous administration of domperidone in male and female hypothyroid patients were observed in respectively different basal TSH values, that is, less than 100 μU/ml in males and more than 100 μpU/ml in females.

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The concentration of plasma prolactin during the period of premature ovulation induced by human chorionic gonadotropin (HCG) or luteinizing hormone releasing hormone (LH-RH) in diestrous rats was determined at 3 hr intervals from 1700 hr on the day of diestrus (day 0) to 2300 hr on the day of proestrus (day 1). Premature ovulation was induced by either a single injection of 10 IU HCG at 1700 hr on day 0 or three injections of 1 μg LH-RH at 1 hr intervals from 1700 to 1900 hr on day 0 In saline-treated controls, the concentration of prolactin iri plasma was low during diestrus but increased on the afternoon of proestrus with a peak value at 1700 hr, followed by an abrupt decline at 2300 hr on the same day. However, there was no significant rise in the plasma prolactin level throughout the period of observation in HCG-treated rats. In the LH-RH-treated group, the prolactin level in plasma did not change until 1100 hr on day 1, but significantly increased at 1400 hr on the same day then declined by 2300 hr, though no significant difference was observed at any time when compared to HCG-treated rats.
These results indicate that no prolactin surge occurred during the period of premature ovulation.

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A new protein termed islet-activating protein (IAP) has recently been extracted from the culture medium of Bordetella pertussis, and shown to enhance insulin secretion either in vivo in rats or in vitro in isolated pancreatic islets due to activation of native calcium ionophores. However, it has not been clarified whether or not IAP enhances the secretion of insulin in human pancreatic islets. In order to examine the effect of IAP on human pancreatic islets, pancreatic tissues were obtained from seven patients who had appeared normal in a glucose tolerance test prior to pancreatectomy. Insulin secretion was significantly increased in IAP treated pancreatic islets by the glucose and the arginine stimuli. It is concluded that IAP enhances the insulin secretion in response to insulin secretagogues in human pancreatic islets, suggesting the possible clinical application of IAP to diabetic patients.

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A TRH test was performed in patients with Cushing's syndrome and isolated ACTH deficiency, and serum TSH was measured. A TRH-induced TSH showed low response in patients with Cushing's syndrome but showed excessive response in patients with isolated ACTH deficiency. However, in both diseases TRH-induced TSH response showed a tendency to normalize after the treatment.
Urinary 17-OHCS excretion was measured in patients with Cushing's syndrome and isolated ACTH deficiency before and after the treatment. There was a definite inverse correlation between the logarithm for urinary 17-OHCS excretion and the peak TSH response to TRH. These results suggested that glucocorticoids regulate not only ACTH but also TSH secretion.

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Ovulation and pseudopregnancy (psp) can be induced by cervical stimulation in persistent estrous rats maintained in a constant lighting condition (LL-psp rats). Different from the pattern of prolactin (PRL) secretion in usual psp rats maintained in a daily light-dark cycle (LD-psp rats), PRL secretion in these rats during the psp period does not occur in the form of two daily surges. The object of this study was to investigate the role of the external LD cycle for the expression of PRL surges.A large amount of PRL was released in LL-psp rats immediately after cervical stimulation, which is in contrast to LD-psp rats whose first secretion of PRL after cervical stimulation is known to depend on the time of day rather than the time of stimulation.
The effect of the change in the lighting condition on the pattern of PRL secretion was investigated in LD- and LL-psp rats. Two surges of PRL were induced in LLpsp rats on Day 5 (Day 0=day of cervical stimulation), if they were moved from LL to LD on Day O. Conversely, PRL surges diminished in LD-psp rats on Day 5 if they were moved from LD to LL on Day O. When the change in lighting conditions was made on Day 5, different results were obtained: In LL-psp rats two daily surges were not established on Day 8 in spite of an application of LD condition from Day 5. In LD-psp rats the two surges were still observed on Day 8, though the time of occurrence was shifted.
These results suggest that there is a critical period at and shortly after the time of cervical stimulation during which external LD cycle can work as an entraining agent for the expression of PRL surges. Once PRL secretion is coupled to the external LD cycle, the oscillation continues even in LL condition in a free-running manner. Exposure to LL condition during this critical period inhibits the establishment of two daily PRL surges throughout a psp period.

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A peptide with insulin-like activity was isolated from human plasma. In the purification, insulin-like activity (ILA) was monitored by radioreceptor assay for insulin, using human placental membrane and [¹²⁵I]-insulin. ILA was extracted from Cohn fraction III with acid-ethanol and chromatographed on Sephadex G-75 in 1% formic acid. When the active fractions were subjected to ion-exchange chromatography with CM-cellulose, the ILA was adsorbed to the column at pH 5.0 and was eluted with a gradient of ammonium acetate. The chromatographic behavior of the ILA was not identical to that of somatomedin A as determined by radioreceptor assay (RRA) for the latter. On isoelectric focusing of the ILA from the CM-cellulose column, insulin-like activity was distributed over a wide pH range. The ILA that was focused at pH 7.5-9.0 was further purified by gel filtration on Sephadex G-50 in 1 M acetic acid. The specific activity of the basic ILA was approximately 200 mU insulin equivalent /mg protein. The apparent molecular weight of the material was estimated to be 7, 000. It stimulated [¹⁴C]-glucose oxidation in rat epididymal fat cells and had sulfation activity in chick chondrocytes. Furthermore, the basic ILA had a potent mitogenic activity in Balb/c-3T3 cells. Thus, the basic ILA is qualified as an insulin-like growth factor'(IGF). It is obviously different from somatomedin A, and may be closely related to IGF-I or somatomedin C. Subsequently, RRA for the basic ILA was developed and serum concentrations of the basic ILA were determined. The serum concentrations of the basic ILA were high in acromegalics and low in patients with hypopituitarism. Thus, the basic ILA is entitled to be one of the IGFs.

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Insulin binding to circulating erythrocytes was studied in 31 maturity onset-type diabetic patients with varying degrees of insulin response to oral glucose. Specifically bound-insulin fraction to erythrocytes ranged from 4.9 to 12.7% at a tracer concentration of insulin. A negative correlation was found between the binding and fasting serum insulin concentration (r=-0.45). When the binding was compared with sum of serum insulin concentrations at 0, 30, 60, 90, and 120 min after the oral administration of 50 g glucose (ΣIRI), a better correlation was obtained (r=-0.63). Patients were classified into group A (ΣIRI<100μU/ml), group B (100 μU/ml<ΣIRI <200μml) and group C (ΣIRI>200 μU/ml). Scatchard analysis of the competition data from each group indicated that erythrocytes from group A showed the highest concentration of receptors (60 sites/erythrocyte) while the lowest from group C (36 sites/erythrocyte). The receptor affinity was not significantly different among the groups.
These results suggest that insulin receptors on human erythrocytes are regulated by the ambient insulin concentration as shown in receptors on insulit targen cells. Therefore, erythrocytes seem useful for the study of iesulin receptors in conditions associated with altered insulin sensitivity.

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Cytosols from human benign prostatic hypertrophy contained progestin-binding components which bound to R 5020, ORG 2058 and progesterone in a high affinity fashion. Most of the protein bound to R 5020 was recovered in the precipitate with 0-30% saturation of ammonium sulfate. The R 5020-binding protein showed sedimentation coefficients of 3.6 S and 8.4 S, and was eluted in the void volume of a Sephadex G-200 column. This protein was clearly distinguished from the dihydrotestosterone-binding protein by its precipitability by ammonium sulfate, heat stability and susceptibility to delipidization. R 5020 and ORG 2058 binding were markedly inhibited by the addition of R 1881, therefore, most of the binding to progestin in cytosols from the benign prostatic hypertrophy seems to be also the sites for R 1881. Although nuclear extract by 0.4 M KC1 showed R 1881 binding, the extract did not contain the R 5020-binding protein, and this suggested that the progestin-bindingprotein observed in the cytosols does not seem to be the steroid receptor.

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To elucidate the factors regulating ovarian follicular development during lactation in the rat, plasma and pituitary levels of FSH, LH and prolactin (PRL) were determined for each day of lactation along with the histological examination of size-distribution of ovarian follicles.
Post-partum surges in FSH and LH were observed at 1700 hr on Day 0 of lactation (Day 0=day of parturition). Plasma FSH values were within the range of diestrous levels during Days 1 to 21 whereas pituitary content of FSH exceeded the values of 1400hr of proestrus (the highest level during the estrous cycle) from Day 3 onward. On the other hand, concentrations of plasma LH were generally below the range of diestrous values througout lactation. From Day 1 onward pituitary content of LH increased slowly but did not attain proestrous levels until Day 14. High concentrations of plasma PRL were observed from Day 4 to 10, although the time of suckling stimulus was not controlled. Pituitary content of PRL had abruptly increased by Day 3. Thereafter, high levels were maintained until Day 17, followed by a sudden decline on day 18.
After post-partum ovulation, the number of healthy follicles larger than 201 μm in diameter abruptly decreased until Day 6. From Day 3 to 7, a few healthy follicles of 201-400 μm were present, but larger follicles were absent. After Day 8, follicles larger than 401 μm were always present.
On the basis of these results it is suggested that during the early stages of lactation, the strong suckling stimulus and the consequent high levels of PRL result in a decreased plasma LH level which is insufficient to cause maturation of the follicles. Ovaries during early stages of lactation, however, were still responsive to exogenous gonadotropins initiating follicular maturation under the influence of normal suckling stimulus and high levels of PRL.

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27 patients with Cushing's disease were treated over a period of 18 years at the Departments of Medicine and Surgery, Nagoya University School of Medicine and the following results were obtained. 1) Adrenalectomy. 21 of 27 patients with Cushing's disease underwent adrenalectomy. 19 patients had total bilateral adrenalectomy and 2 patients unilateral adrenalectomy. 4 patients died, the cause of death not being related directly to adrenalectomy. 9 of 15 bilaterally adrenalectomized patients had hyperpigmentation even though they had been given substitution therapy with cortisol 20-30mg daily. They had elevated plasma ACTH levels, which were not completely suppressed by 2 mg of dexamethasone or 2.5 mg of bromocriptine per day. 2) Adenomectomy. 5 patients had adenomectomy via the transsphenoidal approach. 3 patients were cured but one of them has required postoperative substitution therapy with cortisol for hypopituitarism for one year until today. 2 of 5 adenomectomized patients had a recurrence of Cushing's syndrome after remission for 6-8 months. One of these recurrent cases has been subsequently treated successfully with bromocriptine, a dopaminergic drug. 3) Medical treatment. 2.5mg per day of bromocriptine has been effective in 2 patients without a pituitary adenoma and ineffective in the other 4 patients with a pituitary adenoma. 24 mg per day of cyproheptadine, an antiserotoninergic drug was not effective in any of the 4 patients with a pituitary adenoma.

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Female mice of the C57BL/Tw strain were injected daily with 1 μg estradio1-17β(E₂), 1 or 5 μg testosterone (T) and 5α-dihydrotestosterone (5α-DHT), the dose being increased varying from 5 to 100 μg for 5 days from the day of birth. These mice were ovariectomized at 90 days of age and kept for 50 days until sacrifice. Permanentanovulatory ovaries were found in 30-40% of mice treated neonatally with large doses of 5α-DHT. All of the E₂-treated and 42% of the 5 μg T-treated mice showed permanent anovulation in the ovaries at 90 days of age, while none of the 1 μg T-treated mice had such anovulatory ovaries. Estrogen-independent, permanent vaginal changes occurred in mice receiving injections of 5 μg T or 5-100 μg 5α-DHT, but not in those given the injections of 1 μg T.

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A 23-year-old man of high stature, with hypogonadism and bitemporal-upperquadrantic visual defects was found to have a pituitary tumor. He had a slightly enlarged struma, while he did not show any signs of hyperthyroidism. His serum TSH level (10.4 μU/ml) was slightly elevated in spite of increased levels of serum thyroid hormone (T₃ 249 ng/dl, T₄ 12.0 μg/dl). Neither the elevated serum TSH levels nor thyroidal uptake of ¹²³I were suppressed after 7 days of 75 μg triiodothyronine administration. Serum TSH levels did not increase further after TRH administration. Hypofunction of the anterior pituitary gland was observed. Following transsphenoidal hypophysectomy, his serum thyroid hormone and TSH levels returned to the normal range. Immunohistochemical examination revealed the existence of numerous TSH positive cells. From these data we concluded that the patient had a pituitary tumor which secreted inappropriate amounts of TSH.

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Described here is a 27-year-old female, who had centripetal obesity, broad reddishpurple striae on the lower abdomen and hypertension. Serum cortisol levels, the results of a dexamethasone suppression test and an adrenal scintigram with ¹³¹I-19-iodocholesterol were all compatible with Cushing's syndrome due to an adrenal adenoma that secretes cortisol autonomously. This was confirmed by gross and microscopic examination of the removed adrenal tumor. In addition, the patient had markedly diminished T₄ and T₃ concentrations in serum. Basal TSH levels were not elevated and did not rise significantly after TRH injection. Serum T₄ and T₃ concentrations were elevated to the normal range when the hyperadrenocorticism was corrected. The results indicate that the patient had “corticogenic hypothyroidism.”.

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Daily subcutaneous injection of 200μg 5α-dihydrotestosteron to SHN female mice for the first 5 days of postnatal life resulted in the stimulation of normal and neoplastic mammary development at advanced ages and it also induced the ovarian anovulatory syndrome and stimulated pituitary prolactin secretion. Daily subcutaneous injections of 1mg 5α-dihydrotestosterone to pregnant mice from day 12 to day 15 of pregnancy (prenatal treatment) had no effects on their offspring. Long-term effects of 5α-DHT on normal and neoplastic mammary development in mice were generally not so marked as those observed previously with 5β-dihydrotestosterone which is biologically inactive in the adult.

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Insulin liposomes (dipalmitoyl phosphatidylcholine or dimyristoyl phosphatidylcholine/cholesterol=7/2) were prepared under strongly acidic conditions maintaining the biological activity of insulin. Although these were apparently noncharged liposomes, the association of insulin with membrane of liposomes was unexpectedly very large, and the uptake % of insulin was high. The distribution of vesicle-size of liposomes was narrow; the average diameter was 0.1 μm and no multilayered structures were observed by electron microscopy. Oral administration of the insulin liposomes (15- 30 IU/rat) in streptozotocin-diabetic rats did not result in any distinct tendency to reduce the level of blood glucose.

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Antibody against synthetic 1-34 humanPTH synthesized by Niall et al.(1974), was developed in rabbits. Synthetic 1-34 hPTH was found to be a good immunogen for rabbit. The relative importance of various structural parts of 1-34 hPTH molecule with regard to immunological specificity was determined by reference to inhibition of specific binding of ¹²⁵I-1-34 hPTH to the antibody by analogues of 1-34 hPTH (NLeu⁸-NLeu¹⁸ 1-34 hPTH, NLeu⁸-NLeu¹⁸-Tyr³⁴hPTH) and by 1-34 bPTH. The immunological recognition site in 1-34 hPTH molecule was found to be located around the 8 to 18 amino acid sequence, because the binding affinity to the antibody of this analogue (NLeu⁸-NLeu¹⁸1-34 hPTH) was less than that of the native hormone in the antibody. Furthermore, other immunological recognition sites were located in the C- and N-terminal regions of this molecule, as reported by Segre et al.(1976) and Visser et al.(1979).
This antiserum could measure only 1-34 hPTH molecule in serum, since it did not crossreact with partially purified 1-84 hPTH.
In order to evaluate the advantage of 1-34 hPTH radio-immunoassay (RIA) in the diagnosis of parathyroid dysfunction, serum PTH levels in various diseases were measured by both 1-34 hPTH RIA and 1-84 PTH RIA and the values obtained by these assays were compared.
There was a good correlation between the values obtained by 1-34 hPTH RIA and those by 1-84 PTH RIA. However, in patients with chronic renal failure, the incidence of cases with high serum PTH level was 90% when measured by 1-84 PTH RIA while it was 39% when measured by 1-34 hPTH RIA. Serum PTH levels in primary hyperparathyroidism were abnormally high and those in hypoparathyroidism were low in both assays. Some patients with senile osteoporosis had a high serum PTH level. The incidences of cases with a high serum PTH level in this disease were equal in both assays.
In conclusion, these two site specific RIAs (1-34 PTH RIA and 1-84 PTH RIA) were useful in the evaluation of PTH secretion and / or metabolism.

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Adrenocortical tissues of male adult Wistar rats were fractionated by isopycnic density gradient centrifugation. Fractions were analyzed for density, protein and marker enzymes for lysosomes and mitochondria with rat liver being used as a reference tissue for subcellular enzyme distribution. Both lysosomes and mitochondria of adrenal cortex showed unimodal distribution profiles of marker enzymes with their modal isopycnic density values at 1.165. This value was significantly lower than the corresponding ones for lysosomes and mitochondria in rat liver but was very close to those in porcine adrenal cortex. Modal isopycnic density as well as distribution profiles of marker enzymes for lysosomes and mitochondria remained unchanged 24 hr after 0.1 or 10 units of ACTH (Cortrosyn Z) administration. As in porcine adrenal cortex, lysosomes in rat adrenal cortex were characterized by a higher content of cathepsin D than those in rat liver.

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