A patient with encephalopathy developed triphasic changes in the clinical course, starting with diabetes insipidus (DI), then the syndrome of inappropriate ADH secretion (SIADH), and followed by the final phase of DI. The clinical course of encephalopathy was very rapid. The patient lost consciousness completely within only one day after the onset. During the early phase, he lapsed into a condition of “brain death”. We could not identify the etiology of the encephalopathy. The triphasic change referred to above is similar to previous reports of cats model after stereotactic destruction of the supraopticohypophyseal tract. We speculate that our case may have been associated with neurohypophyseal dysfunction caused by supraopticohypophyseal tract damage.

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Epidermal growth factor (EGF) has been found to be mitogenic in a variety of tissues. We investigated the biological effect of EGF on early pregnant human decidua and the non-pregnant decidualized human endometrium in the primary cell culture. EGF had a stimulatory action on cell proliferatiohn in the early pregnant decidual cells and an inhibitory effect on prolactin (PRL) secretion from the decidual cells. The addition of progesterone into culture medium suppressed cell proliferation of decidual cells, whereas it enhanced PRL secretion from decidua. The analysis of the specific receptor for EGF in the early pregnant decidua and non-pregnant decidualized endometrium revealed that both tissues had a single component EGF receptor with a dissociation constant of nM order. These results suggest that EGF may play a role in the growth and function of endometrial stromal cells.

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To confirm the utility of the bromodeoxyuridine (BrdU) labeling method in the study of cell proliferation in mouse uterine tissues, changes in the labeling index in the luminal and glandular epithelia, the periluminal, periglandular and deep stromal regions and the myometrium were surveyed in normal adult mice during the estrous cycle and early pregnancy, in prepubertal mice and in ovariectomized adult and young animals treated with estrogen and/or progesterone. All results obtained were consistent with those obtained in previous histometric and autoradiographic studies and proved the effectiveness of the BrdU labeling method in the study of the uterus as well as many other organs. A marked rise in the labeling index was found in the luminal epithelium at metestrus, as well as on the proestrous morning, indicating the occurrence of extensive cell proliferation in the absence of estrogen stimulation. The change in the labeling index in adult mice was much more evident in the luminal epithelium than in the glandular epithelium in all conditions examined. On the other hand, the change in the stroma was more eminent in the periglandular region than in the periluminal and deep regions in most conditions. In immature mice, a great increase in labeling incidence occurred not only in luminal epithelium but also in muscle layers along with the process of puberty and at the time of estrogen stimulation. A moderate increase in the incidence also occurred in all other areas of the uterus including the perimetrium. Again, the increase was more prominent in the periglandular area than in other stromal regions.

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The effects of PRL and FSH on testicular LH receptors were studied in hypophysectomized (hypox) mice. From the eleventh day after hypophysectomy, they were given 100μg ovine (o) PRL and/or 2μg oFSH in two injections per day for 10 days. Hypophysectomy reduced the weight of testis, epididymides and seminal vesicles, and the LH binding to the testis. Treatment, with oPRL and/or oFSH in hypox mice resulted in an increase in the weight of testis and epididymides, and the LH binding per testis. There was no: difference between the testicular LH binding in oFSH-and oPRL-treated mice. Histological examination showed that oPRL and/or oFSH treatment in hypox mice restored normal spermatogenesis. Administration of oFSH to hypox mice led to an increase in the number of typical Leydig cells, whereas oPRL was not effective. These results suggest that either PRL or FSH stimulates the LH binding to the testis, but that the action of PRL and FSH on the increase in testicular LH binding is different.

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Insulin-like growth factor-1 (IGF-1) is synthesized primarily by the liver in response to growth hormone (GH). Thyroid hormone plays a major role in mediating pituitary GH secretion. In order to clarify the effect of thyroid hormone on IGF-1 gene expression. we measured hepatic IGF-1 mRNA levels in rats with thyroid dysfunction. Female Wistar rats were rendered hypothyroid by surgical thyroidectomy or hyperthyroid by daily injections of thyroxine (12μg/day) for 2 weeks. Northern gel analysis of hepatic poly (A) RNA revealed the multiple sizes of the RNA transcripts ranging from 1.6 to 9.0 kb. After 4 weeks, hepatic IGF-1 mRNA levels were suppressed in hypothyroid rats, to<20% of control euthyroid animals. These suppressed mRNA levels were restored to euthyroid levels by thyroid hormone replacement for 2 weeks. Hyperthyroid rats, however, did not contain altered levels of hepatic IGF-1 mRNA as compared to euthyroid rats. The r-actin mRNA hybridization signal was not altered in hypothyroid or hyperthyroid rats.
These results suggest that thyroid hormone regulates the in vivo expression of hepatic IGF-1 mRNA, probably through the mechanism of GH regulation.

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Age-related changes in hypothalamic luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH) secretion were studied in young (6 months), middle-aged (12 months) and old (18 months) female rats. The LHRH levels in the mid-hypothalamic area were higher in intact middle-aged and old females than in young ones. Additionally, there was no age difference in the hypothalamic LHRH levels in male rats. In order to clarify the significance of this age-related increase in female rats, we examined the effects of progesterone treatment in estrogen-primed ovariectomized young and old rats on the LHRH levels in the median eminence (ME) and on plasma LH levels. We found phasic changes in ME-LHRH and plasma LH levels in estrogenprimed rats following progesterone treatment in rats of both ages, but the progesterone-induced change in ME-LHRH levels tended to be delayed in old rats compared with young females. This delay may correspond to the delayed onset, slow and low magnitude of plasma LH increase in old females. The ME-LHRH levels were generally higher in old rats than in young rats. Nevertheless, we found that the increase in plasma LH in response to progesterone treatment in estrogen-primed ovariectomized females was smaller in old rats than young rats. These results suggest that the LHRH secretory mechanism changes with age in female rats. Such alterations may result in the accumulation of LHRH in the mid-hypothalamic area and an increase in MELHRH.

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As the first step in surveying the molecular mechanism of androgen-responsive gene expression in rat seminal vesicles, the effect of androgen on the mRNAs was examined by in vitro translation assay. When the in vitro translation products of mRNAs from castrated animals (48h) were compared with those from castrated and testosterone-treated animals (48 h) by SDS-PAGE, several discrete bands which were stimulated or repressed in response to androgen were observed in addition to major peptide bands of SVS IV and SVS V. From these findings, we constructed a partial cDNA library from the seminal vesicle poly (A+) RNAs of androgen-treated rats and screened by differential colony hybridization. Two distinct cDNA clones, pSv-1 and pSv-2, whose mRNAs were differentially stimulated in response to androgen and seemed to be expressed specifically in the seminal vesicles, were isolated. pSv-1 and pSv-2 hybridized to mRNAs of 1, 600 and 3, 500 nucleotides in length, respectively. These cDNA sequences, newly isolated in the present study, may provide useful probes for the study of molecular mechanism of androgenresponsive gene expression.

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When the in vitro translation products of mRNAs from castrated animals (48h) were compared with those from androgen-treated animals (48 h) to survey the molecular mechanism of androgen-responsive gene expressions in the rat seminal vesicles, some peptide bands which were repressed in response to androgen were observed. From these findings, we constructed a partial cDNA library of poly (A+) RNAs which had been isolated from the seminal vesicles of castrated rats (48 h) and modestly enriched with respect to the concentration of androgen-repressed mRNAs by sucrose density gradient centrifugation, and screened by differential colony hybridization. One cDNA clone, pSvr-1, whose mRNA is markedly induced within 24h after castration of the animal in the seminal vesicles as well as in the ventral prostate, was isolated. pSvr-1 hybridized to a mRNA of 1, 700 nucleotides in length. Partial sequence analysis showed that this clone had highly homologous but not identical sequences to those reported for rat sulfated glycoprotein-2. This cDNA clone may provide a useful probe for the study of the negative regulation mechanism of gene expression by androgens.

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To determine whether exogenous GH induces feedback of GH release in children, growth hormone-releasing factor (GRP) tests were performed before and after 10-day GH administration. Sixteen non-obese short boys, aged 5-14 yr, with normal GH response to pharmacological tests were studied.
Mean basal and peak serum GH levels in GR F tests before and after exogenous GH were not significantly different. The subjects were divided into two groups, A and B, according to the percent change in integrated areas under the GH curves in GRF tests (GH AUC) before and after 10-day GH administration. Group A consisted of 6 boys with decreased GH AUC and group B consisted of 10 boys with increased GH AUC. Mean peak GH in GRF tests and mean GH AUC were significantly higher before exogenous GH in group A than in group B. The boys in group A were all prepubertal, while 4 boys in group B had begun their early pubertal change. The mean age in group A (7.8±1.8 yr) was significantly lower than that of group B (11.9±2.4 yr). GH AUC before exogenous GH showed a significant correlation with the percent change in AUC (=-0.742, p<0.01).
These data demonstrated that the exogenous GH suppressed the GH response to GRF in prepubertal children with good response to GRF before exogenous GH, while it exaggerated the GH response to GRF in older children with relatively poor response before GH.

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In 111 thyroid cancer patients consisting of 89 papillary carcinomas, 17 follicular carcinomas, 2 medullary carcinomas, 1 squamous cell carcinoma and 2 malignant lymphomas, the levels of 12 tumor markers, including thyroglobulin (Tg), were measured in the serum by radioimmunoassay and radioimmunoassay related methods. Serum levels of Tg were elevated in 58.6%, those of CA-M26 in 15.7%, CA 19-9 in 5.3%, CT in 3.6%, NSE in 3.6%, CA 15-3 in 2.6%, CA 125 in 2.6%, CEA in 0.9%, CA-M 29 in 0%, ferritin in 0%, SCC in 0% and AFP in 0% of cases.
Among the patients, there was a case of thyroid carcinoma secreting thyroglobulin and CA 19-9, both of whose titer decreased after surgery.
Immunohistochemical studies were carried out on 57 of the above mentioned patients plus 6 anaplastic carcinomas, 15 adenomas, 5 adenomatous goiters, 6 Hashimoto's thyroiditis, 15 Graves' disease and 15 normal subjects. CA 19-9 was positive in 58% of the papillary carcinomas, EGF in 73% of papillary carcinomas, 67% of anaplastic carcinomas, and 33% of follicular carcinomas, while EGF-R was found in 73% of the papillary carcinomas, and 33% of the follicular carcinomas. Enhanced expression of ras p 21 oncogene and (c-myconcogene) was demonstrated in 100%(100%) of anaplastic carcinomas, in 100%(67%) of follicular carcinomas and in 63%(90%) of papillary carcinomas.
Our results indicate that a better tumor marker is required and more extensive molecular oncology research should be pursued.

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Two patients with the rare association of Cushing's syndrome and primary hyperparathyroidism are reported. Initially, both patients suffered from Cushing's syndrome due to adrenal cortical adenomas with typical features and laboratory findings. Five years after treatment of the Cushing's syndrome by removal of the tumor, asymptomatic mild hypercalcemia was incidentally noticed in both patients, which suggested the occurrence of primary hyperparathyroidism. An enlarged parathyroid gland was removed surgically in both cases and was histologically shown to be a parathyroid adenoma. The levels of serum calcium returned to normal after parathyroidectomy. Papillary adenocarcinoma of the thyroid in one patient and adenomatous goiter in the other were also incidentally detected at operation. These findings suggest that Cushing's syndrome resulting from an adrenal cortical adenoma may be another presentation of multiple endocrine neoplasia type I.

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Responses of plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I), and milk production to subcutaneous (sc) injection (s) of two synthetic human growth hormone-releasing factor (hGRF) analogs were studied in dairy cows. Two mg of each hGRF analog dissolved in 5ml saline per cow were injected into the shoulder area of each experimental animal, and jugular venous blood samples were collected via an indwelling catheter or by venipuncture. Plasma GH and IGF-I concentrations were measured by radioimmnoassay methods.
In dry cows, the mean concentration of plasma GH after a single sc injection of hGRF analogs rose to 22.0-28.3ng/ml at about 5h from 1.4-1.7ng/ml at 0h (just before injection), and returned to the level before injection after 10-12h. On the other hand, the plasma IGF-I began to increase after a lag of 4-6h following a single injection of hGRF analogs, and reached maximum values of 71.1-89.4ng/ml at 20h from 43.7-46.4ng/ml at 0h. The IGF-I concentration at 24h after a single injection of hGRF analogs was still higher than the value for the dry cows given saline.
In lactating cows, the plasma concentration of GH at 2h after daily sc injections of hGRF analogs during 14 consecutive days (an injection period) was higher than those for the lactating cows which received saline. Also, during the injection period, the concentration of IGF-I was higher in the lactating cows which received hGRF analog injections than in the cows which received saline injections. During the last 7 days of the injection period, the administration of hGRF analogs increased the mean milk yield by 11-19% in comparison with those for the saline in jected cows. A positive correlation was observed between the mean plasma IGF-I concentration and the mean milk yield in the lactating cows treated with hGRF analogs throughout the injection and a postinjection (11 consecutive days after cessation of hGRF analog injection) periods.
The results demonstrate that a single sc injection of hGRF analogs stimulates both GH release and the circulating level of IGF-I in dry cows, and that daily sc injections of hGRF analogs over 14 days enhance milk production, and plasma GH and IGF-I levels in lactating cows.

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Thyroid microsomal antigen is considered ;to be identical with thyroid peroxidase (TPO). Although there have been many reports concerning changes in microsomal autoantibody during the course of antithyroid drug therapy for Graves' disease, little is known about this matter in relation to TPO autoantibody (TPOab). Therefore, in this paper, we studied serial changes in the latter autoantibody. Initial levels of serum TPOab (%immunoprecipitation) in 13 patients with hyperthyroid Graves' disease ranged from-11.3% to+84.5%(mean±SD, 38.9±31.8%). Of three patients w ith persistently increased serum TPOab throughout drug therapy, all had recurrence of hyperthyroidism after the drug was discontinued. Of seven patients whose TPOab levels were initially high but subsequently decreased, four had remission of the disease after drug therapy. Inhibition by TPOab of the TPO activity was also demonstrated by both guaiacol and iodide assays, and changes in this inhibitory activity during therapy varied among individuals. This inhibition was not correlated with disease remission. The decrease in serum TPOab observed in some antithyroid drug-treated patients may reflect a decline in disease activity or may be a direct effect of the drug.

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The effect of sterol carrier protein₂ (SCP₂) purified from rat liver on the formation of cholesterol esters by acyl-CoA: cholesterol acyl-transferase (ACAT: EC 2.3.1.26) in rat adrenal microsomes was studied. The rate of incorporation of [1-¹⁴C] oleoyl-CoA into cholesteryl oleate was determined in the presence or absence of exogenously added cholesterol or SCP₂, or both. The addition of SCP₂ had no effect on the formation of cholesterol esters from endogenous cholesterol by ACAT in rat adrenal microsomes. In contrast, the formation of cholesterol esters from exogenous cholesterol by ACAT was dose-dependently increased by the addition of SCP₂. These experiments showed that SCP₂ had an enhancing effect on cholesterol esterification by ACAT in rat adrenal microsomes most likely by modulating the availability of exogenous cholesterol and that SCP₂ may participate in the formation of cholesterol esters in the rat adrenal gland.

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Recent Studies have demonstrated that glucagon-like peptide-1 (GLP)(7-37) has more potent insulinotropic activity than glucagon. We therefore examined the effect of GLP-1 (7-37) on liver metabolism using rat liver perfusion system. Ten nM GLP-1 (7-37) did not affect glucose, ketone body and cAMP outputs from the perfused liver. Whereas, the same dose of glucagon stimulated these outputs significantly. When 10nM GLP-1 (7-37) perfused 5 min before the administration of 10nM glucagon, the above stimulatory effects of glucagon were not affected. These results indicate that truncated GLP-1 has no effect on hepatic glycogenolysis and ketogenesis dissociating from its potent insulinotropic activity.

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Immunohistochemical studies of the gastrointestinal tract were carried out to characterize the cells exhibiting immunoreactivity for chromogranin A (CGA), a glycosylated protein primarily found in secretory granules of the adrenal medulla. Double immunostaining for gastrointestinal hormones and CGA revealed that in the bovine gastrointestinal tract CGA immunoreativity occurs in mucosal epithelial cells containing gastrin, glucagon, substance P or motilin, but not in those containing somatostatin. Combined staining with anti-CGA serum and Grimelius' silver demonstrated frequent association of the two stains in a variety of endocrine cells. However, intracellular distribution of the two stains was different: CGA-immunoreactivity was detected in both supra- and infranuclear cytoplasm, whereas Grimelius' silver was mostly localized in the infranuclear region. These results suggest that CGA is the target of Grimelius' silver, as postulated recently (Rindi et al., 1986), but that some subcellular structure-related modification of molecules such as sialation is necessary for the positive Grimelius reaction.

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Recombinant human insulin-like growth factor I (IGF-I) was administered subcutaneously to each of 5 normal human subjects at doses of 0mg/kg (control), 0.06mg/kg, or 0.12mg/kg successively at one week intervals. After 0.06mg/kg or 0.12mg/kg IGF-I injections, plasma IGF-I levels increased from 185±17ng/ml (Mean±SEM) to maximal levels of 396±21ng/ml at 3 hours and from 169±14ng/ml to 480±27ng/ml at 4 hours, respectively. These two peak values were statistically different (p<0.05). After 0.06mg/kg and 0.12 mg/kg IGF-I administration, blood glucose levels decreased from 85±2mg/dl to minimal levels of 73±3mg/dl at 3 hours and from 83±1mg/dl to 50±4 mg/dl at 2 hours, respectively. These two minimal values were statistically different (p<0.001).
Serum insulin and C-peptide levels were decreased in a dose dependent manner after IGF-I administration. There were no changes between blood urea nitrogen levels before and 4 hours after IGF-I administration. The urinary GH concentration decreased after 0.06mg/kg IGF-I administration, but increased and maintained normal values after 0.12mg/kg IGF-I administration.

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