Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These twoacromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two monthsafter surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level18months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramideprovokedGH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.

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A 51-year-old woman had symptoms of thyrotoxicosis which disappeared spontaneously within two months. She was diagnosed as a case of silent thyroiditis on the basis of both the clinical course and the laboratory data such as low uptake of radioactive iodine and technesium. She also had petechiae in her arms which were diagnosed as an idiopathic thrombocytopenic purpura (I. T. P.) This case would seem to expand the spectrum of the coexistence of autoimmune thyroid diseases and I. T. P. which is believed to be an autoimmune disease.

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We studied the suppressibility of cortisol secretion in 15 patients with Cushing's disease by measuring morning plasma cortisol level as well as the 24-hour urinary free corisol (UFC) excretion following single doses of increasing amounts of dexamethasone (ranging from 0.5 to 32mg) given at 11 p.m. The mean plasma cortisol level in patients with Cushing's disease was twice as high as in normal subjects, whereas the mean UFC in these patients was 6 times as high. Plasma cortisol in seven patients were suppressed by less than 4mg of dexamethasone (in 2 cases, less than 0.5mg; in 3 cases, less than 2mg; and in 2 cases less than 4mg). In these cases, basal plasma cortisol and UFC were less than 25μg/dl and 350μg/day, respectively. Among the other eight patients, plasma cortisol was partially suppressed in 5 cases and not suppressed in 3 cases by high doses of dexamethasone (16-32mg). In these cases the basal plasma cortisol and UFC were more than 25μg/dl and 350μg/day, respectively. There was a significant correlation between the basal plasma cortisol and UFC (r=0.687, p<0.01). These data suggest that the suppression by increasing amounts of dexamethasone in most cases with Cushing's disease was related to the severity of hypercortisolism.

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We have evaluated the residual pancreatic B cell function by glucagon load test in 28 patients with non-insulin-dependent diabetes mellitus (NIDDM) of a duration of 20 years or more. The increase in serum C-peptide at 6 minutes after glucagon administration (ΔC-peptide) was used as an index of residual B cell function. There was much lessΔC-peptide in patients treated with insulin than in those treated with sulfonylurea (p<0.05), and it was significantly correlated with the body mass index (r=0.40, p<0.05). Long term metabolic control assessed by the average annual mean fasting blood glucose for the observation period (mean, 21 years) was not correlated with ΔC-peptide (r=-0.13). The prevalence of retinopathy which needed photocoagulation therapy and of neuropathy in ptaients with poor residual B cell function (ΔC-peptide≤0.3ng/ml) was the same as that in those with good residual B cell function (ΔC-peptide≥1.0ng/ml). The present study shows that the residual B cell function is not correlated with long term glycemic control and the prevalence of diabetic complications in long-standing NIDDM patients.

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The comparative biological activities of intracerebroventricular (icy) injection of α-rat and α-human atrial natriuretic peptide (rANP and hANP, respectively) in the arginine vasopressin (AVP) release in conscious rats and the binding properties of these peptides to their specific receptors have been investigated. An icy injection of 5μg rANP inhibited the AVP release induced by osmotic and hemorrhagic stimuli. In contrast, 20μg of hANP was needed to exert an inhibitory effect on the AVPrelease. The receptor binding studies were carried out by using rat hypothalamic membrane preparations. The binding studies revealed that the potency of rANP was greater than that of hANP in displacingradioligand from its binding sites. Scatchard analysis revealed that the dissociation constant forrANP was significantly lower than that for hANP (0.52±0.04 vs 1.20±0.16nM, P<0.01). The binding capacity of these peptides was similar. These results suggest that the greater biological potency of rANP compared with hANP in the inhibition of AVP release is caused by the differencein the binding potency of these peptides

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Transient neonatal hypothyroidism due to transplacental transferof maternal blocking type TSH receptor antibodies (TRAb) was found in a baby born to a 27-yr-old mother, who had been receiving thyroxine medication for primary myxedema. Maternal IgG inhibited radiolabelled TSH binding to its receptor (TBII), TSH-stimulated thyroid adenylate cyclase (AC) activation (TSII) and TSH-stimulated ³H-thymidine uptake (TGII) in cultured rat thyroid cells (FRTL-5). At birth, the baby's IgG showed similar activities to maternal IgG but all these activities decreased gradually, and disappeared fromher serum within 12 weeks of age. In the baby, initially nonvisualized thyroid was clearly visualized on 99 m-Tc thyroid scintigraphy when all these blocking activities disappeared, TSII and TGII being decreased more slowly than TBII, and thebaby remained euthyroid after discontinuation of thyroxine. Thisstudy suggests that such IgGs induced hypothyroidism and thyroidatrophy in the mother and were responsible for transient neonatal hypothyroidism in the baby.

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In order to investigate whether endogenous GHRH and somatostatinwere involved in the mechanism of the paradoxical GH rise after TRH injection, changes in serum GH and plasma GHRH were examinedbefore and after TRH injection in 12 cancer patients and changesin serum TSH and GH were similarly studied in 76 cancer patientsincluding 31 GH-responders and 45 GH-nonresponders to TRH. TRH stimulated GH secretions without altering the circulating GHRH concentration in 4 of the 12 cancer patients.
There was neithera significant correlation between the increase from the basal tomaximum GH and GHRH after TRH injection in the 12 cancer patients nor a reciprocal relationship between the increase in GH and TSH after TRH injection in the 76 cancer patients.
These findings suggested that the paradoxical GH rise after TRH injection in cancer patients was exerted by its direct action at the pituitary level, and not mediated through the hypothalamus.

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We saw a total of 4 episodes of the recurrence of subacute thyroiditis in 3 patients out of 222. The recurrent episodes were similar to the first episodes of subacute thyroiditis. The titers of various viral antibodies were not increased significantly during the clinical course of the recurrence. Regarding the HLA typing, A26, B35 and C3 were positive in all 3 patients. The association between the occurrence of subacute thyroiditis and the presence of HLA-B35 and C3 has hitherto been reported, although the association of HLA-A26 with recurrent type of subacute thyroiditis was observed and described for the first time in this report.It is suggested that HLA-A26 may somehow be related to the predisposition to the recurrence of subacute thyroiditis which developed after more than 10 years.

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To investigate the relationship between TSH and abnormal thyroid stimulator (s) in patients with hyperthyroid Graves' disease in whom normal thyroid hormone levels in the serum were maintained by antithyroid drug therapy and in patients with euthyroid Graves' disease, determinations were made of the TSH concentration, action of thyroid stimulating immunoglobulins (TSAb and TBII), and T3 suppression.
Out of thirty-three patients with hyperthyroid Graves' disease, twelve patients with subnormal TSH levels were all non-suppressible according to the T3 suppression test results and the detectability of TSAb and/or TBII was as high as 75%.
In three out of five patients with euthyroid Graves' disease, the serum TSH level was subnormal. All three showed non-suppressibility in the T3 suppression test and positive action of either TSAb or TBII. One of them became clinically thyrotoxic when the TSAb activity was further increased and TBII became positive, and was therefore diagnosed as having hyperthyroid Graves' disease.
The present findings suggest that there are still abnormal thyroid stimulator (s) in patients with hyperthyroid Graves' disease who have low TSH, even if their thyroid hormone concentrations remain normal. Moreover, it is likely that some of the patients with euthyroid Graves' disease are actually in a state of subclinical hyperthyroidism because of the presence of abnormal thyroid stimulator (s).

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Circulating thyroid peroxidase (TPO)-like substance in healthy human peripheral blood was studied to clarify the immunological role of TPO. By using a highly sensitive radioimmunoassay system combined with murine monoclonal antibodies, TPO-like substance was measurable in 6 out of 84 sera. Characterization of this circulating substance by gel filtration revealed that the molecular weight of a major peak corresponded to that of trypsinized TPO. From these findings it is possible that peripheral blood lymphocytes are exposed to a low level of TPO as well as to thyroglobulin.

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Serum levels of IGF-I were radioimmunoassayed after acid ethanol extraction in 1075 normal subjects from infants through young adults, and the normal range for each age was established. The mean value for infants which was relatively low increased gradually with age, and rose sharply after that reaching the peak levels at mid adolescence, then it decreased slowly to the young adult levels. Significantly higher mean values were observed in females at the age of 9, 10, 11 and 12 years. Each of 23 cases with pituitary dwarfism exhibited a lower concentration than the lower limit of the bone age matched normal range. All of the 59 normal variant short children except three showed normal values, but the values were distributed over the lower side of the range.

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To study the factors involved in the low thyroid hormone levels in patients with chronic renal failure (CRF), we investigated thyroid functions just before and after hemodialysesl (HD) in 32 such patients who were on maintenance HD. In addition, we measured serum thyroid hormone binding inhibitor activities (THBI) in another set of 37 patients.
None of the patients had been suspected of having thyroid diseases. HD duration and aging did not have a significant effect on the results of the thyroid function tests. Before each HD, the serum concentrations of T3, T4, FT3, FT4, rT3., PBI, FT3I, FT4I, FT3/T3, FT4/T4, T4/TBG, T4/TSH and FT4/TSH were lower, and those of TSH, TBG, and thyroglobulin (Tg) were higher in the patients than in normal controls. The thyroid hormone concentrations were negatively correlated with the BUN and creatinine levels. The Tg levels were positively correlated with the BUN levels. After each HD, almost all the thyroid function tests including T4/TBG ratio showed improvements, which indicated that hemodilution and a decrease in the T4-binding affinity of TBG with thyroid hormones were the major factors in the low thyroid hormone levels in CRF patients. However, even after HD, T3, FT3, rT3, T4/TSH and FT4/TSH were still lower and TSH and Tg were still higher in the patients. These data suggested that the CRF patients were in a subclinical hypothyroid state.
THBI was high in patients with CRF and did not change following HD. NEFA did not seem to contribute to the high THBI before HD, because they were in the normal range. However, as NEFA became very high after HD and possessed THBI, we calculated the corrected THBI (C-THBI) by subtractng the effect of NEFA from total THBI. C-THBI was high before HD and decreased after HD. Therefore, it was suggested that this C-THBI contributed to the abnormalities in the affinity of TBG with thyroid hormones.
From these studies, it is concluded that (1) the patients with CRF may be in a suclinical hypothyroid state, although hemodilution was seen to have a strong effect on the thyroid hormone concentrations, and (2) C-THBI may have an effect on the affinity of TBG with thyroid hormones and play an additional role in low thyroid hormone levels in these patients. The mechanisms of hypothyroidism and the nature of C-THBI remain to be clarified.

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The present study was designed to investigate the involvement of the renal nerve in glucocorticoid hyp rtension and to assess the role of the renin-angiotensin system in dexamethasone-induced hypertension. The elevated blood pressure in dexamethasone treated rats showing a significant increase in plasma renin concentration (PRC) and activity (PRA) was attenuated dose-dependently by the angiotensin I converting enzyme (ACE) inhibition. Bilateral renal denervation caused a partial decrease in the elevated blood pressure, abolished the increased PRC and PRA, and reduced the dose-dependent decrease in blood pressure with ACE inhibition in dexamethasone treated rats. Although the reduction in body weight and increases in urine volume, urinary sodium excretion and hematocrit were clearly seen following dexamethasone administration, dexamethasone-treated renal denervated rats showed the same degree of change in any of the variables as dexamethasone-treated sham-operated rats. Thus, our results indicate that the stimulation of the renin-angiotensin system through the activation of the renal nerve may be partially responsible for the dexamethasone-induced high blood pressure and, therefore, bilateral renal denervation reduces, partially but significantly, the elevated blood pressure, suggesting that the attenuation of oversecretion of renin contributes to the lowering of the blood pressure.

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7B2 (a novel pituitary protein) is a secretory protein in the neuroendocrine tissues and an increase in the plasma 7B2 concentration was noted in some patients with various endocrine tumors, including small cell carcinoma of the lung and acromegaly, suggesting that 7B2 is a possible marker for these tumors. Using a radioimmunoassay, the 7B2 concentration was measured in pleural fluid samples obtained from 36 patients with lung cancer and benign pulmonary disease to assess its concentration as a marker for small cell carcinoma of the lung (SCCL) or malignant effusion. 7B2-immunoreactivity (IR) was present in pleural fluid and its concentration was much higher than in plasma. However, there was no significant difference between pleural fluid 7B2 in patients with SCCL and in other histological types of lung carcinoma or in malignant and nonmalignant patients. In the chromatographic analysis of pleural fluid on gel permeation chromatography and reverse-phase high-performance liquid chromatography, there was no molecular heterogeneity between malignant and nonmalignant effusion. These results suggest that pleural fluid 7B2-IR is not a useful marker for SCCL or malignant effusion.

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We previously found that splenectomy caused a 1-day delay in ovulation in cycling rats. In the present study, the role of the spleen or splenocytes in corpus luteum function was investigated by comparing long-term splenectomized (SPX) rats with intact controls. When the rats were cervically stimulated on the day of proestrus, both SPX and control rats showed prolonged diestrus for 16 days associated with an increase in serum progesterone (P). However, in SPX rats, 20α-dihydroprogesterone (20α-OHP) concentrations were double those of controls throughout the period of pseudopregnancy. The concentration of total progestin (P plus 20α-OHP) was also higher in SPX rats. All of these phenomena were normalized by injecting the animals with splenocytes. Taken together with our previous findings, these results indicate that splenocytes are involved in the control of ovarian function.

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The human prostate contains a protein which binds with progesterone in high affinity and low capacity fashion. Characteristics of the progestinbinding protein in the prostate have been disputable; whether it is progesterone receptor or not. Therefore, the characteristics of the progestin binder in the benign hypertrophic human prostate was examined in the present study. After photoaffinity labeling with ³H-R 5020, the binder in the prostate migrated to site of 42K on polyacrylamide gel electrophoresis under denaturing conditions, and the mobility was apparently different from that of the progesterone receptor in the human uterine endometrium. There was no protein in the prostate immunoreacted with a monoclonal antibody raised against the human progesterone receptor. It was concluded that the progestin-binding protein in human prostate was different from the progesterone receptor observed in female human organs.

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In order to assess the possible involvement of thyroid hormone in a human atrial natriuretic peptide (αhANP), we investigated the plasma and urine ANP concentration in patients with primary hyperthyroidism and hypothyroidism. Plasma and urine were extracted through Sep-Pak C₁₈ cartridges and the urine ANP concentration was corrected by urine creatinine (cre. mg/dl) and expressed as fmol/mg·cre. The plasma ANP concentration in patients with untreated hyperthyroidism (32.3±7.0 fmol/ml; n=22) was higher than in normal subjects (p<0.01 vs control; 6.2±0.7 fmol/ml). After restoration to euthyroidism, the plasma ANP concentration (patients with treated hyperthyroidism) fell to normal (8.9±1.9 fmol/ml). The plasma ANP concentration in patients with untreated hypothyroidism (14.1±3.0 fmol/ml; n=7) was higher than normal, but in two of them there was mild renal dysfunction and an incomplete right blundle branch block in the electrocardiogram. It was possible that these factors contributed to the observed increase in plasma ANP. However, a significant positive correlation was found between plasma ANP and free thyroxine (n=40, r = 0.449;p<0.01) and free triiodothyronine (n=40, r=0.546; p<0.01). The urine ANP concentration in patients with untreated hyperthyroidism was markedly higher than in normal subjects (p<0.01), but in untreared hypothyroidism not significantly different from normal.

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A 26-year-old man with hypothalamic hypodipsia-hypernatremia syndrome is reported, who presented with adipsia, hypernatremia, and impaired osmolalitymediated arginine vassopressin (AVP) secretion. A chorionic gonadotropinsecreting tumor was detected in the anterior hypothalamus and treated with external irradiation. After the treatment, hypernatremia persisted and was not corrected by fluid loading, osmolality-mediated AVP secretion remained impaired. Despite the absence of signs of hydropenia, hypovolemia was suggested by low blood pressure and elevated plasma indices of the renin-angiotensin system, and supported by blood volume determination. The plasma aldosterone concentrations were inappropriately low for the renin-angiotensin status. The plasma atrial natriuretic polypeptide (ANP) level was normal in spite of hypovolemia and increased more than double after fluid loading. Hypernatremia, primarily caused by hypodipsia and impaired osmolality-mediated AVP secretion, secondarily sustained ANP secretion and suppressed aldosterone release, which conceivably contributed to the development and perpetuation of hypovolemia in this patient.

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A male patient with hypogonadotropic hypogonadism has been treated by pulsatile administration of luteinizing hormone-releasing hormone (LHRH)(20-25μg, every 2 hours, sc) for 4 years 6 months. His plasma testosterone (T) concentration began to increase after 4 weeks of treatment and reached the normal range in week 5. He showed complete secondary sexual develop ment after 1 year of treatment. His sperm count was normalized after 1 year of treatment. He was married after 29 months of therapy, and has a healthy male child. Blood type tests showed his paternity of the child. During the long duration of pulsatile LHRH therapy, his gonadotropin secretion has been stimulated by LHRH and his T level has been maintained with no observable side effects. There are no other reports of patients treated by pulsatile LHRH injection for such a long duration, but finding in this patient indicated that long-term pulsatile LHRH therapy is a useful and safe method for treatment of hypothalamic hypogonadotropic hypogonadism.

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