In order to study the prognosis of Graves' disease, 236 patients, who had been diagnosed as having had Graves' disease more than 10 years before, were examined. Although one patient had died of leukemia and 2 patients had been operated on for breast cancer after ¹³¹I therapy, and another 6 patients had died between the ages of 20 and 50, the patients were doing quite well.
Generally, the prognosis of Graves' disease is not considered to be serious if the thyroid function is controlled. Among the 72 patients who had been treated with ¹³¹I therapy, 15 patients (21%) showed low serum levels of both T₃ and T₄ and were considered to be suffering from late-onset hypothyroidism. About 67% of the ¹³¹I-treated patients were considered to be almost euthyroid, but serum TSH levels were high in half of them, suggesting latent hypothyroidism.
The incidence of hypertension seemed to be significantly higher in the TSH-elevated euthyroid group compared with the TSH-nonelevated patients. An excessive reaction of the hypothalamus and/or pituitary gland might have an unfavorable effect not only on the apparent hypothyroidism, but also on the latent hypothyroidism after the therapy for Graves' disease.

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The effect of glucose and 2-deoxy-D-glucose on the extrathyroidal monodeiodination of thyroxine (T₄) to 3, 5, 3′-triiodothyronine (T₃) and 3, 3′, 5′-triiodothyronine (reverse T₃ ; rT₃) was studied in human skin fibroblasts in culture.
When the fibroblasts were maintained in glucose-free Eagle's MEM fortified with 3% fetal calf serum, intracellular T₄ was unchanged, intracellular T₃ decreased, and intracellular rT₃ markedly increased as compared with those in Eagle's MEM containing 3% fetal calf serum and 100 mg/dl glucose. In this study, the ratio of T₃ to T₄ fell, and the ratio of rT₃ to T₄ and rT₃ to T₃ rose remarkably in fibroblasts in glucose-deprived media.
,,,,,,,,,When the fibroblasts were maintained in Eagle's MEM containing 3% fetal calf serum and various concentrations of 2-deoxy-D-glucose, intracellular concentrations of thyroid hormone were decreased as compared with those in a 2-deoxy-D-glucose-free control medium. The ratio of rT₃ to T₄ and of rT₃ to T₃, however, augmented although the ratio of T₃ to T₄ did not change in fibroblasts in the media with 2-deoxy-D-glucose.
Cellular energetic deprivation derived from the glucose-free medium and the medium containing 2-deoxy-D-glucose influenced the extrathyroidal monodeiodination of the thyroid hormone. Thus glucose might be an important regulatory factor for the extrathyroidal monodeiodination of T₄ by shifting from T₃ to rT₃ or vice versa, in addition to the feedback system of the pituitary-thyroidal axis.

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We examined the method of radioimmunoassay of the Disc T₄ (dried blood spot T₄) for the purpose of mass screening of neonatal hypothyroidism and tried the parallel assay of T₄ and TSH in dried blood spotted on filter paper at the fifth day of life, and we compared the results.
By changing the volumes of T₄ antibody and T₄ antigen solutions, it is possible to measure thyroxine using two discs 3mm in diameter. Disc T₄ values obtained in 45 unknown samples by this method were in good correlation with serum T₄ values of the same subjects (Y = 0.97X + 0.06). The coefficients of variation were 5.6 to 18.9% in the range of 5.3 to 10.7 μg/100ml of Disc T₄ (within assay), and 7.9 to 20.8% in the range of 2.4 to 10.3 μg/ 100ml of Disc T₄ (between assay).
We measured both Disc T₄ and Disc TSH of 26,067 newborn infants born between June 1978 and May 1979. Out of 26,067 measurements, four cases of primary hypothyroidism, fourteen cases of TBG deficiency and two cases of transient hypothyroidism were dis-covered. Out of the four cases of primary hypothyroidism, three showed low Disc T₄ (1.3 to 4.0 μg/100ml) and high Disc TSH (200 to 240 pu/ml), one showed normal Disc T₄ (7.1 μg/100ml) and high Disc TSH (30 pu/ml). It was thought the last case might be mild hypothyroidism. In 14 cases of TBG deficiency, Disc T₄ was not detectable to 3.4 μg/100ml while Disc TSH was within the normal range. In two cases of transient hypothyroidism, Disc T₄ measurements showed normal range (6.5, 10.6 μg/100ml), and Disc TSH showed high values (41,120 pu/ml). Therefore, Disc TSH was more sensitive and showed less false positive cases than did Disc T₄ for screening hypothyroidism. Although no secondary hypothyroidism existed in the 26,067 measurements, it continues to be important to measure Disc T₄ for the discovery of secondary or tertiary hypothyroidism.

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Urinary excretion of cyclic 3′, 5′-adenosine monophosphate (UcAMP) has been studied by several researchers in an attempt to diagnose primary hyperparathyroidism (1°CHPT), but the results have been conflicting. In secondary hyperparathyroidism, little is known about the behavior of UcAMP.
14 patients with 1°CHPT, 12 patients with hypoparathyroidism (including 2 with pseudohypoparathyroidism), 6 patients with nonparathyroid neoplasms, 44 patients with other normocalcemic diseases including secondary hyperparathyroidism and 16 control subjects were studied with regard to their UcAMP.
Nephrogenous cyclic AMP (NcAMP) was calculated as the difference between total UcAMP and cAMP derived from circulating plasma (plasma cAMP × creatinine clearance).
1) UcAMP, expressed as a function of creatinine excretion (μ mol/g.creatinine), was a good index discriminating 1°CHPT from other diseases. Absolute amounts of cAMP in 24-hour urine were less valuable in this respect. But the patients with a relatively low excretion of creatinine, for instance those with hyperthyroidism, were sometimes difficult to differentiate from 1°CHPT by the ratio UcAMP/g.creatinine.
The following results were obtained :
CAMP was measured by radioimmunoassay employing a YAMASA Kit (YAMASA, Choshi, Japan), and creatinine by Brod & Sirota's method.
2) UcAMP, either expressed in terms of 24-hour excretion or of the ratio to creatinine, was very low in patients with advanced renal diseases. Even in patients with 1°CHPT, UcAMP was not elevated when their renal function had been impaired, rendering the differential diagnosis by the UcAMP less clear cut.
3) UcAMP, expressed as a function of GFR (n mol/100ml GF, GF=glomerular filtrate), reflected parathyroid function more correctly than other expressions : GFR-corrected UcAMP (n mol/100ml GF, mean ± S.D.) was 3.50 ± 0.47 in control subjects, 2.29 ± 0.63 in hypoparathyroidism and 11.25 ± 5.57 in 1°HPT.
4) Two out of three patients with 1°CHPT, whose UcAMP per g.creatinine or per 24-hour urine was within normal limits because of renal damage, showed a definite increase in urinary cAMP when it was expressed as a function of GFR.
5) NcAMP was raised in all 9 patients with 1°CHPT (>2.81 n mol/100ml GF; normal range of values was 0.54-2.42) including a case of chemical type (plasma iPTH=0.43 ng/ml, normal value : <0.5 ng/ml) in whom UcAMP was within the normal range.
6) NcAMP (n mol/100ml GF) was also raised in several examples of normocalcemic patients with Cushing's syndrome, chronic pancreatitis and hypothyroidism in whom plasma iPTH was elevated (indicating secondary hyperparathyroidism). On the other hand, an increase in NcAMP (n mol/100ml GF) was found without elevated iPTH levels in a few examples of patients with pheochromocytoma and hyperthyroidism (indicating false positive).
7) When NcAMP was estimated as a function of the plasma calcium concentration, however, patients with various diseases in whom NcAMP overlapped with that of patients with 1°CHPT could be separated.
8) NcAMP was decreased in one patient with multiple myeloma with bone lesions (0.61 n mol/100ml GF), and increased in another with renal carcinoma without apparent bone metastases (4.71 n mol/100ml GF); the latter was highly suggestive of “ectopic hyperparathyroidism”.
From these results, it may be concluded that UcAMP or NcAMP, expressed as a function of GFR, reflects the parathyroid function not only in patients with hypoparathyroidism and 1°CHPT but also in secondary hyperparathyroidism. The determination of UcAMP, and especially NcAMP, is extremely useful in the diagnosis of 1°CHPT when interpreted as a function of serum calcium level and is useful in differentiating patients with hypercalcemia, either PTH mediated or not.

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The mechanism of secretion of adrenal steroid hormones from adenomas of primary aldosteronism and Cushing's syndrome was studied in 10 patients with primary aldosteronism and in 3 patients with Cushing's syndrome in in vivo and in vitro experiments.
In all of the 10 patients with primary aldosteronism, ACTH stimulated aldosterone secretion from the adenomas more significantly than did angiotensin II and III. DOC and cortisol which were contained in the adenomas were also stimulated more significantly by ACTH than by angiotensin II and III.
Responses of the adenomas of Cushing's syndrome to various stimulations were less than those of primary aldosteronism. Secretion of cortisol and aldosterone from the adenomas of Cushing's syndrome was stimulated by ACTH and angiotensin II to a similar degree.
From these studies, it seems that secretion of adrenal steroid hormones from adenomas of primary aldosteronism is more sensitive to extraadrenal stimulations than that of Cushing's syndrome, and ACTH is the main factor in the control of the secretion of adrenal steroid hormones from the adenomas.

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Congenital adrenocortical unresponsiveness to ACTH is characterized by hyperpigmentation, muscular weakness, and episodes of hypoglycemia, with lethargy or coma and convulsion, and without signs or symptoms of salt wasting. Endocrinological evaluation reveals low levels of serum and urinary glucocorticoids, elevated levels of plasma ACTH and unresponsiveness to exogenous ACTH. On the other hand, aldosterone secretion or excretion is normal and is elevated during a low sodium diet.
We reported on two patients with this syndrome. Case A, a 4 year-old-girl, showed skin hyperpigmentation, hypoglycemia, convulsion and coma. She was tall with a marked advance of bone age. Case B, a 4 year-old-boy, showed skin hyperpigmentation, fatigability and muscular weakness. Both of them revealed low urinary excretion of THE, THF, cortolone, and β-cortolone and low levels of plasma cortisol. The levels of urinary glucocorticoids and plasma cortisol did not respond to ACTH administration. During a low sodium diet, urinary aldosterone excretion was elevated, urinary sodium excretion was decreased, and the patients were able to conserve sodium normally.
We also summarized other reported cases and discussed the etiology of this syndrome.

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A 17-year-old youth was admitted because of proteinuria noted during a routine examination at his high school. His parents and three siblings were living in good health and there was no familial tendency to hypertension and no consanguinity. On physical examination, he was 161cm in height and weighed 43Kg, and his facial expression was female-like. Neither webbed neck nor cubitus valgus was noticed. Severe hypertension ranging from 190/120 to 230/130 was noted. No axillary or pubic hair was present, and the breasts were prepubertal in size. A gynecological examination revealed the presence of labia and vagina.
Laboratory findings on admission were summarized as follows : The urine gave a (-) - (+) test for protein, renal function was revealed as normal, serum potassium ranged from 3.2 to 4.2mEq/L, the specimen of arterial blood showed pH 7.421, and an electrocardiogram revealed left ventricular hypertrophy and U wave changes in leads V₂, V₃ V₄. X-rays showed a bone age of 12 years, and chromosome analysis revealed a karyo type of 46, XY. Endocrinological studies confirming the presence of a 17α-hydroxylase deficiency were summarized as follows :
1) Plasma ACTH was markedly elevated.
2) Plasma renin activity was markedly suppressed showing no response to exercise.
3) Plasma progesteron, plasma DOC and plasma corticosteron were extremely high. In contrast, plasma aldosteron was extremely low.
4) Plasma 17α-OH progesteron and plasma cortisol were markedly reduced. Urinary excretion of 17-OHCS was extremely low.
5) Plasma testosteron and urinary 17-KS were markedly reduced.
The patient was treated with 2mg then 1mg dexamethasone daily for half a year. After one month of therapy, the blood pressure was down to 160/100mmHg, and the serum potassium had risen from 3.2mEq/liter to 5.6mEq/liter. Plasma progesteron, plasma DOC, plasma corticosteron and plasma ACTH decreased to a normal level. Subsequently suppressed plasma renin activity elevated to a normal value. After 6 weeks of this treatment, a laparotomy was performed. Ovaries and uterus were absent, but bilateral testes were found at the external inguinal ring. Microscopic examination of the testis showed Sertoli cell adenoma.
We have reported here a case of 17a-hydroxylase deficiency with male pseudohermaphroditism and discussed the endocrinological data and histological findings of the testis.

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The effects of glucagon on the adrenergic system have been studied in experimental and clinical conditions.
1. in vitro studies:
In the first experiment a continuous flow incubation system was developed in which the secretory response to these drugs was characterized by a serial fluorimetric assay of catecholamines in the effluent medium. Pig adrenal medulla or human pheochromocytoma were studied. There was an initial massive release of catecholamines which declined to basal levels (0.02,μg/mg) after 1.5 hours. When 10^-4 glucagon was infused for 10 minutes following 2 hours of preincubation, both adrenaline and noradrenaline outputs rose abruptly to concentrations of 0.08 μEg/mg and 0.07 μEg/mg respectively. In the second experiment the effect of these drugs on the in vitro release of catecholamines from the isolated in vitro chromaffin granules of the pig adrenal medulla were studied. The results were the same as in the previous experiment.
2. clinical studies:
The effects of glucagon were studied on the blood pressure and urinary catecholamine levels of healthy control subjects, of patients suffering from essential hypertension, thyroid disease, diabetes mellitus and acromegaly. Glucagon induced a slight but constant increase in blood pressure. By contrast no significant urinary catecholamine elevation was evoked. There was no difference in the effect of intravenous glucagon between normal subjects and patients suffering from the above-mentioned disorders.

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The chronic effects of the oral administration of an angiotensin converting enzyme inhibitor (captopril, 63-80 μg/kg/day) on blood pressure and the renin-angiotensin-aldosterone system were studied in normotensive male Wistar rats. The blood pressure (BP), plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate concentration (PRS), plasma aldosterone concentration (PAC), and renal renin content (RRC) were measured 2, 9, 19, 29 and 58 days after the administration of the agent. Blood pressure was determined in unanesthetized rats, and blood samples were obtained by de-capitation. Furthermore, blood pressure responses to bolus injections of angiotensin II (AII, 80 ng/kg), angiotensin I (AI, 80 ng/kg) and bradykinin (BK, 10 μg/kg) were examined in unanesthetized rats which had been given the agent for 20 days. The BP of the rats which had been given captopril for 9 days or more was significantly lower than in the control rats. The reduction in heart weight in the captopril rats reached a statistically significant level 58 days after the administration of the agent. The PRA and the PRC markedly increased, and the PRS and the PAC both decreased in the captopril rats. The RRC which was reduced after 2 days of captopril administration markedly increased thereafter. In the captopril rats, significant negative correlations were observed between PRC and PRS (r=- 0.43, p<0.01), and between BP and PRC (r=-0.60, p<0.001). The PRC significantly correlated with the RRC in the control rats (r=0.44, p<0.01) while such a relationship did not exist in the captopril rats. Although the pressor responses to All were similar in the captopril and the control rats, the responses to AI were reduced to 50% of the responses to All in the captopril rats. The blood pressure reduction in response to BK in the captopril rats was 2.3 times as great as that in the control rats. Thus, it is suggested that the increases in PRA, PRC and RRC in the captopril rats may be related to both the blood pressure reduction and interruption of the negative feedback inhibition of renin synthesis and release by AII, and that the decrease in PRS in the captopril rats is due to the increased consumption and probably to the decreased rate of substrate production in the liver which is secondary to the decrease in plasma AII. The lack of a significant positive correlation between PRC and RRC in the captopril rats seems to demonstrate that captopril may modify the relationship between them. The results also show that the chronic administration of captopril lowers blood pressure in normotensive animals. The blood pressure reduction by captopril may be related to the decreased kininase activity which is suggested by the enhanced depressor responses to BK, as well as the lowered plasma level of AII.

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