The results of the statistical survey on Japanese patients with malignant exophthalmos performed in 1978 are reported.
While 15,442 patients with Graves' disease were seen in 9 thyroid clinics, 121 cases (0.8%) were diagnosed as malignant exophthalmos. Exophthalmos was present in 30.1% of 8,801 cases of Graves' disease.
Two hundred and twelve patients with malignant exophthalmos reported from 13 institutions were analyzed. The male-female ratio of the patients was 1 : 1.06, and 22.2% of them was not associated with hyperthyroidism. The age distribution of the patients' first visit peaked at the 5th decade.
A family history of thyroid disorder was found in 11.8%. Twenty-one percent of the patients had previous treatments for hyperthyroidism. Aggravation of eye symptoms was reported in some patients treated with antithyroid drugs or radioiodine. Goiter was not palpable in 16% of the cases, and estimated weight of the thyroid was smaller in patients without hyperthyroidism. The consistency of the goiter was elastic firm in 35% of the cases. Thyroid histology revealed Hashimoto's thyroiditis in 6 out of 20 patients studied. Thyroid function varied widely from hypothyroid to hyperthyroid ranges, being mostly in euthyroid or mildly thyrotoxic ranges. Few patients showed a normal TRH-test or T₃ suppression test. Antithyroglobulin and antimicrosomal antibodies by TRC were detected in 17.8% and 63.5%, respectively.
The grade of proptosis ranged up to 29mm with the maximum right-left difference of 7mm. The incidences of eye symptoms were as follows : pain 30.5%, conjunctival injection and chemosis 89.3%, diplopia 66.3%, restriction of eye motion 51.6%, lagophthalmos 27.0%, corneal lesion 44.4%, visual field defect 9.4%. Upper and lateral gaze was most often limited.
Abnormalities on funduscopy, roentgen study and CT were found in 18%, 5%, and 94% respectively. A follow up study up to 5 years revealed amelioration with treatment in 36%, no change in 55%.
The treatment reported effective included adrenocortical steroids, radiation and thyroid hormones, however, the effect of steroids and radiation on proptosis was considered temporary in most cases.

抄録全体を表示

An investigation was made using 110 patients with simple goiter, which was characterized by euthyroid (serum T₃, T₄, and T₃-U : normal), negative antithyroid antibodies (thyroid test, microsome test : negative) and relatively soft diffuse goiter. Out of the 110 cases, the TRH test was performed in 105, and the T₃ suppression test was performed in 93 after each TRH test, while satisfactory biopsies of the thyroid were performed in 31.
The results revealed that 24 of the 110 cases (21.8%) showed an abnormal response to TRH. Seven of these (6.7%) showed either a negative or a hypo-response (peak value of TSH was less than 4.9μU/ml), and 17 cases (16.2%) revealed a hyper-response (peak value of TSH was more than 35μU/ml).
In 7 cases with no or hypo-response, serum T₃ (1.59 ± 0.15ng/ml : Mean ± SE) was found to be significantly higher as compared with those of normal responders (1.29 ± 0.03ng/ml) or hyper-responders (1.31 ± 0.08ng/ml). For the T₃ suppression test, 3 of 93 cases (3.2%) were non-suppressible. All of the 3 non-suppressible cases showed a normal response to TRH, and there was no definite correlation between negative or hypo-responders and non-suppressible cases. One of the 3 non-suppressible cases revealed focal thyroiditis with epithelial hyperplastic change by needle biopsy. As determined by histologic examination of the needle biopsy specimen, 15 of the 31 cases (48.4%) had normal follicles with-out lymphocytic infiltration, 7 (22.6%) had suspected chronic thyroiditis, 4 (12.9%) had suspected focal thyroiditis with hyperplastic change, 4 (12.9%) had suspected diffuse epithelial hyperplastic change, and 1 (3.2%) had suspected adenomatous goiter which showed considerable variation in follicular size, interfollicular hemorrhage and slight stromal fibrosis. Basal TSH levels and peak TSH response to TRH were greater in the suspected chronic thyroiditis than in normal follicles without lymphocytic infiltration. These results indicate that simple goiter may not be one disease unit, but may include chronic thyroiditis, the first stage of hyperthyroidism and adenomatous goiter, etc.

抄録全体を表示

Since tolbutamide is one of drugs in lowering the blood sugar level by the increase of endogenous insulin secretion, it has been thought that the drug will be able to use clinically the same diagnostic process of the dysfunctions in the human pituitary gland as the insulin-induced hypoglycemia. However, recently Hoshino reported that the tolbutamide inhibited the secretion of cortisol from the adrenal cortex within 30 min after the administration of the drug and in addition, he found also that the PRL levels in the serum were not increased by the tolbutamide-induced hypoglycemia in normal subjects, in whom the PRL levels in the serum were clearly increased by the insulin-induced hypoglycemia. The present study was thus designed to clarify as to whether or not the inhibitory effect of the tolbutamide on several trophic hormones in the pituitary gland such as GH, ACTH, PRL and TSH would be observed in primary hypothyroidism, in which it has been known that at least the production and the release of both TSH and PRL in the pituitary gland are surely increased.
Both of the hypoglycemia induced by insulin or tolbutamide were applied to 6 out of 24 healthy normal subjects (ages; 30-62 yrs, male; 11, female; 13) and 3 primary hypothyroidism (ages; 28, 25, 56 yrs in each, female in all) in the present study. Although the other normal subjects were used to search only the change of the serum GH level in the tolbutamide hypoglycemia, the values of GH, PRL, TSH, ACTH and cortisol in the serum were measured by the method of radioimmunoassay up to 120 min after the injection of tolbutamide or insulin. Five more patients with primary hypothyroidism were employed to study the effect of the tolbutamide on the PRL secretion from the pituitary gland.
Although the tolbutamide stimulated the secretions of GH and ACTH in the pituitary glands of both normal subjects and primary hypothyroidism, the peak values of both trophic hormones in the serum in the tolbutamide group were only 1/3rd times as high as those obtained in the insulin group. These facts were much more strikingly observed in primary hypothyroidism. Such a possible inhibitory effect of the tolbutamide on the pituitary was clearly appeared in the PRL secretion, in which no increase of PRL in the serum was observed in all of normal subjects used herein and a clear decrease of the serum level of PRL was observed in 6 out of 8 primary hypothyroidism. In contrast, the hypoglycemic episodes produced by either tolbutamide or insulin did not affect the secretion of TSH even in primary hypothyroidism.
The facts suggested strongly that an inhibitory effect of the tolbutamide would be appeared the most strongly in PRL, being a questionable extents in GH or ACTH and that no effect of the drug on the TSH secretion was observed.

抄録全体を表示

Cyproterone acetate (CA), an antiandrogenic synthetic steroid with inhibitory effects on gonadotropin secretion, has been used in the treatment of precocious puberty (PP) in Europe for the last decade. CA has been proven to be effective in reducing the clinical manifestations of sexual maturation without serious side effects. However, the effect of CA on adult height in patients with PP is still controversial, and the mechanism of action of this drug in PP remains to be investigated. We recently collected reports of 74 cases (17 males and 57 females) of PP treated with CA through a questionnaire sent to 14 hospitals all over the country. They comprised 50 cases of idiopathic PP, 14 cases of PP secondary to organic brain lesions, 7 cases of PP secondary to congenital adrenal hyperplasia and 3 cases of McCune Albright syndrome. In this report, the effect of CA on clinical manifestations, linear growth and pituitary-gonadal and adrenocortical functions as well as side effects were studied by summing up these questionnaires.
The CA therapy was started between one and thirteen years of age and was continued for three to 54 months. CA was administered orally in a dose ranging from 44 to 147mg/ m2 /day in all but four patients. CA was markedly effective in 15, moderately effective in 38, slightly effective in 17 and ineffective in only four patients on a clinical basis. Minor clinical side effects such as excessive weight gain (one case), gynecomastia (two cases), headache (two cases), depression (one case) and easy fatigability (one case) were observed in 6 out of 74 patients, however, CA was not discontinued or tapered off because of these side effects in any of the patients.
Plasma cortisol concentrations were depressed occasionally during the CA therapy, but there were no definite clinical signs of depressed adrenocortical function. The mean basal level of LH and the mean response after LH-RH stimulation were significantly reduced by CA, while FSH secretion and its responsiveness to LH-RH were not significantly affected. Plasma testosterone levels were abruptly suppressed by CA in two out of three boys, but they rose again after prolonged therapy. The mean serum estradiol level in girls was suppressed to a similar degree with LH though this was statistically insignificant because of a smaller amount of data. These findings suggest that the suppression of LH secretion from the pituitary is the most important mechanism of action of CA on PP.
In order to evaluate the effect of CA on linear growth, the ratio of height age (HA) and bone age (BA), the predicted adult height estimated by the method of Bayley and Pinneau and the ratio of the increase of height age (ΔHA) to the increase of bone age (ΔBA), were studied in 34 patients in whom change of BA could be followed up for more than one year. HA/BA ratios were increased after the treatment with CA in 25 out of 34 cases. Predicted adult heights were also increased in 24 out of 28 cases evaluated, and AHA/ABA ratios during the CA therapy were more than 1.0 in 26 out of 34 cases. The increase of predicted height and the ΔHA/ΔBA ratio of more than 1.0 were statistically significant, while the increase of HA/BA ratio was statistically significant only in a group of 14 cases in whom the change of BA could be followed up for more than two years. These data suggest that treatment with CA exerts a beneficial effect on linear growth in PP and that this effect may be further increased by a longer period of the therapy.

抄録全体を表示

This study was designed to obtain indicators for endocrine responsiveness in human breast cancer. In this study steroid receptors in breast cancer tissue were first characterized as follows : estradiol-17β (E₂) -estrogen receptor (ER) had a dissociation constant (Kd) of 5.50 ± 0.39 × 10^-10M in premenopause or 5.60 ± 0.43 × 10^-10M in postmenopause, R5020progesterone receptor (PR) had a Kd of 4.80 ± 0.63 × 10^-10M in premenopause or 4.20 ± 0.40 × 10^-10M in postmenopause, 5α-dihydrotestosterone (DHT) -androgen receptor (AR) had a Kd of 5.04 ± 0.55 × 10^-10M in premenopause or 4.12 ± 0.47 × 10^-10M in postmenopause, and R1881-AR had a Kd of 2.90 ± 0.50 × 10^-10M, determined by charcoal adsorption at 4°C. Such steroid receptors were sedimented to 7-6S and 5-4S regions, and the 7-6S binding was easily dissociated during 5-20 percent sucrose gradient centrifugation. R1881-cytosol bindings contained AR and PR. Cytosolic steroid receptor levels were determined in each case. Maximal binding sites (Bm; fmol/mg cytosol protein) analyzed by Scatchard plots analysis were as follows : 65.6 ± 11.4 (premenopause) and 81.0 ± 17.1 (postmenopause) in ER (NS), 19.2 ± 4.4 (premenopause) and 44.4 ± 10.3 (postmenopause) in PR (p<0.05), 71.6 ± 17.6 (premenopause) and 77.9 ± 12.1 (postmenopause) in AR (DHT) (NS), and 25.3 ± 7.5 (premenopause) and 14.4 ± 9.5 (postmenopause) in AR (R1881) (NS). The nuclear receptor was determined by exchange assay. Nuclear PR and AR were detected in few cases. Nuclear ER was detected where in some cases cytosolic ER was not detected. The necessity of determining nuclear ER whenever ER is present or absent in the tumor cell will be discussed.
In examining the nuclear binding of a steroid receptor complex, the ER and PR of rabbit uterine cytosol were substituted for those of breast cancer tissues. The nuclear binding was dependent upon the dose and incubation time of the rabbit-steroid uterine cytosol complex. The dissociation constant of the nuclear binding of the E₂-ER complex was 6.1 × 10^-11M, and that of the R5020-PR complex was 1.5 × 10^-10M in a case. In determined cases, even when the ER or PR was present in either the cytoplasm or nucleus of the tumor cell, the steroid-receptor complex formed in the rabbit uterine cytosol did not bind to the tumor nuclei in some cases. These results suggest that part or all of the nuclear receptor-binding sites of breast cancer tissues are defective in some tumor nuclei.
When the E₂ -ER complex bound to the tumor nuclei, the nuclear RNA synthesis was stimulated in the time-dependent process of the E₂-ER complex. Through the determined cases, even when the E₂-ER complex bound to the tumor nuclei, the nuclear RNA synthesis was not stimulated in some cases.
The above results suggest that the presence of a steroid receptor, the nuclear binding of a steroid-receptor complex, or the stimulation of nuclear RNA synthesis by steroid receptors occurring in breast cancer cells are more precise indicators of endocrine responsiveness in human breast cancer.

抄録全体を表示

Aldosterone secretion can be assessed by measurements of plasma aldosterone concentration (PAC), aldosterone metabolic products in urine, and aldosterone secretion rate (ASR). Blood sampling and determination of PAC have practical and methodological advantages, however, plasma aldosterone shows a diurnal variation and several episodic secretory peaks in normal subjects and various forms of hypertension. Methods based on diurnal urinary excretion integrate the aldosterone secretion over a 24 hour period, thereby minimizing the effect of an intermittent secretory burst. Measurements of urinary aldosterone-18-glucuronide (Aldo-18-g), which represents only about 10 percent of the aldosterone metabolites, have been used in most laboratories because of the less complicated methodology. 3α, 5β-tetrahydroaldosterone (3α, 5β-THAldo) isolated from human urine is the most abundant aldosterone metabolite and represents about 35 per cent. 3α, 5β-THAldo formation in the liver is in contrast to the renal and hepatic origin of Aldo-18-g. To determine ASR, radioisotope-labeled aldosterone has to be injected intravenously, and urine has to be collected during the following 24 hours. Therefore, the characteristics of these parameters must be taken into account for assessing aldosterone secretion.
Urinary 3α, 5β-THAldo, PAC and urinary Aldo-18-g excretion were determined in normal subjects, patients with essential hypertension and patients with primary aldosteronism (PA) in basal condition and in the 9α-fluorohydrocortisone (9αFF) suppression test. The relationship between creatinine clearance (Ccr) and aldosterone parameters was studied in the patients with essential hypertension.
1. Urinary 3α, 5β-THAldo excretion or ASR may be suitable parameters for assessing hyperaldosteronism if PAC or urinary Aldo-18-g excretion is within the normal range in basal condition in the patients with PA.
2. The elevation in PAC and the decrease in urinary Aldo-18-g excretion were observed depending on the degree of changes of Ccr in the patients with essential hypertension.
3. The determination of urinary 3α, 5β-THAldo in the 9αFF suppression test proved to be a most useful tool for the diagnosis of PA, while the determination of urinary Aldo-18-g was not a suitable parameter.
From these results the determination of 3α, 5β-THAldo in hypertensive patients might be a suitable way to detect abnormalities of aldosterone secretion, and it should be noted that proper parameters should be selected for assessing the aldosterone secretion in various forms of aldosterone disorders.

抄録全体を表示