Twenty patients with thyrotoxic Basedow's disease complicated by atrial fibrillation lasting more than one month despite treatment with antithyroidal drugs were treated with radioiodine supplemented with an antithyroidal drug or inorganic iodine.We classified the 20 patients on the basis of atrial fibrillation reversion into two groups, one with reversion (group I) and the other without reversion (group II).
In all 12 patients in group I, T₄ and T₃ decreased to hypothyroid levels in 3.2±1.3 months, and one month later all patients had their sinus rhythm restored while T₄ and T₃ remained below normal (2.6±1.1 μg/dl and 77.9±34.4 ng/dl, respectively).Although T₄ and T₃ also decreased within 3.5±1.8 months in all 8 patients in group II, one month later, atrial fibrillation persisted while T₄ and T₃ (10.4±5.3 μg/dl and 157.7±67.5 ng/dl, respectively) rose significantly compared to those in group I (P<0.001 and P<0.01, respectively).For reversion of atrial fibrillation it is important that te onset of hypothyroidism is rapidly induced by radioiodine and that hypothyroidism continues for at least one month.

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The role of the cingulate cortex in regulating male sexual behavior was studied in testosterone propionate-treated castrated male rats.Males with lesions in the anterior part of the cingulate cortex showed lower levels of mount, intromission and ejaculation activities than shamoperated control males and males with lesions in the posterior part of the cingulate cortex or the frontal cortex.In male rats in which lateral connections of the anterior cingulate cortex were bilaterally interrupted by sagittal cuts, the sexual activity was much lower than in the control rats, being comparable to that of the anterior cingulate cortex lesion group, but transection of the anterior connections by a transverse cut made in the anterior part of the anterior cingulate had no effect.These results suggest that the anterior cingulate cortex and its lateral connections are critical in regulating male sexual behavior in male rats.

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The effects of androgen and epidermal growth factor (EGF) on cell proliferation and the expression of mRNA and protein of androgen receptor (AR) were examined in an androgen-sensitive human prostatic cancer cell line, LNCaP, by Northern and Western blot analyses.The addition of 1 nM dihydrotestosterone (DHT), at which the proliferation of the cells was most stimulated, did not change the level of AR mRNA but increased the level of AR protein by reducing the turnover rate of the AR protein.EGF also stimulated the proliferation of the cells but repressed the expression of AR mRNA and protein.This repression was found to be exerted primarily at the level of transcription.When DHT and EGF were added simultaneously to the cells, the level of AR mRNA was reduced to the same degree as was accomplished by the addition of EGF alone.On the other hand, the level of AR protein increased but this increase was about 70% of that attained following the addition of DHT alone.The stimulatory effects of EGF and DHT on cell proliferation were found to be additive.These results indicate that EGF down-regulates the level of AR mRNA and thereby also that of AR protein irrespective of the presence of DHT, and that EGF stimulates the proliferation of LNCaP cells through a different pathway from that of DHT.

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We have examined a hypothyroid patient with stimulating type anti-thyrotropin (TSH) receptor antibodies and without blocking type anti-TSH receptor antibodies.Although she had high serum TSH (240μU/ml) and low free triiodothyronine (FT₃, 0.49pg/ml) concentrations, which agree with physical findings of hypothyroidism, she had an unusually high free thyroxine (FT₄) concentration (3.56ng/dl).Incubation of her serum with ¹²⁵I-T₄, followed by precipitation with 12.5% polyethylene glycol (PEG) disclosed a higher binding of ¹²⁵I-T₄ (34.4%) than in normal controls, being 5-7%. In addition, binding of ¹²⁵I-T₄ to her serum gamma-globulin was completely displaced by the addition of unlabelled T₄. From these results it was concluded that her serum contained anti-T₄ autoantibodies. Treatment with synthetic T₄ was begun and her thyroid function was monitored by sensitive TSH radioimmunoassay (RIA) and RIA of FT₄ after PEG treatment.Since both sensitive TSH RIA and FT₄ RIA results after PEG treatment give results concordant with the physical findings, it was concluded that both of the RIA results are useful for the evaluation of thyroid function in patients with thyroid hormone autoantibodies.

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We describe a female child with pituitary gigantism and precocious adrenarche. From two years of age she showed unusual overgrowth, and at 5 years old she was 133.5cm (+ 5.5 SD) tall and weighed 40.5kg. Her precocious manifestations were pubic hair, acne vulgaris, hirsutism, and advanced bone age. Endocrinological examination revealed markedly increased serum growth hormone (GH) and prolactin (PRL), which responded paradoxically to a TRH test. In addition, the concentrations of serum dehydroepiandrosterone (DHA) and its sulfate (DHAS) were increased to adult levels, moving in accordance with changes in ACTH, which suggested that these androgens were secreted from the adrenal glands functionally. These androgens seemed to be responsible for her partial precocity. Prior reports have suggested that GH and/or PRL overproduction might have played a role in the induction of adrenarche. Also, in previous reports of 9 gigantism patients under 10 years old, the manifestation of precocious adrenarche was suggested in 8. Further investigation of the influence of GH and PRL on adrenal androgen production in children with pituitary gigantism is required. On the other hand, in short children with normal GH secretion, attention should be paid to whether or not the GH therapy in early childhood induces precocious adrenarche.

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This study was undertaken 1) to determine whether or not renin is present in synovial fluid in patients with rheumatoid arthritis and osteoarthritis, and, if present, 2) to investigate whether it is synthesized in synovial fluid, or it is only transported from the circulation into the synovial cavity. The active renin concentration (indirect) was measured with angiotensin I radioimmunoassay kits. Inactive renin was converted into active renin with Sepharose-bound trypsin. Both active and inactive forms of renin were found in synovial fluid.They were significantly higher in patients with rheumatoid arthritis (n=9) than in those with osteoarthritis (n=16). In plasma, the concentration of inactive renin was significantly higher (P<0.001) in the former. Albumin, transferrin, α₂-macroglobulin, ceruloplasmin and immunoglobulins G and M were also found in synovial fluid.In each disease, a plot of the log ratio of synovial fluid to the serum concentration against the log molecular weight of each protein gave an approximately straight line curve, suggesting that these proteins are derived from the circulation and are transported into the synovial cavity. In contrast, the ratio of synovial fluid to plasma concentrations of active renin was significantly higher than that predicted on the basis of the above-mentioned interrelationships in both diseases, whereas the ratio of inactive renin was significantly lower. These findings suggest that 1) inactive and active renin are filtered into the synovial fluid from thecirculation, and that 2) inactive renin is converted into the active form in the fluid.

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A case of immunoblastic lymphoma, involving only the thyroid and the adrenal glands, is presented. The patient had clinical symptoms and findings of Addison's disease, and computed tomography (CT) demonstrated bilateral adrenal tumoral enlargement. He also had euthyroid diffuse multinodular goiter. The diagnosis of the patient was based on the cytological examination of the aspiration materials from both endocrine glands. The patient received “m-BNCOD” chemotherapy regimen and replacement therapy for Addison's disease. At the end of three courses, a partial response was obtained.

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In our studies of the growth-promoting effect of a cytokine, interleukin-1 (IL-1), on cultured porcine granulosa cells, we found that the potency of IL-1 action correlated with the serum concentration in the culture medium and that IL-1 acted synergistically with insulin to increase the number of cells in the presence of low serum concentrations (0.1-1%). With granulosa cells maintained in a quiescent state under serum-free conditions, we therefore examined the effects of combined treatment with IL-1 and peptide growth factors, including insulin, on [³H] thymidine incorporation by these cells. IL-1 by itself enhanced [³H] thymidine incorporation in a concentration-dependent manner. Moreover, IL-1 acted synergistically with insulin, epidermal growth factor (EGF), or fibroblast growth factor (FGF) to enhance [³H] thymidine incorporation. Combinations of maximally effective concentrations of insulin (1μg/ml), EGF (1ng/ml), or FGF (50ng/ml) with the maximally effective concentration of IL-1 (10ng/ml) increased the levels of [³H] thymidine incorporation to 10-, 22-, and 20-fold, respectively, over the control values.
Whereas IL-2 (0.1-100ng/ml) did not affect [³H] thymidine incorporation, tumor necrosis factor a (TNFα) stimulated [3H] thymidine incorporation by itself and reproduced the actions of IL-1 to act synergistically with insulin, EGF, or FGF. When IL-1 and TNFa were added together in relatively low concentrations (1 ng/ml each), the combination had synergistic effects in enhancing [³H] thymidine incorporation. The present study demonstrates that cytokines and peptide growth factors act synergistically to markedly enhance porcine granulosa cell growth in vitro.

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Several studies have shown that pituitary folliculo-stellate (FS) cells exhibit local functions within the pituitary gland. On the other hand, we have shown previously that activin A increases the number of FSH-producing gonadotropes in cultured rat anterior pituitary cells. In this study, we investigated whether FS cells exert an influence on the action of activin A. FS cells were prepared by culturing the dispersed rat anterior pituitary cells in media containing 15% fetal calf serum and 6 mM glutamine for 15 days. Most cells had the morphological characteristics of FS cells and S-100 protein immunoreactivity, a specific marker of FS cells. The number of FSH cells, which was higher in activin A-treated than in control cultures, was reduced to the control level by incubation with activin A plus conditioned media from FS cell-enriched cultures (FSCM). This inhibitory effect of FSCM was neutralized by a follistatin antibody, but not by anti-S-100 protein or anti-basic fibroblast growth factor. Furthermore, follistatin suppressed activin A stimulated increases in the number of FSH cells in a similar inhibitory pattern to that of FSCM. Meanwhile, the number of FSH cells was not affected by FSCM or follistatin in the absence of activin A. These results suggest that FS cells are involved in the regulati of the function and/or the morphogenesis of the FSH cell-lineage by affecting the action of activin A, and that this paracrine effect of FS cells is mediated by follistatin.

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When tarsometatarsal skin of 13-day-old chick embryos that had been cultured in medium containing 5% delipidized FCS with or without retinol (20μM) and/or hydrocortisone (20nM) for 1 day was cultured in a chemically defined medium without either the hormone or retinol for 1 day, epidermal DNA synthesis of hydrocortisone-and/or retinol-pretreated skin was inhibited when compared to that of control skin. The addition of epidermal growth factor (EGF, 10ng/ml) to retinol- or hydrocortisonepretreated skin further inhibited the epidermal DNA synthesis. Epidermal DNA synthesis in retinoland hydrocortisone-pretreated skin was more strongly inhibited than in retinol-or hydrocortisonepretreated skin, but was not further inhibited by EGF. In epidermis which was induced to differentiation toward keratinization by hydrocortisone or mucous metaplasia by retinol, EGF inhibited DNA synthesis. The extent of [¹²⁵I]-EGF binding to the epidermis of retinol- and hydrocortisone-pretreated skin was 160-180% that in control skin, with no change in affinity. Hence there is no correlation between EGF-binding and the mitogenic activity of EGF.

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Patients with autoimmune insulin antibody are characterized by hypoglycemic attacks and antibodies to insulin in serum without prior insulin administration. In the present report, a patient with hypoglycemia due to autoimmune insulin antibody associated with primary empty sella syndrome and polymyositis appeared to have high urinary immunoreactive insulin (IRI) in the face of normal urinary C peptide. Consequently, the urinary IRI/C peptide ratio was apparently high. The amelioration of hypoglycemic attacks and polymyositis by prednisolone treatment was accompanied by the disappearance of the antibodies and complete normalization of the urinary IRI and IRI/C peptide ratio. No comparable rise in the urinary IRI and IRI/C peptide ratio was observed in the patients with other disorders studied. Glucose clamp and glucose tolerance study showed decreased sensitivity to exogenous or newly secreted insulin, prolonged half disappearance time of serum insulin, and normal disappearance of blood glucose. These results were consistent with the idea that autoantibodies buffered the effect of exogenous or newly secreted insulin and maintained a relatively constant level of serum free insulin which was not high enough when a large amount of glucose was loaded, but was too high after prolonged fasting, which eventually caused hypoglycemic attacks.

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Periodic paralysis has been known to be associated with thyrotoxicosis in Japan. The incidence was 8.6% among male and 0.4% among female thyrotoxic patients according to a survey performed in the three major thyroid clinics in Japan in 1957. To determine the changes in the incidence during the intervening 34 years, the same type of survey was carried out again in 1991 at the same three major thyroid clinics previously involved. The incidence of paralysis in 1991 was 4.3% among male and 0.04% among female thyrotoxic patients, indicating more than a 40% decrease in the incidence. The possible cause of the decrease is related to the changes in food consumption, namely, to the fact that less carbohydrate and more potassium were taken in 1991 than in 1957.

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The DNA from a pituitary adenoma of a patient with multiple endocrine neoplasia (MEN) type 1 was analyzed to detect a point mutation of the Gsα gene (gsp) by the PCR direct-sequencing method. The patient had galactorrhea, amenorrhea and acromegalic features. Hormonal examination revealed high serum levels of PRL and GH. The tumor was histologically diagnosed as a mixed GH cell-PRL cell adenoma in which GH and PRL were produced by different cells. Sequence analysis of the DNAs extracted from paraffin sections of pituitary, parathyroid, and pancreas tumors demonstrated the substitution of thymidine for cytidine in codon 201 of the Gsα gene that resulted in replacement of arginine (CGT) with cystein (TGT) only in the pituitary adenoma, but not in the parathyroid and pancreas tumors. These results suggest that a pituitary specific point mutational activation of the Gsa gene may be involved in the development of the pituitary adenoma in this patient.

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The role of protein phosphatases in the regulation of insulin release from rat pancreatic islets was studied with protein phosphatase inhibitors, okadaic acid and calyculin A. Okadaic acid inhibited glucose-and glyceraldehyde-induced insulin release dose-dependently and also inhibited the potentiation of glucose-induced release either by adding forskolin, an activator of adenylate cyclase or by increasing K⁺ concentration to 25 mM. At a non-stimulatory concentration of 3 mM glucose, a high concentration (2μM) of okadaic acid inhibited insulin release induced by high K⁺ or 12-Otetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, but a low concentration (1μM) of okadaic acid did not significantly inhibit TPA-induced insulin release. Calyculin A also inhibited glucose-induced insulin release, and the effect was greater than that of okadaic acid. The data suggest that protein phosphatases may play an important role in the regulation of insulin release.

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