We examined whether seminiferous tubular function develops normally after discontinuation of long-term gonadal suppression in premature male rats. Wistar male rats 4 weeks old were subjected to the injection of gonadotropin-releasing hormone (Gn-RH) agonist or normal saline solution as control for 12 weeks. The rats were sacrificed 0 and 6 weeks after discontinuation of the treatment. Histological examinations of the seminiferous tubules immediately after cessation of the Gn-RH agonist treatment demonstrated a stage-related change in specific germ cells. Seminiferous tubules of Gn-RH agonist-treated rats were narrow and irregular in shape, and contained significantly fewer spermatids and pachytene spermatocytes at stages VII to XIV than those in controls. A complete development of spermatogenesis was histologically observed 6 weeks after cessation of the treatment. Leydig cells became atrophic without any reduction in cell number immediately after the treatment, but Leydig cells grew rapidly and were similar in appearance to those in control rats 6 weeks after cessation of the treatment. Serum testosterone concentrations were noticeably suppressed immediately after cessation of the treatment (P<0.01 vs. control) and reached a similar level to those of controls 6 weeks after the cessation. Testes weights were significantly lower in Gn-RH agonist-treated rats than in control rats and had not fully developed 6 weeks after cessation of the treatment (P<0.01 vs. control). These results suggest that the testicular function develops normally after cessation of the long-term gonadal suppression in premature rats, although the increase in testicular weight may be slightly influenced.

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Although increased thyroxine sulfate (T₄S) levels have recently been detected in fetal serum and amniotic fluid, changes in patients in a high thyroxine (T₄) state remain unclarified. This study was conducted to determine the changes in T₄S in thyroid hormone regulation in women receiving suppressive T₄ therapy. With a highly sensitive and specific radioimmunoassay, we measured the serum and urinary concentrations of T₄S in 16 premenopausal women with benign nodular goiter before and after three months administration of T₄ (3.2μμg/kg/day). Serum levels of other thyroid hormones were also measured. Significant increases in mean serum T₄ levels post-treatment (11.1 vs. 6.6μg/dL pre-treatment; P<0.01) were found, although only low T₄S levels were detectable in serum both pre- and post-T₄ treatment. The mean urinary or creatinine corrected urinary T₄S values post-treatment were significantly increased (20ng/dL or 396 ng/g creatinine vs. 12ng/dL or 174ng/g creatinine pretreatment, P<0.01). There was a significant correlation between increased creatinine-corrected urine T₄S and increased serum free T₄. Our results indicate that the sulfation of T₄ may be related to the regulation of thyroid hormone metabolism in T₄-treated subjects with relative hyperthyroxinemia.

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Insulinoma in a patient with pre-existing diabetes is exceedingly rare. Only a small number of well-documented cases have been reported in the world during the last 40years. We describe a case with non-insulin-dependent diabetes mellitus who after seven years of sulfonylurea treatment experienced recurrent episodes of hypoglycemia. Endogenous hyperinsulinism was found and radiographical examination and transhepatic venous sampling confirmed an insulin secreting pancreatic tumor. After surgical excision of the tumor, patient was relieved from hypoglycemic attacks but required to initiate insulin injection for the treatment of hyperglycemia.

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CrossLaps peptide [Glu-Lys-Ala-His-Asp-Gly-Gly-Arg], a part of the C-telopeptide of the α₁-chain of type I collagen of bone, is a recently developed biochemical marker of bone turnover. In this study, the clinical utility of measurement of urinary CrossLaps was investigated in eleven premenopausal women who received a gonadotropin-releasing hormone (GnRH) agonist for 6 months for treatment of adenomyosis (n=1) or leiomyomas (n=10). Along with urinary CrossLaps, the levels of various biochemical markers, and serum estradiol, calcitonin and intact parathyroid hormone (i-PTH) were measured, and lumbar spine bone mineral density (BMD) was also monitored before, during, and at the end of the course of GnRH agonist therapy. Apart from CrossLaps, markers of bone resorption tested were urinary pyridinoline, deoxypyridinoline and hydroxyproline. Markers of bone formation tested were serum osteocalcin and bone-specific alkaline phosphatase (B-ALP). Serum estradiol levels decreased to undetectable levels at 2 months of GnRH agonist therapy. The values for all biochemical markers increased significantly throughout the therapy. The degree of an increase in CrossLaps levels was greater than that in all other markers. Mean lumbar spine (L2-L4) BMD was decreased by 7.2% at 6 months of treatment. The percent change in BMD at 6 months of treatment correlated inversely with the percent change in CrossLaps levels from the baseline to 1, 2, and 5 months of treatment. These results indicate that measurement of urinary CrossLaps might be a useful tool to predict the risk of bone loss caused by hypoestrogenism including GnRH agonist therapy.

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We previously reported that IA-2 autoantibodies (Ab) facilitated the diagnosis of Japanese insulin-dependent diabetes mellitus (IDDM), but the number tested was not large enough to investigate whether IA-2Ab can improve the diagnostic accuracy. In this report, sera from 78 patients with less than 2year-disease duration (the mean (range) ages were 19.2 (6-52) years old) were tested in order to clarify that the combination of IA-2Ab and glutamic acid decarboxylase 65 (GAD65)Ab would improve the test sensitivity for IDDM. Both of the autoantibodies were frequently detected in Japanese abrupt-onset IDDM but the frequency of GAD65Ab was higher than that of IA-2Ab (69% and 47%, respectively, P=0.024). The two autoantibodies were discordant in respect to both positivity and titer. The positivity for IA-2Ab decreased with the increasing onset-age of the patients (76, 47, 37, 21% for each quartile of age tested), but the frequency of GAD65Ab was unaffected. Among the youngest quartile (≤-12years old), IA-2Ab, in combination with GAD65Ab, significantly improved sensitivity (68% to 92%, P<0.05), but when we tested patients over 12 years old, IA-2Ab caused little, if any, improvement in sensitivity. We confirmed that IA-2 antibody was detected in IDDM among Japanese, as seen in Caucasians, but the test sensitivity was improved only in young IDDM patients among Japanese.

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Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually hypercalcemia. We report a Japanese male patient with JMC who presented with rachitic signs on radiographs, hypercalcemia (13mg/dl) and low %TRP at age 3 months (mo). Hypercalcemia was treated from age 3 mo to 11 yr. Progressive widening, splaying and fragmentation of the metaphyses have been recognized on radiographs which resulted in shortened tubular bones and consequent short stature [107cm (-6.5SD)] at age 13yr. Hypercalcemia tended to normalize, and %TRP became normal at age 13yr. Repeated measurements of serum PTH and PTH-related protein (PTHrP) levels showed that they were low or normal in the face of hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the PTH/PTHrP receptor. Direct sequencing of PTH/PTHrP receptor complementary DNA from skin fibroblast cells revealed a CAC to CGC transversion yielding a strictly conserved His²²³ to Arg substitution found in 90% of DNA fragment in the second transmembrane domain of the receptor. This mutation created a restriction site SphI (G/ CATG/C). Direct sequencing of genomic DNA and also restriction enzyme digestion revealed heterozygous transition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and calcium homeostasis are age-dependent in JMC, and that the His²²³-Arg substitution is the same as that found in four Caucasian patients with a similar phenotype irrespective of the ethnic difference, and that the preferential expression of an abnormal allele of the PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic DNA suggests the importance of allele expression.

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The pathogenesis of hypothalamic progestin-nonresponsive amenorrhea is unclear and this disease often fails to respond to treatment. The pulsatile patterns of diurnal and nocturnal secretion of serum LH as well as serum levels of melatonin were examined to improve the understanding of the pathogenesis and to develop strategies for the management of a severe type of hypothalamic amenorrhea. Four types of LH pulsatile patterns were observed: a) no pulse during the day or night (Group 1); b) more than 1 pulse only at night (Group 2); c) only 1 pulse during the day and more than 2 pulses at night (Group 3); and d) more than 2 pulses during the day and at night (Group 4). Serum estradiol was less than 30pg/mL, and the serum PRL and PRL response to TRH did not differ among the four groups. The basal level and the pulse amplitude of LH increased successively from Group 1 to Group 4. The serum level of melatonin at night was noticeably increased in Group 1 and correlated negatively with the LH pulse frequency at night. After 6-month hormone replacement therapy with estrogen and progesterone, the rate of improvement in ovarian function were 0%, 33.3%, 57.1% and 67.0% in Groups 1, 2, 3, and 4, respectively. In 5 patients, the LH pulse pattern was re-examined at 6 months, the LH pulsatile pattern was changed from that of Group 1 to that of Group 4, with a decrease in serum concentrations of nocturnal melatonin, indicating improved ovarian function. In conclusion, classification of patients according to the LH secretion pattern is useful in establishing the severity of hypothalamic disturbance in hypothalamic progestin-nonresponsive amenorrhea and in predicting its prognosis; in addition nocturnal melatonin can be used as a marker for severer cases of hypothalamic amenorrhea.

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An opinion survey concerning the management of Graves' hyperthyroidism was conducted among the council members of the Japan Thyroid Association. The selection of 3 major treatments by 90 respondents for their patients was 98.6±4.2% for antithyroid drug (ATD), 7.8±12.6% for partial thyroidectomy and 5.2±8.1% for radioiodide. They expressed a movement away from the past trend of surgery because of postoperative complications and unsatisfactory therapeutic results, and they assumed a further reduction in the future. On the other hand, the frequency of radioiodide treatment was not considered to have decreased greatly, and they expected a slight increase in the future. Of the respondents, 65% suggested that hyperthyroidism should be completely cured even if the patient would fall into hypothyroidism. The major reascns for choosing surgery or radioiodide after ATD were the adverse effects of ATD and the age and social backgrounds of the patients. Large goiter size was the 3rd reason for surgery but was a minimal indicator for radioiodide. As for ATD treatment, none of the respondents reported the routine application of any uniform fixed-time therapy protocol. Japanese Graves' patients were shown to be less responsive to ATD than Caucasian patients. This was assumed to result at least from high iodide intake, and half of them had ordered their patients to restrict iodide intake. Furthermore, 78% of them had treated with a combined therapy of ATD and thyroid hormone. Most of them apply this for selected patients mainly to lower TSH receptor antibody activity, to better control their patients and to reduce the goiter size. All but 8 (9%) did not give T₄ (or T₃) after the cessation of ATD, and they felt this to be unnecessary, doubtful about the effect, unsuitable or even possible to induce recurrence. The excellent findings reported by Hashizume et al. (N Engl J Med 324: 947-953, 1991) are well known among them. However, most of them did not agree with the efficacy of the protocol to reduce TRAb or to improve the remission rate, and 90% of the respondents did not intend to apply the protocol immediately. In conclusion, the Japanese thyroidologists were shown to highly prefer ATD, and they intended to treat their patients for longer periods of time only by ATD until clinical remission is achieved. The combination therapy is widely used, but most of them do not consider it effective. The therapeutic protocol reported by Hashizume et al. was not accepted widely in Japan.

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Electrical activities of septum-diagonal band neurons (SD neurons) antidromically activated by electrical stimulation of the fimbria were recorded in urethane anesthetized male rats. The mean basal firing rate of antidromically identified SD neurons (2.3Hz) was not different from that of unidentified ones (2.2Hz). The mean latency of antidromic activation by the fimbria stimulation was 4.2 ms. Iontophoretically applied CRH and LHRH affected 60% and 40% of identified SD neurons, but only 19% and 13% of unidentified SD neurons, respectively. The ratio of response to no response to both peptides was significantly different in unidentified SD neurons from that in identified SD neurons. These results suggest that SD neurons mediate the effect of CRH and LHRH on hippocampal neurons.

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Serum levels of LH, FSH and testosterone (T) were measured by radioimmunoassays in 36 patients with advanced prostate cancer before and during androgen ablation therapies. Both leuprolide acetate (LH-RH agonist: LHRH-A) and diethylstilbestrol diphosphate (DES-DP) administration decreased serum LH significantly to an undetectable level (LHRH-A: P<0.01, DES-DP: P<0.05). LHRH-A and DES-DP diminished serum FSH to 20% of the pre-treatment level (P<0.005) and to an undetectable level (P<0.001), respectively. LHRH-A and DES-DP decreased serum T to the castration level and an undetectable level, respectively (P<0.001). Serum levels of the same 3 hormones before and after DES-DP administration were measured in 8 patients who received DES-DP after LHRH-A treatment or castration because of relapse of the disease. DES-DP lowered serum FSH further than LHRH-A to an undetectable level (P<0.005) and diminished T further than previous treatments to an undetectable level (P<0.05 vs. LHRH-A, P<0.01 vs. castration). These results suggest that 1) DES-DP is able to reduce T production from extra-testicular site(s), and achieve the minimal serum T level, and 2) this DES-DP action appears to be one off the mechanisms of the effectiveness of estrogen on refractory prostate cancer after castration or LHRH-A. In addition, basal (independent of LH-RH) FSH secretion in elderly men is about 20% of total FSH secretion and DES-DP inhibits the basal FSH secretion at the level of the pituitary.

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We report a rare case of Cushing's syndrome due to bilateral adrenocortical adenomas in a 45-year-old female. She suffered from diabetes mellitus and hypertension for a decade, but her appearance was not Cushingoid. The plasma cortisol level in the morning was at the upper limit of the normal range, but did not show a diurnal rhythm or was suppressed by 1mg of dexamethasone. The plasma level of ACTH was undetectable, and it failed to respond to human CRH (hCRH). Plasma cortisol responded well to synthetic ACTH. The urinary 17-OHCS level was high, and was not suppressed by 4 mg of dexamethasone. While these findings were consistent with a diagnosis of adrenocortical adenoma, computed tomography showed several nodules in both adrenal glands that suggested the presence of huge nodular adrenocortical hyperplasia or bilateral adrenocortical adenomas. Bilateral adrenalectomy demonstrated the presence of three adenomas, two in the right and one in the left adrenal. Analysis of the extract from each adenoma revealed that two of the three produced an excess amount of cortisol. Magnetic resonance imaging (MRI) of the brain suggested the presence of a pituitary adenoma. Prior to adrenalectomy, TSH, GH or LH showed a low response to TRH, GHRH or LHRH, respectively. Since normal responses were restored after bilateral adrenalectomy, these abnormalities were attributed to hypercortisolemia.

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A 34-year-old woman and a 54-year-old woman were treated with interferon-alpha (IFN-α) for chronic hepatitis C. Three months after the cessation of the IFN-α therapy, each patient developed hypothyroidism with the presence of thyroid-stimulation-blocking antibody (TSBAb) and TSH-binding inhibitor immunoglobulin (TBII). These two patients were treated with thyroxin, and both TSBAb and TBII activities gradually decreased. Although both TSBAb and TBII became negative several months after the start of the replacement therapy, the replacement dosage of L-thyroxine could not be reduced. Thyroid biopsies showed that the follicular epitheliums were flattened in both cases with lymphocytic infiltration. These findings suggest that IFN-α may induce hypothyroidism and the transient emergence of TSBAb and TBII.

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A case of hyperaldosteronism caused by adrenal cortical cancer observed in a 32-year-old man was reported. The patient showed marked hypertension and hypokalemia, but neither obesity nor hyperglycemia was observed. Endocrine studies revealed hyperaldosteronism and concurrent excessive secretion of cortisol, but diurnal rhythms of plasma ACTH and cortisol were normal. Imaging studies revealed a large left adrenal mass, and the positive accumulation of radiolabelled material by adrenal scintigraphy was observed both in the tumor and the contralateral adrenal gland. The removed tumor was predominantly composed of dark compact cells with marked nuclear pleomorphism, and mitotic figures and sinusoidal invasion were also observed. The analysis of steroidogenic enzyme activities revealed that the activity of aldosterone-synthesizing enzyme (P-450aldo) which was usually undetectable in normal adrenal tissues and adenomas other than aldosterone-producing adenoma (APA) was detectable as one-third of that of APA. Although activities of other enzymes were reduced, the expression of P-450aldo activity was considered to be the specific character of this cancer.

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A prospective long-term follow-up study was performed with conventional divided doses (group C:10mg 3 times daily, N=58) and a small single daily dose (group S:15mg once daily, N=54) of methimazole (MMI) for the treatment of Graves' hyperthyroidism. Within 8 weeks, almost 80% of the patients in both groups became euthyroid. The mean time required to achieve a euthyroid state was 5.6 ±2.7 weeks in group C and 5.8±3.1 in group S. TSH binding inhibitor immunoglobulin (TBII) levels before therapy were 44.2±22.7% and 47.1±23.9% in group C and group S, respectively. A similar gradual fall in TBII levels was observed in both groups over a two-year period of treatment. MMI doses were gradually reduced to a maintenance dose (5mg daily) after the patients became euthyroid. The patients were treated for 28±9 months and were followed up after therapy was stopped (observation period in patients who remained in remission was 12-130 (75±34) months and the interval to relapse in reccured cases was 1-98 (20±27) months). The rates of recurrence in group C were 41% at 1 yr, 54% at 2 yrs, 56% at 4 yrs and 61% at 6 yrs. In group S, these were 44%, 53%, 56% and 63%, respectively. No differences between relapse rates were observed with the two different dosage regimens. Adverse effects occurred more frequently in group C patients (24%) than in group S patients (13%). These results show that there is no difference in the clinical and immunological course or in the long-term remission rate of Graves' hyperthyroidism when the treatment is initiated with either a small single daily dose (15 mg) or the conventional regimen (10mg 3 times daily).

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To determine whether patients with medullary thyroid carcinoma (MTC) develop other endocrine neoplasms or their relatives develop MTC, we investigated the mutations in the RET proto-oncogene in patients with multiple endocrine neoplasia type 2B (MEN 2B, N=1) and sporadic MTC (N=6). DNA from MTC tissue and the peripheral blood was screened by polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) analysis of exons 10 and 11. PCR products of exons 13 and 16 were also analyzed by AluI and FokI restriction enzyme digestion methods, respectively, and then sequenced. We did not find structural abnormalities in exon 10 or 11, or at codon 768 in exon 13, but a mutation at codon 918, ATG to ACG, was found in the peripheral blood and the MTC tissue from a patient with MEN 2B. The same mutation was also found in tumor tissue from 2 of 6 patients with sporadic MTC, but not in their peripheral blood.

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We report herein rare cases who developed hyperthyroid Graves' disease after surgical treatments for thyroid nodules. We have seen only 4 such cases in the course of 1680 consective cases (0.24%) of thyroidectomies in which partial thyroidectomy was carried out from 1966 to 1993. It is of interest that because 2 of these three cases (67%) were associated with positive TGHA and/or MCHA at the time of surgery, the presence of autoimmune thyroiditis may predispose to Graves' disease, but surgical treatment of the thyroid glands may not be related to the development of Graves' disease, because the hyperthyroid symptoms appeared 2 to 27 years (mean: 12 years) after the surgery.

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A 44 year-old woman developed hyperthyroidism due to the coexistence of Graves' disease and an autonomously functioning thyroid nodule (AFTN). Anti-thyrotropin receptor antibody (TRAb) was strongly positive (83.2%), and a thyroid scan initially showed diffuse uptake of Tc-99m pertechnatate in both lobes and further increased uptake in accordance with the right lobe nodule. The nodule in the right lobe was histologically diagnosed as thyroid follicular adenoma. After she was maintained in a euthyroid state by treatment with Methymazole (MMI), thyroid uptake of Tc-99m in the nodule became lower and was slightly suppressed by T3 administrations probably due to its dependence on TSH. Subtotal thyroidectomy was performed and she subsequently became euthyroid with negative TBII activity. It is concluded that she had a coexisting functioning nodule with Graves' disease (Marine-Lenhart syndrome) and that the nodule changed from hot to cool along with the anti-thyroid treatment, unlike usual cases of this syndrome showing a cold nodule on the initial imaging under the hyperthyroid state. Repeated Tc-99m pertechnatate thyroid scans were helpful in evaluating the reaction of MMI and TSH in both lesions separately in the present case.

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Reduction of goiter size is one of the criteria necessary to determine clinical remission in antithyroid drug (ATD)-treated Graves' patients. To facilitate goiter reduction or to achieve quick remission, a short-term steroid treatment was administered to 5 Graves' patients. These patients had been treated with ATD for a considerable period of time, had maintained euthyroidism with negative or weak thyrotropin-binding inhibitor immunoglobulin (TBII), but still had an enlarged goiter and remained T₃ unsuppressive. Betamethazone was initially given 1.5mg daily and then gradually tapered to 0mg for 3 months. Compared to the 6-month observation period or the pre-medication period, goiter reduction exceeding 0.7cm was achieved in all 5 patients during the steroid treatment. These reductions partly reversed to an extent smaller than pre-treatment levels in 2 patients, but continuous goiter reductions were observed for at least 3 months after steroid cessation in 3 patients. In 2 of these reduced goiter patients, T₃ suppressibility was confirmed, and they were diagnosed in remission. During steroid administration, serum T₃ and TSH concentrations were lowered but reversed shortly, serum Ft₄ concentrations did not change, and TBII levels became negative in all patients including the 2 with weak positive values before the treatment. In conclusion, a short-term steroid treatment for goitrous ATD-treated Graves' patients appears promising in achieving goiter reduction or remission.

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We report a rare case of primary hypothyroidism in which thyroid function was changed from hypothyroidism to hyperthyroidism in the course of pregnancy and finally returned to hypothyroidism in the early post-partum period. She delivered an infant with neonatal Graves' thyrotoxicosis. Serum thyroid-stimulating antibodies (TSAb) and thyroid stimulating-blocking antibodies (TSBAb) coexisted in these patients. The triphasic changes in thyroid function may be explained by altered balance between TSAb and TSBAb in relation to pregnancy and delivery in the present case, although cellular immunity could be independently involved in atrophic changes in the postpartum period.

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The role of the ventral projections of the dorsal raphe nucleus (DRN) in regulating lordosis was examined in female rats. The ventral neural fibers of the DRN were transected by the horizontal circle-cut (VC), anterior (AVC) or posterior half-circle cut (PVC) at the same time as ovariectomy. Three weeks after the surgery, all the rats were implanted with a Silastic tube containing estradiol (E2). The behavioral test was started one day after E2-implantation, and 5 tests in total were carried out every other day. The results showed that the VC females had a higher lordosis quotient (LQ) than control rats. Furthermore, as well as females with the VC, a high score LQ was observed in the AVC rats but not in the PVC females, compared to those in the control animals. These results suggest that the anteroventral neural fibers of the DRN are involved in the lordosis inhibiting mechanisms in female rats.

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Although the number of patients with primary hyperparathyroidism (pHPT) has increased since biochemical screening came to be widely employed, few data are available concerning the clinical analysis of Japanese patients. We therefore tried to determine the recent clinical and biochemical state of Japanese patients with pHPT. Clinical and biochemical data were analyzed in a series of 103 pHPT patients who had been hospitalized in Kobe University Hospital during a 17 year period from 1979 to 1995. The data were obtained from the hospital records and additionally from information through questionnaires performed in 1995. Patients were 29 males and 74 females. The average ages at diagnosis were 53.4±16.0 (SD) year-old and 53.9±15.2 year-old, respectively. The major clinical symptoms were nephrolithiasis (35.9%), thirst/polyuria (33.0%), easy fatigability (20.4%) and back pain/lumbago (16.5%), but 19.4% of the patients were asymptomatic. Out of 87 cases who received parathyroidectomy, 10(11.5%) were diagnosed with parathyroid carcinoma. Age- and sex- corrected bone mineral density (BMD) of the radius was significantly lower in the group with back pain/lumbago than in the group without the symptom. Similarly, radial BMD was lower in the group with a high serum alkaline phosphatase value. Patients with nephrolithiasis had a lower urinary calcium/creatinine ratio (UCa/ UCr; 0.305±0.188mg/mg) than the patients without nephrolithiasis (0.400±0.160mg/mg). This inconsistent result suggests that some important factors except urinary calcium would contribute to urinary stone formation in pHPT. Our data mostly agreed with previous reports on a Caucasian population except for a relatively high prevalence of parathyroid carcinoma, but the negative correlation between nephrolithiasis and urinary calcium was not easily explicable. This finding should be confirmed by analyzing a larger number of cases.

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We report a 54-year-old female with high grade fever, fatigue, and painless swelling of the thyroid gland. Based on findings of high gallium-67 citrate uptake in an enlarged thyroid gland accompanied by severe systemic inflammation including an increase in various cytokines and histology of biopsied specimens indicating typical chronic thyroiditis, a diagnosis of acute exacerbation of Hashimoto's thyroiditis was made. All clinical symptoms were relieved by oral naproxen following a prolonged hypothyroid status. This may be the first case report describing painless acute exacerbation of Hashimoto's thyroiditis, and may provide insight into the clinical spectrum of acute inflammatory reactions in Hashimoto's thyroiditis.

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We report on a 61-year-old woman with untreated Graves' disease associated with painful thyroiditis. On examination, the left lobe of the thyroid gland was firm and tender but the right lobe was not. A diagnosis of Graves' disease was made based on the results of thyroid function tests including the percentage of thyroidal radioactive iodine uptake (RAIU) and the presence of thyroidstimulating antibodies (TSAb). However, ultrasonogram results and inflammatory findings (C-reactive protein concentration and erythrocyte sedimentation rate) also indicated the presence of inflammation in the thyroid gland. She was first treated with aspirin, and later with prednisolone. Her clinical course was similar to that in cases of subacute thyroiditis, but neither her HLA type nor aspiration cytology findings indicated the type of thyroiditis. With the resolution of the thyroiditis, her serum levels of thyroid hormone and TSAb decreased, although RAIU increased. Finally, she became euthyroid without antithyroid drug treatment. The serum levels of antithyroid antibodies, TSH-binding inhibitor immunoglobulins (TBII) and TSAb increased transiently and then decreased during the course of the illness, indicating that the mechanism(s) of the production and/or degradation of TBII and TSAb is similar to that for antithyroid antibodies in the present case. The present findings also indicate that remission may occur in some patients with Graves' disease after painful thyroiditis is resolved.

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With a euglycemic hyperinsulinemic clamp method, whole-body insulin resistance was assessed in 6 cases with acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy. The glucose infusion rate (GIR) correlated well with the plasma IGF-I level but poorly with that of GH. Further improvement in insulin sensitivity occurred 3-4 months after operation without substantial changes in plasma levels of both GH and IGF-I or glycemic control. These results indicate that GH excess can induce insulin resistance in association with plasma IGF-1 and also through undefined secondary effect.

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The identification of unique point mutations in patients with pseudohypoparathyroidism (PHP) with Albright's hereditary osteodystrophy (AHO) in different ethinic backgrounds has proved that defects within the G_sα gene account for G_sα deficiency in those patients. To search a mutation hot spot of the G_sα gene in Japanese patients, we have screened exons 2-13 of the G_sα gene for mutations in three unrelated Japanese PHP patients with AHO. We could find no abnormalities by denaturing gradient gel electrophoresis and no mutations of sequencing of exon 7 in these subjects. This suggests that mutations in exon 7 of the G_sα gene may not be a common cause of PHP with AHO in Japanese.

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Urocortin (Ucn) possesses high homology with CRH and is considered to be a ligand to type-2 CRH receptor. We investigated the effect of Ucn on hormone release from cultured GH-producing human pituitary adenoma cells in vitro. GH-producing human pituitary adenoma cells were superfused on a Sephadex G-25 column. Both Ucn (10nM) and CRH (10nM) elicited an increase in GH release from the pituitary adenoma cells in one patient with acromegaly. In contrast, GH release from the pituitary adenoma cells was stimulated by Ucn but not by CRH in the other patient with acromegaly. These preliminary findings suggest that type-2 CRH receptors are expressed in some population of GH-producing human pituitary adenoma cells and that Ucn might be involved in GH secretion from tumorous tissues in patients with acromegaly.

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