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Objective In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH. Design Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting. Results Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II. Conclusion The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

The present study reports a case of recurrent malignant pelvic solitary fibrous tumor (SFT) that induced non-islet cell tumor hypoglycemia via high-molecular-weight insulin-like growth factor-II in a 72-year-old male patient. The tumor recurred ~12 years after the complete resection of the original mass. The recurrent tumor, which had directly invaded the left ureter and perirectal fat tissue, could not be completely excised due to its fragility and adhesiveness. At 13 days post-surgery, the patient presented with rectal perforation, and an urgent rectal resection and colostomy was performed. Neither recurrence of the tumor nor hypoglycemic symptoms were observed 9 months after the surgery. High molecular weight insulin-like growth factor-II was detected in the serum and tumor specimens by western blot analysis and immunohistochemistry. The present case report suggests that certain SFTs can relapse even ≥10 years after a presumed complete resection of the primary tumor, and that performing a safe and complete resection of these tumors can be challenging, due to their adhesiveness or physical presentation; therefore, the indications for surgery should be considered with caution.

Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature.A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia.An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.

β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P

Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs).The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively.Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0.Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available.The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fisher's exact test).This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of

Determination of serum growth hormone (GH) levels is mandatory for diagnosis of GH deficiency and excess. In the present study, we, the Study Committee for GH and Its Related Factors, The Foundation for Growth Science, Japan measured GH values in serum samples using all the commercially available kits in Japan. Significant discrepancies in the GH values were observed among the kits in spite of using the unified recombinant human GH-based standards. To deal with the discrepancies, we established a formula using a linear structural relationship model and were able to standardize the GH values. We propose to use the formula to diagnose GH deficiency and excess in Japan.

To describe the unique association of corticotropin-independent Cushing syndrome caused by cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change.We report the clinical, laboratory, radiologic, and pathologic findings from 2 patients who presented with androgen excess and typical signs and symptoms of Cushing syndrome.Endocrine investigations showed high serum cortisol concentrations that lacked diurnal rhythm, undetectable plasma corticotropin concentrations, and absence of serum cortisol suppression after overnight dexamethasone suppression tests. Serum levels of adrenal androgens were elevated. Computed tomography of the abdomen revealed unilateral adrenal masses (largest lesional diameters 4.0 and 3.1 cm). On the basis of the plurihormonal hypersecretion and the imaging characteristics, adrenocortical carcinoma was considered as a possible diagnosis. However, histopathologic analysis in both patients revealed black adrenal cortical adenomas with myelolipomatous change. After surgery, adrenal androgens normalized, and the signs and symptoms of Cushing syndrome and androgen excess resolved. There was no evidence of recurrent disease at last follow-up.A unique form of corticotropin-independent Cushing syndrome is described: cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. Although most patients with corticotropin-independent Cushing syndrome associated with androgen excess prove to have adrenocortical carcinoma, the clinician should be aware of the possibility of benign, black adrenal adenomas in this clinical setting.

In Japan, the growth hormone (GH) assay has been standardized since April 2005 through use of a uniform recombinant human GH (rhGH) standard. Since then, GH values measured using the rhGH standard have been approximately 40% lower than previous values measured using kit standards based on the WHO standards for hGH of pituitary origin. However, the Japanese criteria for evaluating treatment outcomes for acromegaly have remained the same: a nadir GH during a 75 g OGTT1 µg/L is considered cured, 1≤GH2.5µg/L is considered inadequately controlled, and ≥2.5 µg/L is considered poorly controlled, instead of these levels were lowered to 60%, i.e. from 1 to 0.6 µg/L for cured and from 2.5 to 1.5µg/L for inadequately controlled (termed as "newly proposed criteria" in this study). We investigated the effects of standardization of the GH assay on the evaluation of post-surgical disease activity in 50 patients with acromegaly (M/F 19/31, 21-72 yr.). Post-surgical nadir GH levels during OGTT were positively correlated with the IGF-I SD score 3 months after TSS. Five of 6 patients whose post-surgical nadir GH levels ranged between 0.6 and 1 µg/L had normal serum IGF-I levels 3 months after TSS. Rates of improvement in glucose metabolism did not differ when patients were classified based on the present criteria vs. the newly proposed criteria. In conclusion, the current Japanese remission criteria for acromegaly still accurately reflect post-surgical disease activity in most patients, though long-term observation is still required.

Patients with growth hormone (GH) deficiency (GHD) have a clinical feature of visceral adiposity and it has been reported that these patients have an increased active cortisol (F)/inactive cortisone (E) metabolite ratio. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an enzyme expressed in liver and adipose tissue that acts principally as a reductase converting E to F. In the present study, we investigated the effects of GH or IGF-I on the activity of 11beta- HSD1 in 3T3-L1 cell homogenates and its mRNA expression. First, we showed that 11beta-HSD1 activity and mRNA levels were low in preadipocytes and increased throughout the process of adipogenesis. When fully differentiated adipocytes were treated with GH for various times, the activity of 11beta-HSD1 was significantly decreased after 4 h and 8 h but was restored to basal levels after 24 h. After 8 h of GH stimulation, 11beta-HSD1 mRNA levels were decreased compared with basal levels. IGF-I treatment of adipocytes resulted in rapid decreases in 11beta-HSD1 activity as well as mRNA levels; however, IGF-I treatment for 24 h increased 11beta-HSD1 activity. In long-term cultured adipocytes, GH or IGF-I showed only inhibitory effects on 11beta-HSD1 activity. In conclusion, 11beta-HSD1 activity was suppressed by GH or IGF-I in differentiated adipocytes, probably due to a reduction of 11beta-HSD1 mRNA levels. These data suggest that under the conditions of low GH or IGF-I concentrations, 11beta-HSD1 activity in adipose tissue is maintained at high levels, leading to an increase in active cortisol that induces adipogenesis and/or lipogenesis. Thus, visceral adiposity in patients with GHD might be related to increased 11beta-HSD1 activity.

ObjectiveThe purpose of this study was to investigate the influence of age on GH and IGF1 axis, and complications in patients with acromegaly.Subjects and methodsFrom the medical records, we retrospectively analyzed clinical features and complications in 87 newly diagnosed patients with active acromegaly (34 males, 53 females; aged 18–82 years) who were admitted to Tokyo Women's Medical University between 1999 and 2006. We divided the patients into three groups according to age: ≤30 years old (young group), 31–60 years old (middle-aged group), and ≥61 years old (elderly group).ResultsThe median GH levels in young, middle-aged, and elderly groups were 18.5, 8.8, and 6.7 μg/l respectively, and the IGF1 levels were 810, 717, and 740 μg/l respectively. The values were not significantly different among the groups. However, the serum IGF1 SDS were significantly higher in the elderly group (10.2) than those in young and middle-aged groups (6.6 and 6.2 respectively, PConclusionThis study suggests that the relatively high IGF1 secretions in elderly patients might be involved in the progression of clinical complications in acromegalic patients. Therefore, awareness of the early symptoms and examination of serum GH and IGF1 are important for patients with acromegaly.

It has been reported that patients with acromegaly may have an increased risk of developing several types of cancers, such as colorectal, breast and prostate tumors. However, some reports do not support these findings and therefore the prevalence of cancers in patients with acromegaly remains controversial. In this study, we determined the prevalence of benign and malignant neoplasms in patients with acromegaly. A retrospective chart analysis was performed on 140 patients with active acromegaly who had attended our outpatient clinic (M/F 54/86, age 55 +/- 25 yr, range 21-86). Colon cancer was found in 10 patients, thyroid cancer in 5, breast cancer in 4 and gastric cancer in 2. When compared with the local population, the standardized incidence ratios (SIRs) for thyroid cancer in patients with acromegaly were 61.74 (95% confidence interval (CI): 0.51-114.63) for females and 272.4 (95% CI: 29.12-876.71) for males. The SIRs for colon cancer in the acromegalic patients were 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for male patients in comparison with the local population. Of the benign tumors, multinodular goiter and colonic, gastric and gallbladder polyps were observed in 57% (47/83), 40% (35/87), 23% (10/43), and 14% (11/77) [corrected] of the patients, respectively. This study suggested that patients with acromegaly have an increased risk of colon cancer and polyps. Moreover, it is speculated that the risk for thyroid cancer is increased in male patients. It is therefore recommended that patients with acromegaly should undergo screening colonoscopy and ultrasonography of the thyroid.

GH therapy was approved in 2006 for treatment of adult growth hormone deficiency (GHD) in Japan. Until then, GH was used only to treat short stature in children with GHD and the treatment was stopped when the final height was reached. In the present study, we investigated metabolic co-morbidities experienced by adults with childhood-onset (CO) GHD after the cessation of GH. Forty-two patients with COGHD (M/F 22/20, age at follow up when the retrospective analysis was carried out: 18-52 yr) treated with GH in childhood were studied. We reviewed the medical records of these patients to determine the metabolic co-morbidities that developed after cessation of GH. The median age was 19 yrs (range: 14-38) at cessation of GH, and the following co-morbidities were observed: hypertriglyceridemia in 15 (41%) patients, non-alcoholic fatty liver disease (NAFLD) in 11 (29%) patients, hypercholesterolemia in 10 (26%) patients, diabetes mellitus (DM) in 4 (10%) patients, and hypertension in 1 (2.4%) patient. The median BMI when these complications became overt was 23.5 kg/m(2) for those with hypertriglyceridemia, 26.0 kg/m(2) for those with NAFLD, 20.9 kg/m(2) for those with hypercholesterolemia, and 27.2 kg/m(2 ) for those with DM. More than two co-morbidities were experienced by 32% of men and 30% of women. In conclusion, adults with COGHD after the cessation of GH have multiple metabolic co-morbidities. Lifelong GH replacement might be important for improving the overall metabolic profiles in these patients.

In TSH-secreting pituitary adenomas (TSHoma), octreotide (OCT) therapy reduces tumor size and TSH secretion in some cases but not in others. As OCT acts through various types of somatostatin receptors (SSTRs), the different responses of TSHoma to OCT might be explained by the differences of SSTR expression. We therefore studied the expression of subtype-specific SSTR mRNA transcripts in tumor tissues by RT-PCR. Type 2 (SSTR2) mRNA transcripts were detected in all 8 tumors but those of SSTR3 and SSTR5 were demonstrated only in 5 of them. Serum TSH levels were decreased by OCT administration test in all patients but OCT therapy was effective in two patients out of three. SSTR5 mRNA was detected in two tumors from the responder, but not in one tumor that was resistant to OCT. These observations suggest that the temporal decrease of TSH by OCT may be mediated by SSTR2, and that the long term response to OCT therapy may be related with the expression of SSTR5. Therefore, the expression of SSTR5 in TSHoma may be a useful marker for predicting the outcome of the therapy, but further studies with larger numbers of patients are necessary.

In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.

In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 micro/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.

The Growth Hormone (GH) and Its Related Factors Study Committee of the Foundation for Growth Science, Japan, has been conducting a quality control study for 15 years to improve the equality of diagnosis of GH deficiency. It found that the greatest differences in measured GH values were due to the different potencies of the kit standards, which were primarily adjusted to WHO standards for human GH of pituitary origin. With the collaboration of kit makers and the Study Group of Hypothalamo-Pituitary Disorders of the Ministry of Health, Labor and Welfare, all GH kits in Japan have begun using the same recombinant human GH standard since April 2005. As a result the diagnostic cut-off peak GH has changed from 10 to 6 ng/ml.

Octanoylated ghrelin (1-28) (intact ghrelin) is rapidly and easily degraded to desoctanoyl forms or smaller fragments (degraded ghrelin). Plasma levels of intact and degraded ghrelin were examined in 30 patients with anorexia nervosa (AN) (body mass index, 8.81-22.4 kg/m(2)) and 16 age-matched healthy women using several assay methods. Plasma levels of ghrelin measured using immunocomplex transfer-enzyme immunoassay, which specifically detects intact ghrelin, were lower in AN than controls. Plasma ghrelin levels in AN measured using the active ghrelin ELISA kit, which is advertised as specifically detecting intact ghrelin, did not differ significantly from controls. Plasma levels of desoctanoyl ghrelin using the desacyl-ghrelin ELISA kit, N-terminus ghrelin using the ghrelin active RIA kit, and C-terminus ghrelin using the ghrelin total RIA kit were significantly higher in AN than controls, and displayed significant negative correlations with body mass index. Plasma levels of ghrelin determined using immunocomplex transfer-enzyme immunoassay or active ghrelin ELISA during iv glucose infusion were suppressed in both AN and controls, whereas plasma levels of degraded ghrelin levels were not significantly decreased in AN. Plasma levels of intact ghrelin are therefore not higher in AN than controls, whereas degraded forms of ghrelin are elevated in AN. Rapid suppression of plasma intact ghrelin, but not degraded ghrelin, occurs in AN in response to glucose infusion. The profiles of intact and degraded forms of ghrelin in plasma of AN patients differ from those of healthy women.

We report an 80-year-old man who presented with non-islet cell tumor hypoglycemia (NICTH) in association with hepatic recurrence of gastric cancer. His serum potassium was reduced from 3.9 to 3.1 mmol/l 5 weeks after gastrectomy, and he subsequently developed hypoglycemic coma. He was diagnosed as having NICTH because of the presence of serum big IGF-II and positive staining for IGF-II in gastric cancer cells obtained at surgery. A computed tomography showed multiple liver metastases. His hypoglycemia was refractory to steroid therapy. This case suggested that NICTH could develop in association with hepatic metastases of gastric cancer. Unexpected hypokalemia may be a manifestation of occult NICTH.

We describe a rare case of hypoglycemia associated with a high molecular weight form of insulin-like growth factor II (big IGF-II) produced during the development of malignant fibrous histiocytoma (MFH). A 66-year-old man was referred to our department for further evaluation of hypoglycemia. At the age of 59, he had been diagnosed as having a MFH in the retroperitoneum, and underwent incomplete resection of the tumor. He had no symptoms of hypoglycemia at that time. Within the last few years, he developed symptoms of hypoglycemia in the early morning. Computerized tomography scans of the abdomen showed multiple tumors around the peritoneum and the liver. Serum insulin levels were decreased although no other hormonal deficiencies were observed. Serum IGF-II levels were elevated as a result of big IGF-II production. Taken together, these results indicated that hypoglycemia in this patient was associated with the production of big IGF-II by the MFH. The most effective therapeutic modality in patients with non-islet cell tumor hypoglycemia is resection of the tumor. In our case, as complete resection was impossible, dexamethasone and glucagon were administered and proved to be effective for preventing hypoglycemia.

A 13-year-old girl with Graves' disease, whose younger sister had systemic lupus erythematosus, developed polyarthralgia, fever, neutropenia, hypergammaglobulinemia, and microscopic hematuria after treatment with propylthiouracil (PTU) for 2 years. Myeloperoxidase-anti-neutrophil cytoplasmic antibodies were strongly positive. Anti-single- and anti-double-stranded DNA antibodies were positive, whereas LE cells and anti-Sm antibodies were negative. PTU was discontinued and all symptoms subsided gradually. Two years later, the microscopic hematuria had disappeared completely. Both patients had the identical HLA-DR alleles (HLA-DR9). These present two cases in siblings suggest that both sisters had lupus diathesis, and that the elder sister developed a PTU-induced lupus-like syndrome.

In serum, insulin-like growth factors (IGFs) are primarily present as a approximately 150 kDa ternary protein complex, which consists of IGFs, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Like IGF-I and IGFBP-3, serum levels of ALS depend on growth hormone (GH). To date, the diagnostic relevance of ALS in adult GH deficiency (GHD) has remained uncertain. To clarify the clinical utility of ALS measurement in adults, we measured serum ALS levels in patients with adult GHD or acromegaly. We also measured the levels of serum IGF-I and IGFBP-3 in these patients to compare the utility of ALS with IGF-I and IGFBP-3 as a marker of GH secretion. Serum ALS was measured by radioimmunoassay (RIA) kit, and serum IGF-I and IGFBP-3 were measured by immunoradiometric assay (IRMA) kits in 56 patients with adult GHD (adult-onset (AO)/child-onset (CO), 13/43) and 43 patients with acromegaly. Serum ALS levels were less than 5th percentile in 40 of 56 (71%) patients with adult GHD (32/43 (74%) for CO and 8/13 (62%) for AO), and more than 95th percentile in 38 of 43 (88%) patients with acromegaly, respectively. Serum IGF-I levels were less than -1.96 SD in 43 of 56 (77%) patients with adult GHD (35/43 (81%) for CO and 8/13 (62%) for AO) and more than +1.96 SD in 42 of 43 (98%) patients with acromegaly, respectively. Serum IGFBP-3 levels were less than -1.96 SD in 51 of 56 (91%) patients with adult GHD (42/43 (98%) for CO and 9/13 (69%) for AO) and more than +1.96 SD in 31 of 43 (72%) patients with acromegaly, respectively. These data suggested that measurement of ALS offers no advantage over measurements of serum IGF-I and IGFBP-3. Furthermore, our results indicate that serum IGFBP-3 is the most suitable marker of GH secretion for adult GHD, especially CO, while IGF-I may be the most useful in acromegaly.

Objective The purpose of this study was to survey the clinical characteristics, complications, and therapeutic outcome in patients with acromegaly. Patients and Methods The clinical features of 65 patients with acromegaly (31 males, 34 females; mean age: 50±2 yr.) who were admitted to Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. Results The retrospective analysis revealed that the diagnosis of acromegaly was preceded by approximately 8.1±1.1 years of signs and symptoms of the disease. Forty-six of the 65 patients (71%) had macroadenomas, 16 (25%) had microadenomas, and the remaining three had empty sella. The rate of biochemical cure or remission was 81% for microadenoma (13/16), 64% for macroadenoma without extrasellar extension (9/14), and 13% for macroadenoma with cavernous sinus extension (2/15). Eighteen (28%) patients had impaired glucose tolerance (IGT) and 32 (49%) had diabetes mellitus (DM). After treatment for acromegaly, glucose metabolism was analyzed again in 38 patients, and it improved in 26 patients with IGT or DM. Twenty-five of 65 patients (38%) had hypertension. Of 26 patients who underwent barium enema or colonoscopy, 10 had colonic polyps and 4 had colon cancer. Conclusion This study suggests that long-term excessive growth hormone (GH) secretion causes many complications. Therefore, awareness of the early symptoms and signs of acromegaly and long-term careful management of complications, along with therapy to reduce serum GH/insulin-like growth factor (IGF)-I levels, are important for patients with acromegaly.(Internal Medicine 40: 987-992, 2001)

Malnutrition is one of the risk factors for bone loss in patients with anorexia nervosa (AN). To clarify the effects of nutritional status on bone metabolism, we examined the relationship between serum levels of nutritional indicators [insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3] and markers for bone metabolism [serum osteocalcin and urinary excretion of C-terminal telopeptide of collagen type I (CrossLaps)] in 45 AN out-patients, including 8 severely malnourished patients who required hospitalization and iv hyperalimentation (IVH). Compared to healthy subjects, serum IGF-I and IGFBP-3 were lower, whereas IGFBP-2 was higher in out-patients who had a body mass index (BMI) less than 16.5 kg/m2. In these patients, urinary excretion of CrossLaps, a marker of bone resorption, was higher, whereas serum osteocalcin, a marker of bone formation, was lower than those in control subjects. All of these parameters were normal in patients whose BMI ranged from 16.5–18.5 kg/m2. Ser...

This case of hepatocellular carcinoma (HCC) with alcoholic liver fibrosis, which was not associated with hepatitis viruses, was accompanied by hypoglycaemia. The immunoreactive insulin level was low and other hormonal examinations were almost normal. Immunohistochemical studies showed a high level of insulin-like growth factor II (IGF2) peptide in the HCC section and the size heterogeneity of serum IGF2 investigated by western blot revealed a large form at approximately 15 kDa. These results suggest that the HCC with alcoholic liver fibrosis produced IGF2 and that the hypoglycaemia was caused by tumour-associated IGF2.

The Foundation for Growth Science has been controlling the use of GH by its registration system, which includes a scoring system for the eligibility for GH treatment according to the diagnostic criteria for GH deficiency (GHD) established by the Study Group for Hypothalamo-pituitary Disorder of the Ministry of Health and Welfare. Until 1995, 28,876 patients with GHD (19,432 boys and 9,444 girls) had been registered as eligible for GH treatment. The number of patients registered in a year increased gradually till 1990 due to the unlimited hGH supply by recombinant techniques and the change in the criteria for GH treatment and the number registered became stable after 1990. The frequency of GH-treated patients is calculated to be 55.2/100,000 persons (72.2/100,000 in boys and 37.1/100,000 in girls) in patients born between 1960 and 1990. The highest frequency was 148.4/100,000 persons (191.7/ 100,000 boys and 103.7/100,000 girls) in 1981, when 2,278 patients (1,508 boys and 770 girls) were born. Eligibility for GH treatment is assessed according to the scoring system which is basically dependent on peak GH values in provocation tests so that standardization of GH values measured with the various commercial GH kits is required to avoid inequality of patients' access to the treatment. In samples obtained by GRF test in 10 normal volunteers, hGH was measured with seven human GH (hGH) kits at a laboratory center. Since the RIA value has been used historically for the diagnosis of GHD, the mean of two RIA measurements was selected as the basis for the standardization procedure and the linear regression formula was used for each hGH kit. After the freely available supply of hGH obtained by recombinant DNA techniques, the role of the Foundation for Growth Science has changed to avoid hGH abuse. Even with this regulation, the frequency of registered patients may indicate a tendency to GH overuse.

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-I and also through undefined secondary effect.

Clinical trials of human GH therapy for Turner syndrome were started in 1986. The number of patients enrolled from 1986 to 1989 was 375. The age at the start of treatment ranged from 5 to 18 with a mean of 10 years. About half of the enrolled patients stopped receiving the therapy within 3 years. A total of 115 patients were treated for more than six years with recombinant hGH. Fifty-one patients received hGH at a weekly dosage of 0.5 IU/kg and 64 received 1.0 IU/kg by daily sc injection. Both treatment groups showed a statistically significant growth increase during the initial 4 years of treatment. The high dose increased height velocity to a significantly greater degree for the initial 2 years as compared with the low dose so that the increase in height over the 6 year treatment with 0.5 IU/kg/W and 1.0 IU/kg/W, as expressed by the SD score (δSDS) for chronological age, was 1.5 and 1.8, respectively. Ninety percent of the patients above the age of 14 exceeded their projected adult height. During the 6 years of treatment, 260 patients stopped or ceased GH therapy. In 31 percent of the patients, the height was above - 2SD for normal girls. In 27% of the patients, the growth rate was not sufficient when they stopped treatment. The final height (FH) of Turner patients was tentatively designated to be the height when the growth rate became

Untreated acromegaly is associated with a twofold to fourfold increased mortality risk compared to the population. Recently, new therapeutic modalities have been developed and may contribute to an improvement in treatment outcomes in patients with acromegaly. In the current study we determined the clinical features and recent therapeutic outcomes in patients with acromegaly. The initial symptoms, selected therapeutic modalities, and outcomes in 125 patients with acromegaly (M/F, 49/76, 19–86 years) who were admitted to our institution between 2001 and 2010 were analyzed using medical charts. The basal GH levels and IGF-I SD scores in the patients ranged from 0.17 to 90.21 μg/L and 1.9–13.6, respectively. Acral enlargement (face, hands, and feet) without overt complications was essential to the diagnosis in 49 % of the patients. In these cases, it required 5 years to establish the diagnosis of acromegaly after symptom onset. Twenty (16 %) and 13 (10 %) patients had diabetes mellitus and hypertension 6 years prior to the diagnosis of acromegaly, respectively. In 35 patients with microadenomas, the rate of controlled cases following transsphenoidal surgery was 93 %. In 90 patients with macroadenomas, the remission rate was 79 % with multidisciplinary treatment. In cases in which the tumor extended beyond the lateral tangent of the internal carotid artery (Knosp grade ≥3), the remission rate was 33–56 %. Improvements in surgical techniques and medical therapies may contribute to increased rates of controlled cases in patients with acromegaly, although advanced lateral extension of the tumor remains a critical determinant of the therapeutic outcome.

We describe a case of pituitary gigantism with low levels of growth hormone (GH), elevated insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 (IGF-BP-3). The patient had characteristic clinical features of gigantism and acromegaly. The basal serum GH levels ranged from 1.2-1.9 micrograms/L, which were considered to be within normal limits. Serum GH response to either insulin-induced hypoglycemia or GH-releasing hormone was blunted. Frequent blood samplings during daytime and at night showed nonpulsatile GH secretion. Serum prolactin, IGF-I and IGF-binding protein-3 levels were elevated. After unsuccessful surgery, bromocryptine treatment normalized serum prolactin without affecting serum GH and IGF-I levels. Combined administration of octreotide and bromocryptine reduced serum GH and IGF-I levels. GH bioactivity as measured by Nb2 cell proliferation assay was within reference range. In the present case, nonpulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-I and IGF-BP-3 and cause clinical acromegalic gigantism.

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).

Measurements of insulin-like growth factor-I (IGF-I) are useful not only for diagnosis and management of patients with growth hormone (GH)-related disorders but also for assessing nutritional status. We reported population-based references of serum IGF-I in 1996. However, they did not properly reflect data in the transition period from puberty to maturity. The aim of the present study was to re-establish a set of normative data for IGF-I for the Japanese population. The study included 1,685 healthy Japanese subjects (845 males, 840 females) from 0 to 83 years old. Subjects suffering from diseases that could affect IGF-I levels were excluded. Obese or extremely thin adult subjects were also excluded. IGF-I concentrations were determined by commercially available immunoradiometric assays. The reference intervals were calculated using the LMS method. Median IGF-I levels reached 310 ng/mL in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years. The mean pretreatment IGF-1 SD scores in patients with severe GH deficiency (GHD) obtained from the database of the Foundation for Growth Science and from clinical studies for adult GHD were -2.1±1.6 and -4.9±2.5, respectively. The present study established age- and gender-specific normative IGF-I data for the Japanese population and showed the utility of these references for screening patients with severe GHD.

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age 49.6 +/- 10.0 years) undergoing dialysis were enrolled in the study. Body weight, skinfold thickness, and midarm muscle circumferences (MAMCs) were measured for anthropometric nutritional indices. Blood samples were collected to measure the following endocrinological, biochemical and hematological indices: IGF-I, growth hormone, (GH), total protein, prealbumin, albumin, transferrin, hematocrit, and lymphocyte count. Nutritional indices were measured again 1 month later to calculate the percent difference among them. Moreover, 2 patients who showed a decrease in IGF-I and suffered from malnutritional complications, such as hypoproteinemia and emaciation, which could not be successfully treated by conventional therapies were selected in order to confirm the nutritional role of IGF-I mediated by recombinant human GH (r-hGH). The serum IGF-I concentration distribution ranged from 22 to 225 ng/ml. In 15 patients (10 males, 5 females), it fell from 22 to 82 ng/ml below the normal range. Partial correlation coefficient analysis demonstrated that baseline IGF-I and the percent difference of each the body weight, MAMC, prealbumin and albumin were highly significantly correlated (r = 0.431, 0.641, 0.624 and 0.348, respectively; p = 0.014, 0.001, 0.001 and 0.028, respectively). The percent difference of IGF-I did not correlate significantly with that of any other nutritional index during the 1-month observation without administration of r-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been shown that both insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) are produced by thyroid cells in culture and that the cells respond to IGF-I with increased DNA synthesis, suggesting an autocrine/paracrine role of IGF-I in the regulation of thyroid cell growth. We investigated the tissue contents of immunoreactive IGF-I (irIGF-I) and IGFBPs in human papillary carcinoma and compared them with those of normal thyroid tissue. When irIGF-I was measured after separation of the IGFBPs by gel-filtration, its content in carcinoma tissue was not different from that in adjacent normal tissue (566 +/- 58 vs. 424 +/- 75 pg/mg protein, N = 10). Nor was there any difference in the abundance of IGF-I mRNA expression determined by slot blot analysis. On the other hand, IGFBP activity measured in terms of 125I-IGF-I binding was significantly higher in cancer extracts. Western ligand blot analysis of IGFBPs revealed several species (24-42 kDa) of IGFBPs. The IGF-I-binding activity of 38-41 kDa species (corresponding to IGFBP-3) was not different between extracts of cancer tissue and those of normal tissue, whereas that of 28-32 kDa species was significantly higher in cancer tissue extracts. Since IGFBPs have been reported to modulate cellular responses to IGF-I, the present data suggest that higher IGFBP activity in cancer tissue is involved in regulating growth of thyroid papillary carcinoma cells.