Clinical features and therapeutic outcomes of acromegaly during the recent 10 years in a single institution in Japan.

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.

Favorable Impacts of Growth Hormone (GH) Replacement Therapy on Atherogenic Risks in Japanese Children with GH Deficiency.

Growth hormone (GH) affects body composition and atherogenic risk factors. Severe hyperlipidemia may develop in GH-deficient adults as a consequence of continuous GH deficiency. We investigated changes in lipid profiles in 158 Japanese children (103 boys and 55 girls) with GH deficiency who had been enrolled in the Pfizer International Growth Database Japan during 3 yr of GH replacement therapy to evaluate whether GH treatment has beneficial effects on atherogenic risk factors. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and atherogenic index were evaluated before treatment and then once a year during treatment. The mean baseline TC was within the normal range in both boys and girls. Seventeen (16.5%) of the 103 boys and 18 (32.7%) of the 55 girls, however, had a TC level over 200 mg/dl before treatment. The mean TC level showed a significant decrease in girls. In a separate analysis, patients of both sexes with a TC level > 200 mg/dl showed significantly decreased TC. LDLC decreased significantly only in girls, while HDLC showed no change in either sex. The atherogenic index decreased significantly in girls. GH replacement therapy in children with GH deficiency had beneficial effects on lipid metabolism and atherogenic risk in both sexes. Early GH treatment would produce lipid metabolism benefits in these patients.

Adult height after growth hormone treatment in Japanese children with idiopathic growth hormone deficiency: analysis from the KIGS Japan database.

OBJECTIVE: To identify factors affecting adult height in Japanese patients with idiopathic growth hormone deficiency (GHD), who received growth hormone (GH) treatment during childhood. METHODS: A retrospective pharmaco-epidemiological study of the effect of GH treatment on adult height standard deviation scores (SDS) was conducted in 374 Japanese patients with idiopathic GHD. During childhood, GH (0.146 +/- 0.023 mg/kg/week) was administered for a mean of 6.4 +/- 2.6 years. RESULTS: The mean adult height was 160.6 +/- 6.3 cm (-1.75 SD; n = 232) in boys and 146.9 +/- 7.3 cm (-2.20 SD; n = 158) in girls after GH therapy. The mean increases in height SDS in boys and girls with severe GHD were 2.13 SD and 1.66 SD, respectively (p < 0.05). These increases were greater than those observed in patients with moderate GHD and mild GHD. The mean adult height of male patients with GHD and gonadotropin deficiency (166.8 cm) was significantly higher (p < 0.05) than that of isolated GHD patients who were either receiving (159.1 cm) or not receiving (160.5 cm) gonadal suppression therapy. The mean adult heights of female patients were 149.6, 146.7, and 146.9 cm, respectively, and these values did not significantly differ. CONCLUSION: Linear multiple regression analyses of Japanese patients with severe GHD (n = 61) revealed three independent variables that influenced adult height: gonadotropin deficiency, initial height SDS and height velocity during the first year after the initiation of GH therapy.

Effects of GH assay standardization on evaluation of treatment outcomes for acromegaly in Japan.

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 OGTT <1 µg/L is considered cured, 1≤GH<2.5µg/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.

Glucocorticoid- and androgen-secreting black adrenocortical adenomas: unique cause of corticotropin-independent Cushing syndrome.

OBJECTIVE: To describe the unique association of corticotropin-independent Cushing syndrome caused by cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A case of corticotroph carcinoma that caused multiple cranial nerve palsies, destructive petrosal bone invasion, and liver metastasis.

A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 µg/dl) levels. The patient underwent transsphenoidal surgery followed by γ-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed.

Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II.

We report two patients with vitamin D deficiency due to unbalanced diet. The patients initially presented with severe hypocalcemia, normophosphatemia and markedly elevated serum PTH levels. Although nutritional vitamin D deficiency was suspected from their history of gastrointestinal problems and dietary restriction, we conducted Ellsworth- Howard test to exclude the possibility of pseudohypoparathyroidism (PHP). Both patients showed no incremental response of urinary phosphate excretion. However, the urinary cAMP response to exogenous PTH was different between the two. Case 1 showed a blunted response (5-fold and 1.54 micro mol/h increase) and case 2 showed a normal response (39-fold and 3.04 micro mol/h increase). According to the criteria of Ellsworth-Howard test, the data of case 1 was compatible with PHP type I, and of case 2 with PHP type II. The final diagnosis of vitamin D deficiency was established in both patients based on very low serum 25-hydroxyvitamin D levels (less than 5 ng/mL) and the effect of treatment. After calcium supplementation with or without vitamin D, their biochemical abnormalities disappeared. They maintained normocalcemia without medication after correction of their unbalanced diet. The present study indicated that patients with vitamin D deficiency occasionally showed biochemical findings suggestive of PHP and that such patients could exhibit not only PHP type II pattern of response to exogenous PTH but also of type I pattern. Thus our clinical observation suggests the complexity of PTH resistance in vitamin D deficiency and underscores the importance of diet to prevent the disorder.

Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas.

CONTEXT: Cabergoline is effective for hyperprolactinemic hypogonadism. However, the rate of cabergoline-induced pregnancy in women with prolactinoma remains unknown. Also unknown is whether cabergoline can control tumor growth and thereby achieve successful pregnancy in patients with macroprolactinomas. METHODS: Eighty-five women with macroprolactinomas (n = 29) or microprolactinomas (n = 56) received prospective, high-dose cabergoline therapy for infertility based on individual prolactin suppression and/or tumor shrinkage. The patients included 31 bromocriptine-resistant, 32 bromocriptine-intolerant, and 22 previously untreated women. Conception was withheld until three regular cycles returned in women with microadenoma and until tumors shrank below 1.0 cm in height in women with macroadenoma. Cabergoline was withdrawn at the fourth gestational week. RESULTS: Cabergoline normalized hyperprolactinemia and recovered the ovulatory cycle in all patients. All adenomas contracted, and 11 macroadenomas and 29 microadenomas disappeared. Eighty patients (94%) conceived 95 pregnancies, two of which were cabergoline-free second pregnancies. The dose of cabergoline at the first pregnancy was 0.25-9 mg/wk overall and 2-9 mg/wk in the resistant patients. Of the 93 pregnancies achieved on cabergoline, 86 resulted in 83 single live births, one stillbirth, and two abortions; the remaining seven were ongoing. All babies were born healthy, without any malformations. No mothers experienced impaired vision or headache suggestive of abnormal tumor reexpansion throughout pregnancy. CONCLUSION: Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumor size and bromocriptine resistance or intolerance. Cabergoline monotherapy could substitute for the conventional combination therapy of pregestational surgery or irradiation plus bromocriptine in macroprolactinomas.

Gender differences in serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly.

Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/ml; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/ml; p<0.02, 7.3 vs. 9.2 SDS; p<0.02 and 79.6 vs. 141.5; p<0.05). When the subjects were divided into two groups: age 50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients 50 yrs (684 vs. 680 ng/ml; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly.

Genes up- or down-regulated by high calcium medium in parathyroid tissue explants from patients with primary hyperparathyroidism.

To investigate genes modulated in the parathyroid glands by calcium, expression levels of mRNA for all genes expressed in parathyroid tissue explants (PTEs) obtained from patients with primary hyperparathyroidism (I degrees -HPT) were analyzed by oligo-DNA microarray. PTEs obtained from 4 patients with I degrees -HPT were precultured in normocalcemic medium (Ca(++) 1.0-1.1 mM) for 7 days and then cultured in hypocalcemic medium (Ca(++) 0.60 mM) or hypercalcemic (Ca(++) 1.60 mM) medium containing 4 mg/dl phosphate for an additional 7 days. As expected, expression levels of mRNA for PTH and chromogranin A were decreased to less than 50% in the hypercalcemic medium when compared with those in the hypocalcemic medium. Furthermore, oligo-DNA microarray analyses revealed that 7 genes were up-regulated by more than 2-fold and more than 30 genes were down-regulated by more than 1/2 in PTEs. Interestingly, 9 of these genes (up-regulated genes: chemokine ligand 8, multiple C2 domain and transmembrane region protein 1; down-regulated genes: matrix metallopeptidase-9, B-box and SPRY domain-containing protein, nitric oxide synthase 2A, PTH, cartilage acidic protein 1, chromogranin A, and fibrin 1) were involved in calcium metabolism or calcium-signaling pathways in the parathyroid tissue. However, the expression level of mRNA for alpha-klotho was variable, and it was not constantly decreased in hypercalcemic medium under the present experimental conditions. Although it was not possible to use normal parathyroid tissue, this is the first reported study to have investigated the expression levels of mRNA for all genes in human parathyroid adenomas that are modulated by high calcium concentration in organ culture.

Successful treatment of postsurgical hypoparathyroidism by intramuscular injection of vitamin D3 in a patient associated with malabsorption syndrome due to multiple abdominal surgeries.

A 56-year-old patient with postsurgical hypothyroidism and hypoparathyroidism associated with gastrointestinal malabsorption syndrome was prescribed with L: -thyroxine and 1alpha(OH)D(3) at a massive daily dosage of 600 and 39 mug, respectively. Although the patient became nearly euthyroid, she had been hypocalcemic, requiring frequent intravenous injection of calcium gluconate to prevent tetany. Because the serum level of 1,25(OH)(2)D hardly increased after an oral intake of 21 microg 1alpha(OH)D(3), vitamin D(3) was administered intramuscularly. After stoss therapy (600,000 IU), the patient has been receiving 300,000 IU vitamin D(3) at intervals of 2-4 months so that she remained slightly hypocalcemic (7-8 mg/dl). At 1.5 years later, serum levels of 25(OH)D and 1,25(OH)(2)D were maintained at about 60 ng/ml and 30-50 pg/ml, respectively, and renal function was maintained well. These data suggest that intramuscular injection of 300,000 IU vitamin D(3) at an interval of a few months to maintain a slightly increased serum level of 25(OH)D and a slightly decreased serum level of calcium is a safe and cost-effective treatment in such a parathyroid hormone-deficient hypoparathyroid patient with malabsorption syndrome.

Iodide-induced chemokines and genes related to immunological function in cultured human thyroid follicles in the presence of thyrotropin.

BACKGROUND: It is well known that iodide exacerbates thyroid function in subclinical hypothyroid patients with autoimmune thyroiditis. To investigate the immunological mechanism of iodine-induced thyroid dysfunction, we studied the effect of iodide in cultured human thyroid follicles, which respond to physiological concentrations of human thyrotropin (TSH) (0.3-10 microU/mL) and maintain the Wolff-Chaikoff effect. MATERIALS AND METHODS: Thyroid follicles obtained from Graves' patients at subtotal thyroidectomy were precultured in medium containing 0.5% fetal calf serum and 10(-8) M iodide for 5 days, and then cultured with the medium containing bovine TSH (30 microU/mL) and low (10(-8)M) or high (10(-5)M) concentrations of iodide. After 3-72 hours of culture, the effect of iodide on thyroid cell mRNA expression was analyzed by microarray and reverse transcriptase-polymerase chain reaction. RESULTS: After 48 hours of culture, iodide nearly doubled the mRNA expression levels of the immunity-associated genes (intercellular adhesion molecule-1, transforming growth factor beta 1-induced protein, early growth response gene 1, guanylate-binding protein 1, and annexin A1) and decreased the mRNA expression of sodium-iodide symporter to less than 20%. Further, the mRNA expression levels of chemokines (CCL2, CXCL8, and CXCL14) increased nearly twofold, whereas their receptors did not show any significant response. Real-time polymerase chain reaction analyses confirmed that iodide increased the mRNA expression levels of these genes in a time- and concentration-dependent manner. Immunohistochemical studies revealed that the chemokines were expressed mainly in the thyroid follicular cells in addition to the immune cells. The iodide-induced increase in CCL2 was greater in thyroid follicles obtained from thyroid gland that had been moderately infiltrated with the immunocompetent cells. CONCLUSION: We have demonstrated that iodide stimulates thyroid follicular cells to produce chemokines, particularly CCL2, CXCL8, and CXCL14. These chemokines and intercellular adhesion molecule-1 would attract immunocompetent cells into thyroid gland. These in vitro findings suggest that iodide at high concentrations may induce thyroid dysfunction through not only biochemical but also immunological mechanisms, particularly in patients with autoimmune thyroid disorders.

Novel gain of function mutations of the calcium-sensing receptor in two patients with PTH-deficient hypocalcemia.

Among 15 patients with PTH-deficient idiopathic hypocalcemia, we found two novel missense mutations in the calcium-sensing receptor (CaSR). Patient 1, who developed severe hypocalcemia (5.0 mg/dL) and seizures after birth, had a heterozygous de novo missense mutation in the transmembrane domain (A844P). The patient is currently receiving a minimum dose of 1alpha-OHD(3) (0.5 microg/day) to maintain the serum calcium level at 6 mg/dL and thus prevent seizures. Patient 2 had asymptomatic hypocalcemia (7.5 mg/dL) and also had a heterozygous missense mutation in the extracellular domain (E228G). These findings suggest that gene analysis of CaSR should be performed in patients with idiopathic hypocalcemia, particularly when it occurs in the neonatal period.

Hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal Cushing's syndrome.

Although cardiovascular complications are the major determinant of the prognosis of Cushing's syndrome (CS), factors contributing to the cardiovascular lesions are still unclear. We investigated clinical factors determining cardiac function in patients with adrenal CS. Fifty patients with adrenal CS were studied. Patients were divided into 3 groups based on their NYHA classification and electrocardiographic (ECG) findings: group A with NYHA grade 0 and normal ECG, group B with NYHA grade I and abnormal ECG, and group C with NYHA grade II or higher. Clinical and echocardiographic findings were compared between the groups. Heart failure of grade I or higher was seen in 40% and grade II or higher was seen in 8% of the patients. Age, HbA1c, and prevalence of diabetes mellitus were positively correlated and serum potassium levels were negatively correlated with the severity of cardiac dysfunction. Decreased ejection fraction (EF) and the ratio of the peak to late transmittal filling velocities (E/A), and increased left ventricular mass index (LVMI) were frequently observed. Multivariate analysis demonstrated that serum potassium and HbA1c levels were independent factors contributing to EF, while serum potassium and cortisol levels were independent factors contributing to LVMI. These results clearly demonstrated that hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal CS. Strict control of these conditions is warranted for the prevention of cardiac dysfunction in adrenal CS.

Association of polymorphism at position 49 in exon 1 of the cytotoxic T-lymphocyte-associated factor 4 gene with Graves' disease refractory to medical treatment, but not with amiodarone-associated thyroid dysfunction.

BACKGROUND: Recently, the G allele of the cytotoxic T-lymphocyte-associated factor 4 (CTLA-4) exon 1 single-nucleotide polymorphism (CTLA-4 A/G(49)) has been identified as the most informative marker in patients with Graves' disease. Patients with the G/G genotype are refractory to medical treatment and frequently relapse after discontinuation of antithyroid drugs. Therefore, we analyzed CTLA-4 A/G(49) in patients who had been treated with (131)I. Further, a preliminary report has suggested that amiodarone-associated thyroid dysfunction (AATD) has a relationship with human leukocyte antigen (HLA) class I and class II. METHOD: CTLA-4 genotypes in exon 1 (A/G(49)) and CT60 were analyzed in 415 Japanese patients with Graves' disease and 65 patients with AATD. RESULTS: The frequencies of the G alleles and G/G genotype at the both polymorphisms were significantly higher in Graves' patients compared with normal subjects. Compared with CT60, the frequencies of the G alleles and G/G genotypes at the A/G(49) were more significantly higher in patients with persistently positive thyrotropin receptor antibody despite >5 years of antithyroid drug therapy, compared with those whose thyrotropin receptor antibody became negative in <5 years (p < 0.0001). Consequently, the frequencies of the G/G genotype and G allele at the A/G(49) were also significantly higher in patients with Graves' disease who received (131)I therapy (p < 0.05). However, there was no significant difference in the A/G polymorphisms in the 65 patients with AATD. CONCLUSIONS: The G/G genotype in exon 1 (A/G(49)) is frequently expressed in Graves' disease patients who are refractory to antithyroid drug treatment. Therefore, the G/G genotype in A/G(49) would be a useful predictor of Graves' patients who are suitable for radioiodine therapy. Although the number of analyzed patients was small, our preliminary data suggest that the CTLA-4 gene polymorphisms might be unassociated with AATD.

Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study.

Ghrelin increases hunger sensation and food intake in various patients with appetite loss. Anorexia nervosa (AN) begins with psychological stress-induced anorexia and some patients cannot increase their food intake partly because of malnutrition-induced gastrointestinal dysfunction. The effects of ghrelin on appetite, food intake and nutritional parameters in anorexia nervosa (AN) patients were examined. Five female restricting- type AN patients (age: 14-35 y; body mass index: 10.2-14.6 kg/m(2)) had persistently complained of gastrointestinal symptoms and failed to increase body weight. They were hospitalized for 26 days (6 days' pretreatment, 14 days' ghrelin-treatment, and 6 days' post-treatment) and received an intravenous infusion of 3 microg/kg ghrelin twice a day. Ghrelin infusion improved epigastric discomfort or constipation in 4 patients, whose hunger scores evaluated by visual analogue scale questionnaires also increased significantly after ghrelin infusion. Daily energy intake during ghrelin infusion increased by 12-36 % compared with the pre-treatment period. Serum levels of total protein and triglyceride as nutritional parameters significantly increased after ghrelin treatment. There were no serious adverse effects including psychological symptoms. We found that ghrelin decreases gastrointestinal symptoms and increases hunger sensation and daily energy intake without serious adverse events in AN patients. Although the present study had major limitations of the lack of a randomized, placebo-controlled group, non-blindness of the investigators and the small number of patients recruited, it would contribute to further investigations for therapeutic potential of ghrelin in AN patients.

Autoimmune thyroid diseases in 65 Japanese women with Turner syndrome.

Turner syndrome (TS) is associated with a number of complications including thyroid disease. In this study, the prevalence of thyroid disease was evaluated in Japanese women with TS. The medical charts of 65 TS women (age 30+/-9 years old, range: 15-61), treated with estrogen replacement therapy or with antiosteoporotic pharmaceuticals at our outpatient clinic, were reviewed. History of thyroid disease, titer of thyroid autoantibodies, and thyroid function were recorded. Thyroid autoantibodies were undetectable in 28 of 65 women (43%), and thyroid function was normal in all these women. Of the 37 women with thyroid autoantibodies (57%), 3 had Graves' disease and 20 women were hypothyroidism and diagnosed as Hashimoto' s thyroiditis. The resting 14 women with euthyroidism were also considered to be so-called probable cases of Hashimoto' s thyroiditis. In 20 women with hypothyroidism, 14 (70%) received replacement therapy with levothyroxine. The replacement with levothyroxine started between age 17 and 60 (median: 31 years old). These data showed that more than half of Japanese women with TS in adulthood had thyroid autoantibodies. In women with TS, monitoring of thyroid hormone is important to detect hypothyroidism earlier and start adequate replacement therapy.

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders.

Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg(-1) per day, p.o.) or ARB (olmesartan, 5 mg kg(-1) per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-beta mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

Insulinoma with six islet cell tumors associated with severe hypoglycemia.

A 43-year-old woman was admitted to hospital due to loss of consciousness. Her fasting plasma glucose and serum immunoreactive insulin levels were 14 mg/dL and 5 microU/mL, respectively. She needed continuous glucose infusion to avoid hypoglycemia. A dynamic abdominal CT scan revealed two hypervascular tumors in the pancreas. A pancreatectomy was performed and her blood glucose level was normalized. The pathological examination revealed six insulinomas but we could not find either parathyroid tumors or obvious pituitary tumor, which denied the possibility of multiple endocrine neoplasia type I. However, long-term follow-up will be necessary for monitoring the development of other tumors.

Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy.

CONTEXT: About 10% of pheochromocytomas are malignant. Exact survival has not been reported, nor has an analysis of the efficacy of chemotherapy on survival time. OBJECTIVE: The aim of this study was to analyze the survival curves and survival times of patients with malignant pheochromocytoma and to determine the efficacy of chemotherapy on prolongation of life. DESIGN: An inception cohort and Kaplan-Meier survival analysis was conducted. PATIENTS AND OUTCOME MEASURES: Thirty-two patients with metastasized malignant pheochromocytoma were analyzed for survival. Twenty-five patients had undergone excision of their primary tumors. Survival curves were compared among the 16 patients in this group treated with combined chemotherapy using cyclophosphamide, vincristine and dacarbazine (CVD) and the nine patients not treated with chemotherapy. RESULTS: The survival curve of the 32 patients declined continuously and linearly to at least 20 yr after the diagnosis of pheochromocytoma. The 50% survival rate was estimated to be 14.7 yr. In the 25 patients whose primary tumor was excised, patients who already had metastases at the time of pheochromocytoma diagnosis had better survival than those whose metastases were found later. The survival rate after diagnosis of metastasis was worse in the CVD group than in controls. When the effects of CVD were examined after stratifying several factors, female gender and adrenal origin of tumor were found to be negative prognostic factors for CVD chemotherapy. CONCLUSION: The present study revealed a long survival time. CVD chemotherapy was not shown to extend survival, especially for women and patients with adrenal gland-derived primary tumors.