Cells of the thyroid tissue, either diseased or normal, can accumulate altered mitochondrial genomes in primary lesions and in surrounding parenchyma. Depending on the experimental approaches and the extent of the mutational process, it has been possible to demonstrate the occurrence of homoplasmic or heteroplasmic point mutations, presence of a common deletion and random large-scale mtDNA aberrations in various pathological states. Point somatic mutations documented in 5-60% of thyroid tumors do not concentrate in obvious hotspots but tend to cluster in certain regions of the mitochondrial genome and their distribution may differ between carcinomas and controls. Large-scale deletions in mtDNA are quite prevalent in healthy and diseased thyroid; however, the proportion of aberrant mtDNA molecules accounts for a very small part of total mtDNA and does not seem to correlate with pathological characteristics of thyroid tumors. Common deletion is most abundant in Hurthle cell tumors, yet it also occurs in other thyroid diseases as well as in normal tissue. The principal difference between the common deletion and other deletion-type mtDNA molecules is that the former does not depend on the relative mtDNA content in the tissue whereas in a subset of thyroid tumors, such as radiation-associated papillary carcinomas and follicular adenomas, there is a strong correlation between mtDNA levels and prevalence of large-scale deletions. Relative mtDNA levels by themselves are elevated in most thyroid tumors compared to normal tissue. Distinct differential distribution and prevalence of mutational mtDNA burden in normal tissue and thyroid lesions are suggestive of the implication of altered mtDNA in thyroid diseases, especially in cancer.

View full abstract

Generalized lipodystrophy is a rare disorder of adipose tissue, whose etiology remains unknown. Pathophysiology of this disorder is characterized by generalized loss of body fat associated with an infrequent form of diabetes mellitus (lipoatrophic diabetes). Main features of this form of diabetes mellitus are the severe insulin resistance and the absence of ketoacidosis. Lipodystrophy can be congenital or acquired. In the acquired form, metabolic disturbances usually begin in the first years of life and the response to conventional treatment is very poor. Some alterations in serum adipocytokines have been described in this disease. We report the case of a 74-year-old woman with acquired generalized lipodystrophy who presented with low-normal serum concentrations of leptin, low adiponectin and resistin levels, and high serum levels of TNFα. Patient was initially treated with fenofibrate, metformin and high doses of subcutaneous insulin achieving an adequate metabolic control. During this period, serum adipocytokines were periodically measured. We comment on the different etiopathogenic mechanisms and the therapeutic modalities of this rare syndrome.

View full abstract

A 75-year-old male showed combined anterior pituitary hormone deficiency (CPHD). Basal and TRH-stimulated PRL levels were undetectable. Basal and GRH-stimulated GH levels were very low, and could barely be measured by means of an ultrasensitive enzyme immunoassay. In addition, basal TSH levels were under the normal limit, and TRH-stimulated TSH secretions were impaired. On the other hand, the secretions of ACTH, LH and FSH remained intact. There was no mutation of Pit-1 gene in this patient, and immunohistochemical studies using human pituitary and the patient's serum showed no positive staining. The HLA types frequently detected in lymphocytic hypophysitis were recognized, supporting the view that the CPHD in this case may be caused by lymphocytic hypophysitis, although magnetic resonance imaging of the pituitary gland showed no specific findings. Interestingly, a high titer of anti-glutamic acid decarboxylase antibody, suggested that the patient suffered from type 1 diabetes mellitus (DM). Five years ago, his thyroid function was normal and the treatment of DM with oral hypoglycemic agent was effective, indicating that the onset of both diseases at least occurred within the last half decade. We report here a rare case of SPIDDM with CPHD which might be caused by lymphocytic hypophysitis.

View full abstract

Incidental discovery of an adrenal mass, the so-called adrenal incidentaloma, has been increasing due to the advances in non-invasive diagnostic imaging tools. The criteria of diagnosis for preclinical Cushing's syndrome (preCS) in Japan were made by Nawata et al. supported by the Ministry of Health and Welfare in 1995. The results of suppression of cortisol by dexamethasone (DEX) (plasma cortisol above 3 μg/dl after 1 mg of DEX and above 1 μg/dl after 8 mg of DEX) are essential for the diagnosis of preCS due to an adrenal adenoma. However, plasma cortisol levels after the two doses of DEX suppression tests were found to be discrepant and repeated DEX suppression tests sometimes yielded different results. Therefore, we examined the cortisol values of DEX suppression tests in patients with preCS using four different cortisol assay kits: Amerlex cortisol kit (AMA), SPAC-S cortisol kit (SPA), ADVIA-Centaur cortisol assay (ADV) and ECLusys 2010 cortisol assay (ECL). The diagnosis for preCS was done using the AMA kit. Correlation between the kits was good. However, cortisol levels measured by SPA, ADV and ECL were lower than those measured by AMA. In the 1 mg DEX test, the cortisol levels measured with the SPA, ADV and ECL kits were suppressed in 2 patients with preCS. With 8 mg of DEX, cortisol levels measured with the SPA and ADV kits were suppressed in 2 patients with preCS. The diagnosis of preCS is decided by the cortisol kit used, but the cortisol levels differ among the kits. It is suggested that the lack of the standardization of cortisol measurement is one of the causes of confusion in the diagnosis of preCS.

View full abstract

An 84-year-old woman was admitted to our hospital for the examination and treatment of painful right thyroid swelling on August 2, 2002. Thyroid ultrasonography showed a mass of about 6 cm in diameter at the right thyroid lobe. Aspiration biopsy cytology (ABC) of her mass showed a thyroid carcinoma. Her neck mass was cold on ¹²³I scintigraphy and hot on both early- and delayed- phase ²⁰¹Tl scintigraphy. Whole body ⁶⁷Ga scintigraphy scan showed a strong hot accumulation in the area from the right thyroid lobe to the right lateral lobe. Multiple lung tumors were observed from chest computed tomography (CT) scans. She was diagnosed as having an anaplastic thyroid carcinoma with metastatic lung tumors. As her thyroid carcinoma was inoperable, percutaneous injection therapy of lipiodol and ethanol (lip-PEIT) against the primary thyroid carcinoma was performed twice a week. However, the thyroid carcinoma gradually enlarged and oppressed her trachea. Two months after the initiation of lip-PEIT, parathyroid hormone-related protein (PTHrP)-dependent hypercalcemia was diagnosed because serum levels of calcium, phosphate and intact-PTHrP were 2.72 mmol/l (10.9 mg/dl), 0.71 mmol/l (2.2 mg/dl), 3.2 pmol/l, respectively. The hypercalcemia was reduced by the use of pamidronate. After one week she died of an airway obstruction caused by the developing thyroid carcinoma. Carcinoma cells with a mixed papillary and squamoid pattern were positively stained immunohistochemically by anti-PTHrP(1-34) antisera. Herein, we report a rare autopsy case of a PTHrP-producing thyroid carcinoma.

View full abstract

It is well known that manifest thyroid dysfunction causes mood disorders. In the literature there are few studies related with subclinical thyroid dysfunction and anxiety. We aimed to determine if there exists a relation between the anxiety and subclinical thyroid dysfunction. This study was carried out in the Meram Medical Faculty of Selçuk University, Department of Endocrinology and Metabolism. Eighty-five outpatients were enrolled into the study. In the presence of normal fT₃ and fT₄, patients were grouped as subclinical hyperthyroid with TSH lower than 0.1 mU/L (n = 24), subclinical hypothyroid with TSH higher than 4.5 mU/L (n = 32) and euthyroid subjects (n = 29). Beck's Anxiety Inventory (BAI) was administered to all patients. There was no any statistically significant difference between euthyroid and study groups in terms of age, gender, weight and height (p<0.05). One-way ANOVA showed that both of the subclinical hypothyroid and subclinical hyperthyroid groups had significantly higher anxiety scores than euthyroid group (F: 11.4, p<0.001). Manifest hypothyroidism and hyperthyroidism, as causes of mental and neurological dysfunction have been known for a long time, but the relation between subclinical thyroid dysfunction and anxiety is less well studied. We have found that subclinical thyroid dysfunction increases the anxiety of patients whether hyperthyroid or hypothyroid. Overlap of symptoms common to both thyroid dysfunction and anxiety is an important limitation in this study. Mood changes especially anxiety due to subclinical thyroid dysfunction may have an important impact on the patient's quality of life. Negative effect on quality of life may be an indication of treatment in these patients. It is the first study evaluating anxiety in subclinical hypothyroidism in the literature.

View full abstract

We found a case of a papillary thyroid carcinoma that was accompanied by a familial adenomatous polyposis (FAP) in a 29-year-old female. She had hundreds of adenomas inside the entire colon and a congenital hypertrophy of the retinal pigmented epithelium (CHRPE). The patient underwent a total thyroidectomy and a central compartment neck node dissection. Gross examination of the thyroid identified two solid and cystic lesions. The pathological finding of thyroid cancer revealed a mixture of a peculiar nuclear clearing, cribriform, morula formation, trabecular and papillary pattern. The patient's brother had undergone a total colectomy due to FAP at the age of 25. Genetic analyses of the patient's family members revealed that she and her brother had the same germline mutation, in which five nucleotides (AAAGA) were deleted from codon 1309 of the adenomatous polyposis coli (APC) gene exon 15. Strong and frequent immunoreactivities of β-catenin and p53 were evident in the tumor tissue. At the time of writing, a preventive colectomy was still under consideration for the patient. Genetic counseling was given to the other family members, who were not attacked by this disease, in order to allay their fears of cancer.

View full abstract

Transplantation of adrenal cortical tissue may represent an alternative treatment to reestablish glucocorticoid secretion in adrenal insufficiency. In the present work, performed in adrenalectomized rats and adrenalectomized rats with a complete autotransplanted adrenal into the spleen, several hormones and biochemical parameters were measured and compared to control animals, in order to examine hormone interactions. Rats were sacrificed three weeks after surgery, and plasma and tissue samples were obtained for hormone and biochemical measurements. In adrenalectomized animals, plasma corticosterone, aldosterone and insulin levels were profoundly decreased, whereas in autotransplanted rats plasma corticosterone levels showed a partial recovery, aldosterone plasma concentrations remained low, and plasma insulin levels increased to values close to those of the controls. Both groups showed a marked elevation of plasma ACTH levels, as well as significantly increased plasma glucagon concentrations. In autotransplanted animals, most of the biochemical parameters, which were altered in adrenalectomized rats, returned to normal levels. These results suggest that increased glucagon levels in adrenalectomized and autotransplanted animals, may contribute to the marked increase of plasma ACTH, and could also be important in the recovery of plasma glucose and hepatic glycogen observed in autografted rats. Since high glucagon concentrations alone were unable to normalize carbohydrate levels in adrenalectomized animals, it appears that glucagon can act only in the presence of corticosterone.

View full abstract

The gene responsible for multiple endocrine neoplasia type 1, MEN1, encodes the 610-amino acid-protein, menin. Although menin has been reported to bind AP-1 transcription factor JunD and suppress its transcriptional activity, little is known about its molecular mechanisms and physiological role. To better understand the function of menin and its significance in tumorigenesis, we investigated the effect of wild-type and mutant menin proteins on AP-1 transactivation. In COS cells, wild-type menin suppressed JunD-mediated transactivation in a dose-dependent manner, while it augmented c-Jun-mediated transactivation also in a dose-dependent manner. These effects were lost or reduced in all menin mutants examined. Electrophoretic mobility shift assay using AP-1 binding elements as a probe revealed that menin does not affect binding of c-Jun to DNA. Coexpression of menin mutants did not affect the function of wild-type menin. Coexpression of JunD amino-terminal fragment abolished menin-mediated enhancement of c-Jun transactivation, suggesting that Menin-JunD interaction may negatively regulate the enhancing effect of menin on c-Jun-mediated transactivation in COS cells.

View full abstract

Circulating human GH (hGH) consists of several molecular isoforms. It was previously reported that the proportion of 20 kilodalton hGH (20K-hGH) was elevated in the serum of patients with active acromegaly. In this study, we investigated the effects of octreotide and transsphenoidal adenomectomy on the proportion of 20K-hGH in the serum of 7 acromegalic patients. To achieve an acute effect, octreotide (100 μg) was subcutaneously injected as a bolus. To observe the chronic effects of octreotide therapy and surgery, serum samples were obtained by repetitive blood sampling before and 3 to 8 weeks after treatment. Serum levels of 20K-hGH and 22 kilodalton hGH (22K-hGH) were determined by specific enzyme-linked immunosorbent assay. A bolus injection of octreotide elicited a parallel decrease in serum 22K-hGH and 20K-hGH, resulting in an unchanged proportion of 20K-hGH to total circulating hGH. The proportion of 20K-hGH was decreased in 4 of 4 patients 4 to 7 weeks after surgery and in 2 of 4 patients after chronic treatment with octreotide for 3 to 8 weeks. The proportion of serum 20K-hGH was positively related to mean serum 20K-hGH as well as serum total hGH levels, but not with serum IGF-I levels. These findings suggest that high serum levels of 20K-hGH or total hGH per se might elicit a chronic change in the clearance kinetics of 20K-hGH and increase the proportion of 20K-hGH in acromegalic patients.

View full abstract

Annexin 5, a novel calcium-phospholipid binding protein, is thought to be involved in hormone secretion by the anterior pituitary gland. Gonadotropin releasing hormone stimulates annexin 5 synthesis, which, in turn, enhances gonadotoropin secretion. On the other hand, annexin 5 was shown to inhibit prolactin release in vitro. To understand the nature of the opposing effects of annexin 5 on these two major pituitary hormones, the present study examines the inhibitory effect of annexin 5 on prolactin release in relation to thyrotropin stimulating hormone (TRH) using primary cultures of anterior pituitary cells of adult female rats. While recombinant rat annexin 5 was found to have little effect on basal prolactin release, it significantly inhibited TRH-stimulated prolactin release. Addition of specific anti-annexin 5 serum to the culture increased basal prolactin release in a concentration dependent manner, and no further increase in prolactin release was observed following application of TRH in the presence of anti-annexin 5. The enhanced basal prolactin release induced by anti-annexin 5 was reversed by the simultaneous administration of indomethacin, an inhibitor of cyclooxygenase. These results demonstrate that endogenous pituitary annexin 5 exerts an inhibitory effect on prolactin release and suggest that this is attained by suppression of eicosanoid synthesis in vitro.

View full abstract

Glucocorticoid replacement therapy needs to be tailored to individual patient's requirements in order to avoid risk of over or under medication. We measured bone mineral density (BMD) of lumbar spine using dual X-ray absorptiometory in 10 patients with Addison's disease and 5 patients with isolated ACTH deficiency receiving glucocorticoid replacement therapy. We also examined the effect of glucocorticoid replacement on BMD. Decreased %BMD (less than 80% of age-matched controls) was found in 2 female patients who had received hydrocortisone at a dose of 14.8 and 15.4 mg/m²/day. In contrast, no patient receiving a hydrocortisone dose of less than 12.4 mg/m ²/day had decreased %BMD. There was no correlation between %BMD and hydrocortisone dose (mg/m²), duration of therapy, or cumulative hydrocortisone dose when treated with appropriate dose of hydrocortisone (<13.6 mg/m²). There was also no statistically significant difference in %BMD with age. We concluded that long-term glucocorticoid replacement therapy does not induce bone loss in patients with glucocorticoid deficiency unless an excessive dose of hydrocortisone is given.

View full abstract

A recent western study reports that t(2; 3)(q13; p25) translocation resulting in the expression of the Pax8-PPARγ fusion gene in patients with thyroid follicular carcinoma (FTC) occurs with high incidence (63%). Furthermore, the products of the fusion gene were shown to suppress the function of PPARγ in a predominantly negative manner, conferring them with an oncogenic potential. We examined the expression of this fusion gene in FTC in Japanese patients. From 1989 to 2000, six cases with FTC were surgically treated at our institute. In these carcinoma samples, the expression of mRNAs for the Pax8-PPARγ fusion product was analyzed by nested RT-PCR. Their expression was also studied in other thyroid nodules (12 adenomatous goiters, 12 follicular adenomas, 12 papillary carcinomas and 12 normal thyroid tissues) obtained at surgery during the same period. Pax8-PPARγ fusion mRNA was not detected in any FTC samples nor in the other samples. Furthermore, none of the 6 FTCs, one follicular adenoma or one normal thyroid analyzed by fluorescence in situ hybridization (FISH) exhibited Pax8-PPARγ gene fusion. These findings are in contrast to previous reports and indicate that ethnic background may affect the translocation.

View full abstract

ACTH and 17-hydroxyprogesterone (17OHP) levels during clitoro- and labinoplasty for CYP21A2 deficiency have not been reported. In this study, we measured these levels during surgery. Intensive glucocorticoid supplement (IGS Tx; intravenous bolus injection of daily dose (14.6 to 22.2 mg/m²) of hydrocortisone followed by continuous infusion of three times the daily dose for 24 hours) was done to eight patients for surgery. ACTH and 17OHP levels were generally suppressed during operation by this protocol, but mid-surgical elevations of ACTH and 17OHP levels were observed in four out of the eight. In another three patients than the eight as described, oral dexamethasone pretreatment (1 mg/m²) was administered for two days before surgery in addition to IGS Tx. ACTH and 17OHP levels were completely suppressed throughout operation, indicating that this kind of additional pretreatment is more effective approach.

View full abstract

Lymphocytic hypophysitis is a rare inflammatory disease of the pituitary gland that is being increasingly recognized as a cause of hypopituitarism. This condition may be due to an autoimmune pituitary destruction which usually occurs in young women during pregnancy or in the immediate postpartum period. We describe a case of cystic pituitary mass in a thirty-eight year-old woman presenting with nausea, vomiting, cold intolerance, blurring of vision and the presence of disagreeable odors for a one-month period. She had secondary amenorrhea and galactorrhea for three months. Combined anterior pituitary stimulation test confirmed the diagnosis of hypopituitarism. Magnetic resonance imaging scan with enhancement showed a huge cystic sellar mass with suprasellar extension and thickening of the pituitary stalk. Transsphenoidal exploration was performed with preoperative diagnosis of pituitary macroadenoma with cystic necrosis. Histological examination revealed lymphocytic hypophysitis characteristic of diffuse, dense lymphocytes and plasma cells infiltration with surrounding interstitial reactive fibrosis. Postoperatively, the patient's olfactory function returned to normal but combined anterior pituitary stimulation test showed persistence of hypopituitarism with mild hyperprolactinemia. Prednisolone, thyroxine and estrogen replacements were started and clinical symptoms were much improved. In summary, we report an extremely rare case of a woman with cystic lymphocytic hypophysitis with cacosmia and hypopituitarism, confirmed by histological examination.

View full abstract

The present study was conducted in an attempt to treat streptozotocin (STZ)-induced hyperglycemia by transplanting β cells derived from pancreatic ductal cells. Ductal cells obtained from neonatal rats were cultured in vitro. Approximately 70% of the cells were converted to insulin-secreting cells by incubating with betacellulin and activin A. Differentiated cells responded to a depolarizing concentration of potassium, tolbutamide and a high concentration of glucose, and insulin secretion increased by 2.5-, 2.3- and 1.6-fold, respectively. We then prepared pseudoislets using the differentiated cells, which exhibited greatly improved glucose-responsiveness, with a high concentration of glucose inducing a 3-fold increase in insulin secretion. We transplanted these pseudoislets into the portal vein of STZ-treated nude mice. Before transplantation, the plasma glucose concentration was above 400 mg/dl, and after transplantation it was markedly reduced, the effect of which persisted for two weeks. These results indicate that STZ-induced hyperglycemia can be treated by transplanting pseudoislets consisting of β cells derived from ductal cells.

View full abstract