From mini-puberty to pre-puberty: early impairment of the hypothalamus-pituitary-gonadal axis with normal testicular function in children with non-mosaic Klinefelter syndrome.

PURPOSE: Klinefelter syndrome (KS) is a genetic disorder caused by the presence of an extra X chromosome in males. The aim of this study was to evaluate the hypothalamic-pituitary-gonadal (HPG) axis and the clinical profile of KS boys from mini-puberty to early childhood. PATIENTS AND METHODS: In this retrospective, cross-sectional, population study, 145 KS boys and 97 controls aged 0-11.9 years were recruited. Serum FSH, LH, testosterone (T), Inhibin B (INHB), sex hormone binding globulin (SHBG) and anti-Müllerian hormone (AMH) were determined. Auxological parameters were assessed. To better represent the hormonal and clinical changes that appear in childhood, the entire population was divided into 3 groups: ≤ 6 months (group 1; mini-puberty); > 6 months and ≤ 8 years (group 2; early childhood); > 8 and ≤ 12 years (group 3; mid childhood). RESULTS: During mini-puberty (group 1), FSH and LH were significantly higher in KS infants than controls (p < 0.05), as were INHB and T (respectively p < 0.0001 and p < 0.005). INHB was also significantly higher in KS than controls in group 2 (p < 0.05). AMH appeared higher in KS than in controls in all groups, but the difference was only statistically significant in group 2 (p < 0.05). No significant differences were found in height, weight, testicular volume, and penile length. CONCLUSIONS: No hormonal signs of tubular or interstitial damage were found in KS infants. The presence of higher levels of gonadotropins, INHB and testosterone during mini-puberty and pre-puberty may be interpreted as an alteration of the HPG axis in KS infants.

Adverse pathophysiological influence of early testosterone therapy on the testes of boys with higher grade sex chromosome aneuploidies (HGAs): a retrospective, cross-sectional study.

PURPOSE: Higher grade aneuploidies (HGAs) of the male sex chromosomes are a rare genetic group of pathologies caused by nondisjunction meiotic events. The aim of this study was to evaluate the impact of early androgenic therapy on the testicular secretory hormone profile, and the pathophysiological implications. PATIENTS AND METHODS: In this cross-sectional study, 18 HGA subjects aged 6-8 years were recruited. They were divided into two groups, based on whether or not they had previously undergone testosterone therapy (group 1: 11 untreated subjects; group 2: 7 treated subjects). Serum FSH, LH, testosterone (T), inhibin B (INHB) and anti-Müllerian hormone (AMH) were determined, and auxological parameters were assessed. Five group 1 patients and four group 2 patients were treated with hCG (human chorionic gonadotropin) for inguinal cryptorchidism; their hormone profile and auxological parameters were assessed both pre- and post-hCG treatment. RESULTS: Group 1 subjects showed significantly higher testicular volume and higher levels of AMH and INHB (p < 0.0001). Subjects who had undergone hCG therapy showed a significantly higher testicular volume, penis length (respectively, p = 0.008 and p = 0.0005 for group 1 and p = 0.04 and p = 0.001 for group 2) and T (p = 0.005 for group 1 and p = 0.004 for group 2). CONCLUSIONS: HGA patients undergoing early testosterone therapy show an earlier and persistent suppression of testicular secretory function. At this age, the testes are still responsive to stimulation with hCG. The selection of patients to be treated must be accompanied by a thorough clinical and hormonal evaluation.

A multicenter evaluation of immunoassays for follicle-stimulating hormone, luteinizing hormone and testosterone: concordance, imprecision and reference values.

BACKGROUND: Numerous laboratories in Italy use radioimmunoassay to determine concentrations of sex hormones (FSH, LH, testosterone). A comparison of assay methods is thus an important starting point for the achievement of universally accepted reference values. AIM: To carry out an external quality assessment for FSH, LH, and testosterone. MATERIALS AND METHODS: Fifteen aliquots from 5 serum pools were assayed in multiple replicates by 16 Italian laboratories with 5 automated immunoassays (Abbott Architect, DiaSorin Liaison, Perkin-Elmer AutoDelfia, Roche Elecsys, Siemens Immulite 2000), and 1 radioimmunoassay (Adaltis). RESULTS: The variance was below 12% for FSH, between 11.61% and 14.76% for LH, and between 9.57% and 12.48% for testosterone. Assay precision was good, except for Elecsys at low concentrations of FSH and for Immulite at low concentrations of LH and testosterone. ARCHITECT showed a negative bias for FSH and LH and a positive bias for testosterone; Liaison a positive bias for LH; Elecsys a positive bias for FSH and a negative bias for testosterone; Immulite a positive bias for FSH; AutoDelfia a negative bias for FSH and a positive bias for testosterone. Reference ranges at the low end varied widely, even among laboratories using the same assay. CONCLUSIONS: The analytical performances of widely used immunoassays for FSH, LH, and testosterone show a fair to strong degree of consistency. A careful evaluation of reference ranges by clinical and laboratory experts needs to be carried out, in order to reach a consensus.

Levothyroxine therapy in preventing nodular recurrence after hemithyroidectomy: a retrospective study.

AIM: To determine the effect of levothyroxine (L-T4) therapy on the recurrence rate of nodular disease in patients previously treated with lobectomy for benign nodular goiter. METHODS: Two hundred and thirty-tree patients (38 males, 195 females; age 49.9+/-13.1 yr) with no post-surgical evidence of nodular disease in the remnant, were followed- up yearly with serum TSH and ultrasound (US). Nodular recurrence was defined as a lesion of at least 5 mm at US. Patients were divided in 2 groups based on whether or not they had been treated with L-T4 after surgery: Group 1 (45 patients) who did not receive any L-T4, and Group 2 (188 patients) treated with L-T4. Group 2 was further subdivided in Group 2a (123 patients) receiving L-T4 substitutive therapy (TSH>or=0.5 and

Hashimoto's thyroiditis associated with idiopathic retroperitoneal fibrosis: case report and review of the literature.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease of unknown origin, characterised by an inflammatory proliferative fibrosing process occurring in the retroperitoneum. Hashimoto's thyroiditis (HT) is a form of chronic thyroiditis that in some cases shows an extensive replacement of thyroid parenchyma by fibrous tissue. We report the rare association of IRF with HT in a 68-year-old woman presenting with pulmonary oedema, acute renal failure due to bilateral hydronephrosis and a firm diffuse goitre with hypothyroidism. The so far reported cases of IRF associated with chronic thyroiditis are reviewed, and the possible aetiopathogenetic link between these two entities is discussed.

Sarcoidosis of the thyroid gland associated with hyperthyroidism: review of the literature and report of two peculiar cases.

Sarcoidosis is a systemic disease characterized by non-caseating granulomas that rarely involve the thyroid gland. Thyroid sarcoidosis has seldom been documented, and few cases have so far been described in association with hyperthyroidism. Here, we review the literature on this association, report two patients presenting with hyperthyroidism and histologically-proven sarcoidosis, and discuss related clinical, biochemical, pathological and genetic findings.

Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: A multicenter study.

BACKGROUND: The routine measurement of serum calcitonin (CT) has been proposed for patients with nodular thyroid disease (NTD), to detect unsuspected medullary thyroid carcinoma (MTC) before surgery. OBJECTIVE: To assess the prevalence of hypercalcitoninemia and MTC in NTD patients; to compare the ability of CT measurement and fine needle aspiration cytology (FNAC) to predict MTC; to identify age groups of NTD patients who should be better candidates than others to undergo routine measurement of CT. PATIENTS AND METHODS: 1425 consecutive patients, referred from April 1, 2003, through March 31, 2004, to four Italian endocrine centers due to NTD, were grouped depending on age, and underwent basal and, in some cases, pentagastrin (Pg)-stimulated CT measurement, FNAC and, when indicated, surgery. Serum CT concentrations were measured by an immunoluminometric assay (ILMA). RESULTS: Hypercalcitoninemia was found in 23 out of 1425 patients. MTC was discovered in 9 patients, all >40 yr old and showing high CT levels. Sensitivity of basal and Pg-stimulated CT to predict MTC before surgery was 100% for both tests, whereas specificity was 95 and 93%, respectively. CT specificity reached 100% when a cutoff value of 20 pg/ml was taken. FNAC showed an overall 86% sensitivity. When >10 mm MTC nodules were considered, FNAC sensitivity approached 100%. On the contrary, a correct cytological diagnosis was obtained in only one out of five patients with <10 mm MTC nodules (microMTC); in one patient with histologically proved microMTC, FNAC even demonstrated a benign lesion. Hypercalcitoninemia or MTC were associated with chronic thyroiditis in 30 or 33% of cases, respectively. C-cell hyperplasia was found in 57% of hypercalcitoninemic patients without MTC. CONCLUSIONS: Basal CT measurement detects elevated CT values in 1.6% of NTD patients. Although CT is not a specific marker of MTC, its routine measurement represents a useful tool in the pre-operative evaluation of NTD patients, particularly those >40 yr old presenting with nodules <10 mm, even when FNAC does not show malignant features. To our knowledge, this is the first trial using ILMA to assess the ability of pre-operative CT measurement to predict MTC in a large series of NTD patients.

Thyroid hemiagenesis and incidentally discovered papillary thyroid cancer: case report and review of the literature.

Thyroid hemiagenesis (TH) is a rare congenital abnormality in which one thyroid lobe fails to develop. Its prevalence is uncertain, because the absence of one thyroid lobe does not usually cause clinical symptoms. The detection of TH is usually incidental when the evaluation of other thyroid disorders is requested. It is more frequently found in female than in male patients (3:1 ratio) and in the left lobe compared to the right lobe. We report the case of a 54-yr-old man, presenting with a large multinodular right-sided goiter, with mediastinal extension and dysphagia. Thyroid scan and ultrasound study showed the absence of the left lobe. The patient underwent surgery for compressive symptoms, and the operation confirmed the absence of the left lobe. Histological examination demonstrated a multi-nodular goiter with papillary carcinoma. To our knowledge, this case represents the first reported case of association between TH and papillary thyroid carcinoma in a male patient, and the second in which the tumor arose in the right lobe.

Mortality for pancreatic cancer among aluminium smelter workers in Sardinia, Italy.

To investigate the relationship between exposure to polycyclic aromatic hydrocarbons (PAHs) and mortality for specifc cancer sites, 1152 men, employed for at least 1 year at a prebake aluminium smelter, were followed-up from 1972 until 31 December 2001. Exposure to PAHs was estimated from a detailed reconstruction of the working history experienced in the plant by each cohort member and from several environmental and personal shift-sampling measurements available, by task and working department, since 1979. Furthermore, information on smoking habits, previous jobs before engagement in the smelter and main clinical findings observed during the follow-up were collected from the personal medical files. This study showed no increased mortality for lung cancer or bladder cancer associated to exposure to PAHs. Mortality for pancreatic cancer, based on 6 observed deaths, was significantly higher than expected in the whole cohort (SMR 2.4; 95%CI 1.1-5.2) and particularly among workers employed in the anodes factory of the plant (SMR 5.0, 95%CI 2.1-12.1), where a relatively consistent exposure to PAHs has been estimated. The nested case-control study planned for pancreatic cancer cases, confirmed that, also after controlling for cigarette smoking, PAH exposure experienced in the anodes factory was associated with a significant increased risk of pancreatic cancer. A pre-existent diabetes mellitus and a potential occupational exposure to pesticides experienced in previous agricultural jobs were found as concurrent significant covariates increasing the risk. In conclusion, the relatively high exposure to PAHs, experienced in the anodes factory and particularly in the green-mill department of this prebake aluminium reduction plant, cannot be ruled out as one of the main factors in the multifactorial aetiology of the pancreatic cancers observed in this study.

Primary paraganglioma of the thyroid gland.

We describe the case of a 46-yr-old euthyroid woman, who was submitted to right lobectomy plus isthmusectomy because of a 30 mm large, rapidly growing thyroid nodule. Two cytological examinations of fine needle aspiration biopsy (FNAB) specimens were not diagnostic. Histology showed a neoplasm composed of nests of chief cells, almost completely replacing thyroid parenchyma, infiltrating the capsule and surgical resection margins, and invading perithyroid tissues. Immunohistochemical analysis revealed that the tumor stained positively to chromogranin, synaptophysin, NSE, S-100 protein and tyrosine hydroxylase, whereas no immunoreactivity was detected against cytokeratin, thyroglobulin, TTF-1, calcitonin and CEA. A diagnosis of thyroid paraganglioma (PG) was finally made. No complications developed following operation. Laboratory analysis and imaging study excluded multicentric disease, metastases to neck or extracervical organs, and multiple endocrine neoplasia (MEN). We report this unusual case, underscore its clinical and immunohistochemical features and discuss differential diagnosis.

Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation.

We report the case of a 72 yr-old woman who underwent total thyroidectomy and resection of neck lymph nodes because of a firm nodule in the right lobe, which was consistent with medullary thyroid carcinoma (MTC) on cytological examination. Histology showed multifocal bilateral MTC; a 2 mm papillary thyroid carcinoma (PTC) was also detected in the right lobe, next to a focus of MTC; five cervical lymph nodes contained MTC. In one right perithyroidal lymph node, concurrent metastases of MTC and PTC were demonstrated. DNA analysis showed a point mutation in exon 14 at codon 804 of the RET proto-oncogene locus, as frequently found in cases of familial MTC (FMTC). To our knowledge, this case represents the first documented case of concurrent lymph node metastases of MTC and PTC in a patient with RET proto-oncogene germline mutation. We report this unique case, discuss related thyroid malignancies, and suggest possible underlying pathogenetic mechanisms.

Postpartum thyroiditis presenting as a cold nodule and evolving to Graves' disease.

We describe the case of a 30-year-old woman who, five months after giving birth, was referred with a solitary nodule in her anterior neck. Laboratory analysis, ultrasonography, pertechnetate (Tc99m) thyroid scan and cytological examination of fine needle aspiration biopsy performed on the nodule led us to diagnose postpartum thyroiditis (PPT). Twenty-eight months after parturition, overt hyperthyroidism developed, with raised thyroperoxidase and thyroid stimulating hormone receptor antibody titres, diffuse high uptake of Tc99m at thyroid scan, and high vascular flow throughout the gland at Color-Power imaging. The diagnosis of Graves' disease (GD) was established. The differential diagnosis of thyrotoxicosis in the postpartum period, and the possible aetiological relationships between PPT and GD are discussed. To our knowledge, this is the first published report of a PPT presenting as a cold nodule, and evolving to GD.

Riedel's thyroiditis and fibrous variant of Hashimoto's thyroiditis: a clinicopathological and immunohistochemical study.

The aim of this study was to analyze and compare clinico pathological aspects of Riedel's thyroiditis (RT) and the fibrous variant of Hashimoto's thyroiditis (HTFV), and to show their immunohistochemical features. We reviewed 6 cases of HTFV and 4 cases of RT. Compared to RT, HTFV patients had hypothyroidism, no pressure symptoms, and frequently diagnostic fine-needle aspiration biopsy (FNAB) cytology. At histology, invasion of surrounding tissues and presence of occlusive phlebitis distinguished RT from HTFV. At immunohistochemistry, RT--compared to HTVF--was characterized by: 1) a more abundant fibrous reaction, and granulocytic, monocytic and eosinophil infiltration; 2) few plasma-cells, CD8+ T- and B-lymphocytes. The results of our study add further evidence regarding the separation of RT and HTFV in their peculiar clinical, laboratory, cyto-histological and immunohistochemical aspects.

[The management of thyrotoxicosis: a schematic approach]. / Approccio schematico alla terapia delle tireotossicosi.

Thyrotoxicosis is a well defined clinical entity, determined by an increase of plasma levels of thyroid hormones (T3 and T4). A number of causes of thyrotoxicosis are known, and it is therefore very important for the treatment to establish its etiology. In fact, metimazole or propylthiouracil are indicated for the thyrotoxic states caused by thyroid gland's hyperfunction (hyperthyroidism), but are not effective when thyrotoxicosis is determined by a follicular damage and disruption with leakage of preformed thyroid hormones, or in case of thyrotoxicosis factitia. Besides medical therapy, other two therapeutic options are available for the treatment of thyrotoxicosis: radioiodide administration (131I) and surgery. The physician can decide the best therapy on the basis of the following factors: etiology of thyrotoxicosis; patient's age and needs; presence/absence of concomitant diseases or pregnancy; presence of ophthalmopathy; goiter's size; advantages and disadvantages of each therapeutic option. A problem of particular regard is when and if to treat subclinical thyrotoxicosis (low TSH values, and normal plasma levels of thyroid hormones). On the basis of the natural history and of its consequences on the cardiovascular system and skeletal integrity, the authors propose to begin therapy whether subclinical thyrotoxicosis develop in the following four subgroups of subjects: patients with nodular goiter; women in post-menopause; patients with cardiac diseases; patients with osteoporosis.

Riedel's thyroiditis: clinical, pathological and imaging features.

Riedel's thyroiditis (RT) is an extremely rare form of chronic thyroiditis, characterised by a fibroinflammatory process which partially destroys the thyroid, often involving surrounding tissues. We describe an unusual case of RT in a 38-year-old woman, and discuss its typical clinical, pathological, ultrasound, radionuclide scanning and magnetic resonance findings. We conclude that the diagnosis of RT is highly suggestive in the presence of a hard gland (or nodule), fixed to adjacent structures; 'cold' on Tc99 scan; hypoechoic with absence of vascular flow, invading the adjacent neck structures on ultrasound; hypointense in T1- and T2-weighted MR images; and showing fibrous tissue fragments with inflammatory cells at cytological examination. Thyroidectomy has to be performed to confirm the diagnosis and to relieve pressure symptoms.

Binding of [3H]CB 34, a selective ligand for peripheral benzodiazepine receptors, to rat brain membranes.

The 2-phenyl-imidazo[1,2-a]pyridine derivative CB 34 is a ligand for peripheral benzodiazepine receptors. The binding of [3H]CB 34 to rat cerebrocortical membranes was characterized. Specific binding was rapid, reversible, saturable and of high affinity. Kinetic analysis yielded association and dissociation rate constants of 0.2x10(8) M(-1) min(-1) and 0.29 min(-1), respectively. Saturation binding experiments revealed a single class of binding sites with a total binding capacity of 188+/-8 fmol/mg protein and an apparent dissociation constant of 0.19+/-0.02 nM. Specific [3H]CB 34 binding was inhibited by ligands selective for peripheral benzodiazepine receptors, whereas, with the exception of flunitrazepam and diazepam, ligands for central benzodiazepine receptors were inactive. Of the brain regions examined, the density of the [3H]CB 34-binding sites was greatest in the hypothalamus and lowest in the cerebral cortex. [3H]CB 34 is thus a potent and selective ligand for peripheral benzodiazepine receptors and should be proven useful for studies of the roles of these receptors.