Clinical significance of thyrotropin measurement by immunoradiometric assay and thyrotropin-releasing hormone test

The levels of serum TSH were measured by a sensitive immunoradiometric assay (IRMA) method and the responses of TSH to TRH stimulation were observed in three groups of hyperthyroidism, primary hypothyroidism and secondary hypothyroidism. The levels of serum TSH were found to be undetected in 98% (1/51) of the patients with hyperthyroidism, very high in 100% (35/35) of the patients with primary hypothyroidism and normal in 91% (30/33) of the patients with secondary hypothyroidism. TRH test showed no responses of TSH in all patients with hyperthyroidism, high responses in all patients with primary hypothyroidism and blunt responses in 69% (11/16) of patients with secondary hypothyroidism. The results indicate that the measurement of serum TSH by IRMA is a sensitive index in the diagnosis of hyperthyroidism and primary hypothyroidism, but can not be differentiated the secondary hypothyroidism from normal conditions. TRH test may be helpful in the differential diagnosis between secondary hypothyroidism and normal conditions.     

Transfected glucocorticoid receptor and certain GR fragments evoke cell death in malignant lymphoid, not myeloid cell lines

We compared the data from four growth hormone (GH) immunoassays for analyzing 24-h GH profiles in four apparently normal subjects and four obese subjects (508 serum samples). The detection limit was 0.02 microgram/L for one immunochemiluminometric assay (ICMA), 0.1 microgram/L for two IRMAs, and 0.4 microgram/L for one RIA. All GH pulses with a peak ICMA value > 1 microgram/L were detected by each of the other methods. Overall, the correlation coefficient between the values obtained with all four assays exceeded 0.90. However, for GH concentrations < or = 0.25 microgram/L, acceptable concordance (r2 > or = 0.80) was reached only between the ICMA and one IRMA; between the ICMA and the RIA, concordance was acceptable only for GH concentrations > or = 10 micrograms/L. In the normal subjects, the percentage of undetectable values was 0% with the ICMA but 29% with one of the IRMAs; in obese subjects, the corresponding values were 12% and 38%.     

Development of a luminescent bioassay for thyroid stimulating antibodies

The hyperthyroidism of Graves Disease (GD) is due to thyroid stimulating antibodies (TSAb) which are thyrotropin (TSH) agonists. They are detected routinely by measuring their ability to inhibit TSH binding to the receptor (TBII), which does not reflect their true biological activity. Current bioassays which measure cAMP by RIA, are not suitable for routine use. We have developed a luminescent bioassay for TSAb, by introducing a cAMP responsive luciferase construct into CHO cells stably expressing the human TSH receptor (TSHR). Clone lulul displays dose dependent TSH response detectable from 10 microU/ml and maximal at 10 mU/ml when a >25 fold increase in light output is obtained. 34 euthyroid sera were tested to determine a reference range, with values >1.5 relative light units (R.L.U.) being considered positive. An international TSAb standard responded in a dose dependent manner with 10 mIU/ml giving an R.L.U. of >10. The assay was adapted to a 96 well format for automatic readout and 100 treated GD samples (50 TBII negative and 50 TBII positive) were tested, 73% being positive. In contrast only 4% of 79 control sera from individuals with Hashimoto's, non-thyroid autoimmunity or multinodular goitre produced R.L.U. >1.5. When 44 of the GD sera were compared in a traditional salt-free bioassay, 61% were positive compared with 75% in the new luminescent assay. In conclusion, we have developed a luminescent bioassay for TSAb, using unfractionated serum which is capable of high throughput suitable for routine use.     

Comparison between TRH-stimulated TSH and basal TSH measurement by a commercial immunoradiometric assay in the management of thyroid disease

In order to assess the current diagnostic role of the TRH test following the introduction of more sensitive "second generation" TSH assays, we studied a series of 259 outpatients, 237 women and 22 men, mean age 44.7 years (range 12-82), 91 of whom (35%) with untreated simple goiter, 133 (51%) with simple nodular goiter on steady state I-thyroxine treatment, 18 (7%) with overt or subclinical hyperthyroidism and 17 (7%) with overt or subclinical hypothyroidism, compared to a control group of 26 euthyroid healthy subjects. Serum TSH was measured by a commercial immunoradiometric assay (clinical sensitivity 0.1 microU/ml). TSH response to TRH was evaluated 30 minutes after giving 200 micrograms TRH i.v. bolus, the results being analyzed both as absolute increase (delta-TSH=stimulated TSH minus basal TSH) and as relative increase (R-TSH stimulated TSH/basal TSH). Using cut-off values of 0.3-3.2 microU/ml, basal TSH measurement was able to detect hypothyroidism (specificity = 100%) and to exclude hyperthyroidism (sensivity = 96.9%), but failed to accurately prove hyperthyroidism (specificity = 93.4%) and, above all, to exclude hypothyroidism (sensitivity = 35.3%) in our ambulatory patients. The delta-TSH values showed a basal TSH dependent linear increase (r = + 0.87, p < 0.001) both including only patients (n = 139) with basal TSH level in the euthyroidism range and including all patients (n = 223) having TSH responsive to TRH. All the patients with detectable basal TSH level displayed detectable TSH response to TRH, as did 19 (= 23.5%) of 81 patients with undetectable (< 0.1 microU/ml) basal value. In particular: a) for subnormal but detectable basal TSH ranging between 0.1 and 0.2 microU/ml, TSH was always hyporesponsive (delta-TSH < or = 2.5 microU/ml), while between 0.2 and 0.3 microU/ml TSH was hyporesponsive in 72.2% and normoresponsive (delta-TSH > 2.5 and < or = 11.9 microU/ml) in the remaining 27.8%; b) for basal TSH values within the normal range (0.3-3.2 microU/ml). TSH was hyporesponsive in 13.7%, normoresponsive in 74.8% and hyperresponsive in 11.5%; c) for high basal TSH values TSH was always hyperresponsive. The analysis of R TSH showed relatively constant values in the range of euthyroidism and hypothyroidism (m +/- SD: 7.4 +/- 2.3 and 7.7 +/- 3.1, respectively), and a marked differentiation of hyperthyroid patients whose R-TSH values were significantly lower (4.2 +/- 3.4) but had a wide individual variability. Linear regression analysis of basal or stimulated TSH and circulating thyroid hormones showed a close negative relationship, being highly significant between delta-TSH and T4 (r = 0.57, p < 0.001) and delta-TSH and FT4 (r = 0.46, p < 0.001). In conclusion, after the introduction of current second generation TSH immunoradiometric assay, the diagnostic role of the TRH test is greatly limited but not to be excluded: it can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidism and in the precise evaluation of the degree of TSH suppression in patients with a subnormal basal TSH, either for endogenous thyrotoxicosis or I.-thyroxine treatment.     

Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly

Traditionally, suppression of GH measured by polyclonal RIA to less than 2.0 microg/L after oral glucose was accepted as evidence of remission after transsphenoidal surgery for acromegaly. Recently, with newer, more sensitive GH assays, a cut-off of less than 1.0 microg/L has been suggested. With the development of accurate insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) assays, additional tools are now available for assessing postoperative GH secretion. There has, however, never been a systematic comparison of sensitive GH, IGF-I, and IGFBP-3 assays in defining disease status in a large cohort of postoperative patients with acromegaly. Therefore, we evaluated how the use of modern assays impacts on our assessment of disease activity in these patients. Sixty postoperative subjects with acromegaly and 25 age-matched healthy subjects were evaluated with nadir GH levels after 100 g oral glucose as well as baseline IGF-I and IGFBP-3 levels. GH was assayed by polyclonal RIA, sensitive immunoradiometric assay (IRMA), and highly sensitive enzyme-linked immunosorbent assay. The mean nadir GH determined by IRMA was 0.09 +/- 0.004 microg/L in the healthy subjects, with the upper limit of the normal nadir being 0.14 microg/L (mean + 2 SD). Subjects with acromegaly were divided into those with active disease (n = 22), defined by elevated IGF-I levels, and those in remission (n = 38), defined by normal IGF-I levels. GH determined by IRMA failed to suppress into the normal range defined by our healthy subjects in all patients with active disease; nadir GH determined by IRMA ranged from 0.33-5.0 microg/L in this group. In 50% of the active group, nadir GH levels determined by IRMA were less than 1.0 microg/L, a GH nadir previously considered normal by strict criteria. When nadir GH levels in the subjects with active disease were measured by polyclonal RIA, there was overlap with the range of RIA values in the healthy subjects. Thus, the IRMA was superior to the RIA in that the overlap between these two groups was eliminated. Subjects with acromegaly in remission included those with normal GH suppression (n = 23; mean nadir GH by IRMA, 0.10 +/- 0.006 microg/L) and others with abnormal GH suppression by IRMA (n = 15; mean nadir GH by IRMA, 0.35 +/- 0.07 microg/L). The latter group may have persistent GH dysregulation detected by the sensitive IRMA. GH levels measured by enzyme-linked immunosorbent assay confirmed the IRMA results. IGFBP-3 levels were significantly higher in subjects with active acromegaly (4940 +/- 301 microg/L) vs. those in healthy subjects (2887 +/- 153 microg/L; P < 0.0001) and those in the subjects in remission (2966 microg/L; P < 0.0001). IGFBP-3 levels correlated overall with IGF-I levels (r = 0.765; P < 0.0001), but IGFBP-3 levels were not predictive of disease status because 32% of the subjects with active acromegaly had normal IGFBP-3 levels. In addition, failure of GH to suppress adequately was not associated with a higher IGFBP-3 level among the subjects in remission. These data indicate that the IRMA is superior to the RIA in distinguishing between patients with active disease (defined by elevated IGF-I levels) and healthy subjects. We also show that GH levels after oral glucose measured with highly sensitive GH assays can be much lower in subjects with active disease than previously believed; values less than 1.0 microg/L may be found in up to 50% of patients. In addition, in 39% of patients in apparent remission with normal IGF-I levels, GH determined by highly sensitive assays fails to suppress normally; it remains to be determined whether these patients are at higher risk for recurrence of active disease.     

Why regular physical activity favors longevity]

AIM: A formula for calculating the minimum suppressive levothyroxine dose in prolonged suppression tests using body weight and TSH level is derived from a large number of cases. METHOD: In 1239 euthyroid patients (TSH > 0.30 mU/l) a suppression test with levothyroxine substitution for at least 6 weeks was performed. The hormone dose was primarily based on the initial TSH level using the empirical value TSH x 100, with a range between 50 and 150 micrograms per day. RESULTS: In 900 patients (73%), the TSH level was suppressed during the medication (TSH < 0.30 mU/l). Among them, we found 211 cases with an intermediate TSH suppression (TSH between 0.10 and 0.20 mU/l). Following the formula f = levothyroxine dose [microgram]/(body weight [kg] x initial TSH level [mU/l]) an average factor of 1.57 was calculated to obtain the suppressive dose in this group. As usually a complete TSH suppression (< 0.10 mU/l) is required, we recommend factor 2 for practical use. A consideration of the body weight revealed that 313 patients actually received a hormone dose equivalent to 2 x weight x TSH. In this group, a TSH suppression was found in 262 patients (84%), a factitial hyperthyreosis was not observed. When contemplating the three subgroups of this collective, who received daily doses of 50, 75 and 100 micrograms levothyroxine, respectively, we neither found a significant difference in the average body weight, nor in the value of the suppressed TSH. However, the correlation between the average initial TSH levels in these groups and the respective suppressive hormone doses clearly demonstrates their dependence on the thyroid regulation. CONCLUSION: The minimum suppressive levothyroxine dose does not only depend on the body weight, but also on the initial TSH level. It can be estimated using the formula 2 x body weight x initial TSH (range between 50 and 150 micrograms per day).     

Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels

Few data are available on the visualization of somatostatin receptors in vivo in patients with thyrotropin (TSH)-secreting adenoma. We studied five patients with TSH-secreting adenomas using single-photon emission tomography (SPET) after administration of indium-111 pentetreotide. The intensity of 111In-pentetreotide uptake by the tumours was correlated with the degree of TSH suppression after a single administration of 100 microg octreotide s. c. Five patients (three women and two men) aged 27-46 years were investigated. Except for one patient with acromegaly, all had pure TSH-secreting tumours. One patient was previously untreated, while two had received octreotide, one antithyroid drugs, and one radioiodine. In all patients SPET demonstrated increased uptake of 111In-pentetreotide by the pituitary adenoma. The target to non-target ratio (T/nT) of 111In-pentetreotide uptake was higher than 10 in three patients. Administration of 100 microg octreotide s. c. caused a significant reduction in TSH levels from 4.8+/-1.4 mU/l to a nadir of 3.1+/-1.1 mU/l after 6 h (P<0.001 by ANOVA). Suppression of TSH secretion ranged from 30% to 60% of the baseline value. The T/nT ratio showed a trend toward a direct relationship with the degree of TSH inhibition after acute octreotide administration (r=0.67; P=NS). Our study showed that 111In-pentetreotide scan visualized somatostatin receptors in all five of the patients with TSH-secreting pituitary adenomas, confirming the frequent presence of somatostatin receptors in these rare tumours, even though the correlation with the TSH inhibition after a single administration of octreotide did not reach significance.     

Thyrotropin-secreting pituitary adenoma

Thyrotropin (TSH)-secreting pituitary adenoma (TSPA) is a rare cause of hyperthyroidism and detailed reports of this entity in Taiwan are uncommon. We report a patient with TSPA with symptoms of hyperthyroidism and describe the presentation, endocrine and histologic findings, and treatment. The patient, a 42-year-old man, presented with a 2-year history of weight loss, palpitation, anxiety, and bad temper. He had increased basal serum thyroxine (T4, 18.3 micrograms/dL) and triiodothyronine (T3, 250 ng/dL) concentrations. The TSH concentration was normal (4.6 microIU/mL) and showed impaired response to stimulation by TSH-releasing hormone. Tests for antithyroid antibodies were negative. Thyroid scintigraphy showed mild thyroid enlargement. The thyroid uptake of radioactive iodine (131I) was high at 2 hours (34%) and 24 hours (63%) after 131I administration. Other serum hormone concentrations were within normal limits. Magnetic resonance imaging of the brain showed a microadenoma in the pituitary region. Octreotide and bromocriptine tests showed 78.4% and 58.3% inhibition of TSH, respectively. The patient underwent trans-sphenoidal pituitary tumor excision, and the symptoms of hyperthyroidism subsided after surgery. Six months after the operation, there was no evidence of recurrence of the tumor or symptoms of hyperthyroidism. Hormonal supplements were also not necessary. In conclusion, TSPA is a rare cause of hyperthyroidism. However, in patients with symptoms of hyperthyroidism and increased basal serum T1 and T3 concentrations, but normal or even elevated serum TSH concentrations, TSPA should be considered in the differential diagnosis.     

Thyrotropic action of human chorionic gonadotropin

Hyperthyroidism or increased thyroid function has been reported in many patients with trophoblastic tumors. In these cases, greatly increased human chorionic gonadotropin (hCG) levels and suppressed TSH levels suggest that hCG has thyrotropic activity. Recent investigations have clarified the structural homology not only in the hCG and TSH molecules but also in their receptors, and this homology suggests the basis for the reactivity of hCG with the TSH receptor. The clinical significance of the thyrotropic action of hCG is now also recognized in normal pregnancy and hyperemesis gravidarum. Highly purified hLH binds to recombinant hTSH receptor and is about 10 times as potent as purified hCG in increasing cAMP. The beta-subunits of hCG and hLH share 85% sequence identity in their first 114 amino acids but differ in the carboxy-terminal peptide because hCG beta contains a 31-amino acid extension (beta-CTP). A recombinant mutant hCG that lacks beta-CTP showed almost identical potency to LH on stimulation of recombinant hTSH receptor. If intact hCG were as potent as hLH in regard to its thyrotropic activity, most pregnant women would become thyrotoxic. One of the roles of the beta-CTP may be to prevent overt hyperthyroidism in the first trimester of pregnancy when a large amount of hCG is produced by the placenta. Nicked hCG preparations, obtained from patients with trophoblastic disease or by enzymatic digestion of intact hCG, showed approximately 1.5- to 2-fold stimulation of recombinant hTSH receptor compared with intact hCG. This suggests that the thyrotropic activity of hCG may be influenced by the metabolism of the hCG molecule itself. Deglycosylation and/or desialylation of hCG enhances its thyrotropic potency. Basic hCG isoforms with lower sialic acid content extracted from hydatidiform moles were more potent in activating adenylate cyclase, and showed high bioactivity/immunoactivity (B/I) ratio in CHO cells expressing human TSH receptors. This is consistent with the finding that the beta-CTP truncated hCG with higher thyrotropic potency is substantially deglycosylated and desialylated in the beta-subunit relative to intact hCG because all four O-linked glycosylation sites occur within the missing C-terminal extension. The desialylated hCG variant also interacts directly with recombinant hTSH receptors transfected into human thyroid cancer cells. There is thyroid-stimulating activity in sera of normal pregnant women, and this correlates with serum hCG levels. The thyroid gland of normal pregnant women may be stimulated by hCG to secrete slightly excessive quantities of T4 and induce a slight suppression of TSH, perhaps being about 1 mU/L less than nongravid levels, but not high enough to induce overt hyperthyroidism. Maternal thyroid glands may secrete more thyroid hormone during early pregnancy in response to the thyrotropic activity of hCG that overrides the normal operation of the hypothalamic-pituitary-thyroid feedback system. Biochemical hyperthyroidism associated with hyperemesis gravidarum has been attributed to hCG. In patients with hyperemesis gravidarum, thyrotropic in serum correlated with hCG immunoreactivity, and the severity of vomiting as indicated by clinical and biochemical parameters correlated with the degree of thyroid stimulation. To understand the thyrotropic action of hCG, it is necessary to know whether hCG activates the same domain of the TSH receptor as does TSH. The identification of the molecular structure of the hCG isoform with the highest thyrotropic potency will resolve the enigma of gestational thyrotoxicosis and the hyperthyroidism associated with trophoblastic disease and hCG-producing tumors.     

Bacillus thermoamyloliquefaciens KP1071 alpha-glucosidase II is a thermostable M(r) 540,000 homohexameric alpha-glucosidase with both exo-alpha-1,4-glucosidase and oligo-1,6-glucosidase activities

The lethality of acute renal failure exceeds 50% due to multiorgan dysfunction. In such critically ill patients a reduction of thyroid hormone concentrations without clinical symptoms or laboratory evidence of hypothyroidism frequently occurs. Selenium has recently been shown to play a major role in thyroid hormone metabolism. The aim of this study was to investigate the possible influence of selenium on thyroid hormone metabolism in acute renal failure. Changes in thyroid metabolism were related to the severity of multiorgan failure and to the clinical course. Thyroxine (T4), tri-iodothyronine (T3), free-T4, free-T3, thyrotropin (TSH), serum creatinine, and plasma selenium concentrations in 28 patients (mean age 60 +/- 13) with acute renal failure and multiple-organ dysfunction syndrome were determined initially, and every 3 days after hospital admission. The plasma selenium concentration was found to be reduced compared to normal controls (32 +/- 14 vs. 70-120 micrograms/L). T4 (56 +/- 15 nmol/L, normal range 64-148), T3 (1.31 +/- 0.38 nmol/L, normal range 1.42-2.46), free-T3 (3.1 +/- 1.0 pmol/L, normal range 4.7-9.0), and free-T4 (10.8 +/- 4.0 pmol/L, normal range 10.3-25.8) values were low in 50-70% of the patients at the time of presentation. Plasma TSH concentrations were within the normal range (0.59 +/- 0.79 mU/L, normal range 0.25-3.1), and no clinical symptoms of hypothyroidism were observed. T4 concentration was higher in patients who survived acute renal failure compared to nonsurvivors (62 +/- 22 vs. 51 +/- 16 nmol/L, p < 0.05). Plasma selenium concentration was lower in patients with a severe organ dysfunction syndrome (36 +/- 10 vs. 29 +/- 19 micrograms/L) and correlated with the number of organ failures in these patients (r = -0.247, p < 0.05). T4 and free-T4 values paralleled decreasing selenium concentrations (r = 0.35, p < 0.05). Thyroid hormone levels were reduced in patients with acute renal failure without an increase in TSH. An increase in T4 concentrations became apparent during treatment and may be related to a favorable outcome in acute renal failure. Thyroid hormone concentrations paralleled plasma selenium levels, indicating a possible influence of selenium on thyroid function in acute renal failure.     

Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.     

The porphyromonas gingivalis prtP/kgp homologue exists as two open reading frames in strain 381

Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels increase in patients with heart failure with the progression of clinical symptoms and with the deterioration of hemodynamics; consequently, assay methods for these peptides may be useful in the follow-up of cardiac patients. Non-competitive immunoradiometric assay (IRMA) methods for ANP or BNP do not generally require preliminary extraction and/or purification of the plasma sample, and so may be more suitable than competitive immunoradiometric assay (RIA) methods for the routine assay of plasma peptide concentrations. We evaluated the analytical characteristics and clinical usefulness of two IRMAs for plasma ANP and BNP, to verify whether these methods may be considered suitable for the follow-up of patients with heart failure. Both methods are based on the solid-phase sandwich IRMA system, which uses two monoclonal antibodies prepared against two sterically remote epitopes of peptide molecule; the first antibody was coated on the beads solid-phase and the second was radiolabeled with 125I. Blood samples were collected from a brachial vein in ice-chilled disposable polypropylene tubes containing aprotinin and EDTA after the patient had rested for at least 20 min in the recumbent position. Plasma samples were immediately separated by centrifugation and stored at -20 C until assay. The IRMA methods showed a better sensitivity and a wider working range sensitivity (about 2 ng/l) than those of RIA methods. Moreover, the normal range found with these methods (ANP = 16.1 +/- 8.6 ng/l, 5.2 +/- 2.8 pmol/l, BNP = 8.6 +/- 8.2 ng/l, 2.5 +/- 2.4 pmol/l) was similar to that generally reported using the most accurate methods, such as the other IRMAs or RIAs, using a preliminary extraction and purification of plasma samples with chromatographic procedures. Our results obtained in patients with different degrees of heart failure indicate that plasma ANP and BNP increase with the progression of clinical symptoms (NYHA class) (ANOVA p < 0.0001). Indeed, circulating levels of ANP (R = -0.701, no. = 86) and BNP (R = -0.745, no. = 55) were significantly (p < 0.0001) and negatively correlated with the left ventricular ejection fraction values. Furthermore, a close curvilinear regression (R = 0.960, no. = 215) was found between ANP and BNP values, because plasma BNP progressively increases more than plasma ANP in patients with different stages of heart failure. In conclusion, IRMA methods are preferable for the measurement of plasma ANP and BNP for experimental studies and routine assay because they are more practicable, sensitive and accurate than RIA procedures. Finally, BNP assay appears to be better than ANP for discriminating between normal subjects and patients with different degrees of heart failure.     

First results of radioiodine therapy of multifocal and disseminated thyroid gland autonomy and use of a TcTUs-adapted dose concept

AIM: The presented study examines prospectively the efficiency of a dose concept for radioiodine therapy (RIT) adapted to the pretherapeutic 99mTc-pertechnetate thyroid uptake under suppression (TcTUs) in patients with multifocal (MFA) and disseminated (DISA) autonomy. This concept considers the total thyroid as target volume and uses target doses from 150 Gy to 300 Gy according to the TcTUs, which is as a measure for the "autonomous volume" of the thyroid. METHODS: The data of 75 patients (54 female, 21 male; age 71 +/- 9 years) with MFA of DISA were evaluated. RIT was performed on patients presenting with normal values for free triiodothyronine and thyroxine and endogenous suppression of the basal thyrotropin (TSH). The following target dose were used for a TcTUs of 1.5-2.5% 150 Gy, for 2.51-3.5% 200 Gy, for 3.51-4.5% 250 Gy, and for > 4.5% 300 Gy. The radiation dose to be administered was calculated using a modified Marinelli formula. The therapy was considered as successful. When the basal TSH was above 0.5 mU/l and autonomous areas had disappeared in thyroid scintigraphy or the TcTU was below 1.5%, respectively. The average follow-up period was 8 +/- 4 months. RESULTS: The success rates average to 92%. Only in one case a subsequent subclinical hypothyroidism and in a further case an immunogenic hyperthyroidism occurred. CONCLUSION: The presented data indicate that even patients with a marked autonomy (TcTUs > 3.5%) can thus expected to be cured by of a one time therapy with success rate of over 90% using the presented dose concept. The rate of early hypothyroidism can altogether be estimated as very low.     

Synthesis and biological evaluation of 1,2,5-oxadiazole N-oxide derivatives as hypoxia-selective cytotoxins

A role of psychic stress in precipitating hyperthyroid Graves' disease has been suggested, but the evidence in support of this pathogenetic mechanism is conflicting. In this study we investigated the possible occurrence of Graves' disease in patients with panic disorder, a psychiatric condition characterized by recurrent endogenous stress. The study group included 87 consecutive patients suffering from panic disorder since 1 to 30 years: 17 males (mean age 31.3, range 26-43 years) and 70 females (mean age 37.6, range 15-73 years). Two hundred and sixty-two normal subjects with no present or past history of psychiatric disorder served as controls. Patients were submitted to a full evaluation of the thyroid that included physical examination, assays for free thyroid hormones, TSH, thyroglobulin (TgAb), thyroperoxidase (TPOAb) and TSH receptor (TRAb) antibodies, and thyroid echography. The prevalence of circulating TgAb and/or TPOAb in patients with panic disorder did not differ from that in the control group. Twelve patients with panic disorder (13.7%) had circulating TgAb and/or TPOAb, but none had TRAb. Three out of 12 patients with thyroid antibodies, indicating a genetic susceptibility to autoimmune thyroid disease, had a family history of clinical thyroid autoimmunity, and 4 of them had a hypoechogenic pattern of the thyroid at ultrasound suggesting autoimmune thyroiditis. None of the patients with panic disorder had a previous history of hyperthyroidism. On examination, clinical hyperthyroidism or endocrine ophthalmopathy were not found in any of them. A small goiter was appreciated by palpation in 16 patients (18.3%). Free thyroid hormones and TSH were within the normal range in all patients but one: a 55-year old lady with normal serum free thyroid hormones and undetectable TSH. During an 18-month follow-up she did not develop hyperthyroidism and her TSH spontaneously returned in the normal range. Considering the individual duration of panic disorder, evidence for previous or present Graves' hyperthyroidism was not found for a total of 478 patient-years of exposure to recurrent endogenous stress in the whole study group, and for a total of 39 patient-years in patients with a genetic susceptibility to autoimmune thyroid disease. In conclusion, we found that recurrent endogenous stress did not precipitate Graves' hyperthyroidism in a series of 87 patients with panic disorder, encompassing a total of 478 patient-years of exposure to stress. Failure to activate the hypothalamic-pituitary-adrenal axis by endogenous stress due to panic disorder as opposed to exogenous stress due to life-events might explain why panic disorder does not precipitate Graves' hyperthyroidism.     

Hypothyroidism and hyperthyroidism in major depression revisited

BACKGROUND: The aim of our study was to evaluate the prevalence of thyroid abnormalities among depressed outpatients and to examine the response to treatment of those subjects with relatively low or high thyroid hormone levels. METHOD: Outpatients (N = 200) 18 to 65 years of age who met DSM-III-R criteria for major depression were screened for the presence of thyroid abnormalities using a number of thyroid indices. Of these patients, 166 were then treated openly with the antidepressant fluoxetine for 12 weeks. We assessed whether patients with relatively low or high thyroid hormone levels had a different response to treatment compared with other patients. The 17-item Hamilton Rating Scale for Depression (HAM-D-17) was administered during the study to assess changes in depressive symptoms. Thyroid function was assessed by measuring T3, T4, free T4 index (FT4I), T3 uptake (T3U), and serum thyroid-stimulating hormone (TSH) levels. RESULTS: No clinical cases of hyperthyroidism or hypothyroidism were detected. Of the patients examined, 5 (2.6%) had slightly elevated TSH levels (range, 4.7-8.2); none of these had T4 or FT4I levels below the normal range. Subnormal levels of T4 or FT4I were found in 1 subject (0.5%). T3 and T3U levels were below the normal range in a larger number of patients (7.6% and 15.0% respectively), but only 1 of these patients had elevated TSH levels. None of the patients had levels of TSH below the normal range, and only 3 subjects (1.5%) had T4 levels above the normal range. No relationship was found between response rate (assessed as either change in HAM-D-17 score or as remission of depressive symptoms with a HAM-D-17 score < or = 7 for 3 consecutive weeks) and each of the thyroid tests, even after adjusting for baseline severity of depression. CONCLUSION: In depressed outpatients, it appears that hypothyroidism and hyperthyroidism are extremely uncommon and that the presence of subtle thyroid function abnormalities does not have an impact on treatment outcome.     

Medical therapy of Graves' disease: does thyroxine prevent recurrence of hyperthyroidism?

Sixty patients with Graves' disease (GD) hyperthyroidism were distributed in two randomized groups. Patients in group A (n = 30) received carbimazole by a titration regimen, and patients in group B (n = 30) were treated with higher doses of carbimazole plus T4. Clinical and analytical evaluations were done at baseline, during treatment (18.4 +/- 2.6 months), and after, until the relapse of hyperthyroidism, or for 4.98 +/- 1.6 yr in patients who did not relapse. There were no differences in clinical parameters, thyroid hormones, or TSH binding inhibitory immunoglobulins (TBII) levels between the two groups, either at baseline or at the end of treatment. Serum TSH persisted undetectable in 16 out of 60 patients (group A: 9; group B: 7), after treatment. Relapse occurred in 38 patients (63.3%), (group A: 18 (60%) vs. group B: 20 (66.7%)). Patients who relapsed had bigger goiters at baseline (P = 0.02) and at the end of treatment (P = 0.03). Eighty-seven percent (14/16) of patients with undetectable TSH after therapy relapsed, vs. 54.5% (24/44) of those with normal TSH (P = 0.01). Undetectable TSH at the end of treatment was the only independent variable in the logistic analysis to predict relapse. Treatment modality did not influence the relapse rate. This study has found that, in Spanish patients, the use of high doses of carbimazole with T4 offers no advantages in the treatment of GD hyperthyroidism.     

Management and outcome of borderline ovarian tumors incidentally discovered at or after laparoscopy

OBJECTIVE: The optimal antithyroid drug regimen for Graves' disease remains a matter of controversy. The European Multicentre Trial Group has investigated the effects of methimazole drug dose on the long-term outcome of Graves' disease. DESIGN: Extended follow-up of patients from a prospective multicentre trial, designed to study methimazole dose effects on the outcome of Graves' disease. We have reported previously that the relapse rates did not differ after a medication-free observation period of 12 months; the relapse rates were 37% and 38%, respectively. In this paper, we describe the outcome in these patients after a mean observation period of 4.3 +/- 1.3 years and have looked for potential predictors of this outcome. PATIENTS: Three hundred and thirteen patients with Graves' disease were randomized to treatment with a constant dose of 10 or 40 mg of methimazole for 1 year, with levothyroxine supplementation as required. MEASUREMENTS: At the time of inclusion into the trial: thyroid size, T4, T3, TSH-binding inhibiting immunoglobulins, urinary iodide excretion, thyroid uptake, Crook's therapeutic index of hyperthyroidism (a measure of clinical disease severity). At the time of follow-up examination: TSH, T4, T3, thyroid size, thyroid ultrasound, THS-binding inhibiting immunoglobulins. RESULTS: The overall relapse rate was 58%. There was no difference in relapse rates between patients treated with either 10 or 40 mg of methimazole (58.3 vs. 57.8%). Five patients had become spontaneously hypothyroid, without obvious relationship to antithyroid drug dose. Patients who relapsed and patients who remained in remission did not differ with respect to: age, goitre size, ophthalmopathy, median iodine excretion, serum T4 or serum T3, Crook's therapeutic index and thyroid uptake at the time of study entry. Thus, none of these variables was potentially suitable for predicting outcome. This finding was confirmed by Cox's proportional hazard regression. Thyroid volume, measured by ultrasound, did not differ between patients in remission and patients with relapse. There was no difference in the course of endocrine eye signs, in the requirement for steroid and radiotherapy for eye signs, or in thyroid echostructure between patients in the 10 and in the 40 mg group, nor was serum TSH different in patients who had remained in remission (0.8 +/- 0.6 mU/l in the 10 mg group, 1.0 +/- 0.8 mU/l in the 40 mg group). CONCLUSIONS: The dose of methimazole in Graves' disease therapy can safely be kept to the minimal required dose. This will provide the same chance of remission as higher doses, and provide the best balance of risk and benefit.     

Altered bioavailability due to changes in the formulation of a commercial preparation of levothyroxine in patients with differentiated thyroid carcinoma

OBJECTIVES: In July 1995 we began noticing an unusually high rate of elevated TSH levels in patients with differentiated thyroid cancer treated with levothyroxine-specifically the brand Levothroid-becoming more obvious from September 1995. Faced with the possibility that these findings had some relationship to the drug taken, we carried out a prospective study, changing this brand of levothyroxine for another. DESIGN AND PATIENTS: We studied 58 patients with differentiated thyroid carcinoma (50 women and eight men; aged 22-75 years) who were being treated with levothyroxine and who had previously had adequate TSH suppression. Their Levothroid tablets were changed to the same dose of Dexnon tablets, and their clinical and analytical response was evaluated 2 months later. The patients were divided into two groups according to their TSH level at the start of the study: group 1, 42 patients with TSH > 0.2 mU/l (not suppressed) and group 2, 16 patients with TSH < or = 0.2 mU/l (suppressed). RESULTS: After 2 months with Dexnon the TSH levels in group 1 fell significantly (P < 0.0001) also decreasing in group (P < 0.09). The free T4 and free T3 rose significantly in both groups. After the change to Dexnon, 17 patients (40%) in group 1 had suppressed TSH and 26 (62%) had free T4 levels above the upper limit of normal vs none at baseline (P < 0.001). The group 2 patients maintained their inhibited TSH values after treatment with Dexnon, and the free T4 was above the upper limit of normal in 15 (94%) vs 3 (19%) at baseline (P < 0.001). The Levothroid tablets collected from the patients in both groups formed part of those which the manufacturer later withdraw from the market. These batches possessed the correct dosage, but they had been made from 'non-micronized' raw materials from another supplier. CONCLUSIONS: The most probable cause of the inadequate TSH suppression in our patients was the reduction in bioavailability in certain batches of Levothroid, although we are unable to rule out the possibility that the results obtained after the changeover to Dexnon were due to its greater bioavailability. Simple changes in the manufacture of levothyroxine tablets may produce important variations in their bioavailability, having an adverse effect on the clinical control of the patients, and causing extra expense by the need for repeated patient visits and thyroid function tests.     

Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis

OBJECTIVE: Non-tumour causes of hyperprolactinaemia, including prolactin-elevating drugs, must be excluded. There is a general view that such drugs are unlikely to raise serum PRL above 3000 mU/I, but the literature is confusing. We report 8 patients receiving treatment with neuroleptic drugs, whose serum PRL concentrations were grossly elevated. METHODS: Prolactin was measured using a 2-site immunofluorometric assay (Abbott Laboratories; reference range < 500 mU/l). Seven of the eight women (age range 24-49 years) were symptomatic (galactorrhoea, oligo- or amenorrhoea). RESULTS: Prolactin concentrations ranged from 3600 mU/l to 7300 mU/l. All patients had a normal pituitary CT scan. Five patients were treated with bromocriptine without detriment to their mental state. CONCLUSION: Prolactin can rise to concentrations associated with prolactinomas in patients on neuroleptic drugs. As it is rarely possible to stop the drugs to see if the PRL concentration will decline to normal, neuroradiology is required in these patients to exclude a vision-threatening macroprolactinoma before deciding on medical treatment.     

Plasma lipoprotein(a) levels in patients with hyperthyroidism

Thyroid function and regulation were studied in 14 consecutive male outpatients with asymptomatic human immunodeficiency virus (HIV) infection (CDC II/III, n = 8) or AIDS (CDC IV, n = 6) who were free of concomitant infections and hepatic dysfunction, and in eight healthy, age- and weight-matched male controls. Blood was sampled every 10 minutes over 24 hours for measurement of thyrotropin (TSH). Thereafter, thyroid hormones and TSH responsiveness to thyrotropin-releasing hormone (TRH) were measured. Triiodothyronine (T3) and thyroxine (T4) did not differ between HIV-infected patients and controls, but HIV patients had lower thyroid hormone-binding index ([THBI] HIV patients, 1.01 +/- 0.02; controls, 1.11 +/- 0.03; P < .02), free thyroxine (FT4) index (94 +/- 3 v 110 +/- 4, P < .01), FT4 (11.8 +/- 0.4 v 14.3 +/- 0.4 pmol/L, P < .01), and reverse triiodothyronine (rT3) values (0.18 +/- 0.01 v 0.26 +/- 0.02 nmol/L, P < .001) and higher thyroxine-binding globulin ([TBG] 20 +/- 1 v 16 +/- 1 mg/L, P < .02) values. Mean 24-hour TSH levels were increased in HIV patients (2.39 +/- 0.33 v 1.44 +/- 0.16 mU/L, P < .05), associated with increased mean TSH pulse amplitude and TSH responsiveness to TRH. No differences were observed between asymptomatic HIV-seropositive and AIDS patients. In conclusion, there is a hypothyroid-like regulation of the pituitary-thyroid axis in stable HIV infection, which differs distinctly from the euthyroid sick syndrome in non-HIV-nonthyroidal illnesses.(ABSTRACT TRUNCATED AT 250 WORDS)