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Thyroid hormones differentially regulate the distribution of rabbit skeletal muscle Ca(2+)-ATPase (SERCA) isoforms in light and heavy sarcoplasmic reticulum.

The sarcoplasmic reticulum (SR) is composed of two fractions, the heavy fraction that contains proteins involved in Ca2+ release, and the light fraction enriched in Ca(2+)-ATPase (SERCA), an enzyme responsible for Ca2+ transport from the cytosol to the lumen of SR. It is known that in red muscle thyroid hormones regulate the expression of SERCA 1 and SERCA 2 isoforms. Here we show the effects of thyroid hormone on SERCA expression and distribution in light and heavy SR fractions from rabbit white and red muscles. In hyperthyroid red muscle there is an increase of SERCA 1 and a decrease of SERCA 2 expression. This is far more pronounced in the heavy than in the light SR fraction. As a result, the rates of Ca(2+)- ATPase activity and Ca(2+)-uptake by the heavy vesicles are increased. In hypothyroidism we observed a decrease in SERCA 1 and no changes in the amount of SERCA 2 expressed. This promoted a decrease of both Ca(2+)-uptake and Ca(2+)-ATPase activity. While the major differences in hyperthyroidism were found in the heavy SR fraction, the effects of hypothyroidism were restricted to light SR fraction. In white muscle we did not observe any significant changes in either hypo- or hyperthyroidism in both SR fractions. Thus, the regulation of SERCA isoforms by thyroid hormones is not only muscle specific but also varies depending on the subcellular compartment analyzed. These changes might correspond to the molecular basis of the altered contraction and relaxation rates detected in thyroid dysfunction.

Animals↗

The effect of fenclofenac on thyroid function tests in vivo and in vitro.

Clinically euthyroid patients on long term maintenance therapy with the non-steroidal anti-inflammatory drug fenclofenac (Flenac) show an unusual and abnormal pattern of serum thyroid function tests. In all twelve patients studied, total T4 concentrations were grossly subnormal (mean 28.4 +/- 9.9 (SD) nmol/l and total T3 levels low-normal (mean 1.4 +/- 0.3 (SD) nmol/l), whereas rT3 (mean 0.36 +/- 0.06 (SD) nmol/l) and basal TSH levels (mean 1.9 +/- 0.5 (SD) mu/l) were within their respective normal ranges. Free T4 levels were low normal (mean 11.0 +/- 1.0 (SD) pmol/l) while TSH, T4 and T3 responses to intravenous TRH were similar to those found in euthyroid subjects. These effects appear to be due predominantly to in vivo inhibition of binding of thyroid hormones to carrier proteins in serum, rather than in vitro drug interference in the radioimmunoassays employed. Fenclofenac does, however, interfere in those laboratory methods employing serum proteins as binding agents. Thus the Thyopac 4 method for serum total T4 grossly over-estimates T4 levels, while thyroid hormone binding capacity (Thyopac 3) is low. Since fenclofenac is one of the most potent drugs interfering with routine indices of thyroid status, it is suggested that suspected thyroid dysfunction is excluded before commencing therapy with the drug.

Adult↗

Hyperthyroidism after treatment with lithium.

The association between treatment with lithium and hypothyroidism is well documented. Reports of hyperthyroidism are rare and it is less well known among patients treated with lithium. It may be overlooked simply because the clinician will be watching for hypothyroidism, the reverse phenomenon. This paper describes the cases of four patients who have been on long term lithium treatment, all of whom developed Graves' disease, or an atypical form of hyperthyroidism. Some suggestions are offered to account for the mechanism underlying this unusual association. Although hyperthyroidism may be rare among patients receiving lithium, astute clinical observation and appropriate laboratory tests are called for to detect the early stages of such thyroid dysfunction and to provide appropriate intervention.

Adult↗

Adhesive capsulitis of the hip after bilateral adhesive capsulitis of the shoulder.

Adhesive capsulitis of the hip is a not a common clinical presentation. We report a case of adhesive capsulitis of the hip in a patient with hypothyroidism and previous adhesive capsulitis of the shoulder who was receiving thyroid-hormone replacement. The adhesive capsulitis of both hip and shoulder were treated successfully with physical therapy. Orthopedic surgeons should be aware of this diagnosis and its association with shoulder adhesive capsulitis and thyroid dysfunction, to allow them to recognize it and intervene early.

Bursitis↗

[Thyroid diagnosis in general practice].

The selection of appropriate diagnostic procedures in presumptive thyroid diseases should be based on clinical signs and symptoms. To exclude primary thyroid dysfunction, basal TSH levels measured by a sensitive system should be employed. Further hormonal analyses are indicated in patients with suppressed TSH levels (fT4J, fT4 or the T4/TBG ratio and total T3) and in those with elevated TSH (fT4J, T4/TBG ratio without total T3). When TSH levels are partially suppressed thyroid autonomy must be excluded. Thyroid antibodies may be employed in patients with spontaneous hypothyroidism and hyperthyroidism, homogeneous technetium uptake with no eye signs. In patients with thyroid enlargement, ultrasound investigation including volumetry is the first line investigation. Nodular abnormalities must be investigated by technetium uptake in euthyroid and hyperthyroid individuals. Cytological investigations are indicated in cold nodules, especially in those showing reduced echogenicity.

Humans↗

Endocrine and reproductive dysfunction following fractionated total body irradiation in adults.

The endocrine and reproductive sequelae of total body irradiation for haematological malignancy have been studied in 21 patients (11 male) who were treated with 10 Gy in five fractions or 12 or 13.2 Gy in six fractions over 3 days. Eighteen patients (eight male) aged 16-49 years underwent dynamic tests of the hypothalamic-pituitary axis with insulin hypoglycaemia, thyrotrophin releasing hormone (TRH) and gonadotrophin releasing hormone stimulation and basal measurement of prolactin, sex steroids and thyroid hormones. Growth hormone responses (mean peak 64 +/- 36 mU/l, range 21-146 mU/l) and cortisol responses (mean peak 831 +/- 122 nmol/l, range 626-1105 nmol/l) were all within the normal range. Two patients had minimally elevated serum prolactin levels (445 and 588 mU/l, normal less than 350 mU/l). Serum thyroxine levels (57-133 nmol/l) were normal but six patients had elevated basal thyrotrophin (TSH) levels (6-9 mU/l) and seven had an exaggerated TSH response to thyrotrophin releasing hormone, indicating radiation-induced damage to the thyroid. Amenorrhea developed within 3 months of irradiation in all females and oestradiol levels were low, at 37-108 pmol/l (mean 58 +/- 22 pmol/l). Severe oligospermia or azoospermia was noted in men tested 5-70 months after irradiation and testicular volume was below the normal adult range in five of seven men assessed. Serum testosterone levels (12.4-35 nmol/l) were normal. Gonadotrophin-releasing hormone-stimulated gonadotrophin levels were elevated in all patients. However, two men have fathered two children each; one has refused semen analysis, but the other has a sperm count of 7 x 10(6)/ml (60 per cent motile, 20 per cent abnormal forms) 70 months after irradiation. When given by the above fractionated regimens, the endocrine sequelae of total body irradiation are limited to gonadal failure requiring oestrogen replacement in women and severe impairment of fertility in men. Subclinical thyroid dysfunction has been seen in 39 per cent of patients there is no evidence of direct damage to the hypothalamic pituitary axis.

Adolescent↗

Radio-active iodine uptake in vitiligo.

Vitiligo and thyroid disease are commonly associated disorders. Twenty-two clinically euthyroid vitiligo patients were studied for functional assessment of thyroid by radioactive iodine uptake assay. Half of them showed abnormal uptake values at 24 hours. Of these patients, 90% had lower values indicating a tendency towards developing hypothyroid state. Subclinical thyroid dysfunction in vitiligo appears to be an adaptive change.

Adult↗

Hypothyroidism following treatment for head and neck cancer.

One hundred ninety-six head and neck patients were studied to determine the effects of radiation therapy and surgery on thyroid function. Serum thyroid-stimulating hormone (TSH) levels were obtained as a screening test for primary hypothyroidism. Elevated TSH levels were found in 57 of the 196 patients (29.1%). The highest incidence of abnormal TSH values (66%) occurred in the group treated with combination radiation therapy and surgery, including partial thyroidectomy. TSH levels rose early in the posttreatment period with 60% of the abnormal values occurring within the first three posttreatment years. Posttreatment thyroid dysfunction was twice as common in women (48.6%) as in men (25.4%). When serum thyroxine levels by radioimmunoassay (T4RIA) were correlated with the elevated serum TSH levels, a similar pattern was seen with 65% of the patients in Group 3 having a decreased T4RIA level indicating overt hypothyroidism. Pretreatment levels of thyroid function including thyroid antibody studies should be established for all patients. Serial TSH levels should be done every three months during the first three posttreatment years and semiannually thereafter as long as the patient will return for follow-up care. All patients treated with combination radiation therapy and surgery who develop elevated TSH levels should be treated with thyroid replacement therapy. Patients receiving radiation therapy alone should receive replacement thyroid therapy if they develop a depressed T4RIA value or a pattern of gradually increasing TSH levels.

Autoantibodies↗

The evidence for a narrower thyrotropin reference range is compelling.

Debate and controversy currently surround the recommendations of a recent consensus conference that considered issues related to the management of early, mild, or so-called subclinical hypothyroidism and hyperthyroidism. Intimately related to the controversy is the definition of the normal reference range for TSH. It has become clear that previously accepted reference ranges are no longer valid as a result of both the development of more highly sensitive TSH assays and the appreciation that reference populations previously considered normal were contaminated with individuals with various degrees of thyroid dysfunction that served to increase mean TSH levels for the group. Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter. The remainder with higher values are outliers, most of whom are likely to have underlying Hashimoto thyroiditis or other causes of elevated TSH. Importantly, data indicating that African-Americans with very low incidence of Hashimoto thyroiditis have a mean TSH level of 1.18 mU/liter strongly suggest that this value is the true normal mean for a normal population. Recognition and establishment of a more precise and true normal range for TSH have important implications for both screening and treatment of thyroid disease in general and subclinical thyroid disease in particular.

Humans↗

Chronic administration of anabolic androgenic steroid alters murine thyroid function.

PURPOSE: The administration of anabolic-androgenic steroids (AAS) to improve athletic performance has increased notably during the past three decades, even among nonathletes. Thyroid function is affected by AAS use in humans, although the mechanisms of the effects of AAS are unclear. We evaluated the effects on thyroid function of supraphysiologic doses of nandrolone decanoate (DECA), which is one of the most anabolic-androgenic steroids (AAS) used. METHODS: Male Wistar rats were treated with vehicle or 1 mg.100 g(-1) body weight (b.w.) of DECA, once a week for 8 wk, intramuscularly. We analyzed thyroperoxidase (TPO) activity, type 1 iodothyronine deiodinase (D1) activities in liver, kidney, pituitary, and thyroid, and serum levels of total T3, total T4, free T4, and TSH. Parametric and nonparametric t-tests were employed for statistical analyses. RESULTS: Treated animals showed a significant increase in the weight of kidneys and heart, and a decrease in the relative testis weight. Retroperitoneal adipose tissue was only slightly decreased. DECA treatment induced a significant increase in the absolute and relative thyroid gland weight. The concentrations of total serum T3, free T4, and TSH decreased significantly with treatment, but total serum T4 levels were unchanged. Thyroperoxidase activity was unaltered, whereas liver and kidney D1 activities were significantly increased, but pituitary and thyroid D1 did not change. CONCLUSION: Our data indicate that DECA exerts direct actions on the thyroid gland and in the peripheral metabolism of thyroid hormones and might lead to thyroid dysfunction.

Animals↗

The effect of pre-operative potassium iodide therapy on antibody production.

Previous studies have suggested that iodide may increase the incidence of thyroid disease and anti-thyroid antibodies in predisposed individuals. This study has considered the effects of pre-operative potassium iodide (60 mg twice daily, for 10 days) on the immune system of patients with Graves' disease. The treatment regimen used maintained all patients in a clinically and biochemically euthyroid state prior to surgery. Potassium iodide significantly increased serum thyrotropin receptor antibody levels and B cell activity as determined by increased immunoglobulin production from mitogen stimulated peripheral blood lymphocytes. These effects were not observed in the two control groups of Graves' disease patients. Our in vivo findings would support previous in vitro work showing that potassium iodide does act on the immune system and this may be the mechanism by which iodide induces thyroid dysfunction in predisposed individuals.

Antibody Formation↗

Update on endocrinology.

Endocrinology covers diverse groups of organs and diseases. In this article, advances in the investigation of thyroid dysfunction, the management of Paget's disease of bone and the investigation and management of polycystic ovary syndrome are discussed.

Calcitonin↗

Influence of hormonal disturbances on transplacental and multigeneration carcinogenesis in rats.

Thyroid dysfunction (induced by thyroidectomy or administration of thyroxin and methylthiouracil) during the postnatal period was tested as a modifying factor on carcinogenesis induced transplacentally by N-methyl-N-nitrosourea (MNU). It resulted mainly in inhibition of tumours of the nervous system and kidney in rats of two subsequent generations, but thyroid carcinogenesis was increased. Postnatal disturbance of oestrous function (induction of persistent oestrus syndrome) in female rats increased the incidence of tumours of the central nervous system induced transplacentally by MNU or 7,12-dimethylbenz[a]anthracene. No such effect was seen in animals of the F2 generation.

9,10-Dimethyl-1,2-benzanthracene↗

Effects of zinc deficiency on thyroid function.

Interactive combinations of altered zinc and thyroid states were studied in rats to assess pathophysiologic effects. Clinical signs of zinc deficiency or thyroid alteration were limited to effects on growth rate. Changes in organ and glandular weights and serum thyrotropin levels reflected changes in serum thyroid hormone concentrations. Significantly (probability less than .001), zinc-deficient rats had enhanced hepatic thyroxine-5'-monodeiodinase activity. In addition, the zinc-deficient state was found to be protective against thiouracil-induced suppression of the microsomal-monooxygenase and thyroxine-5'-monodeiodinase enzyme complex. This protective effect was evident by greater thyroxine-5'-monodeiodinase and reduced nicotinamide-adenine dinucleotide phosphate cytochrome c reductase activities, as well as cytochrome P-450 content, in zinc-deficient/thiouracil-treated animals. Thus, the enzyme complex had increased triiodothyronine-generating capacity in conditions of zinc deficiency, which may be important because of the greater biological reactivity of triiodothyronine. Primary zinc deficiency conditions of the magnitude seen in this study and in this-age rat did not appear to alter serum thyroid hormone levels or organ/glandular function. However, concurrent zinc deficiency and altered thyroid status did change thyroid hormone response and disposition, which may be important to populations at risk because of thyroid dysfunctional states.

Animals↗

Amiodarone: a multifaceted antiarrhythmic drug.

Synthesized as an antianginal compound 40 years ago, amiodarone has emerged as a uniquely effective antiarrhythmic compound in recent years. It has numerous properties, the most prominent being the ability to lengthen repolarization in the atria and ventricles associated with bradycardia without the significant potential for torsades de pointes. Amiodarone effectively controls a wide spectrum of atrial and ventricular antiarrhythmic disorders, but its limiting side effects, such as thyroid dysfunction, pulmonary fibrosis, and dermatologic changes, may limit its long-term use in some patients. What aspects of the multiplicity of the properties of amiodarone are relevant to its unusual efficacy is not known. Deiodination and other structural changes in the amiodarone molecule have has led to a the loss of thyroid and pulmonary effects in the resulting derivative, dronedarone, which is in advanced clinical development.

Adrenergic beta-Antagonists↗

Multimodal distribution versus logarithmic transformation of thyroid volumes in adolescents: detection of subgroup with subclinical thyroid disorders and its impact on the assessment of the upper limit of normal thyroid volumes.

Our objective was to evaluate whether there is a multimodal distribution of thyroid volume (ThV) in iodine-replete adolescents and to examine the relation between excessive ThV and the presence of thyroid hypoechogenicity (HE), serum thyroperoxidase antibodies (anti-TPO) and TSH levels >4.5 mU/l. ThV was measured by ultrasound in adolescents aged 13 yr (N = 1083) and 17 yr (N = 1089) from 22 schools in 6 districts of eastern Slovakia and expressed as ml and ml/m2 body surface area. For each age group the multimodal distribution of ThV values was tested by computing their frequency at intervals of 0.5 m/m2 and plotting the cumulative frequency on a probability scale in which each segment with normal distribution should give a straight line. In all examined subjects the HE was evaluated by ultrasound; in 924 (42.5%) of those anti-TPO was estimated by radioimmunoassay and TSH by immuno-electrochemiluminiscent assay. The medians of urinary iodine found in 55-164 spot urine samples from each of 6 districts (total number = 1003) were 126-142 microg/l, indicating an iodine-replete status. There was a trimodal distribution of ThV in each group, 80-85% in the lowest, 10-15% in the middle, and 5-7% in the upper segments. In the 10th ThV decile of the 17-yr group the frequency of HE (33/109 = 30.3%), anti-TPO (13/62 = 21.0%) and TSH (6/62 = 9.7%) was significantly higher than that in the 1st-9th decile (71/980 = 7.2%, P<0.001; 23/482 = 4.8%, P<0.001 and 5/482 = 1.0%, P<0.001, resp.). Similar differences were found in the 13-yr group (21/109 = 19.2% vs. 58/974 = 5.9%, P<0.001 for HE, 5/60 = 8.3% vs. 3/320 = 0.9%, P<0.001 for anti-TPO and 2/64 = 3.1% vs. 4/317 = 1.3% (not significant) for TSH >4.5 mU/l. Thus in the 10% of subjects with the highest ThV, the frequency of HE and anti-TPO was 4-5 times higher than in the remaining 90%. Our data indicate that an epidemiological evaluation of a large population of adolescents can detect a group with early signs of thyroid dysfunction (e.g. excessive ThV, increased frequency of HE, anti-TPO and TSH >4.5% mU/l), although such dysfunction may not be clinically apparent. This contrasts with numerous earlier reports which used a logarithmic transformation of the data in similar ThV sets, thus making the data appear homogeneous (unimodal) and with a normal distribution and obscuring the true multimodal distribution. This further prevents recognition of subjects with evidence of disordered thyroid status which thus become falsely included into a normal range.

Adolescent↗

Hypothyroidism in patients with bipolar I disorder treated primarily with lithium.

AIMS: This study evaluated the frequency and clinical significance of abnormal Thyroid Stimulating Hormone (TSH) and Free Thyroxine Index (FTI) in patients with bipolar I disorder treated primarily with lithium. METHOD: We evaluated the medical records of 143 participants in the Pittsburgh study of Maintenance Therapies in Bipolar Disorder who did not have a thyroid abnormality at entry. RESULTS: Thirty-six percent of the 143 patients developed abnormal TSH and/or FTI values. Thirty-eight percent of the 135 patients who received lithium developed abnormal TSH and/or FTI, spent significantly longer time in the acute treatment phase (t = -3.6, df = 133, p = .0004), and had significantly higher mean Hamilton Scale for Depression scores over the course of the maintenance phase (t = -2.3, df = 71.6, p = .03). Time on lithium and development of abnormal TSH and/or FTI were positively correlated (r = .25, p = .004). CONCLUSIONS: Thyroid dysfunction can be frequent in patients exposed to lithium treatment for bipolar I disorder; it also appears to be correlated with a slower response to acute treatment, and may be related to poorer quality of long-term remission. A prospective study is needed to confirm our findings and determine whether more aggressive thyroid replacement can optimize thyroid function to facilitate clinical recovery. DECLARATION OF INTEREST: Supported in part by National Institute of Mental Health Grants MH 029618 (Drs. Frank and Fagiolini) and MH 030915 (Drs. Kupfer and Fagiolini), and the Bosin Memorial Fund of The Pittsburgh Foundation (Drs. Fagiolini, Kupfer, Cook, Scott, Novick and Frank). Dr. Fagiolini is on the advisory board and a consultant to Pfizer Inc, and Bristol Myers Squibb, and is on the speaker bureau of Bristol Myers Squibb, Eli Lilly Italy, Pfizer Inc, and Shire. Dr. Frank is on the advisory board of Pfizer Inc. and Eli Lilly & Company, and is a consultant to Pfizer Italia and Servier Amerique. Dr. Kupfer is on the advisory board of Pfizer, Inc., Forest Pharmaceuticals, Inc., and Solvay-Wyeth Pharmaceuticals, and is a consultant to Servier Amerique.

Adult↗

Mortality in a complete 4-year follow up of 85-year-old residents of Leiden, classified by serum level of thyrotropin and thyroxine.

BACKGROUND: The authors of the source article emphasize the clinical tendency to screen for, detect and treat for thyroid dysfunction in very elderly patients, in which it is a fairly common disorder, often with occult or no symptoms. Published evidence is conflicting on the benefit, if any, of such a program. Accordingly, they devised a prospective, population-based study to determine outcomes, including survival outcome, based on serum levels of thyroid-stimulating hormone (TSH) and thyroxine. METHODS: A cohort of 558 subjects who had their 85th birthday between September 1997 and September 1999 was enrolled after consent of the subject and screening examination that included serum TSH and thyroxine levels. This represented a 79% sample of all 85-year-old residents of Leiden, the Netherlands. Follow up was complete for survival 4 years to the subject's 89th birthday or prior death, although 70 subjects refused the annual re-examination. Thyroid function, disability, cognitive function and number of chronic diseases were analyzed, in addition to mortality, through Cox regression and other statistical methods. RESULTS: In 67 subjects with abnormally high TSH (>4.8 mIU/ L), the mean annual mortality rate was derived as 64 deaths per 1000 per year. In the 491 subjects with normal TSH or low TSH (<0.3 mIU/L), the mean annual mortality rate was derived at 114 per 1000 per year. Laboratory evidence of hypothyroidism (initially low serum thyroxine) was found in only 37 of the 67 subjects. CONCLUSION: In the 13% of elderly subjects in Leiden with abnormally high serum TSH levels, the mean annual mortality rate was significantly lower than the mortality rate in the 87% of the elderly patients with normal or low serum TSH. The significance is based on 95% confidence levels of the Poisson distribution. The rate in the group with high TSH levels had 16 deaths in 264 person-years of follow up (FU). The majority with normal or low TSH levels had 193 deaths in 1698 person-years of FU.

Actuarial Analysis↗