Thyroid Hormone Substitution Research Articles

Thyroid disorders are associated with impaired response to psychopharmacological treatment of major depression

Introduction: The association of thyroid disorders (TDs) and mood disorders is a well-investigated empirical finding. Although TDs are highly prevalent in patients with major depression (MD), the impact of TDs on treatment outcome has been sparsely investigated. Methods: Treatment Response was analyzed in 704 in-patients with MD participating in the Munich Antidepressant Response Signature (MARS) project, a large observational naturalistic psychopharmacological treatment study. TD was defined by thyroid hormone substitution, morphological thyroid gland abnormalities, or thyroid autoimmunity. Treatment response was measured by weekly Hamilton Depression Rating Scale (HDRS) assessments during 6 weeks. All patients were euthyroid at baseline. TSH levels were analyzed for potential prediction of treatment outcome. Results: MD patients with TD (n = 172) displayed a significantly impaired treatment outcome compared to MD patients without TD (n = 532) in response rates after 6 weeks (p = 7.4E-04), remission rate at discharge (p = 0.018) as well as in mean HDRS change after 6 weeks (p = 0.019). These differences were most pronounced under treatment with Serotonin Reuptake Inhibitors (SSRIs). TSH levels were not associated with treatment outcome. Discussion: Our results suggest that MD patients with comorbid TD may be at risk for impaired treatment outcome. Replication and substantiation of these findings could inform differential antidepressant therapy for these patients.

Impact of elevated thyroid-stimulating hormone levels in polycystic ovary syndrome

The objective of this study was to analyse the impact of elevated thyroid-stimulating hormone (TSH) levels on the metabolic and endocrine phenotype in 583 women with polycystic ovary syndrome (PCOS). Endocrine and metabolic parameters were measured in all patients and compared between women with and without elevated TSH levels. Of the 583 women with PCOS, 125 women (21.4%) had thyroid disturbances (thyroid replacement therapy: 109 women, subclinical hypothyroidism: 16 women). Patients with elevated TSH levels had significantly increased fasting insulin, area under the curve–insulin, homeostatic model assessment–insulin resistance, and total cholesterol (TC)/high-density lipoprotein cholesterol (HDL) ratio and lower free thyroxin, insulin sensitivity and HDL (p < 0.05 for all). Euthyroid PCOS women with thyroid hormone substitution showed significant differences in TSH, age, body mass index, HDL and systolic blood pressure compared to those without hormone replacement therapy (p < 0.05 for all). We conclude that hypothyroid disturbances and elevated TSH levels are common findings in PCOS, which are associated with an adverse metabolic profile. Therefore, women with diagnosed PCOS should be screened for thyroid dysfunction.

Sublingual Thyroid Gland

A 22-year old man presented with a factitial hyperthyreosis (300 μg levothyroxine/d). He had a history of congenital hypothyroidism diagnosed in the age of 6 years. Thyroid hormone substitution compliance was irregular because of family problems.

Permanent and transient congenital hypothyroidism in full-term and preterm born infants

Congenital hypothyroidism (CH) is one of the most common endocrine disorders in the infant population. It is also one of the most important causes of foreseeable brain damage and severe mental impairment. Current views on CH pathogenesis, screening schema and treatment standards have been presented. Also outlined have been the newest reports on the impact on CH epidemiology and classification generated by the introduction of low TSH cut-off (6 mU/l).The use of low TSH cut-off allowed the detection of an unsuspected number of children with neonatal hypothyroidism, evolving in mild permanent thyroid dysfunction later in life. Constantly growing, especially in developed countries, number of preterm infants is a separate group of children, mainly with transient fluctuations in thyroid function. Thyroid gland function develops and matures during fetal life, with production of serum thyroxine (T4) beginning around 12 weeks gestation and increasing to term. Infants born prior to term have lower cord serum T4 concentrations which correlate with gestational age or/and birth weight. This is partially a result of lower thyroxine-binding globulin (TBG) concentrations. The cord serum free thyroxine (FT4) concentrations also correlate with gestational age, but they are not proportionately as low as cord T4 concentration. Preterm infants have a postnatal thyrotropin (TSH) surge and rise in serum T4 and triiodothyronine (T3), which is qualitatively similar to, but quantitatively smaller than term infants. In contrast to term infants, preterm infants often experience a fall in serum T4 and T3 in the first week of life to below birth levels. This drop appears to be the result of many factors, including nutritional problems and decreased hepatic TBG production, immaturity of hypothalamic-pituitary control of the thyroid gland, immaturity of the thyroid gland itself, and increased tissue utilization of T4. Several studies have correlated different measures of morbidity and mortality in the preterm infant with lower serum T4 concentrations. This has led to speculation that T4 treatment might be beneficial in improving these complications of prematurity, in particular the neurological outcome. Latest studies do not confirm that hypothyroidism in preterm infants is for them harmless. Many factors, however, influence mental development of those children. Thus, treatment strategies, including thyroid hormone substitution, should consider both the etiology of the hypothyroidism and the impact of aforementioned factors. There is no “hard evidence” to support introducing thyroid hormone supplementation in preterm infants as a rule.

Thyroid Hemiagenesis Associated with Hashimoto’s Thyroiditis

Thyroid hemiagenesis is a rare congenital anomaly resulting from failure of one thyroid lobe development. We report a 23-year-old female presented with Hashimoto's thyroiditis in left lobe, associated with hemiagenesis of right lobe and isthmus which was previously diagnosed as Graves' hyperthyroidism, but developed further into Hashimoto's thyroiditis after being treated with antithyroid drugs. The symptoms of hyperthyroidism in the current case led to the diagnostic confirmation by scintiscanning of an absent lobe. The antithyroid pharmacotherapy by thiamazole was used. However, due to symptoms of hypothyroidism, it was discontinued two months later, so thyroid hormone substitution was reintroduced. Antithyroid antibody studies and ultrasonography documented the presence of Hashimoto's thyroiditis.

Reversal deterioration of renal function accompanied with primary hypothyrodism

Hypothyroidism is often accompanied with decline of kidney function, or inability to maintain electrolyte balance. These changes are usually overlooked in everyday practice. Early recognition of this association eliminates unnecessary diagnostic procedures that postpone the adequate treatment. Two patients with elevated serum creatinine levels due to primary autoimmune hypothyroidism, with complete recovery of creatinine clearance after thyroid hormone substitution therapy are presented. The first patient was a young male whose laboratory tests suggested acute renal failure, and the delicate clinical presentation of reduced thyroid function. The second patient was an elderly woman with a history of a long-term signs and symptoms attributed to ageing, including the deterioration of renal function, with consequently delayed diagnosis of hypothyroidism. Serum thyrotropin and thyroxin levels measurement should be done in all cases of renal failure with undefined renal desease, even if the typical clinical presentation of hypothyroidism is absent. Thyroid hormone assays sholud also be performed in all patients with chronic kidney disease whose kidney function is rapidly worsening.

Hear, Hear! Thyroid Hormone Transporters in Cochlear Development

Hearing is one of the most sensitive functions controlled by thyroid hormone (TH). It therefore appears to be of utmost importance to define the transporters that mediate TH passage within the auditory system because mutations in specific TH transporter genes may be connected to pathological findings. In this issue of Endocrinology, Sharlin et al. (1) provide detailed information on the temporal and spatial expression pattern of several TH transporter candidates in the mouse cochlea where these transporters may act as decisive gatekeepers. These data not only enlarge our understanding about TH traffic and action in the hearing system but also establish a sound basis for further studies such as the analysis of TH transporter-deficient mice. The development of hearing in humans as well as in rodents is highly dependent on sufficient TH supply. TH deprivation particularly during late fetal and neonatal stages can result in hearing impairments or even in deafness if TH substitution is not instituted within a critical time window (2, 3). Consequently, hearing impairment is common in geographic areas with a prevalence of iodine deficiency and is also evident in various forms of thyroid disorders such as congenital hypothyroidism (4) or resistance to TH (5, 6). A major target of TH in the auditory system is the cochlea where TH promotes the terminal differentiation of a variety of cell types. In particular, TH regulates the remodeling of the greater epithelial ridge and the tectorial membrane as well as the differentiation of the sensory epithelium that contains the sound-transducing hair cells. During this complexprocessof cochleadifferentiation, the amount of T3 as the receptor active form of TH is intriguingly tightly regulated by the type 2 deiodinase (Dio2) and type 3 deiodinase (Dio3) (7). The latter enzyme, which inactivates T4 and T3 by inner ring deiodination, is predominantly expressed at late prenatal stages and is thought to prevent a premature stimulation of TH receptors (TR). Consequently, Dio3 knockout mice display an accelerated cochlea differentiation and auditory defects (8). In contrast, Dio2 exhibits outer ring deiodinase activity and is responsible for converting T4 to T3. The postnatal rise in Dio2 activity with a peak at d 7 leads to an amplification of the cochlear T3 levels particularly during the time period when the differentiation of the auditory system is most dependent on sufficient T3 supply (7). Accordingly, Dio2 knockout mice suffer from hearing loss as well, but in contrast to Dio3 / mice, they show a retarded cochlear development (9). In light of these findings, it appears not too surprising that mouse mutants deficient in TR display severe cochlear defects as well (10, 11). Another mechanism by which the amount of T3 can be locally controlled is a differential expression of TH transporters. Studies in mouse mutants have revealed that the inactivation of the TH transporter monocarboxylate transporter 8 [Mct8 (Slc16a2)] results in an impaired transport of T3 via the blood-brain barrier and, consequently, in a hypothyroid situation in the central nervous system (CNS) (12–14). Patients with inactivating mutations in the X-linked MCT8 gene suffer from a severe form of psychomotor retardation and neurological impairments indicating that the human brain may even be more dependent on MCT8 for mediating TH entry into the brain than the mouse CNS (15–17). Other transporters such as the organic anion transporting polypeptide-1c1 [Oatp1c1 (Slco1c1)], the monocarboxylate transporter Mct10 (Slc16a10), or the L-type amino acid transporters Lat1 (Slc7a5) and Lat2 (Slc7a8) have been discussed to contribute signif-

The evaluation of function and the ultrasonographic picture of thyroid in children treated for medulloblastoma

Medulloblastoma (MB) is one of the most frequent and sensitive to radiation aggressive brain tumor in children. Abnormalities of the thyroid function are common complications of head and neck irradiation for childhood cancer. The aim of this study was to assess thyroid function in children treated for medulloblastoma according to the treatment protocol phase. Twenty-three children with MB were enrolled to this study. All patients underwent chemotherapy and radiotherapy to the whole craniospinal axis and boost with the conformal therapy restricted to the tumor bed to a total dose of 54 Gy. Thyroid function was evaluated based on thyroid-stimulating hormone (TSH), free thyroxine (fT4) levels controlled before MB treatment, directly after irradiation and at the end of the treatment protocol. Ultrasonography has been used to detect parenchymal abnormalities. All patients presented normal thyroid hormone range before chemotherapy. Hypothyroidism was found in 12 patients in the course of treatment, in 2 patients hormone deficits diagnosed directly after irradiation, in 10 patients such condition was observed at the end of the whole therapy. All of these patients needed thyroid hormone substitution. None of them presented clinical symptoms of hypothyroidism. Ultrasound-detected abnormalities have been found in 20 patients. It is crucial to monitor the functions of the thyroid gland in children treated for medulloblastoma because of the high risk of hypothyroidism resulting from the treatment. The change in the echogenicity of the thyroid gland may be an early marker for a dysfunction of this organ in children treated for medulloblastoma.

Effets secondaires pancréatiques de la substitution hormonale après thyroïdectomie chez un patient obèse

An obese patient, treated by thyroid hormone substitution after total thyroidectomy in 2001, with a differentiated papillary carcinoma (pT2mN0M0G0), complained about daily vomiting and abdominal pain from 2001 to 2007. Repeated diagnostic set-ups showed a substantial increase of pancreatic enzymes. Symptomatic pharmacological treatments were without effect. Two pharmacological interventions designed as modulated posologies of thyroid hormone substitution were undertaken. Clinical symptoms disappeared instantaneously and definitively. A therapeutic test demonstrated the iatrogenic relation between the pancreatic changes and modalities of thyroid hormone substitution.

Hypothyroidism After Head-and-Neck Radiotherapy in Children and Adolescents: Preliminary Results of the “Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence” (RiSK)

The "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK) has been established to prospectively characterize dose-volume effects of radiation in terms of side effects. The aim of this analysis was to characterize the function of the thyroid gland after radiotherapy to the head-and-neck region in children and adolescents. Detailed information regarding radiation doses to at-risk organs has been collected across Germany since 2001. Thyroid function was evaluated by blood value examinations of thyroid-stimulating hormone, triiodothyronine, and thyroxine. Information regarding thyroid hormone substitution was requested from the treating physicians. Until May 2009, 1,086 patients from 62 centers were recruited, including 404 patients (median age, 10.9 years) who had received radiotherapy to the thyroid gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients with radiation doses of 15 to 25 Gy to the thyroid gland had a hazard ratio of 3.072 (p=0.002) for the development of pathologic thyroid blood values. Patients with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had hazard ratios of 3.768 (p=0.009) and 5.674 (p<0.001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups. Radiation-induced thyroid function impairment, including damage to the thyroid gland and/or hypophysis, can frequently be observed after radiotherapy in children. A structured follow-up examination is advised.

Craniopharyngioma Resulting in Pituitary Gland Insufficiency and Coma in an Adult With Intellectual Disability and Severe Challenging Behavior

Craniopharyngioma Resulting in Pituitary Gland Insufficiency and Coma in an Adult With Intellectual Disability and Severe Challenging Behavior

Craniopharyngioma Resulting in Pituitary Gland Insufficiency and Coma in an Adult With Intellectual Disability and Severe Challenging Behavior

Craniopharyngioma Resulting in Pituitary Gland Insufficiency and Coma in an Adult With Intellectual Disability and Severe Challenging Behavior

Totale Thyreoidektomie bei Knotenstruma

Multinodular goiter is a frequent disease which plays a central role in the daily routine of general and visceral surgeons. Analyses of the national DRG statistics reveal that total thyroidectomy is increasingly replacing partial thyroid resections. This paradigm shift is substantiated by the comprehension of multinodular goiter as a disease affecting the whole organ as well as the fact that total thyroidectomy avoids high risk secondary interventions for incidental thyroid carcinomas and recurrent disease while offering comparable operative risks. However, the available evidence on operative results originates predominantly from thyroid centers and clinical data regarding long-term effects of thyroid hormone substitution following total as well as sub-total thyroidectomy are lacking. Therefore, the preservation of functionally relevant normal thyroid tissue retains its relevancy as an alternative treatment. If a comparably low operative risk can be guaranteed and considering the patient's compliance, life situation and wishes, total thyroidectomy represents the optimal therapy for bilateral multinodular goiter.

Insuffisance rénale aiguë révélant une hypothyroïdie auto-immune

Although the clinic picture is often indicative of muscle manifestations in patients with hypothyroidism, signs and symptoms of this condition are variable from simple elevation of serum muscle enzymes with myalgia, muscle weakness, cramps to rhabdomyolysis with acute renal failure which remains a rare event. Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Hypothyroidism is associated with significant effects on the kidney which the pathophysiology seems to be multifactorial, but the exact mechanisms remain poorly understood. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. The main objective of our observation is to report a case of acute renal failure revealing an autoimmune hypothyroidism in which thyroid hormone substitution led to a significant improvement in muscular, thyroid and renal disorders.

Acute Renal Failure: A Rare Presentation of Hypothyroidism

Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Severe hypothyroidism is associated with significant effects on the kidney. The pathophysiology is thought to be multifactorial, while the exact mechanism remains unclear. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. We describe two patients with acute renal failure due to severe hypothyroidism in whom thyroid hormone substitution therapy led to a significant improvement in renal function.

Hypothyroidism impairs chloride homeostasis and onset of inhibitory neurotransmission in developing auditory brainstem and hippocampal neurons

Thyroid hormone (TH) deficiency during perinatal life causes a multitude of functional and morphological deficits in the brain. In rats and mice, TH dependency of neural maturation is particularly evident during the first 1-2 weeks of postnatal development. During the same period, synaptic transmission via the inhibitory transmitters glycine and GABA changes from excitatory depolarizing effects to inhibitory hyperpolarizing ones in most neurons [depolarizing-hyperpolarizing (D/H) shift]. The D/H shift is caused by the activation of the K(+)-Cl(-) co-transporter KCC2 which extrudes Cl(-) from the cytosol, thus generating an inward-directed electrochemical Cl(-) gradient. Here we analyzed whether the D/H shift and, consequently, the onset of inhibitory neurotransmission are influenced by TH. Gramicidin perforated-patch recordings from auditory brainstem neurons of experimentally hypothyroid rats revealed depolarizing glycine effects until postnatal day (P)11, i.e. almost 1 week longer than in control rats, in which the D/H shift occurred at approximately P5-6. Likewise, until P12-13 the equilibrium potential E(Gly) in hypothyroids was more positive than the membrane resting potential. Normal E(Gly) could be restored upon TH substitution in P11-12 hypothyroids. These data demonstrate a disturbed Cl(-) homeostasis following TH deficiency and point to a delayed onset of synaptic inhibition. Interestingly, immunohistochemistry demonstrated an unchanged KCC2 distribution in hypothyroids, implying that TH deficiency did not affect KCC2 gene expression but may have impaired the functional status of KCC2. Hippocampal neurons of hypothyroid P16-17 rats also demonstrated an impaired Cl(-) homeostasis, indicating that TH may have promoted the D/H shift and maturation of synaptic inhibition throughout the brain.

Hypothyroidism and Endothelial Function: A Marker of Early Atherosclerosis?

Endothelial dysfunction represents an important pathway thereby cardiovascular risk factors promote the development and progression of atherosclerosis. Hypothyroidism is associated with an increased cardiovascular risk, and the assessment of endothelium function is recognised an effective tool for the detection of evidence of preclinical cardiovascular alterations. Both vascular smooth muscle cells and endothelium play pivotal roles in modulating vascular tone and both are potential targets of thyroid hormone action. The pathogenesis of the association between endothelial dysfunction and hypothyroidism is complex and still not well established. The presence of traditional and emerging risk factors may contribute to the development of endothelium impairment, generating a chronic state of injury that triggers abnormal endothelial response. Levothyroxine replacement therapy is currently used for restoring euthyroidism and improving cardiovascular risk of hypothyroid patients. The decision to treat patients with subclinical hypothyroidism should depend on the presence of risk factors, rather than on a TSH threshold. However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events, especially in subclinically hypothyroid patients, remains to be elucidated. Large multicenter, placebo-controlled prospective trials are necessary to address the issue. The article also discusses recent patents in this field. Keywords: Hypothyroidism, endothelium, cardiovascular risk, levothyroxine, DITPA, flow mediated dilation, atherosclerosis, dyslipidemia

Autonomic Nervous System Function in Chronic Exogenous Subclinical Thyrotoxicosis and the Effect of Restoring Euthyroidism

Knowledge on the relationship between the autonomic nervous system and subclinical hyperthyroidism is mainly based upon cross-sectional studies in heterogeneous patient populations, and the effect of restoration to euthyroidism in subclinical hyperthyroidism has not been studied. We investigated the long-term effects of exogenous subclinical hyperthyroidism on the autonomic nervous system and the potential effects of restoration of euthyroidism. This was a prospective single-blinded, placebo-controlled, randomized trial. The study was performed at a university hospital. A total of 25 patients who were on more than 10-yr TSH suppressive therapy after thyroidectomy was examined. Patients were studied at baseline and subsequently randomized to a 6-month thyroid hormone substitution regimen to obtain either euthyroidism or maintenance of the subclinical hyperthyroid state. Urinary excretion of catecholamines and heart rate variability were measured. Baseline data of the subclinical hyperthyroidism patients were compared with data obtained in patients with hyperthyroidism and controls. Urinary excretion of norepinephrine and vanillylmandelic acid was higher in the subclinical hyperthyroidism patients compared with controls and lower compared with patients with overt hyperthyroidism. Heart rate variability was lower in patients with hyperthyroidism, intermediate in subclinical hyperthyroidism patients, and highest in the healthy controls. No differences were observed after restoration of euthyroidism. Long-term exogenous subclinical hyperthyroidism has effects on the autonomic nervous system measured by heart rate variability and urinary catecholamine excretion. No differences were observed after restoration to euthyroidism. This may indicate the occurrence of irreversible changes or adaptation during long-term exposure to excess thyroid hormone that is not remedied by 6-month euthyroidism.

Immunogene Hyperthyreose mit hyperdynamischem Herzversagen und beginnendem zirrhotischem Umbau der Leber

A 58-year-old woman was admitted because of jaundice, ascites and marked oedema. For three years she had suffered from nervousness, decreasing fitness and weight loss, which had been assumed as due to chronic alcoholism. Liver biopsy revealed extensive fibrosis, in part with early cirrhotic transformation. This was followed by cardiac failure with atrial fibrillation (ventricular rate 140/min) and marked pleural effusions. The thyroid was diffusely enlarged and there were signs of exophthalmos. Bilirubin concentration was 3 mg/dl, lactate dehydrogenase activity was 310 U/l, cholesterase 1.3 kU/l and the prothrombin test was 21%. The TSH level was 0.01 microU/ml while the free thyroxine level was 4.7 ng/dl and that of free triiodothyronine 13.5 pg/ml. Chest radiograph revealed cardiomegaly, bilateral peripheral pulmonary congestion and pleural effusions to midfield. Right heart catheterization excluded pulmonary hypertension; cardiac output was 10l/min. The thyroid was enlarged on ultrasound and diffusely echopoor, as in immune thyroid disease. Cardiac failure regressed and thyroid function normalized within ten days on propranolol, 4 x 40 mg and thiamazole 3 x 40 mg daily intravenously. Subtotal thyroidectomy was performed three weeks later with subsequent thyroid hormone substitution. Liver functions were normal six months later and ultrasound showed no signs of cirrhotic change and the ascites had resolved. Hyperthyroidism is frequently associated with changes in liver functions. In extreme cases, high-output cardiac failure may occur, with liver congestion and clinical as well as histological changes like those in liver cirrhosis.

Obesity, energy regulation and thyroid function

Several population-based studies have shown a significant association between TSH-level and BMI (body mass index). About 30% of the rest energy expenditure are regulated by thyroid hormones, which generated the hypothesis that thyroid hormone substitution with TSH-titration into the lower reference levels may prevent body weight gain. The opposite effect of thyroid hormones is appetite stimulation, which may be responsible for body weight gain in case of substitutive medication. The association between TSH and BMI has become a complex topic in the light of the endocrine activity of adipocytes. Adipocytes are not a silent fat mass, but increase the hormone level of leptin, which influences neurones in the hypothalamus, the thyreotropic axis and TSH secretion. BMI is positively correlated with serum leptin. Elevated leptin levels, endogenous in individuals with high BMI or exogenous after leptin injection for treatment of hypothalamic amenorrhoea, shift TSH in the upper reference level. Borderline elevated TSH levels are reversible in case of body weight reduction in obese persons. It remains unclear whether high TSH levels or high leptin level are responsible for obesity or represent secondary phenomenon. Recommendation for daily practice: Borderline elevated TSH-levels in obese patients will decrease in case of body weight reduction without hormone medication. After definitive treatment of hyperthyroidism patient's history for use of carbohydrates (increased during hyperthyroidism) should be noticed and substitution with thyroid hormones aims at TSH in the lower reference level. As body weight gain is observed in all TSH groups, a special concept for prevention and therapy of obesity (diet, daily exercise, behaviour training) should be initiated early and additionally to medication.