triiodothyronine--reverse and Neoplasms

Thyroid hormone (TH) is a pleiotropic agent that has widespread biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The serum concentrations of TH affect its biological activity. Moreover, at tissue level, TH action is regulated by the expression and activity of deiodinases, i.e., the enzymes that mediate the metabolic pathways by activating and/or inactivating TH. The type I and II deiodinases (D1 and D2) initiate TH action by converting thyroxine (T4) into the active TH form (T3), whereas type III deiodinase (D3) mediates the local attenuation of TH by converting T4 and T3 into the inactive metabolites rT3 and T2, respectively. The deiodinase system is a potent mechanism of pre-receptoral control of TH action; it is often altered in such pathological conditions as cancer. D3 is widely expressed in embryonic tissues and in placenta, where it blocks excessive maternal-to-fetal transfer of TH. In contrast, during late neonatal and adult life, D3 is expressed mainly in the central nervous system and skin. Interestingly, D3 expression is re-activated in various types of human cancers. Here we review recent evidence that D3 expression plays a crucial role in human carcinogenesis, and speculate as to its complex role in the regulation of cell proliferation in several neoplastic contexts. It is conceivable that the local modulation of TH action via deiodinases is a powerful molecular tool to manipulate the intracellular TH status, thus influencing the growth and maintenance of selected hormone-dependent cancers.

Topics: Cell Division; Cell Transformation, Neoplastic; Enzyme Activation; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Hypothyroidism; Iodide Peroxidase; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neoplasms, Hormone-Dependent; Organ Specificity; Subcellular Fractions; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adenocarcinoma; Brain Neoplasms; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Female; Glioblastoma; Humans; MCF-7 Cells; Neoplasms; Triiodothyronine, Reverse; Tumor Cells, Cultured

The concentrations of thyroid function determinants may change during severe illness. Our goal was to quantify their changes in children with cancer during chemotherapy, and to correlate them to clinical condition and type of drugs.. During a 3-month period all patients admitted for chemotherapy to the paediatric oncology ward were evaluated for inclusion. Patients with brain tumours, neuroblastoma (cranio)spinal irradiation and use of dexamethasone before the first blood sample were excluded.. Plasma concentrations of T4, T3, rT3, thyroxine-binding globulin (TBG), thyroglobulin (Tg), TSH, IGF-1, cortisol, PRL and physical well-being by means of questionnaires were measured before and during chemotherapy.. In 19 children, 46 courses of chemotherapy and 123 plasma samples were analysed. During chemotherapy, mean concentrations of TSH, T3, Tg and cortisol decreased to 53, 67, 69 and 15% of the baseline value, respectively. Mean plasma rT3 increased to 217% of baseline. In 87% of all courses, one or more thyroid parameter(s) was aberrant. Furthermore, in 23 samples (19%) from 10 patients (53%), the concentration of IGF-1 was below the reference value (adjusted for sex and age). Small changes were seen in scores for clinical condition but none was related to a change in thyroid function determinant. Most changes in thyroid hormones could be attributed to using dexamethasone.. These results demonstrate that, in children, thyroid hormone state changes significantly during chemotherapy, apparently not related to physical well-being but to the drugs administered. Future investigations should focus on the impact for patient care and possibilities of (preventive) intervention.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Female; Glioma; Health Status; Humans; Hydrocortisone; Insulin-Like Growth Factor I; Leukemia; Leukemia-Lymphoma, Adult T-Cell; Male; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prolactin; Rhabdomyosarcoma; Sarcoma, Ewing; Spinal Cord Neoplasms; Thyroglobulin; Thyroid Hormones; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.

Topics: Adult; Aged; Humans; Kidney Failure, Chronic; Middle Aged; Neoplasms; Osmolar Concentration; Triiodothyronine; Triiodothyronine, Reverse

Twenty-four-hour thyrotropin (TSH) profiles in eight severely ill patients were compared with those of six healthy subjects. The profiles were assessed using the cosinor method to evaluate circadian variations and using the Pulsar algorithm to analyze episodic secretion. In the normal subjects, the typical periodicity of TSH secretion showed a mean level in the rhythm (mesor) of 2.03 mU/l. The amplitude (half the extent of rhythmic change in the cycle) was 0.58 mU/l; the acrophase (the delay from midnight (0 degrees) of the highest level in the rhythm) was -9.9 degrees. In contrast, severely ill patients showed only slight and anticipated elevations of serum TSH levels (mesor 0.93 mU/l, amplitude 0.22 mU/l, acrophase +82.4 degrees). Moreover, whereas the episodic TSH secretion in healthy individuals consisted of 5-8 pulses/24 h, mainly clustered around midnight, only one pulse of reduced amplitude was detected in two of the eight severely ill patients and no pulses in the other six. Since earlier studies have indicated that the loss of TSH pulsatility is associated with the relative insensitivity of the thyrotrophs to low thyroid hormone levels and our analytical procedures have demonstrated that 24 h pulsatile pattern of TSH closely overlapped with baseline TSH secretion, it seems reasonable to assume that low-thyroid-hormone state, deficient pulsatile TSH secretion and altered nyctohemeral TSH periodicity do not coincide by chance, but that there is a causal relationship between such abnormalities in severely ill patients.

Topics: Adult; Circadian Rhythm; Female; Humans; Hypothyroidism; Liver Cirrhosis; Male; Middle Aged; Neoplasms; Pulsatile Flow; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Topics: Body Weight; Humans; Neoplasms; Triiodothyronine; Triiodothyronine, Reverse

Although patients with primary hyperparathyroidism (1 degree HPT) were euthyroid, we measured serum thyroid hormone levels in 16 patients with 1 degree HPT together with 17 patients with hypercalcemia due to malignant diseases (HCM). In patients with 1 degree HPT, serum levels of T3, T4 and T3U were within normal range, but serum rT3 (reverse T3) levels (205 +/- 37 pg/ml, mean +/- SD) were significantly decreased as compared with those in normal controls (276 +/- 44 pg/ml, P less than 0.01). A significant inverse correlation was observed between the serum levels of rT3 and parathyroid hormone (PTH) (r = 0.54, P less than 0.05). After parathyroidectomy, serum rT3 levels were significantly elevated (240 +/- 56 pg/ml) compared to preoperative levels (P less than 0.01). Low levels of serum rT3 seemed to be attributed to the high levels of serum PTH. On the other hand, serum levels of T3 and T4 were low and serum rT3 levels were high in patients with HCM. Low serum rT3 allows for the differentiation of patients with 1 degree HPT from those with HCM.

Topics: Adolescent; Adult; Aged; Female; Humans; Hypercalcemia; Hyperparathyroidism; Male; Middle Aged; Neoplasms; Parathyroid Hormone; Thyroid Hormones; Triiodothyronine, Reverse

Thyroid hormones are displaced from their binding proteins in serum during nonthyroidal somatic illness, and FFA have been claimed to contribute. It seems mandatory to evaluate this effect using techniques for the measurements of serum free thyroid hormones in which serum remains undiluted. We measured the effect of 7 common human FFA on the free fraction of T4, T3 and rT3 in serum from healthy subjects using an ultrafiltration technique by which serum is diluted only minimally. In addition we measured the effect of oleic acid on the free fractions of the iodothyronines in pooled serum from healthy subjects and in pooled serum from patients with nonthyroidal illness. All FFA tested were able to displace both T4, T3 and rT3, but to a varying degree, arachidonic and linoleic acid being the most potent ones. A 20% increase in the free fractions of T4, T3 and rT3, respectively, was obtained by adding between 1.7-3.3 mmol/l, 1.3-4.6 mmol/l and 1.0-2.4 mmol/l of the different FFA. A serum pool obtained from patients with nonthyroidal somatic illness was more sensitive to oleic acid than a serum pool obtained from healthy subjects, since 2-3 times less oleic acid was necessary to induce a 20% increase in the free fractions of thyroid hormones. It is concluded that FFA are able to displace both T4, T3 and rT3 from their serum binding proteins in healthy subjects as well as in patients with nonthyroidal illness. However, serum from patients with nonthyroidal illness was more sensitive to the displacing activity of oleic acid than serum from healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cerebrovascular Disorders; Fatty Acids, Nonesterified; Hepatic Encephalopathy; Humans; Kidney Failure, Chronic; Neoplasms; Respiratory Insufficiency; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Ultrafiltration

Topics: Aging; Diabetes Mellitus; Female; Humans; Immune System Diseases; Infections; Neoplasms; Pregnancy; Thyroid Hormones; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine, Reverse

In order to elucidate changes in thyroid hormone metabolism during acute heat stress, we measured sequentially serum thyroxine (T4), triiothyronine (T3), and reverse T3 (rT3) levels in 5 patients with neoplasia during treatment with whole body hyperthermia. The core temperature was raised from 37.0 degrees C to 42.0 degrees C over a 2-hour period, maintained at 42.0 degrees C for 2 hours, and then cooled to 37.0 degrees C over 2 hours. This short period of severe hyperthermia produced a fivefold rise in rT3 and a fall in T3 levels to one half of baseline levels. T4 and free T4 levels increased slightly, but thyrotropin (measured in two patients) did not change. These changes in T3 and rT3 levels were detectable at the fourth hour after onset of hyperthermia, were maximal at 24 and 48 hours, and in one patient were uncorrected after 4 days. We conclude that this reciprocal change in T3 and rT3 levels is a response to stress and may represent in part adaptation to a high environmental temperature by the suppression of theromengic T3. Whole body hyperthermia of short duration for cancer therapy produces profound changes in the peripheral degradation of thyroxine, which last for several days. This must be considered in the management of patients receiving hyperthermia, and the technique itself may prove to be a useful model for the study of adaptation to heat stress.

Topics: Humans; Hyperthermia, Induced; Kinetics; Neoplasms; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

We studied various tests of thyroid function in sick patients with nonthyroidal illness (NTI) in order to determine the utility of each test for differentiating these patience from a group with hypothyroidism. We evaluated each test in 22 healthy volunteers who served as controls, 20 patients with hypothyroidism, 14 patients admitted to medical intensive care unit whose serum T4 was less than 5 micrograms/dl, 13 patients with chronic liver disease, 32 patients on chronic hemodialysis for renal failure, 13 ambulatory oncology patients receiving chemotherapy, 16 pregnant women, 7 women on estrogens, and 20 hyperthyroid patients. On all samples, we measured serum T4, the free T4 index by several methods, free T4 by equilibrium dialysis, free T4 calculated from thyronine-binding globulin (TBG) RIA, free T4 by three commercial kits (Gammacoat, Immophase, and Liquisol), T3, rT3, and TSH (by 3 different RIAs). Although all of the methods used for measuring free T4 (including free T4 index, free T4 by dialysis, free T4 assessed by TBG, and free T4 assessed by the 3 commercial kits) were excellent for the diagnosis of hypothyroidism, hyperthyroidism, and euthyroidism in the presence of high TBG, none of these methods showed that free T4 was consistently normal in patients with NTI; with each method, a number of NTI patients had subnormal values. In the NTI groups, free T4 measured by dialysis and the free T4 index generally correlated significantly with the commercial free T4 methods. Serum rT3 was elevated or normal in NTI patients and low in hypothyroid subjects. Serum TSH provided the most reliable differentiation between patients with primary hypothyroidism and those with NTI and low serum T4 levels.

Topics: Alpha-Globulins; Chronic Disease; Female; Humans; Hyperthyroidism; Hypothyroidism; Kidney Failure, Chronic; Liver Diseases; Neoplasms; Pregnancy; Radioimmunoassay; Reagent Kits, Diagnostic; Renal Dialysis; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Nonthyroidal illness is frequently associated with subnormal serum thyroxine (T4) and free T4 index. To unravel the resultant diagnostic problems, we have studied several variables of thyroid function in the sera of 47 patients hospitalized with nonthyroidal illnesses and seven hypothyroid patients encountered during the same period. Of the 47 euthyroid sick patients, 18 had low T4. Among these 18, free T4 index was normal in only five, whereas free T4 concentration measured by equilibrium dialysis was normal or high in 15 and 3,3',5'-triiodothyronine (reverse T3) normal or high in all 18. Reverse T3, free T4 concentration, and free T4 index were subnormal in all seven hypothyroid patients. Thus, measurement of free T4 index may be misleading in evaluation of thyroid function in patients with nonthyroidal illnesses, whereas measurement of serum concentration of reverse T3 and free T4 is quite discriminating.

Topics: Adult; Aged; Diagnosis, Differential; Diagnostic Errors; Evaluation Studies as Topic; Heart Diseases; Humans; Hypothyroidism; Middle Aged; Neoplasm Metastasis; Neoplasms; Pneumonia; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Uremia

As first described in serious systemic illnesses isolated decreased T3 plasma concentration was related to impaired peripheral conversion of T4, to T3 with preferential production of reverse T3 (rT3). A "low T3 syndrome" was seen in 47 out of 109 patients with extra-thyroidal diseases. Metabolic state, TSH and TSH responses to TRH were normal despite of low T3 concentration. Euthyroidism seems mainly due to T4 itself in these patients.

Topics: Aged; Anorexia Nervosa; Diet, Reducing; Humans; Hypothyroidism; Kidney Diseases; Liver Cirrhosis; Neoplasms; Obesity; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse