Peripheral Resistance To Thyroid Hormone Research Articles

Association between thyroid hormone resistance and obesity: a cross-sectional study and mouse stimulation test.

Thyroid hormone influences key metabolic pathways, and reduced sensitivity to thyroid hormone is considered a new risk factor for adverse metabolic outcomes. However, the association between thyroid hormone resistance and obesity in euthyroid individuals is still unknown. We enrolled 8021 euthyroid individuals, calculated thyroid hormone resistance indices, and analyzed the association between thyroid hormone resistance and obesity by regression analysis. Furthermore, we conducted the thyrotropin-releasing hormone stimulation test in both control and obese mice (n = 5) to demonstrate the association. The euthyroid adults with overweight and obesity had increased thyroid hormone resistance indices (all p < 0.05). BMI and prevalence of overweight and obesity increased (odds ratio of thyroid feedback quantile-based index [ORTFQI] = 1.164, p = 0.036; OR of free triiodothyronine/free thyroxine [ORFT3/FT4] = 1.508, p < 0.001) following the elevation of thyroid hormone resistance indices. Mediation analysis indicated a complete mediation effect (beta coefficient of indirect effect [βInd]= 6.838, p < 0.001) of metabolic disorders in the relationship. Furthermore, in the mice with obesity, the thyrotropin response to thyrotropin-releasing hormone stimulation (68.33-90.89 pg/mL) was comparatively blunted (p = 0.029). Euthyroid individuals with obesity exhibit both central and peripheral thyroid hormone resistance, a phenomenon that is more pronounced in individuals with metabolic abnormalities. Thyroid hormone resistance is associated with an increased prevalence of overweight and obesity mediated by metabolic disorders.

Sensitivity to thyroid hormone and risk of components of metabolic syndrome in a Chinese euthyroid population.

To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population. A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum-free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Chinese-referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio. Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079-1.262, p < .001), TT4RI (OR = 1.115, 95% CI: 1.031-1.206, p = .006), TFQI (OR = 1.196, 95% CI: 1.106-1.294, p < .001), PTFQI (OR = 1.194, 95% CI: 1.104-1.292, p < .001), and lower values of FT3/FT4 ratio (OR = 0.914, 95% CI: 0.845-0.990, p = .026) were associated with MetS. Increased levels of TFQI and PTFQI were associated with abdominal obesity, hypertriglyceridemia, and hypertension. Increased levels of TSHI and TT4RI were associated with hypertriglyceridemia, abdominal obesity, low high-density lipoprotein cholesterol. Reduced levels of FT3/FT4 ratio were associated with hyperglycemia, hypertension, and hypertriglyceridemia. The levels of TSHI, TFQI, and PTFQI were negatively related to SMA and positively related to VAT, SAT, and TAT (all p < .05). Reduced thyroid hormone sensitivity was associated with MetS and its components. Impaired thyroid hormone sensitivity might affect the distribution of adipose tissue and muscle.

Effectiveness and Safety of T3(Triiodothyronine) Therapy for Euthyroid Fibromyalgia

ABSTRACT Background. Clinical features of fibromyalgia syndrome (FMS) resemble those of hypothyroidism although some patients have normal thyroid function tests results. The hypothyroid-like FMS features of these patients may result from partial cellular resistance to thyroid hormone. We treated euthyroid FMS patients with T3 to see if they would respond as do patients with peripheral thyroid hormone resistance syndrome: significant therapeutic effects with supraphysiologic dosages, without target tissue responses typical of thyrotoxicosis. Methods. Seven patients were alternately treated with T3 and placebo over an 8-month period. Phase crossover was response-driven, based on changes in measures of mean tender point sensitivity by algometry, mean symptom intensity by visual analog scales, and mean pain distribution by the percentage method and the ACR criteria. Testing for adverse responses to supraphysiologic dosages of T3 was performed for heart, bone, muscle, and liver. Results. Significant therapeuti...

Urinary Cortisol Metabolites in the Assessment of Peripheral Thyroid Hormone Action: Application for Diagnosis of Resistance to Thyroid Hormone

Urinary cortisol metabolites are altered both quantitatively and qualitatively in thyroid dysfunction. This study was conducted to elucidate the usefulness of urinary cortisol metabolites in the assessment of peripheral thyroid hormone action, particularly in the patients with inappropriate thyrotropin secretion. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) level and gas chromatographical steroid profile were studied in 25 hyperthyroid, 18 hypothyroid, and 24 euthyroid control subjects. Five patients with generalized thyroid hormone resistance and two patients with thyrotropin secreting pituitary tumor were also studied. The ratio of urinary tetrahydrocortisone to tetrahydrocortisol (THE/THF) was significantly elevated in hyperthyroidism (4.58 +/- 1.49) and depressed in hypothyroidism (1.31 +/- 0.55) compared to control (1.93 +/- 0.35). There were good correlations between THE/THF and serum thyroid hormone levels, especially in hypothyroidism. THE/THF can be a good biochemical indicator for deficiency of peripheral thyroid hormone action. Two patients with thyrotropin-secreting tumor showed high THE/THF, which reflected thyroid hormone excess. In contrast, THE/THF in the patients with generalized thyroid hormone resistance was low as compared to high serum thyroid hormone levels. Similar findings were demonstrated with 17-OHCS but discrimination of thyroid hormone resistance was insufficient. Thus, the ratio of the urinary concentrations of cortisol metabolites, THE/THF, appears to be a good marker for peripheral thyroid hormone resistance.

Single base mutation in the hormone binding domain of the thyroid hormone receptor β gene in generalised thyroid hormone resistance demonstrated by single stranded conformation polymorphism analysis

Thyroid hormone resistance is a syndrome of considerable clinical heterogeneity. Three mutations in the c-erb A β gene encoding the human β thyroid hormone receptor have been described in different kindreds. We report here, in a family affected with peripheral thyroid hormone resistance, a unique point mutation in the ligand binding domain of the c-erb A β gene resulting in histidine replacement of an arginine residue at position 438. The region in which the mutation occurred was identified by single stranded conformation polymorphism analysis and confirmed by subcloning and sequencing of the mutant alleles from each of the affected members. Binding of tri-iodothyronine to isolated nuclei from family members was normal suggesting the mechanism of thyroid hormone resistance in this family is not mediated by abnormal binding of ligand and receptor.

CONGENITAL HYPERTHYROIDISM DUE TO INAPPROPRIATE SECRETION OF THYROID STIMULATING HORMONE

The Syndrome of inappropriate secretion of TSH is a rare disease and has been described as a heterogenous group of disorders in juvenile and adult patients who show elevated TSH levels in the presence of elevated thyroid hormone levels.We have observed an infant at age six weeks with congenital goiter who suffered from typical symptoms of hyperthyroidism. In spite of elevated T3 and T4 levels TSH showed basal values between 2 and 8 mU/ml. After TRH-stimulation TSH ranged between 39 and 100 mU/ml. Pituitary adenoma was ruled out; there appeared no relation to Graves' disease.A long term therapeutic trial was performed with the analogue D-thyroxine. TSH gradually returned to normal and the goiter disappeared. After 6 years of observation the physical and psycho-intellectual development and the bone age have been stated to be normal for chronological age, although laboratory data indicated elevated thyroid hormone levels for years.CONCLUSION: Up to now there is evidently no other report on congenital hyperthyroidism due to inappropriate TSH-secretion. Partial pituitary and peripheral thyroid hormone resistance appears to be likely. The long term therapeutic trial with D-T4 has proven to be successful.

Decreased nuclear uptake of [125I]triiodo-L-thyronine in fibroblasts from patients with peripheral thyroid hormone resistance.

The cellular mechanisms that cause the syndrome of generalized, peripheral, and pituitary resistance to thyroid hormones are unclear. In order to investigate the possibility of a defect at the nuclear receptor for T3, we examined: 1) equilibrium binding of [125I]T3 (64 analyses) to the nuclei of intact cultured fibroblasts from 12 patients with both sporadic and familial generalized or selective pituitary resistance, 17 normal subjects, and two apparently normal siblings from affected families; and 2) kinetics of [125I]T3 nuclear uptake (22 analyses) in intact fibroblasts from 4 generalized resistant patients from two different kindreds, compared to one apparently normal sister of one affected patient and 6 normal subjects. Statistical analysis of the equilibrium binding parameters showed no differences in nuclear binding capacity for T3 among all groups. The equilibrium dissociation constants (Kd) also were not significantly different in fibroblasts from the selective pituitary resistant patients, the normal siblings, and the normal subjects. In contrast, the KdS from the general resistant patients were significantly increased (median = 1.94 X 10(-10) M, 5-95% confidence interval = 1.18-2.93 X 10(-10) M 1.11, 0.77-1.25 X 10(-10) M; P less than 0.008). Since there was considerable overlap of the equilibrium binding values among groups, we studied the kinetics of [125I]T3 nuclear uptake in selected cell lines from normal subjects and familial generalized resistant patients. Kinetic analysis of the association curve revealed that, compared to the normal subjects, maximum binding at 10(-10) M [125I]T3 was significantly reduced to 50% in two resistant patients, to 10% in another two patients, and to 65% in one apparently-normal sibling. The empiric parameter lambda that corresponds to the slope at the origin of the curve was not significantly different in any patient compared to normal. The calculated apparent association constant, derived from lambda, and the binding capacity obtained at equilibrium, showed differences that were significant for only one of the patients. We conclude that cultured fibroblasts from patients with familial generalized resistance to thyroid hormone display abnormal kinetics of T3 nuclear uptake which provide a convenient in vitro method for the recognition of thyroid hormone resistance at the cell level. Furthermore, because cultured fibroblasts can be grown under controlled experimental conditions, they are a suitable tissue for further study of the molecular basis of these disorders.

Dopaminergic modulation of TSH and its subunits: in vivo and in vitro studies.

We have studied the effects of dopamine on the secretion of TSH and its subunits in vivo and in vitro. Four normal controls, seven patients with primary hypothyroidism, two patients with peripheral resistance to thyroid hormone (PRTH), and two patients with alpha-secreting pituitary tumours underwent a 3-h dopamine infusion (4 micrograms/kg/min). Serial blood samples were drawn for TSH, PRL, alpha, and TSH-beta subunit. In normal subjects, TSH fell from 2.1 +/- 0.9 (+/- SE) to 0.7 +/- 0.1 microU/ml (P less than 0.05), and alpha declined from 1.5 +/- 0.4 to 1.0 +/- 0.1 ng/ml (P less than 0.01). TSH-beta was at or slightly above the detection limits of the assay before and after dopamine. In hypothyroidism, basal serum TSH was 81 +/- 14 microU/ml. With dopamine, TSH fell to 35 +/- 8 microU/ml (P less than 0.001), while alpha decreased from 3.2 +/- 0.4 to 2.0 +/- 0.3 ng/ml (P less than 0.01). Serum TSH-beta also declined from 0.97 +/- 0.06 to 0.57 +/- 0.05 ng/ml (P less than 0.001). A similar fall in TSH and alpha was seen in the two patients with PRTH. In normals and hypothyroid patients, the percentage change in alpha concentration was significantly less than that observed for intact TSH. This is due presumably to the contribution of the gonadotrophs to the circulating alpha pool. TSH and TSH-beta were undetectable in the two pituitary tumour patients, and alpha declined only slightly in each patient after dopamine. The in vitro effects of dopamine were studied using cultured bovine anterior pituitary cells. Dopamine (10(-4)-10(-8) mol/l) did not change basal TSH, alpha, or TSH-beta release. However, dopamine at all doses significantly blunted TRH (10(-7) mol/l)-stimulated TSH and TSH-beta release, and blunted TRH-mediated alpha release at the two highest dopamine doses. These data suggest that dopamine modulates both TSH and TSH subunit secretion. These effects may be exerted directly at the level of the thyrotroph.

Partial peripheral resistance to thyroid hormone

A 33 year old partially thyroidectomized woman was euthyroid when ingesting 500 μg of L-triiodothyronine (T 3) daily. Her condition was evaluated during therapy with daily T 3 doses between 50 and 500 μg. She was hypothyroid and had a markedly subnormal oxygen consumption rate when taking 50 to 100 μg T 3 daily, and oxygen consumption did not increase greatly above predicted normal values despite serum T 3 concentrations up to 3,200 ng/dl. Her pulse rate, blood pressure, systolic time intervals and exercise tolerance changed minimally and remained within the normal range during the different dosage schedules. Urinary creatine and hydroxyproline, indices of muscle and skeletal protein catabolism, increased normally with higher T 3 doses, but serum cholesterol, creatine phosphokinase, calcium and alkaline phosphatase did not change substantially. Basal and thyrotropin-releasing hormone (TRH) stimulated thyrotropin secretion were suppressed during all T 3 doses. The prolactin response to TRH was normal at 50 μg T 3/day and was reduced by higher doses of T 3. Absorption of T 3, serum T 3 protein binding and T 3 metabolic clearance rates were all within normal limits. The findings in this patient are compared to clinical and biochemical findings in 17 previously described patients. The manifestations of peripheral thyroid hormone resistance are quite variable in the organ systems involved and in the degree of involvement. The molecular basis of the abnormality in our patient remains undefined.