Low Thyroid Hormone Research Articles

Effect of dietary protein on hepatic mitochondrial function and cardiac muscle protein turnover in uremic rats

To define the metabolic consequences of diets low in protein in chronic renal failure, young uremic and sham operated rats were fed isoenergetic diets for three weeks varying in protein content from 22% to 8% casein at the expense of carbohydrate. The results indicate that reducing casein content from 22% (control) to either 16%, 12% or 8% in uremic rats did not result in gross differences in renal function or decreases in liver weight, mitochondrial content or respiration. Atrial muscle protein synthesis was increased 26% while degradation was slightly, but not significantly, decreased in uremic and sham-operated rats fed the 8% casein diet compared to control. In both uremic and sham-operated rats fed the 8% casein diet, serum triiodothyronine (T 3) concentrations and hepatic mitochondrial glycerolphosphate (GP) shuttle activity were significantly increased while malate-aspartate shuttle activity was decreased compared to all other diet groups. The increased serum T 3 level and GP shuttle activity produced by feeding the 8% casein diet suggests a diet induced alteration in hepatic mitochondrial intermediary metabolism which may be of benefit in protecting against the potentially serious consequences of lowered thyroid hormone levels in chronic renal insufficiency.

Increased incidence of hypothyroidism in primary biliary cirrhosis.

We examined the thyroid status of 58 patients with primary biliary cirrhosis (PBC) using total serum thyroxin, thyroid hormone binding ratio, free thyroxin index, serum TSH, antithyroglobulin, and antimicrosomal antibodies. Seven patients were known to be hypothyroid prior to the diagnosis of PBC. Six additional patients were found to have biochemical evidence of hypothyroidism. The prevalence of hypothyroidism was 12% if we include only those six PBC patients with newly diagnosed hypothyroidism or 22% if we include all 13 patients. Five of the 58 patients had evidence for an elevation of thyroid hormone binding capacity. Three hypothyroid patients had normal total thyroxins with low thyroid hormone binding ratios. Two euthyroid patients had elevated total T4s with low thyroid hormone binding ratio and normal FTI. The prevalence of positive antimicrosomal antibodies was 34%, including 11 euthyroid PBC patients. The prevalence of positive antithyroglobulin antibodies was 20% including five euthyroid patients. There was no association between HLA DR3 or DR5 and the patients with hypothyroidism and/or antithyroid antibodies. Because fatigue, lethargy, and anorexia as well as hypercholesterolemia are common features of both hypothyroidism and PBC, patients with PBC should be screened for evidence of thyroid dysfunction. Thyroid disease may precede the diagnosis of PBC by several years. Therefore, the development of cholestatic liver disease in a patient with known autoimmune thyroiditis should arouse suspicion of PBC.

MEADOWFOAM (Limnanthes alba) MEAL AS A FEEDSTUFF FOR DAIRY GOATS AND TOXICOLOGIC ACTIVITY OF THE MILK

The feeding value and goitrogenicity of meadowfoam (Limanthes alba L.) meal (MFM) as a feedstuff for dairy goats and the goitrogenic and toxicologic activity of milk from goats fed the meal were evaluated. Pregnant goats were fed a diet containing 30% raw MFM beginning 12–13 wk prior to parturition. Control goats received a similar diet without MFM. At parturition, MFM-fed does had slightly lower serum thyroid hormone levels than the controls. Kids from MFM-fed does had similar serum thyroid hormone levels at birth and lower levels at weaning compared to control kids. The MFM-fed and control dams had similar thyroid hormone levels at weaning. The growth rate of kids fed MFM was lower (P < 0.05) in the postweaning period than for controls. Milk from goats fed MFM was fed to growing rabbits. Rabbits fed this milk had heavier thyroid weights and higher mortality than rabbits receiving water or milk from control goats. No difference in serum thyroid hormone levels occurred. The results suggest that raw MFM should not be fed to lactating animals until the significance of milk-transferred goitrogenic agents has been fully assessed. Key words: Meadowfoam meal, Limnanthes, goats, glucosinolates, milk, rabbits

Ultrastructural detection of the onset of pituitary thyrotroph sensitivity to lowered thyroid hormone concentrations in the fetal sheep.

The goitrogen methylthiouracil was administered orally to pregnant ewes of known gestational ages to induce hypothyroidism in both mother and fetus. Developing pituitary thyrotrophic cells were studied using electron microscopy to detect the earliest gestational age at which morphological changes occurred in response to lowered plasma thyroid hormone concentrations. At 50 days of gestation, the pituitaries of fetuses exposed to the goitrogen were indistinguishable from untreated control glands. However, at 58 days and subsequent ages, "thyroidectomy' cells were observed in pituitaries of all hypothyroid fetuses. These findings indicate that fetal sheep pituitary thyrotrophs are sensitive to lowered thyroid hormone concentrations by 58 days of gestation, suggesting that thyroid-thyrotroph interaction exists at this early stage of development.

Serum levels of calcium and parathyroid hormone after subtotal thyroid resection for Graves' disease.

The following serum constituents were measured in 19 patients operated on for Graves' disease: calcium, protein, parathyroid hormone (PTH), alkaline phosphatase, thyroxine, triiodothyronine, free thyroxine index, and thyroid-stimulating hormone. Blood was sampled systematically on the day before and 5 days, 1 month, 2, 3, 4 and 6 months after operation. All patients were pretreated with antithyroid drugs, and 2 months before surgery levothyroxine was added. The study showed that the thyroid function was impaired for 3 months postoperatively. Serum calcium level was lowered in the same period. Serum PTH increased with decreasing serum calcium, and vice versa. The results support the theory that the transient fall in serum calcium level is due to lowered PTH sensitivity in bone tissue caused by temporary impaired thyroid function after surgery. On the other hand, a direct action of lowered thyroid hormone on bone tissue is also a possible explanation.

Thyroid activity during hepatocarcinogenesis by N-2-fluorenylacetamide.

During chemical carcinogenesis by N-2-fluorenylacetamide, the hormonal status of female Sprague Dawley rats is largely modified. Thyroids present a modified activity which is evidenced by the histological study as well as T4 and T3 assays. In hypophysis, thyrotropic cells were found in an hyperactive state, a fact which is in agreement with the changes observed in thyroid follicles size and epithelial cells demonstrating an hyperactivity of thyroid glands. Despite this histological result, T4 serum level was lowered. T3 level was also decreased but to a lesser extent. We suggest that the low thyroid hormone level play a role in the relative protection of females versus males toward liver cancer induction by chemicals.

Loss of Thyroid Hormones into Feces in Children on Regular Hemodialysis

In 20 children on hemodialysis in vitro tests of thyroid function were made. Total T4, free T4, and total T3 were below the normal mean. The daily loss of T3 into feces was significantly higher in dialysis children than in healthy controls. The loss of T4 into feces was somewhat higher in dialysis children than in healthy controls. The amount of hormonal iodine loss into feces was calculated. It was significantly higher in children on hemodialysis than in controls. It is concluded that the loss of thyroid hormones into feces is the major cause of low serum thyroid hormone levels in children on hemodialysis.

Atrial fibrillation and isolated suppression of the pituitary-thyroid axis: response to specific antithyroid therapy

Four patients are described with persistent atrial fibrillation associated with normal plasma total thyroxine (T 4) and triiodothyronine (T 3) but an absent plasma thyrotrophin (TSH) response to intravenous thyrotrophin releasing hormone (TRH). Initial cardioversion failed to establish sinus rhythm in three of the four patients. Following specific antithyroid therapy to lower thyroid hormone levels sufficient to allow a normal TSH response to TRH sinus rhythm was established in all four patients, one spontaneously and three after cardioversion. Stable sinus rhythm has persisted in three patients over a 2-yr follow-up period. In the presence of atrial fibrillation, an absent plasma TSH response to TRH should be considered sufficient grounds for antithyroid therapy even if plasma total T 4 and T 3 are within the expected normal range.

Sequential Changes in the Pituitary-Thyroid Axis during Pregnancy and Lactation in the Rat*

Dynamic changes in the pituitary-thyroid axis were studied during pregnancy and lactation by measuring plasma concentrations of TSH, T4, and T3 and the free T4 fraction (FT4F) in the rat. In contrast to human pregnancy, plasma T4 progressively decreased during the second half of pregnancy to as low as 2.6 ±0.2 /μg/dl by term compared with 6.3 ± 0.3 /μg/dl on day 0 of pregnancy (P < 0.01). Plasma T3 concentration underwent a smaller proportional decrease than plasma T4 (66.5 ± 6.2 ng/dl at day 0 vs. 44.6 ± 4.9 at term; P < 0.05). Despite the dramatic drop in T4) plasma TSH remained at normal levels until the 16th day of pregnancy, after which a slight, but significant, increase was seen. FT4F was twice as high during late pregnancy as in nonpregnant rats, but the free T4 concentration index was significantly lower. After delivery, high plasma TSH and low thyroid hormone levels persisted throughout lactation and returned to normal only after weaning. In rats whose pups were removed shortly after delivery (n...

Thyroid function tests in patients on regular hemodialysis.

Serum thyroxine (T₄), triiodothyronine (T₃), the T₃ resin uptake test (T₃RU) and TSH were measured in 85 clinically euthyroid patients on regular haemodialysis; sera were collected immediately before dialysis. 32% of patients had goitres. Serum T₃ was below the normal range in 34% and T₄ in 39%; the T₃RU was in the high normal range in most. Serum TSH was slightly elevated in 13 patients. In 20 patients dialysed for 3 months or less the serum T₄ was normal in 18 and the free thyroxine index (FTI) was normal in every case; mean T₄ and FTI values were significantly lower in patients dialysed for more than 3 months. 16 patients were studied prospectively on two occasions 14 months apart; those initially dialysed for less than 1 year showed a significant fall in mean T₄ and FTI values after a further 14 months of dialysis, while levels were unchanged in those dialysed initially for more than a year. Thyroid hormone levels were measured before and immediately after a single dialysis in 57 patients. Dialysis caused significant acute elevations of T₃, T₄, and FTI, but had no consistent effect on TSH. The TSH and prolactin responses to TRH were investigated in 18 male patients: the mean maximal TSH increment was significantly lower than in controls and peak responses were subnormal in 5 patients. Basal serum prolactin levels were elevated but peak responses were normal. It is concluded that, in patients on regular haemodialysis: (1) goitre may be frequent; (2) <i>in vitro</i> thyroid function tests were often subnormal just before a period of dialysis, but were usually normal immediately after the dialysis; (3) serum T₄ levels fall rapidly in the first year of dialysis; (4) the pituitary responsiveness to low serum thyroid hormone levels and to exogenous TRH is often abnormal in dialysed patients, although they appear to be euthyroid.

Thyroid function and lipid concentration after thyroidectomy in rats

The purpose of this study was to determine whether subjects with high serum thyrotropin (TSH) levels and low-normal serum thyroxine (T 4) levels are euthyroid, as a result of the increased TSH stimulation of the thyroid, or hypothyroid. As a model to study this clinically important problem we analyzed serum cholesterol (Chol), triglyceride (Tg), TSH, T 4, and triiodothyroxine (T 3) before and 7, 10, and 12 weeks after sham operation (SO), hemithyroidectomy (Htx), and total thyroidectomy (Ttx) in 33 male Sprague—Dawley rats. By 7 weeks after Ttx serum TSH levels increased from 861 ± 84 to 9657 ± 644 ng/ml, T 4 decreased from 3.7 ± 0.18 to 0.84 ± 14 ng/ml, and T 3 decreased from 0.317 ± 0.026 to 0.217 ± 0.007 ng/ml ( P < 0.001). Serum Chol increased from 69.6 to 112.5 mg/dl, whereas Tg decreased from 70.93 ± 3.56 to 50.54 ± 4.18 mg/dl ( P < 0.01). After Htx serum TSH levels were higher than before operation and were higher than in the SO group ( P < 0.05); serum T 4 and T 3 levels tended to be lower than before Htx and lower than in the SO group, but this decrease was only significant for both T 4 and T 3 10 weeks after operation ( P < 0.05); serum Chol and Tg levels were the same in Htx and SO animals. Thus, after Ttx (1) serum T 3 and T 4 levels decrease, (2) serum TSH levels increase, (3) serum Chol levels increase, and (4) serum Tg levels decrease. After Htx (1) serum TSH levels increase, (2) serum T 3 and T 4 levels are low-normal or slightly low, (3) serum Chol and Tg levels are normal. It appears that increased TSH stimulation of the thyroid gland can maintain normal serum lipid levels in the presence of low-normal or slightly low thyroid hormone concentrations. Thus, animals with increased serum TSH levels and low-normal or slightly low thyroid hormone levels are either not hypothyroid or serum lipid levels are an insensitive indicator of hypothyroidism.

Neonatal thyroid function in fullterm, small-for-gestational-age and premature newborns

A two-year experience in screening for congenital hypothyroidism has shown new problems concerning evaluation of borderline values especially in prematures. In order to elucidate neonatal thyroid status we examined TSH, T4, T3,reverse T3(rT3) and TBG in 80 full-term(FT),20 small-for-gestational-age(SGA) and 70 pre-mature(P) newborns. Approved by our local ethical committee, blood was drawn together with clinically indicated blood examinations between 5th and 30th day of life.RESULTS: TSH(2,9 uU/ml)did not differ from FT in SGA and P. T4,T3,rT3 and TBG-levels rose with gestational age: T4 89-120ng/ml; T3 1,4-1,7ng/ml; rT3 0,54 - 1,38ng/ml; TBG 23,7-27,3mg/l. FT-values were reached by P at a “gestational” age of 40-42 weeks. There is no difference between SGA and FT. CONCLUSION: Relatively low TBG-levels and a supposed immaturity of thyroid gland seem to account for lowered peripheral thyroid hormones in P. This assumption is supported by the absence of TSH-stimulation of thyroid gland developmentin P in spite of low circulating thyroid hormones.

Effects of age and ovarian function on the pituitary-thyroid system in female rats.

SUMMARY The effects of ovariectomy and ovariectomy and treatment with oestradiol benzoate (OB) on the basal concentration of thyrotrophin (TSH), the total concentrations and concentrations of free tri-iodothyronine (T3) and thyroxine (T4), and the concentrations of TSH, T3 and T4 observed after treatment with thyrotrophin releasing hormone (TRH) were studied in old (16–17 months of age) constant oestrous and young (3–4 months of age) oestrous rats. The untreated old control rats had significantly (P&lt; 0·001) lower basal total T4 concentrations and percentage and absolute concentrations of free T4 and lower percentage and absolute concentrations of free T3 than untreated young rats. The basal levels of TSH in these two groups were similar and the increases in TSH after injection of TRH were identical. Two weeks after ovariectomy, no significant additional differences in hormone concentrations between old and young rats were observed. However, release of TSH induced by TRH was increased by three- to fourfold in old rats after ovariectomy compared with nine- to tenfold in young ovariectomized rats (P&lt;0·01). Basal T4 concentrations remained unchanged in old ovariectomized rats treated for 7 days with 2 μg OB/day compared with both intact and ovariectomized rats. However, T4 concentrations in OB-treated young rats were significantly (P&lt;0·001) reduced. Treatment with OB significantly increased both basal and TRH-induced T3 and TSH levels in old and young rats although the young rats showed a greater response (P&lt;0·001). Two hours after injection of TRH, serum T3 concentrations in old rats increased only after OB treatment and not after ovariectomy alone or in intact rats, whereas T3 concentrations rose in all three groups of young animals. These results indicate that (1) older female rats have lower total T4, free T4 and free T3 concentrations and a lower TSH response to TRH, (2) OB treatment in young rats suppresses serum T4 but increases serum T3 and results in a greater TSH response to TRH and (3) at least one of the mechanisms accounting for the alterations in thyroid function observed in the older female rat, in addition to possible concomitant primary thyroid gland hypofunction, is a hyporesponsiveness of pituitary thyrotrophs to both endogenous negative feedback signals from low serum thyroid hormone concentrations and exogenous TRH stimulation.

The relationship between levels of thyroid stimulating hormone and of thyroxine and triiodothyronine in blood of hypothyroid patients.

Serum TSH values and the free concentration of T4 and T3 in serum expressed as the free T4- and T3-indices showed a curvilinear relationship in 24 patients with manifest hypothyroidism mainly due to extremely elevated serum TSH levels associated with very low thyroid hormone levels. The same degree of negative correlation was found between the log serum TSH concentration and serum free T4-index (r = -0.51, P less than 0.05) and between log serum TSH concentration and serum free T3-index (r = -0.47, P less than 0.05). The correlation coefficients dropped to non-significant levels when the interdependence between the free T3- and T4-indices was taken into account and eliminated by partial correlation analysis. The degree of negative correlation between serum TSH and the thyroid hormones was also of the same order of magnitude in 5 hypothyroid patients studied prosepctively during treatment with L-thyroxine (TSH vs. T4: mean r = -0.71; TSH vs T3: mean r = -0.79).

Parathyroid cysts

Cystic neck masses may be accurately diagnosed by sonography, and some nonfunctioning parathyroid cysts can be cured by percutaneous aspiration. Primary hyperparathyroidism should be considered in all patients with cystic neck masses. Parathyroid cysts can often be recognized from the characteristics of the cyst fluid which is usually clear and colorless, contains elevated parathyroid hormone levels and normal or low thyroid hormone levels, and may contain parathyroid cells. Parathyroid cysts may be multiple; all four parathyroid glands should therefore be identified and appropriately removed or hyperparathyroidism may persist.

Lower serum TRH degradation in chronic renal failure (CRF) in children

Two CRF patients groups were studied, one subjected to periodical hemodialysis (CRF-H) (n=13), and the other not (CRF) (n=10),and were compared with normal controls (C) (n=8). Basal serum T4 and T3 levels both in CRF and CRF-H were significantly decreased in either group versus C, while TSH levels were not significantly different. There were not differences in either group in the TSH and prolactin response peak to a 200 ug load of TRH, but serum TSH and prolactin 1 evels were significantly higher in CRF and in CRF-H than in C at 90 and 120 min. Serum RIA-TRH levels were serially determined after the TRH load; TRH levels in patients were significantly higher than in C until 30 min. Sera from CRF-H patients incubated with TRH showed significantly slower TRH disappearance than in C, starting from 7 min. This decreased TRH degradation could be related with the low thyroid hormone levels in these patients.

The influence of hypophysectomy on NSILA concentrations in the dog: evidence for partially pituitary-independent regulation.

Non-suppressible insulin-like activity (NSILA) was determined in 5 dogs before and after hypophysectomy. All NSILA determinations were carried out on serum samples after acidic Sephadex G-50 chromatography by two different assay systems, i.e. a bioassay and a protein binding assay. The levels of NSILA decreased significantly after hypophysectomy and returned to near normal levels after 2 weeks. T3-, T4- and cortisol levels were drastically reduced during the entire period of the experiment. Several GH determinations after hypophysectomy revealed very low levels. Insulin-induced hypoglycaemia failed to provoke a rise of GH levels as late as 4 months after hypophysectomy. These findings indicate that: 1) The pituitary gland cannot be the site of synthesis of NSILA. 2) NSILA concentrations in the dog are maintained at a near normal level in the presence of very low growth hormone and thyroid hormone concentrations, so that these latter hormones do not appear to be the only regulatory factors concerned in NSILA synthesis.

Thyroid hormone controls glucocorticoid action in cultured GH1 cells

WE have demonstrated that L-triiodothyronine (T3) stimulates growth hormone synthesis three to four-fold1–3 and inhibits prolactin secretion1 in cultured GH1 cells, which constitute a rat pituitary cell line. Others have shown that cortisol also stimulates growth hormone production in GH1 cells4. In GH3 cells, a closely related cell line, cortisol stimulates growth hormone production four- to eightfold and inhibits prolactin secretion approximately fourfold5. Thus, thyroid and glucocorticoid hormones seem to control similar growth hormone and prolactin responses in GH1 and GH3 cells. Studies of the effects of glucocorticoids in these cell lines4,5, however, have used commercial serum preparations containing physiological concentrations of thyroid hormone6. To examine the intrinsic response of these cells to glucocorticoid, therefore, it is necessary to use medium supplemented with serum which contains very low thyroid hormone levels. Using culture medium supplemented with hypothyroid calf serum, we have examined the influence of T3 and cortisol on the induction of growth hormone synthesis in GH1 cells. We report here that in the absence of T3, the cells seem unresponsive to glucocorticoids, whereas in its presence cortisol markedly enhanced growth hormone production. The apparent requirement of T3 for expression of the cortisol response seems independent of any influence of T3 on total cell steroid receptor levels or the nuclear-cytoplasmic distribution of the steroid receptor, and of any effect of cortisol in modulating the level of the T3 nuclear receptor.

Low Thyroid Hormones and Respiratory-Distress Syndrome of the Newborn

To investigate the relation between thyroid function and respiratory-distress syndrome we determined thyroid hormone in cord serum from 39 term and 120 premature newborns. In groups matched for gestational age (33 to 37 weeks) and body length, after exclusion of newborns with birth asphyxia, maternal diabetes and delivery by cesarean section, the newborns with respiratory distress syndrome had significantly lower cord tri-iodothyronine index, higher ratio of thyroxine to tri-iodothyronine and higher thyrotropin concentration than those without syndrome (P less than 0.05 or less). Conversely, the frequency and severity of respiratory-distress syndrome were higher in newborns who had low cord tri-iodothyronine and thyroxine concentration, low free tri-iodothyronine index and high thyrotropin levels. These observations show an association between low thyroid activity at birth and respiratory-distress syndrome and are in accord with animal studies showing accelerated lung maturation due to thyroxine administration.

Effect of butyldiiodohydroxybenzoate on pituitary-thyroid interplay.

The effect of BHDB, an analogue of thyroxine, on the pituitary-thyroid system was studied in the rat. BHDB produced low plasma T4 and T3 concentrations similar to those produced by methimazole, but failed to elevate plasma TSH and to produce goiter because of displacement of T4 from the binding protein. Low plasma thyroid hormone concentrations were due to an increase of fecal loss of thyroid hormones. By releasing excess iodide, BHDB blocked the development of goiter produced by methimazole.