Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease

Non-thyroidal illness syndrome (NTIS) is frequently detected in chronic, systemic diseases. The objectives of the current study is to assess the alterations of thyroid hormones during exacerbation period, recovery of exacerbation and stable phase of chronic obstructive pulmonary disease (COPD) and correlates of these hormonal alterations. A total of 83 stable COPD patients, 20 patients with acute exacerbation and 30 control subjects were evaluated. TT3, fT3, TT3/TT4 levels of both stable and exacerbation COPD groups were lower than control subjects. TSH was also decreased during exacerbation period. In follow-up of COPD exacerbation group, TSH, TT3, fT3 and TT3/TT4 were found to be increased in measurements on the day of discharge from hospital and after 1 month, compared to baseline values. TT3 and TT3/TT4 were lower in severe COPD; whereas TSH, fT3, TT3 and TT3/TT4 were lower in patients with severe hypoxemia. IL-6 and TNF-alpha were higher in both stable and exacerbation phase COPD groups and IL-6 was correlated to TT3 in stable COPD. As a result, there are significant alterations in thyroid hormones of stable COPD patients, which are related to severity of disease and hypoxemia. The hormonal changes are more significant during exacerbation and partially regress after 1 month when the disease is stabilized. We conclude that COPD patients should not be evaluated for thyroid disease during exacerbation of the disease, and thyroid function alterations during stable phase of the disease should be considered cautiously, since thyroid function abnormalities in non-thyroid illness may mimic or mask biochemical abnormalities observed in true thyroid disease.     

Effects of small doses of bovine TSH on serum levels of free and total thyroid hormones, their degradation products, and diiodotyrosine

Bovine TSH was administered iv to 10 normal volunteers in doses of 2.5, 7.5, 15 and 30 mU/kg. Brisk elevations of serum diiodotyrosine occurred already after the smallest dose (mean, +183%) while larger doses had only slight additional effects. T3 rose much higher than T4 (+71% compared to +23% after 15 mU bTSH/kg), and free thyroid hormones exhibited changes similar to total T3 and total T4. The mean absolute increase in serum fT3 ranged from 2.03 to 9.04 pmol/l and proved to be an easily measurable parameter for the TSH effect. Dose-response effects were seen for the increase of fT4, fT3 and T3. TBG and rT3 did not change but the degradation product 3,3'-T2 showed large increments of serum levels. There was no correlation between the response of T3 and T4, fT3 and fT4, or diiodotyrosine and any of the other parameters of thyroid function. The interindividual differences in the magnitude of thyroid hormone response to TSH were considerable, and there was no relationship between this response and thyroid volume by ultrasound. We conclude that direct stimulation of the thyroid gland with bTSH in small doses leads to consistent increases of thyroid hormones, especially T3 and fT3, that the response varies between individuals, and that the precursor diiodotyrosine is released together with thyroid hormones.     

Dynamics of serum thyrotropin and thyroid hormone changes in fasting

This study was designed to address the question of whether decreased hypothalamic TRH secretion was responsible for the transient decline in serum TSH levels characteristic of the early phase of fasting in man. Changes in serum TSH, total T4 (TT4), free T4 (FT4), and total T3 (TT3)/TT4 and total rT3(TrT3)/TT4 ratio values together with plasma TRH levels were evaluated before, during, and after a constant 48-h infusion of either TRH (75 ng/min), or saline, initiated at 10 h into a 6-day fast, in groups of six ambulating, mildly obese female subjects. On the first day of the fast, no change in serum TSH levels was seen with saline infusion relative to control, whereas mean TSH levels rose 2 1/2-fold with TRH infusion. On the second day of the fast, serum TSH levels simultaneously declined in both the saline- (43%, P less than 0.005) and TRH- (52%, P less than 0.005)-infused groups relative to the previous day. On the third day of the fast, after stopping the infusions, mean serum TSH levels fell below control in both the saline- and TRH-treated groups, but subsequently returned to prefasting levels. A distinct circadian pattern of TSH release was present throughout the study. Plasma TRH values were unaffected by fasting in the saline-infused group, but rose 2 1/2-fold in the TRH-infused group. The sequence of changes in the serum thyroid hormone indices were similar for the two groups: a rapid rise in FT4 was followed by a gradual fall in TT3/TT4 ratios during the first 24 h of fast, which was followed by a rise in TrT3/TT4 ratios after 48 h of fast. This study in fasting, mildly obese females suggests that: 1) The transient suppression of serum TSH during early fasting is not TRH mediated. 2) Fasting does not alter plasma TRH levels. 3) A temporal sequence of changes in serum thyroid hormone indices occurs in fasting, this being an initial rise in FT4 (10 h) followed by a fall in both serum TT3/TT4 (12-14 h) and TSH (30-36 h) and finally by a rise in TrT3/TT4 levels (48 h). This sequence of events suggests that the initial inhibition of serum TSH levels in early fasting results from the acute elevation in FT4 levels, and that the reestablishment of normal serum TSH levels with continued fasting is associated with declining serum TT3 levels.     

Lack of Association Between Peripheral Activity of Thyroid Hormones and Elevated TSH Levels in Childhood Obesity

Ob­jec­ti­ve: An elevated thyroid stimulating hormone (TSH) level is a frequent finding in obese children, but its association with peripheral hormone metabolism is not fully understood. We hypothesized that in obesity, the changes in thyroid hormone metabolism in peripheral tissues might lead to dysregulation in the thyroid axis. The purpose of this study was to investigate the association of TSH with thyroid hormones in a group of obese children as compared to normal-weight controls.Methods: Serum TSH, free thyroxine (fT4) and free triiodothyronine (fT3) levels were measured in 101 obese children and in 40 controls. Serum reverse T3 (rT3) levels were also measured in a subgroup of 51 obese children and in 15 controls. Results: Serum TSH level was significantly higher in obese children compared to controls (2.78 vs. 1.99 mIU/L, p<0.001), while no difference was found in fT4, fT3, rT3 levels and in fT3/rT3 ratio. In the obese group, fT3 level positively correlated with fT4 (r=0.217, p=0.033) and inversely with rT3 (r=-0.288, p=0.045). However, thyroid hormone levels and TSH levels were not correlated. Conclusion: In obese children, normal fT4, fT3 and rT3 levels suggest an undisturbed peripheral hormone metabolism. These levels show no correlation with elevated TSH levels.     

Are endogenously lower serum thyroid hormones new predictors for thyroid malignancy in addition to higher serum thyrotropin?

It is well known that TSH plays a major role in the secretion of thyroid hormones, maintenance of thyroid specific gene expression, and gland growth. In this study, we aimed to evaluate association between tests of thyroid functions (fT3, fT4, TSH) and differentiated thyroid carcinoma. 441 patients operated for nodular goiter between 2005 and 2008 were analyzed. Thyroid functions were studied in the period of 1-30 days prior to surgery. In postoperative histopathological examination, differentiated thyroid carcinoma and benign thyroid disease were detected in 166 (37.6%) and 275 (62.4%) patients, respectively. Patients with thyroid malignancy had significantly lower serum fT3 (P = 0.001), lower fT4 (P = 0.022), and higher TSH levels (P < 0.001) compared to patients with benign disease, although all analytes were within the normal range. We subdivided by quartile serum fT3, fT4, and TSH in normal limits into three groups. The odds ratio (ORs) for the risk of thyroid cancer with a serum TSH between 0.63 and 1.67 μIU/ml and 1.68-4.00 μIU/ml, compared with a serum TSH between 0.40 and 0.62 μIU/ml were calculated as 2.60 (95% CIs 1.49-4.54) and 6.50 (95% CIs 3.51-12.03), respectively. There was also a greater risk of thyroid cancer in patients with fT3 levels of 1.57-3.00 pg/ml, compared with patients with fT3 levels of 3.89-4.71 pg/ml (OR 2.95, 95% CIs 1.68-5.20). For fT4, OR for the risk of thyroid cancer between 0.85 and 1.17 ng/dl compared with 1.48-1.78 ng/dl was 2.14 (95% CIs 1.22-3.74). In conclusion, lower fT3, fT4, and higher TSH concentrations within normal limits were related with increased thyroid cancer independent from sex and nodule type. Particularly, the association between lower fT3, fT4 levels and a diagnosis of thyroid cancer is a novel finding.     

Acute and prolonged effects of insulin-induced hypoglycemia on the pituitary-thyroid axis in humans

Secretory activity of the pituitary-thyroid axis and thyroid hormone metabolism show characteristic changes in response to different stressors often referred to as the euthyroid sick syndrome. Hypoglycemia is an acute metabolic stressor inducing various neuroendocrine responses, the effects of which on pituitary-thyroid secretory activity so far have been entirely neglected. We performed stepwise hypoglycemic and euglycemic clamps each lasting 6 hours in 30 healthy men. To assess the potential influence of hyperinsulinemia on pituitary-thyroid hormone release, 2 different rates of insulin infusion were used for the clamps. During the hypoglycemic clamps, serum thyroid-stimulating hormone (TSH) concentration decreased in comparison to the euglycemic condition on average by 28% +/- 4% (P <.001), while serum concentration of free triiodothyronine (fT3), free thyroxine (fT4), and thyroxine-binding globulin (TBG) remained unchanged. The effect did not depend on the rate of insulin infusion. To assess the prolonged effect of acute hypoglycemia on pituitary-thyroid secretory activity, serum TSH and thyroid hormone concentrations were subsequently measured in another 15 healthy men before and 18 hours after 2 consecutive hypoglycemic clamps together lasting about 270 minutes. Compared with values before the hypoglycemic clamps, serum levels of TSH, fT3, and fT4 were found to be still reduced (by 44% +/- 6%, 12% +/- 2%, and 10% +/- 1%, respectively) 18 hours after the last hypoglycemic episode (P <.001 for all comparisons). The observed hormonal changes after hypoglycemia were not accompanied by any change in resting energy expenditure (REE). Data indicate acute as well as prolonged inhibitory influences of hypoglycemia on pituitary-thyroid secretory activity. The pattern of changes suggests that hypoglycemia exerts its influence primarily at a central, ie, pituitary and/or hypothalamic, site of the axis.     

High Serum Bile Acids Cause Hyperthyroidism and Goiter

Background/aims In the duodenal content reflux model of rats, we noted an elevation of serum bile acid and swelling of the thyroid gland. This study was designed to elucidate whether bile acids (BAs) also enhance thyroid function. Methods In varying lengths of period after esophago-jejunostomy without gastrectomy, which causes duodenal content reflux, rats were sacrificed and blood samples were taken from the heart for analyses of BAs and triiodothyronine (T3), thyroxine (T4), free T3 (fT3), free T4 (fT4), and thyroid-stimulating hormone (TSH) in the serum. Results Macroscopically, at 10 and 30 weeks after operation, thyroid glands in the reflux model showed a symmetric enlargement because of the presence of diffuse hypertrophy of the thyroid follicular epithelium. At both time points, no significant differences were detected in T3, T4, fT3, and fT4 levels between the reflux model and the control group, whereas, at 10 weeks after operation, the animals with the reflux showed significantly lower serum TSH levels and greater thyroid weight than those in the control group. An inverse correlation between serum BAs and TSH levels was noted in the reflux model but not in the control group. Microscopically, thyroid follicles were greater in size and number, with paler colloids in the reflux model than the control group. Conclusions The present results suggest that high serum BAs cause hyperplasia of the thyroid follicles and the reduction of TSH. The effects of BAs on thyroid hormones, thus, include the induction of overall hyperthyroidism. Therefore, the strict monitoring of serum TSH levels is of vital importance if BAs are used for the treatment of obesity.     

Hyperthyrotropinemia in obese children is reversible after weight loss and is not related to lipids

CONTEXT: There is some controversy whether T(4) treatment is indicated in obese humans with hyperthyrotropinemia. OBJECTIVE: The objective of this study was to examine whether hyperthyrotropinemia is a cause or a consequence of obesity. DESIGN: The study was designed as a cross-sectional comparison between obese and lean children and includes a 1-yr follow-up study. SETTING: The study was set in a primary care facility. PATIENTS: The patients were 246 obese and 71 lean children. Intervention: The 1-yr intervention program was based on exercise, behavior therapy, and nutrition education. MAIN OUTCOME MEASURES: The main outcome measures were TSH, free T(3) (fT3), free T(4) (fT4), high-density lipoprotein, low-density lipoprotein, and total cholesterol at baseline and 1 yr later. RESULTS: TSH (P = 0.009) and fT3 (P = 0.003) concentrations were significantly higher in obese children than in normal weight children, whereas there was no difference in fT4 levels (P = 0.804). Lipids did not correlate significantly to thyroid hormones in cross-sectional and longitudinal analyses. fT3, fT4, and lipids did not differ significantly in the 43 (17%) children with TSH levels above the normal range from the children with TSH levels within the normal range. Substantial weight loss in 49 obese children led to a significant reduction of TSH (P = 0.035) and fT3 (P = 0.036). The 197 obese children without substantial weight loss demonstrated no significant changes of thyroid hormones. CONCLUSIONS: Because fT3 and TSH were moderately increased in obese children and weight loss led to a reduction, the elevation of these hormones seems to be rather a consequence of obesity than a cause of obesity. Because fT3 and TSH were both increased in obesity and thyroid hormones were not associated to lipids, we put forward the hypothesis that there is no necessity for thyroxine treatment.     

Thyroid dysfunction in African trypanosomiasis: a possible role for inflammatory cytokines

OBJECTIVE Sleeping sickness (African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. The treatments of choice are the antiparasitic agents suramin and/or melarsoprol. Experimental infection of animals with Trypanosoma brucei results in inflammatory lesions in the pituitary and/or the thyroid gland. In biochemical terms, these animals have hypothyroidism. We evaluated the functional integrity of the hypothalamic-pituitary-thyroid axis in patients with African trypanosomiasis before, during and after specific therapy. DESIGN Prospective, controlled, cross-sectional study. PATIENTS AND MEASUREMENTS Sixty-five patients with sleeping sickness (31 female, 34 male; aged 18–66; 32 with haemolymphatic sleeping sickness receiving suramin i.v., 33 with cerebral sleeping sickness receiving melarsoprol) and 13 control subjects (6 female, 7 male; aged 21–60) were enrolled in a cross-sectional study after giving informed consent. Fourteen patients were studied shortly after admission for sleeping sickness, 19 in the middle of the course of treatment, 18 at the end of the 5-week treatment period, and 14 patients after cure. All subjects underwent a TRH stimulation test at 1200 with bolus injection of 400 μ g TRH i.v. Blood was drawn for determination of fT3, fT4, TSH, rT3, TNF-α, IL-1 and IL-6 at 0 minutes and TSH at 60 minutes. All hormones and cytokines were determined by RIA or ELISA. RESULTS Baseline TSH concentrations (mean ± SEM) were elevated in unmedicated patients with sleeping sickness compared to normal subjects (2.6 ± 0.4 vs 1.4 ± 0.2 mU7l;P= 0.01), whereas f T3 (2.7± 0.5 vs 5.8 ± 0.3 pmol/l; P= 0.0002) and fT4 concentrations (10.3 ± 1.2 vs 15.4 ± 0.8 pmol/l; P= 0.007) were low. Stimulated TSH concentrations did not significantly differ from normal controls. Reverse T3 concentration in patients with sleeping sickness were normal (2.2 ± 0.3 vs 2.4 ± 0.2 nmol/l; P= NS). During the course of treatment, baseline TSH, f T3 and fT4 concentrations slowly returned to normal and were indistinguishable from controls after cure. Plasma concentrations of TNF-α (16.0 ± 4.1 vs 2.9 ± 1.4 ng/l in controls; P=0.003) and interleukin-6 (19.2 ± 7.3 vs 1.3 ± 0.2 ng/l; P= 0.0001), but not interleukin-1β (2.0 ± 0.2 vs 0.9 ± 0.2, ng/l P= NS), were elevated, when thyroid function impairment and disease activity were at their maximum, but gradually decreased into the normal range with therapy. We found a negative correlation between baseline cytokine concentrations and fT3 concentrations (TNF-α: r= 0.34, P= 0.003; IL-6: r=–0.43, P= 0.0001). CONCLUSIONS We conclude that unmedicated sleeping sickness is associated with significant impairment of thyroid function, which is reversed with specific therapy. Elevated TSH concentrations and low f T3 and f T4 concentrations suggest primary hypothyroidism in patients with sleeping sickness. However, an additional pituitary and/or hypothalamic component cannot be excluded. This impairment may be due to the elevated plasma cytokine concentrations found in these patients or may be the result of parasitic thyroiditis.     

Thyroid hormones, dementia, and atrophy of the medial temporal lobe

CONTEXT: Thyroid function has been related to Alzheimer disease (AD), but it remains unclear whether thyroid dysfunction results from or contributes to developing AD. OBJECTIVE: The objective of the study was to determine the association between thyroid function and both medial temporal lobe atrophy on brain magnetic resonance imaging (MRI) as putative early sign of AD and risk of dementia. DESIGN AND PARTICIPANTS: This was a population-based cohort study among 1077 elderly subjects aged 60-90 yr and dementia free at baseline (1995-1996). MAIN OUTCOME MEASURES: Nonfasting serum levels of TSH, free T(4) (fT(4)), T(3), and rT(3) were available in 1025 subjects followed up for incident dementia until 2005. In a subset of 489 nondemented elderly, we assessed volumes of the hippocampus and amygdala on brain MRI. Subjects using thyroid medication were excluded. RESULTS: During 5657 person-years of follow-up (mean 5.5 yr), 63 subjects were diagnosed with dementia (46 with AD). TSH and thyroid hormones were not associated with risk of dementia or AD. TSH and T(3) were also not related to brain atrophy, whereas nondemented subjects with higher fT(4) levels had more hippocampal and amygdalar atrophy on MRI. Similar associations were found for rT(3). Excluding subjects with thyroid disorders or incipient AD did not change the results. CONCLUSION: In our study, TSH was related neither to risk of AD nor with early MRI markers thereof, arguing against an important role of thyroid function in the development of AD. Whether the association of higher fT(4) and rT(3) levels with brain atrophy on MRI has functional significance remains to be elucidated.     

Schilddrüsenfunktion nach Gabe jodhaltigen R?ntgenkontrastmittels bei Koronarangiographie - eine prospektive Untersuchung euthyreoten Patienten

In a prospective study, thyroid metabolism in 102 patients undergoing diagnostic coronary angiography was investigated, stratified for thyroid morphology. The thyroid function serum parameters "TT3, rT3, TT4, fT4 and TSH" and the urinary iodine excretion were measured before and three weeks after diagnostic intraarterial administration of the iodine-containing contrast agent. Only patients with euthyroid function were included in order to answer the questions whether or not the administration of non-ionic iodine containing contrast medium leads to significant thyroid function changes in euthyroid patients and whether thyroid morphology is a prognostic factor for the risk of developing hyperthroidism. Serum concentrations of thyroid autoantibodies (TPO-Ab, Tg-Ab, TSH-receptor-Ab) were measured and thyroid ultrasound was performed. According to the ultrasound findings, 4 morphologic groups were formed: normal thyroid glands (n = 37), normal sized but nodular glands (n = 16), diffuse goiter (n = 15) and nodular goiter (n = 34). Twenty-five patients were positive for Tg-Ab; TPO-Ab were found in 13 patients. TSH-receptor-Abs were not detected in all patients. TT3 levels did not significantly change after iodine application (p = 0.30). TT4 and fT4 levels showed significantly different alterations in the 4 groups (fT4 p < 0.001). The amount of iodine given did not influence alteration of serum concentrations of TSH (p = 0.67), TT3 (p = 0.68), TT4 (p = 0.37), fT4 (p = 0.92) and rT3 (p = 0.81). Elevated levels of urinary iodine excretion correlated with the amount of contrast medium given (p = 0.087). Albeit there was a high number of nodular transformed glands and goitrous patients included, and our cohort was recruited in an iodine deficient area, we did not observe hyperthyroidism in any patient. However, thyroid function parameters are significantly altered after coronary angiography independent of antibody status and the amount of contrast agent given, but dependent on thyroid morphology.     

Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat.

We studied the effects of continuous administration of recombinant human interleukin-1 beta (IL-1) on pituitary-thyroid function. Rats were equipped with minipumps loaded with either IL-1 (delivery rate, 0.5, 2.0, or 4.0 micrograms/day, ip, for 1 week) or saline. Infusion of 2.0 and 4.0 micrograms IL-1/day caused a significant decrease in plasma free T4 levels during the first 2-4 days, whereas plasma total T4 levels and T4 binding were significantly lowered throughout the week of the study. The infusion of 0.5 micrograms IL-1/day did not significantly change plasma TSH or total and free T4 levels. During the infusion of 2.0 micrograms IL-1/day, the decrease in plasma free T4 levels was paralleled by a significant decline in plasma TSH values and an impaired TSH responsiveness to TRH administration on the second day of infusion. IL-1 (2.0 micrograms/day) treatment significantly lowered plasma levels of T4-binding prealbumin, whereas it did not influence the plasma T3/T4 ratio or hepatic 5'-deiodinase activity. Plasma rT3 levels remained undetectable in both control and IL-1-treated rats. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at the lower doses of IL-1, temperatures were elevated only on the first 2 days. IL-1 at doses of 2.0 and 4.0 micrograms/day induced a transient decrease in food intake and a suppression of body weight gain. Restriction of food consumption to the level observed in the 2.0 micrograms IL-1 experiment caused small decreases in T3, total and free T4, and TSH levels compared to those in ad libitum fed rats, but had no effects on T4 binding. We conclude that 1) continuous infusion of rats with 2.0 and 4.0 micrograms IL-1/day induces changes in thyroid economy commonly seen during infectious diseases and other systemic illnesses in rats [decreased plasma levels of TSH, T3, and (free) T4; diminished T4 binding; and decreased plasma T4-binding prealbumin levels], 2) the decrease in food intake during IL-1 treatment cannot completely explain the observed changes in thyroid hormone and TSH levels; and 3) it is highly unlikely that the decrease in thyroid hormone binding during chronic IL-1 infusion is caused by decreased food intake. Further studies are needed to clarify whether the observed alterations in thyroid economy during IL-1 infusion reflect direct effects of IL-1 per se or indirect effects caused by the mild illness induced by the cytokine.     

Smoking and early pregnancy thyroid hormone and anti-thyroid antibody levels in euthyroid mothers of the northern Finland birth cohort 1986

Background: Smokers in the general population have lower thyrotropin (TSH) and higher free triiodothyronine (fT3) and free thyroxine (fT4) concentrations, but the results in pregnant population vary from no effect to a decrease in TSH and fT4 concentrations and an increase in fT3 levels. Our objective was to further evaluate the question of whether there is an association between smoking, before and during pregnancy, with maternal thyroid function during pregnancy and with the risk for subsequent hypothyroidism. Methods: Our study population was a prospective population-based cohort (N=9362), the Northern Finland Birth Cohort 1986, with extensive data throughout gestation. The mothers underwent serum sampling in early pregnancy. The samples were assayed for TSH, fT3, fT4, thyroid-peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Abs) (n=5805). Mothers with thyroid dysfunction diagnosed before or during pregnancy were excluded, leaving 4837 euthyroid mothers. The smoking status of mothers and fathers were requested by questionnaires during pregnancy. Subsequent maternal morbidity relating to hypothyroidism 20 years after the index pregnancy was evaluated using national registers. Results: Euthyroid mothers who smoked before, or continued smoking during first trimester of pregnancy, had higher serum fT3 (p<0.001) and lower fT4 (p=0.023) concentrations than nonsmokers. Smoking in the second trimester was associated with higher fT3 (p<0.001) concentrations, but no difference in fT4 concentrations compared with nonsmokers. TG-Abs were less common among smoking than nonsmoking mothers (2.5% vs. 4.7%, p<0.001), but the prevalence of TPO-Ab was similar. Paternal smoking had no independent effect on maternal early pregnancy thyroid hormone or antibody concentrations. The risk of subsequent maternal hypothyroidism after follow-up of 20 years was similar among prepregnancy smokers and nonsmokers. Conclusions: In euthyroid women, smoking during pregnancy was associated with higher fT3 levels and lower fT4 levels; possibly reflecting smoking-induced changes in peripheral metabolism of thyroid hormones. No differences were found in TSH concentrations between smokers and nonsmokers. Our results differ from those of the general population, which usually have shown smoking-induced thyroidal stimulation. This is possibly due to pregnancy-induced changes in thyroid function. Decreases in fT4 levels among smokers might predispose to hypothyroidism or hypothyroxinemia during pregnancy. Despite these changes in thyroid function, smoking did not increase the woman's risk of subsequent hypothyroidism.     

Clinical importance of the level of the free fraction of thyroid hormones

The physiologic importance of the free fraction of thyroid hormones is well accepted for some time. The determination of free thyroid hormones plasma levels by column chromatography and radio-immunoassays has been tested in our laboratory since november 1980. Six hundred and ten patients have been submitted to a precise anamnesis, a clinical examination and a thyroid investigation by scintigraphy and echography. We have compared the following parameters: T4 and fT4, T3 and fT3, TSH, TBG in euthyroidism and in the pathologic status of hyperthyroidism, we have found an excellent correlation (r greater than 0,9) between the values of T4 and T3 and their free fraction. The determination of fT3 and fT4 seems to be specially interesting in comparison of the T4 and T3 because of the low incidence of false abnormal results in those patients regarding the other parameters. Hyperthyroidism is characterized by a lack of correlation between total and free hormones; the levels of the free fraction being widely increased. The determination of the free hormones levels improves the sensitivity and the accuracy of the diagnosis of hyperthyroidism. It permits an early diagnosis of the disease, an earlier detection of the recurrence and makes easier the follow-up of the treated patients. In hypothyroidism, there is a so light decrease in the value of fT3 and fT4 that the TSH estimation remains the method of choice to assure the diagnosis. Thus, we can conclude that the determination of fT3 and fT4 by column chromatography and radio-immunoassays is more discriminating in euthyroidism and hyperthyroidism. In hypothyroidism TSH and fT4 are the most sensitive parameters.     

Serum concentrations of thyrotropin, thyroxine, triiodothyronine and thyroxine binding globulin in female endurance runners and joggers

The effects of endurance training and season on the function of the anterior pituitary-thyroid axis were studied in 18 female runners and their 12 controls, and in 13 joggers and their 11 controls in Northern Finland, with a large seasonal difference in environmental factors. The serum concentrations of thyrotropin (TSH), thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), thyroxine binding globulin (TBG) and oestradiol (E2) were measured during one menstrual cycle in the light training season (autumn) and in the hard training season (spring). The responses of TSH to intravenous TRH stimulation were also measured in the luteal phase of the cycle during the hard training season. Endurance running did not affect the basal or TRH-stimulated serum TSH concentrations, while those of T4 and fT4 in runners were lowered in both seasons and that of T3 in the light training season in relation to control subjects. The serum concentrations of TBG were also significantly lower in runners than their controls in the luteal phase in both seasons. The effect of jogging on thyroid hormones was less pronounced. Serum concentrations of TSH, T4, fT4, T3 and TBG were generally slightly higher in spring than in autumn. Strenuous endurance training seems to have minor changes on the function of the thyroid gland. Depressed T4 levels in runners may rather be due to lowered TBG levels than due to direct effect of training. In spring the function of anterior pituitary-thyroid axis is more active than in autumn.     

PRIMARY HYPOTHYROIDISM WITH GROSSLY ELEVATED PLASMA TOTAL THYROXINE AND TRIIODOTHYRONINE LEVELS

In an elderly patient with clinical primary hypothyroidism and a raised basal TSH, the serum free thyroxine (fT4), total thyroxine (TT4) and triiodothyronine (TT3) were consistently and paradoxically grossly elevated when measured by radioimmunoassay. In part these hormone levels were due to a high titre of endogenous IgG immunoglobulins which bound T4, T3 and reverse T3 (rT3) and thus caused gross interference in the radioimmunoassays. However, when this methodological interference was removed by using a methanolic extract of the patient's serum, the concentrations of TT4 and TT3 were still grossly elevated. It was only when basal TSH and the concentration of fT4 and fT3 were measured by equilibrium dialysis that these hormone levels were found to be consistent with primary hypothyroidism.     

Thyreopathy in primary care

Thyroid gland disorders, as the core of all endocrinopathies, affect 5-7% of the population of the Czech Republic, with women being affected 6-8 times more often than men. Clinically, thyreopathies are divided into hormonal production disorders and morphology disorders. Thyroid hormones fT3, fT4 and TSH serum levels determine the diagnosis of a thyroid gland disorder. Primary hypothyreosis is characterized by reduced fT4 and increased TSH. Low T3 syndrome is a protective reaction of the organism and is associated with conversion of T4 into hormonally inactive triiodothyronine (rT3). Primary hyperthyreosis is characterized by higher fT4 and low TSH levels. Acute thyreoiditis: Inflammatory signs and normal thyroid function, anti-TPO as well as anti-TG are not elevated. Subacute thyreoiditis is manifested as an inflammation, normal anti-TPO and anti-TG, sometimes also hyperthyreosis. Chronic thyreoiditis, Hashimoto's struma is among the most frequent causes ofhypothyreosis in the Czech Republic and it is diagnosed through high anti-TPO and anti-TG levels and higher TSH. Thyreoidal adenomas and carcinomas are clinically usually euthyroid. Determination of tumour markers - thyreoglobulines in papillary and follicular carcinomas and calcitonin in medullar carcinoma that requires genetic assessment (determination of germinal mutations, usually with PCR)--is essential.     

Leptin, thyrotropin, and thyroid hormones in obese/overweight women before and after two levels of energy deficit

The aim of our study was to compare serum concentration of leptin and pituitary-thyroid axis hormones in obese/overweight women before and after two levels of energy deficit with those parameters in lean women on adequate energy intake. Additionally, we attempted to elucidate if the effect of weight reduction could be related to anthropometric and hormonal parameters before treatment. Anthropometric and hormonal parameters—serum leptin, TSH, T4, fT4, T3 and leptin to fat mass (Lep/fm), T3/T4, fT4/T4, T4/TSH, fT4/TSH—were compared in two groups of women (n=18 each)—lean women (C: BMI 22.0±1.2) and overweight/obese (Ov/Ob: BMI 29.9±3.3). Ov/Ob women were subjected to weight-reducing treatment consisting of energy intake equal to 80% of calculated total energy expenditure for the first 4 wk and to 50% for subsequent 4 wk. All baseline hormone concentrations, Lep/fm, and fT4/T4 were higher in overweight/obese group. After 20% energy deficit decrease in BMI, percent body fat (fm%), leptin, T3, and TSH serum concentrations as well as in Lep/fm and T3/T4 was observed; T4/TSH increased, fT4, fT4/T4 and fT4/TSH did not change significantly. Increase in energy deficit from 20% to 50% resulted in normalization of Lep/fm, on the other hand, it provoked greater decline in thyroid hormone plasma concentration, which could hinder further mass reduction. Leptin and TSH levels were positively correlated after 50% energy deficit treatment. Changes in fm% were directly related to baseline T4/TSH, fT4/TSH, and log TSH. In conclusion, TSH serum concentration and its ratio to T4 and fT4 before weight reduction could be a good predictor of successful weight loss.     

Study of the pituitary-thyroid functions at high altitude in man.

The alterations in serum levels of T3, T4, TSH and TBG, TSH response to 100 mug iv TRH, and urinary excretion of T3 and T4 were studied in 8 healthy men at sea level (SL), on days 1, 2, 4, 8 and 16 after arrival by air at high altitude (3,700 m, HA), and during days 5 to 7 after their return to SL. No significant alterations in serum levels of TSH and TBG or TSH response to TRH were observed during exposure to HA or on return to SL. There was, however, an acute elevation in both serum total T3 and T4. Serum total T3 from a mean basal+/-SE value of 128+/-13 ng/dl increased to 320+/-18 on day 1 and remained significantly elevated at 225+/-48 up to day 8 after arrival at high altitude. Similarly serum total T4 increased from basal level of 9+/-0.92 mug/dl to 15.2+/-1.2 and remained elevated till day 16 and it was 11+/-1.19 mug/dl during days 5 to 7 after return to SL. The urinary excretion of both T3 and T4 was decreased. These changes perhaps were the result of complex physiologic adjustments on acute exposure to high altitude, like shrinkage of the T3 and T4 distribution pools, altered binding capacities of thyroid hormones binding proteins, and a reduction in clearance of thyroid hormones from the plasma compartment; and were probably not suggestive of an enhanced thyroid activity. Their actual significance in high altitude adaptation in man is not clearly understood.     

Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide).

Alkylating drugs (cyclophosphamide and ifosfamide) have been in clinical use for the treatment of malignant diseases in the past. They are most useful anticancer agents and cyclophosphamide is also widely used for its immunosuppressive properties. However the effect of alkylating drugs on thyroid hormone parameters have not been evaluated so far. Three groups of patients were prospectively evaluated: Group I: 15 patients with Wegener's granulomatosis and 4 patients with severe scleritis received a single dose cyclophosphamide (15 mg/kg bw/day) and 250 mg prednisone i.v. Group II: 9 patients with malignant lymphomas were treated according to the IMVP 16-protocol. Patients received daily ifosfamide 1000 mg/m2 from day 0 to 4 and vepesid from day 0 to 2. Patients did not receive corticosteroids additionally. Group III: 6 patients with a relapse of malignant lymphomas received ifosfamide 1.500 mg/m2/day from day 0 to 4 i.v. and dexamethasone 40 mg/m2 as well as ara-c and etoposid. All patients received mesna to prevent hemorrhagic cystitis and odansetran or metoclopramide as antiemetic drugs. Alkylating drugs were given as a one hour infusion. Thyroid hormone parameters were determined before and on day 1, 2, 3, 4 after drug administration. We observed a significant increase in T4 and fT4 concentrations and a concomitant fall in TSH in either group one day after the administration of alkylating drugs. The effect was most pronounced in group III: T4 increased from 113 +/- 8 nmol/L to 175 +/- 8 (normal: 58-154) and fT4 from 14.0 +/- 0.8 to 24.8 +/- 2.5 pmol/L (normal 10-25). TSH dropped from 1.27 +/- 0.16 to 0.33 +/- 0.07 mU/L (normal 0.3-4). All changes were significant: p < 0.001. Two of the six patients displayed biochemical hyperthyroidism. Also reverse T3 increased significantly. Two days after drug administration a gradual normalization occurred. However, T3, Tg, TBG, Transthyretin and albumin levels did not change throughout the study period. One patient with coexisting hypothyroidism, who received his last thyroxine substitution therapy one day before the administration of cyclophosphamide (as in group I), also demonstrated an increase in T4, fT4 and rT3 and a fall in TSH concentrations. I.v. administrations of cyclophosphamide and ifosfamide induce a transient increase in T4 and fT4 concentrations and a concomitant fall of TSH in the presence of normal Tg, T3 and thyroid binding protein concentrations. These data suggest, that the changes are not due to a release of thyroid hormones from the thyroid itself, but is likewise related to a release of thyroxine from cellular pools such as the liver.