Change in von Willebrand factor and carotid intima-media thickness in hypothyroid patients with normal thyroid function after levothyroxine replacement therapy

OBJECTIVE: This study examined whether levothyroxine (L-T4) replacement might affect serum markers of endothelium injury, including von Willebrand factor (vWF), factor VIII activity and thrombomodulin (TM), during normalization of increased intima-media thickness (IMT) in the common carotid artery (CCA) in hypothyroid patients after L-T4 replacement therapy. PATIENTS AND METHODS: Thirty-three hypothyroid patients were examined for vWF, factor VIII, TM and CCA IMT before and after 1 year of normalization of thyroid function by L-T4 replacement. CCA IMT was measured from digitized still images taken during scanning by high-resolution ultrasonography as an indicator of early atherosclerosis. RESULTS: Serum factor VIII and vWF increased significantly during 1 year of normalization of thyroid function (from 122.7+/-9.4 to 151.3+/-18.8% (P<0.05) and from 109.9+/-9.6 to 135.2+/-12.4% (P<0.005) respectively), although these values all fell within the respective normal range. Serum TM, in contrast, did not change appreciably in response to L-T4 treatment, moving from 2.57+/-0.15 to 2.74+/-0.18 ng/ml (P=0.086). During 1 year of a euthyroid state, all patients showed a significant decrease in CCA IMT (P<0.0001). Change in serum vWF, but not in factor VIII or TM, showed a positive correlation with that of CCA IMT during L-T4 replacement therapy. Furthermore, the change in serum vWF was significantly and independently associated with change in CCA IMT (r=0.490, P=0.0038). CONCLUSIONS: The present study demonstrated that the improvement of CCA IMT during L-T4 treatment might have the potential to attenuate an elevation of vWF and to attenuate vascular injury by the cardiovascular effects of thyroid hormone in hypothyroid patients.     

Alteration of plasma concentrations of OPG before and after levothyroxine replacement therapy in hypothyroid patients

OBJECTIVE: Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Hypothyroidism is associated with increased morbidity from cardiovascular disease. More recently, one study showed that plasma OPG increases significantly, and decreases markedly with levothyroxine (L-T4) replacement therapy in patients with overt hypothyroidism (oHT). The purpose of this study was to investigate the alteration of plasma OPG concentrations before and after L-T4 replacement therapy, and its association with endothelium-dependent arterial dilation in patients with oHT and subclinical hypothyroidism (sHT). MATERIALS AND METHODS: The study subjects included 20 women with oHT, 20 women with sHT, and 20 healthy women. All patients were then given L-T4 therapy individually to maintain all serum free T3 (FT3), free T4 (FT4), and TSH near or within the respective normal ranges. Plasma OPG concentration was measured in duplicate by a sandwich ELISA method. RESULTS: Plasma OPG levels in oHT and sHT patients before treatment were 3.13 +/- 0.27 and 2.95 +/- 0.24 ng/l, respectively, which were significantly higher than that in controls (2.42 +/- 0.26 ng/l) (p = 0.000). In multivariate analysis, OPG was significantly associated with TSH (r = 0.306, p < 0.05) and endothelium-dependent arterial dilation (r = -0.675, p < 0.01) at baseline. After normalization of thyroid function, OPG levels in both groups decreased markedly (2.53 +/- 0.28, 2.54 +/- 0.21 ng/l) (p = 0.000), and were very close to that in controls. The absolute changes in OPG showed significant positive correlation with the changes in TSH (p < 0.05) and negative correlation with the changes in endothelium-dependent arterial dilation (p < 0.01), and no significant correlation with other parameters in hypothyroid patients during the course of treatment. CONCLUSION: The plasma OPG levels were significantly increased from hypothyroid patients, and were close to those of control subjects after normalization of thyroid function, indicating that OPG acts as an important regulatory molecule in the vasculature and, particularly, that it may be involved in the development of vascular dysfunction in hypothyroid patients.     

Changes in plasma concentrations of osteoprotegerin before and after levothyroxine replacement therapy in hypothyroid patients

CONTEXT: Recent study has shown that overt hypothyroidism (oHT) is associated with increased plasma osteoprotegerin (OPG) levels. OBJECTIVE: Our objective was to examine the plasma OPG level alteration before and after levothyroxine (L-T4) treatment in oHT and subclinical hypothyroidism (sHT). PATIENTS: The study subjects included oHT and sHT patients and healthy individuals (20 subjects in each group). METHODS: All patients were given L-T4 therapy to maintain a euthyroid state. Plasma OPG concentration was measured in duplicate by a sandwich ELISA. RESULTS: Plasma OPG levels in oHT and sHT before treatment were significantly higher than levels in controls (P < 0.01). After normalization of thyroid function, OPG levels in both groups decreased markedly (P < 0.01). The absolute changes in OPG showed a significant positive correlation with the changes in TSH (P < 0.05) and negative correlation with the changes in endothelium-dependent arterial dilation (P < 0.01) in hypothyroid patients during the course of treatment. CONCLUSION: OPG may be involved in the development of vascular dysfunction in hypothyroid patients.     

Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations

Although the normal thyroid gland secretes both levothyroxine (L-T4) and levotriiodothyronine (L-T3), normalization of serum TSH with L-T4-replacement therapy alone in hypothyroidism is generally believed to result in a normal serum L-T3 and to reflect a euthyroid state. However several recent studies suggest that this may not be the case. Accordingly, the relationship between serum free L-T4 and free L-T3 was examined in 20 normal individuals (group A) and in 53 patients with chronic autoimmune thyroiditis, 18 with normal TSH on no L-T4-replacement (group B), and 35 with normal TSH on L-T4-replacement therapy for hypothyroidism (group C). Data were analyzed by applying a one-way analysis of variance with correction for multiple comparisons. Serum TSH values were very similar among the 3 groups. In groups A and B, mean serum free T4 and free T3 were very similar. In group C, the mean free T4 (16+/-2 pmol/l) was significantly higher than the values in groups A (14+/-1) and B (14+/-2) (p<0.001) and the mean free T3 lower (4.0+/-0.5 pmol/l vs 4.2+/-0.5, NS and 4.4+/-0.5, p<0.02). Consequently, the mean molar ratio of free T4 to free T3 was significantly higher in group C than the ratios in groups A and B (p<0.0001), despite very similar TSH values. These findings indicate that in hypothyroid patients L-T4-replacement, that is sufficient to maintain a normal serum TSH, is accompanied by a serum free T4 that is higher than that in untreated euthyroid patients or normal individuals and may not result in an appropriately normal serum free T3 concentration.     

Plasma high density lipoprotein cholesterol in thyroid disease.

The plasma levels of high density lipoprotein cholesterol (HDL-C) were reduced in 16 hyperthyroid female patients compared to 37 euthyroid women (33.5 +/- 8 vs. 51.5 +/- 13 mg/dl (mean +/- SD); P less than 0.001). When 5 patients were restudied after restoration of the euthyroid state, plasma HDL-C increased from 29 +/- 5 to 43 +/- 11.5 mg/dl (P less than 0.05). In addition, in 22 hypothyroid women, HDL-C levels were also diminished compared to the euthyroid group (43.4 +/- 15.5 vs. 51.5 +/- 13 mg/dl; P less than 0.05). Nine patients were restudied after L-T4 replacement therapy; their levels of HDL-C increased but not to a statistically significant degree. The daily administration of 0.3 mg L-T4 to eight normal male volunteers for 1 month did not significantly affect HDL-C levels.     

Atrial natriuretic peptide in hypothyroidism

The effect of hypothyroidism on circulating levels of atrial natriuretic peptide (ANP) was studied in 11 hypothyroid patients (aged 11-65 yr; mean, 31 yr) and 13 normal subjects (aged 28-39 yr; mean, 32 yr). Plasma ANP was 32 +/- 9 (+/- SD) pg/ml in normal subjects and 20 +/- 5 pg/ml in the hypothyroid patients (P less than 0.005). In 7 hypothyroid patients, plasma ANP levels were measured after 10-14 weeks of L-T4 therapy. ANP increased from 22 +/- 5 to 46 +/- 18 pg/ml (P less than 0.02), along with an increase in mean serum T4 from 0.6 +/- 0.5 to 8.1 +/- 2.5 micrograms/dl (P less than 0.001). Thus, hypothyroidism is characterized by decreased circulating levels of ANP which are reversed by L-T4 therapy.     

Low cholesteryl ester transfer protein (CETP) concentration but normal CETP activity in serum from patients with short-term hypothyroidism Lack of relationship to lipoprotein abnormalities

OBJECTIVES: Hypothyroidism is associated with a number of abnormalities in lipoprotein metabolism. Although alterations in neutral lipid exchanges among plasma lipoproteins might be one characteristic feature of hypothyroidism, a few human studies of cholesteryl ester transfer protein (CETP) activity have led to heterogeneous and fragmentary observations. The aim of the present study was to analyse the influence of short-term hypothyroidism on CETP activity, as well as on the structure and composition of lipoproteins. PATIENTS, DESIGN AND MEASUREMENTS: Sixty-six thyroidectomized patients were withdrawn from L-thyroxine (L-T4) treatment for 5 weeks. Subsequently, L-T4 therapy was reinstated for 2 months and patients were compared to 61 matched normolipidaemic controls. Serum CETP activity and mass concentration, serum lipids, apolipoproteins and lipoprotein size distribution were determined in the three groups. RESULTS: Serum CETP mass concentration was significantly decreased in short-term hypothyroid patients, as compared to control subjects (3.22 +/- 0.98 vs. 3.79 +/- 1.2 mg/l, respectively; P < 0.001), and the values were normalized during L-T4 therapy. The ability of endogenous serum lipoproteins to interact with CETP was normal in short-term hypothyroid patients. Concordant observations were made regardless of whether neutral lipid transfers were measured from high-density lipoproteins (HDL) toward apo B-containing lipoproteins or from liposomes toward HDL. The size distribution of HDL was significantly different in short-term hypothyroid patients, compared to either the control or treated subgroups, with significant higher proportions of large-sized HDL2b and HDL2a (HDL2b: 13.6 +/- 6.5% before vs. 8.5 +/- 4.2% during L-T4 therapy, P < 0.05; HDL2a, 33.0 +/- 7.0% before vs. 29.3 +/- 6.9% during L-T4 therapy, P < 0.05). Although serum CETP mass concentration correlated negatively with the HDL2 to HDL3 ratio in control subjects (r = -0.588; P < 0.0001), no significant correlations were observed in hypothyroid patients, regardless of whether they were treated or not. Similarly, whereas the previously recognized positive correlation of CETP mass concentration with serum LDL cholesterol levels was found in control subjects (r = 0.264; P < 0.05), no significant correlations appeared in treated and untreated patients. CONCLUSIONS: Short-term hypothyroidism may constitute an unique situation in which concomitant alterations in serum cholesteryl ester transfer protein concentration and lipoprotein parameters are disconnected.     

Evidence for thyroid hormone as a positive regulator of serum thyrotropin bioactivity

CONTEXT: The regulation of TSH bioactivity in humans is not completely understood. OBJECTIVE: The aim of the study was to investigate the role of serum thyroid hormones in regulating the bioactivity of TSH. DESIGN: We determined in vitro TSH bioactivity and glycosylation in nine patients (six females and three males, age 41.3 yr) with primary hypothyroidism before and after L-T(4) replacement, in 11 age- and sex-comparable controls (seven females and four males, age 37.6 yr), and in two thyroidectomized patients with TSH-secreting adenomas during and after L-T(4) withdrawal. METHODS: In vitro TSH bioactivity was measured by a sensitive and specific bioassay based on cAMP generation by Chinese hamster ovary cells transfected with human TSH receptor. TSH glycosylation was assessed by concanavalin A lectin and ricin column affinity chromatography. RESULTS: In vitro TSH bioactivity in hypothyroid patients was low as compared with controls (0.48 +/- 0.1 vs. 1.1 +/- 0.2; P = 0.004) and increased during L-T(4) (0.48 +/- 0.1 vs. 0.8 +/- 0.1; P = 0.01). A strong significant correlation (r = +0.80; P = 0.004, Spearman) was observed between the absolute increments of serum TSH bioactivity and T(3) during L-T(4) replacement. The degree of sialylation was elevated in hypothyroid patients before treatment (47 +/- 2.4% vs. 29 +/- 4.3%; P = 0.002) and decreased significantly after L-T(4) (47 +/- 2.4% vs. 33 +/- 4.3%; P = 0.02). The mannose content of serum TSH in hypothyroid patients was similar to controls and did not change during L-T(4). In vitro TSH bioactivity also decreased in patients with TSH-secreting adenomas during L-T(4) withdrawal. CONCLUSION: These data indicate that serum thyroid hormone level is a positive regulator of TSH bioactivity.     

Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement

OBJECTIVES: Remnant-like particles (RLPs) reflect chylomicron remnants and very-low-density lipoprotein remnants, which are most likely to be atherogenic particles. To investigate the effect of thyroxine replacement on the metabolism of RLPs in hypothyroidism, we measured serum concentrations of RLPs during an oral fat-loading test in patients with hypothyroidism before and after thyroxine replacement. PATIENTS AND METHODS: Thirteen patients with hypothyroidism, having serum-free thyroxine (FT4) of 4.25 +/- 2.23 pmol/l (mean +/- SD) and TSH of 72.5 +/- 27.7 mU/l, participated in the study. Two-hundred grams of cream containing 32.9% of fat were given to each patient followed by blood draws every 2 h for 8 h. The patients became euthyroid after 3 months of T4 replacement, and the fat-loading tests were then repeated. RESULTS: Fasting levels of serum total cholesterol and low-density lipoprotein cholesterol were remarkably decreased after T4 therapy (P < 0.0005). Serum high-density lipoprotein cholesterol and triglyceride were also decreased by T4 therapy, not so remarkably but significantly (P < 0.05). Activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) increased 52% and 85%, respectively, from the pretreatment values. Serum concentrations of remnant-like particle cholesterol (RLP-C) and remnant-like particle triglyceride (RLP-TG), measured by immunoseparation assays, significantly decreased from 0.14 +/- 0.03 to 0.09 +/- 0.03 mmol/l (P < 0.0005) and from 0.19 +/- 0.11-0.11 +/- 0.07 mmol/l (P < 0.01), respectively. In the fat-loading test, serum low-density lipoprotein cholesterol concentrations were not changed, while serum RLPs concentrations were increased and remained high throughout the test, with the peak value at 6 h in a hypothyroid condition. In an euthyroid condition after T4 therapy, the peak values of RLPs were obtained at 4 h, and the concentrations were decreased rapidly. As the result, areas under the curve of serum RLPs were decreased remarkably after T4 therapy. CONCLUSIONS: Hypothyroidism seems to be associated with a decrease in metabolism of serum RLPs. Such altered metabolism of RLPs may be related to the decreased activities of LPL and HTGL and can be corrected by T4 replacement therapy.     

Hyperthyroidism may affect serum N-terminal pro-B-type natriuretic peptide levels independently of cardiac dysfunction

BACKGROUND AND AIM: It is known that NT-proBNP levels increase in cardiac failure. However, NT-proBNP levels in different thyroid states are still unclear. We aimed to evaluate serum NT-proBNP levels in both hyperthyroid and hypothyroid patients without cardiac insufficiency. SUBJECTS AND METHODS: Thirty-six patients with hyperthyroidism (42.9 +/- 16.7 years), 25 patients with hypothyroidism (35.4 +/- 13.9 years) and 34 age-matched euthyroid subjects (41.4 +/- 13.8 years) were included in the study. After anthropometric evaluations, body fat analyses were determined by bioelectrical impedance. Electrocardiography and echocardiography were used in cardiac evaluations. Serum NT-proBNP was measured by immunoassay. RESULTS: Mean serum NT-proBNP levels in hyperthyroid patients were higher than in both control subjects (13.65 +/- 13.02 vs. 6.50 +/- 4.83 pmol/l, P = 0.002) and hypothyroid patients (13.65 +/- 13.02 vs. 5.98 +/- 5.08 pmol/l, P = 0.003). However, mean serum NT-proBNP levels in hypothyroid patients were not different from those in control subjects. There was a positive correlation between serum NT-proBNP and thyroid hormones (NT-proBNP and FT3: r = 0.324, P = 0.001; NT-proBNP and FT4: r = 0.269, P = 0.009, respectively). Serum NT-proBNP levels were positively correlated with left ventricle end-diastolic diameters (r = 0.232, P = 0.04), interventricular septum thickness (r = 0.315, P = 0.006), and negatively correlated with left ventricular ejection fraction (r = -0.238, P = 0.04). CONCLUSIONS: Serum NT-proBNP levels may increase in hyperthyroidism independently of cardiac insufficiency. Therefore, hyperthyroidism may lead to cardiac ultrastructural changes undetermined by conventional echocardiography and these changes may be responsible for elevation of NT-proBNP levels. In contrast to decreased thyroid hormones, excess thyroid hormones may have a more pronounced effect on serum NT-proBNP levels.     

Treating hypothyroidism improves endothelial function

Hypothyroidism patients have increased cardiovascular risk, although the mechanism is not defined. Endothelial dysfunction may initiate atherosclerosis, is present in patients with hypothyroidism, and therefore may link hypothyroidism and vascular disease. We are unaware of studies examining the effect of thyroid replacement therapy on endothelial function in hypothyroid patients. The present study examined the effect of treatment of hypothyroidism on brachial artery reactivity. Consequently, we measured endothelium-dependent (EDV) and endothelium-independent (EIV) vasodilation using brachial artery ultrasonography in 8 hypothyroid patients (5 men, mean age 48.9 +/- 5.5 years; mean thyrotropin [TSH] 49.0 +/- 37.0 mIU/L) before and after thyroxine treatment. Thyroxine treatment reduced average TSH to 2.9 +/- 0.5 mIU/L and improved EDV (8.0% +/- 4.4% v 3.4% +/- 2.5%, P <.05), whereas EIV was unchanged (20.3% +/- 6.1% v 19.2% +/- 9.4%, P = not significant [NS]). Thyroxine treatment did not alter serum lipids. Thyroid replacement therapy improves endothelium-dependent vascular reactivity in patients with hypothyroidism irrespective of lipid changes.     

Effect of thyroxine replacement on serum IGF-I, IGFBP-3 and the acid-labile subunit in patients with hypothyroidism and hypopituitarism

OBJECTIVE: To describe the effect of T4 replacement in patients with primary and central hypothyroidism on components of the IGF binding protein complex: IGF-I, the acid-labile subunit (ALS) and IGFBP-3. PATIENTS AND METHODS: We determined IGF-I, ALS and IGFBP-3 (by 125I-IGF-II ligand blots and immunoblots) in serum of 19 patients with primary and 11 patients with central hypothyroidism. RESULTS: Mean (+/- SD) free T4 (fT4) increased from 4.4 +/- 2.4 pmol/l at baseline to 18.6 +/- 5.2 pmol/l following T4 therapy. In patients with primary hypothyroidism, IGF-I concentrations increased from 101 +/- 57 to 158 +/- 60 microg/l (P < 0.001) and ALS from 12.6 +/- 4.7 to 15.6 +/- 5.2 mg/l (P = 0.001). IGFBP-3 levels (in arbitrary units, AU), assessed by 125I-IGF-II ligand blot and by Western blot (the intensity of the 45/42-kDa doublet following T4 replacement defined as 1 AU) increased from 0.74 +/- 0.47 to 1 (P = 0.029) and from 0.76 +/- 0.42 to 1 (P = 0.018), respectively. In patients with hypopituitarism, IGF-I and ALS concentrations increased on T4 therapy from 49 +/- 23 to 97 +/- 36 microg/l (P < 0.001) and from 7.8 +/- 4.1 to 11.0 +/- 2.7 mg/l (P = 0.010), respectively. IGFBP-3 remained unchanged during T4 replacement. CONCLUSIONS: T4 replacement increases the serum levels of IGF-I and ALS in patients with primary as well as central hypothyroidism. IGFBP-3 levels increase in response to T4 replacement in patients with primary hypothyroidism but not in those with central hypothyroidism, suggesting that thyroid hormones increase IGF-I and ALS but not IGFBP-3 in patients with GH deficiency.     

Persistent pituitary resistance to thyroid hormone in congenital versus later-onset hypothyroidism

The pituitary and peripheral responses to L-T4 and L-T3 therapy were studied in 12 patients with congenital goitrous hypothyroidism, in 10 patients with an ectopic thyroid and onset of hypothyroidism at 3-8 years of age, and in 6 patients with adult-onset hypothyroidism, after they had had their chronic thyroid hormone replacement therapy discontinued for 30 days. They were first treated with increasing L-T4 (0.1, 0.2 and 0.4 mg daily) followed by L-T3 (0.05 and 0.2 mg daily) after stopping thyroid medication for another month. Ten normal subjects were treated identically. In normal individuals the peak TSH, alpha, and TSH-beta response to TRH was significantly decreased with 0.1 mg L-T4 or 0.05 mg L-T3 daily and was suppressed with 0.2 and 0.4 mg L-T4 or 0.2 mg L-T3 daily; serum cholesterol and triglyceride decreased significantly with 0.2 or 0.4 mg L-T4 or 0.2 mg L-T3 daily; testosterone-estradiol binding globulin (TeBG) increased significantly at the same doses. In congenitally hypothyroid patients receiving 0.2 mg L-T4 daily, the mean peak TSH after TRH was 24 +/- 17 microU/ml, whereas in patients with an ectopic thyroid or adult-onset hypothyroidism the peak TSH was significantly less at 5.9 +/- 8.8 and 5.5 +/- 5.7 microU/ml, respectively. Only at the highest doses of L-T4 (0.4 mg/day) or L-T3 (0.2 mg/day) was the TSH response to TRH suppressed in the congenitally hypothyroid group. The alpha and TSH-beta subunit levels followed those of TSH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrine factors related to changes in total peripheral vascular resistance after treatment of thyrotoxic and hypothyroid patients

OBJECTIVE: Total peripheral vascular resistance (TPR) decreases in thyrotoxicosis and increases in hypothyroidism. Several mechanisms may be involved, including adaptation to changes in heat production and direct non-genomic effects of tri-iodothyronine (T3) on vascular smooth muscle cells. The aim of this study was to see if changes in TPR are related to changes in plasma concentrations of the endothelial hormones adrenomedullin and endothelin-1 as well as other hormones affecting vasculature. DESIGN: A prospective study. SUBJECTS: Eleven hypothyroid patients (pretreatment: thyroid-stimulating hormone (TSH) 68 (38-201) mU/l, T3 0.7 (0.35-1.5) nmol/l, fT4 3.0 (2.0-5.9) pmol/l, median (range)) and 14 with hyperthyroidism (pretreatment: TSH 0.02 (<0.01-0.06) mU/l, T3 6.4 (2.3-13.0) nmol/l, fT4 56.1 (22.9-70.0) pmol/l) were studied before treatment and 3 months after reaching the euthyroid state. Blood collection was carried out simultaneously with the recording of finger arterial pressure (FINAP). Cardiac output and TPR were derived from stroke volume computations by modelling flow from the FINAP signal. RESULTS: Thyroid-function tests of hypothyroid and thyrotoxic patients did not differ after restoration of the euthyroid state. TPR, expressed in arbitrary units (AU), decreased after correction of hypothyroidism (from 1.32+/-0.65 to 0.96+/-0.36 AU, P=0.04) and increased after correction of hyperthyroidism (from 0.75+/-0.18 to 1.10+/-0.35 AU, P=0.007). Adrenomedullin concentrations did not change during the transition from the hypothyroid state 3.2(0.9-11.0) pmol/l to the euthyroid state 4.9(0.9-8.6) pmol/l, but decreased after treatment of hyperthyroidism, from 5.2(0.9-11.0) pmol/l to 2.2(0.9-5.4) pmol/l. Plasma endothelin-1 was undetectable in all samples. Changes in TPR upon treatment correlated with log DeltafT4 (r=-0.65, P=0.001), log DeltaT3, (r=-0.57, P=0.006), Delta noradrenaline (r=0.54, P=0.02) and Delta ANP (atrial natriuretic peptide) (r=-0.59, P=0.004). Multiple linear regression analysis indicated that only T3 was an independent determinant of TPR. Changes in T3 accounted for 46% of the variability in the changes in TPR. CONCLUSIONS: TPR is reduced in thyrotoxicosis and increased in hypothyroidism. Restoration of the euthyroid state normalizes TPR. Changes in TPR are not related to plasma adrenomedullin concentrations, but 46% could be explained by changes in T3. Altered ANP secretion and adrenergic tone may contribute to the T3-induced changes in TPR.     

Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism,and its response to L-thyroxine therapy

Hypothyroidism is associated with intrinsic myocardial changes reflected by alterations in contractility and relaxation. Diastolic function, however, rather than systolic cardiac function, seems to be mostly impaired by thyroid hormone deprivation. Our aim was to evaluate diastolic function at rest and during maximal exercise by means of radionuclide ventriculography in subclinical hypothyroidism before and after restoration of euthyroidism. Ten subclinical hypothyroid patients (50 +/- 8.7 years) (thyroid-stimulating hormone 11 +/- 4.2 microUI/ml) without cardiac disease were studied before and 6 months after levothyroxine (L-T(4)) replacement (thyroid-stimulating hormone 1.9 +/- 1.1 microUI/ml). We compared the basal and post-therapy cardiac parameters with a control group of 14 euthyroid patients (52.5 +/- 10 years) (thyroid-stimulating hormone 2.5 +/- 1.2 microUI/ml). Multigated equilibrium radionuclide ventriculography was performed to assess systolic and diastolic ventricular function. Student's t and paired Student's t tests were applied for statistical analysis. We found a significant difference between the time to peak filling rate (TPFR) at rest before (0.241 +/- 0.002 ms) and after (0.190 +/- 0.012 ms) treatment with L-T(4). A significant difference that disappeared after restoration of euthyroidism was also observed between the basal TPFR values of the subclinical hypothyroid patients and the control group (0.189 +/- 0.01 ms). The same pattern was observed at maximal exercise. Thus, TPFR, a parameter of left ventricular (LV) diastolic function measured by radionuclide ventriculography, is impaired in subclinical hypothyroid patients both at rest and during exercise and returns to normal values after L-T(4) therapy.     

Increased osteoprotegerin serum levels in men with coronary artery disease

Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for the vascular system. However, the role of OPG in human atherosclerosis has not been evaluated. In this study, we assessed OPG serum levels in 522 age-matched men who, on the basis of coronary angiography, had either absence of coronary artery disease (CAD) or presence of single-vessel disease, double-vessel disease, or severe triple-vessel disease. OPG serum levels were positively correlated with age (r = 0.28; P < 0.001) and were higher in men with diabetes mellitus (P < 0.01). OPG serum levels in men without CAD were 5.4 +/- 2.0 pmol/liter, compared with 6.1 +/- 2.1 pmol/liter in single-vessel disease (P < 0.005), 5.9 +/- 2.4 in double-vessel disease (P < 0.05), and 6.3 +/- 2.3 pmol/liter in triple-vessel disease (P < 0.001). Moreover, OPG serum levels were positively correlated with the severity of CAD as determined by a CAD scoring system (r = 0.17; P < 0.01). In conclusion, our data underline that OPG serum levels are associated with the severity of CAD and are increased in elderly men and patients with diabetes mellitus. We conclude that increased OPG serum levels may reflect advanced cardiovascular disease in men.     

Concentrations of somatomedin-C and triiodothyronine in patients with thyroid dysfunction and nonthyroidal illnesses

We studied the possibility of an association between serum somatomedin-C (Sm-C) and thyroid hormone concentrations. For this purpose 34 hyperthyroid patients, 39 patients with primary hypothyroidism, 36 patients with severe nonthyroidal illnesses (NTI), and 63 euthyroid healthy control subjects were examined. The mean concentration of serum dialyzable free triiodothyronine (FT3) was 26.6 +/- 15.4 pmol/l (+/- SD) in hyperthyroidism, 2.8 +/- 1.2 in hypothyroidism, 4.2 +/- 1.1 in NTI, and 5.3 +/- 0.7 in controls. The lowest mean concentration of serum Sm-C (10.1 +/- 3.0 nmol/l) was found in the NTI group and the highest in the hyperthyroid group (16.8 +/- 3.2): these concentrations differed significantly from the mean control level (12.2 +/- 2.2). In NTI patients the serum FT3 and T3 levels correlated significantly with the serum Sm-C levels (r = 0.63; p less than 0.001, r = 0.65; p less than 0.001, respectively). In hypothyroid patients there was a weak correlation between the serum FT3 and Sm-C levels (r = 0.36; p less than 0.05), but no correlations were found in hyperthyroid and healthy subjects. We conclude that the lowered Sm-C levels in NTI do not reflect a hypothyroid state, as normal Sm-C levels were found in hypothyroidism, and that impaired nutritional state of the patients is the most likely explanation for the association between Sm-C and FT3 (and T3) in NTI.     

Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine

OBJECTIVE: Primary hypothyroidism can cause disturbances in normal gonadal function. The aim of this study was to investigate the relationship in men between hypogonadism and primary hypothyroidism and the extent to which free and total testosterone levels rose after introduction of replacement thyroxine. DESIGN: Paired study of patients in a hypothyroid and thyroxine treated state. PATIENTS: Ten men with primary hypothyroidism. MEASUREMENTS: Free and total testosterone, gonadotrophin and prolactin levels before and after thyroxine replacement therapy. RESULTS: Low free testosterone levels (161 +/- 62 pmol/l) demonstrated at the time the men were hypothyroid rose significantly with the commencement of thyroxine replacement (315 +/- 141 pmol/l; P < 0.001). Gonadotrophin levels were not elevated consistent with hypogonadotrophic hypogonadism. Hyperprolactinaemia, which can occur in primary hypothyroidism and cause hypogonadotrophic hypogonadism, was not present in the majority of these patients. However a reduction in prolactin level was evident with thyroxine replacement and a rise in free testosterone levels. CONCLUSION: This suggests an effect of hypothyroidism on gonadotrophin secretion at the level of the hypothalamus-pituitary, either directly or through modulation of prolactin secretion. Low free testosterone may also be a contributing factor to some of the symptoms and signs of hypothyroidism in men.     

Thyroid function and bone turnover

The mechanism of thyroid action on bone was studied in 15 patients with thyrotoxicosis and 14 patients with hypothyroidism. The patients were studied twice: when they were thyrotoxic or hypothyroid and when they had returned to a euthyroid state. Parameters of bone turnover showed a decrease when hyperthyroid patients became euthyroid: serum calcium (2.51 +/- 0.04 vs 2.38 +/- 0.03 mmol/l, P less than 0.05), acid phosphatase (11.7 +/- 0.7 vs 8.3 +/- 0.4 U/l, P less than 0.01), alkaline phosphatase (124 +/- 11 vs 98 +/- 8 U/l, P less than 0.05), the calcium/creatinine ratio (1.03 +/- 0.31 vs 0.43 +/- 0.07, P less than 0.01) and the hydroxyproline/creatinine ratio in the urine (69.9 +/- 12 vs 20.7 +/- 2.4, P less than 0.01). These parameters showed an increase when hypothyroid patients became euthyroid: serum calcium (2.36 +/- 0.03 vs 2.48 +/- 0.04 mmol/l, P less than 0.01), alkaline phosphatase (60 +/- 4 vs 84 +/- 8 U/l, P less than 0.05) and the hydroxyproline/creatinine ratio in the urine (15.9 +/- 4.3 vs 25.3 +/- 3.2, P less than 0.05). Changes in the calcium regulating hormones, parathyroid hormone, calcitonin and vitamin D metabolites, were not observed when hyperthyroid patients became euthyroid. When hypothyroid patients were treated a decrease in serum levels of 1.25-dihydroxyvitamin D (32.6 +/- 4.6 vs 17.9 +/- 2.5 ng/l, P less than 0.01) was observed. Serum growth hormone levels decreased when hypothyroid patients became euthyroid (4.3 +/- 0.5 vs 2.6 +/- 0.4 mU/l, P less than 0.01). The possible mechanisms of thyroid action on bone are discussed. The presented findings are in accordance with a direct effect of thyroid hormones on bone in thyrotoxicosis. An additional factor could be somatomedin, that might also be involved in changes in bone turnover in hyper- and hypothyroidism.     

Plasma viscosity in female patients with hypothyroidism: effects of oxidative stress and cholesterol

Hypothyroidism is associated with atherosclerotic events, however, the mechanism is unclear. We investigated the effects of oxidative stress and cholesterol on plasma viscosity in female patients with hypothyroidism (n = 20; mean age: 45.5 +/- 5.5 years) at baseline and after L-thyroxine replacement therapy (average daily dose being 0.1 to 0.15 mg). Two blood samples were taken after 2.3 +/- 1.2 months. In hypothyroid state plasma viscosity and thiobarbituric acid reactive substance (TBARS; marker of oxidative stress were significantly higher (p < 0.001 and p < 0.001), and plasma protein thiol (antioxidants) levels were significantly lower (p < 0.001) than in the healthy state (female; n = 15). After L-thyroxine replacement therapy, patients reached to euthyroid state. In this state, the levels of plasma viscosity and TBARS were decreased (p < 0.001 and p < 0.001), and protein thiol levels were significantly elevated (p < 0.001). There was a significant correlation between plasma cholesterol and viscosity (r = 0.64, p < 0.001), as well as plasma protein thiol (r = -0.59, p < 0.001) in the patients. The correlation between viscosity and TBARS was weak (r = 0.29, p < 0.01). Therefore hypothyroidism may be associated with atherosclerotic process by different mechanisms.