Myo-Inositol and Selenium Restore Euthyroid State

Home , Autoimmune thyroiditis

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2017; 21 (2 Suppl): 51-59 Myo-inositol plus selenium supplementation restores euthyroid state in Hashimoto’s patients with subclinical hypothyroidism

M. NORDIO, S. BASCIANI

Department of Experimental Medicine, University of Rome “Sapienza”, Rome, Italy

Abstract. – OBJECTIVE : Clinical evidence thyroglobulin (TgAb) and anti-thyroid peroxi - suggests that oral supplementation with myo-in - dase (TPOAb ) are typical features of AIT . In ositol (MI) and selenium (Se) is useful in the such pathologies, among which Hashimoto’s thy - treatment of autoimmune thyroiditis. The pur - pose of this study was to highlight the positive roiditis (HT) is the most representative, thyroid response of Hashimoto’s patients with subclini - gland gets progressively underactive , due to cell cal hypothyroidism (SH) treated with MI and Se and antibody-mediated autoimmune processes 2. (MI-Se) in restoring a normal thyroid function. A mild thyroid failure is called subclinical hy - PATIENTS AND METHODS: A total of 168 pa - pothyroidism (SH), and usually is balanced by a tients with Hashimoto’s thyroiditis (HT) having slight TSH level increase , approximately be - Thyroid Stimulating Hormone (TSH) levels be - tween 3 and 6 µIU/ml were randomized into 2 tween 3-6 µIU/ml . According to the American groups: one receiving MI-Se and the other one Thyroid Association’s (ATA’s) guidelines, the Se alone. normal range for TSH values, with an upper limit RESULTS: TSH, anti-thyroid peroxidase of 4.12 µIU/ml is largely based on National (TPOAb) and anti-thyroglobulin (TgAb) levels Health and Nutrition Examination Survey were significantly decreased in patients treated (NHANES) III data, but it has not been univer - with combined MI-Se after six months of treat - sally accepted. In fact, some have proposed that ment. Also, a significant free serum T4 increase was observed in MI-Se group, along with an the upper normal TSH values should be either 3 amelioration of patients’ quality of life. 2.5 or 3.0 . TSH , a glycoprotein secreted by the CONCLUSIONS: The administration of MI-Se hypophysis, regulates the hypothalamic-pitu - is significantly effective in decreasing TSH, itary-thyroid axis by harmonizing the release of TPOAb and TgAb levels, as well as in enhancing thyroid hormones 4. It plays several key physio - thyroid hormones and personal wellbeing. Such logical roles, from the promotion of thyroid ep - treatment restored euthyroidism in patients di - 5 agnosed with autoimmune thyroiditis. ithelial differentiation and growth , iodide uptake and transport 6, to protection of thyroid cells from Key Words: apoptosis 7. Particularly, on thyroid follicular Myo-inositol, Selenium, Autoimmune thyroiditis, cells, TSH binds to the TSH receptor, stimulating TSH, TPOAb, TgAb, Hashimoto's thyroiditis, Subclinical cell growth and differentiation, in addition to hypothyroidism . thyroid hormone synthesis. This binding with TSH receptors activates adenylyl cyclase, lead - ing to an increase of intracellular cyclic AMP and protein Kinase A phosphorylation, and also Introduction to an activation of cytosolic and nuclear target proteins. At high doses, TSH stimulates the Chronic autoimmune thyroiditis (AIT) is one phospholipase C-dependent inositol phosphate of the most common autoimmune diseases in io - Ca 2+ /diacyglycerol pathway, resulting in a boost 8 dine-sufficient areas , affecting more than 10% of of hydrogen peroxide (H 2O2) generation . Be - females and 2% of males in the overall popula - sides, it has been shown that impairment of TSH tion. Although this illness may often occur in signal transduction leads not only to thyroid dis - children and teenagers, it mainly affects 30-50 orders such as hypothyroidism and hyperthy - years old people 1. Elevated Thyroid Stimulating roidism , but also to the proliferation and differ - Hormone (TSH) and autoantibodies such as anti- entiation of human thyroid carcinoma cells 9.

Corresponding Author: Maurizio Nordio, MD; e-mail: [email protected] 51 M. Nordio, S. Basciani

Currently, a specific treatment for AIT has not vestigate the efficacy of a combined administra - been found yet, however , various studies have tion of MI and Se in AIT to evaluate whether this demonstrated that L-thyroxine (L-T4) 10 and sele - treatment could restore euthyroid state and im - nium (Se) 11 may moderately lower antibodies prove personal well being in HT patients. serum concentrations in HT patients. Particular - ly, in a randomized, placebo-controlled prospec - tive study the administration of Se plus LT4 was Patients and Methods beneficial to AIT patients, reducing serum TPOAb and TSH levels 12 , although L-T4 effica - A total of 168 outpatients (mean age 40 .85 ± cy is quite controversial in patients with already 8. 5 years) with HT were enrolled in this prospec - low TSH levels 13 . Mazokopakis et al 14 have tive randomized controlled trial (RCT) from shown that Se significantly decreased the serum March 2015 to February 2016 . Each participant TPOAb concentrations after a 12 months treat - filled in the informed consent. This study was ment period. Another study demonstrated that 12 approved by the ethics committee of the Italian months of 80 µg sodium selenite administration Society of Phytotherapy and Supplements in Ob - to AIT patients reduced TPOAb and TgAb con - stetrics and Gynecology (SIFIOG). Inclusion cri - centrations, whereas TSH and free thyroxine teria were: age range 22-6 2, TSH levels between 15 (fT 4) levels were unvaried . Likewise, 200 µg 3- 6 µIU/ml , elevated serum TPOAb and/or sodium selenite per day were able to decrease TgAb, normal fT 4 level (0.6-1.8 ng/dl ) and free serum thyroid TPOAb autoantibodies levels after triiodothyronine (fT 3) ( 2.0-3.5 pg/ml ). Exclusion 3 months of treatment in autoimmune thyroid pa - criteria were: debilitating illnesses (e.g. depres - tients 16 . Furthermore, in the same clinical trial, sion, psychosis, severe hepatic or renal failure); the Se effect was evaluated in improving the pa - malabsorption disorders (atrophic gastritis, celiac tients’ wellbeing, as subjects with AIT normally disease); adjuvant treatment with vitamins or have impaired health-related quality of life 16 . trace elements. The primary outcome was the re - Se is an essential trace element for humans ; se - duction of serum TSH levels. The secondary out - lenium-dependent enzymes exert antioxidant and comes were the restoration of TPOAb, TgAb, fT 3 17 anti-inflammatory properties . It has a relevant and fT 4 hormone concentrations as well as the impact on immune function 17 ; de facto , it has quality of life evaluation. been shown to reduce the inflammatory status in Patients were randomized 1:1 into 2 groups: patients with AIT 16 . Se-dependent enzymes, such 84 subjects (control group :A)including 10 men as Glutathione Peroxidase (GPx), substantially and 74 women, and 84 subjects (experimental have the ability to diminish hydrogen peroxides, group: B) , with 9 men and 75 women. The cal - lipid, and phospholipid hydroperoxides ; in this culation of the sample size determined that a way, they limit the propagation of free radicals minimum of 52 patients were required in each and reactive oxygen species, resulting in a reduc - group to have an acceptable statistical power . tion of inflammatory prostaglandins (PGs) and At baseline , both groups had similar values for 18,19 leukotrienes . age, and TSH, TPOAb , TgAb , fT 3 and fT 4 hor - In a previous study 20 from our laboratory , the mone levels. Controls (group A) were given co-treatment with L-selenomethionine plus myo- 16.6 mg L-selenomethionine (corresponding to inositol (MI) demonstrated a beneficial effect on 83 µg Se ) in tablets, and patients in group B SH, restoring a euthyroid state and reducing both were given tablets containing 600 mg MI plus TPOAb and TSH levels, bringing them closer to 16.6 mg L-selenomethionine (= 83 µg Se ) physiological levels . (Tiroxil ®, LO.LI. Pharma Srl, Rome, Italy ). Pa - MI is a carbocyclic polyol precursor of phos - tients were asked to take the supplement with phoinositide synthesis; it is involved in cell sig - water about 2 hours before or after the meal , for naling 21 and, precisely, as a second messenger six months. Subjects were treated daily by oral regulating the activities of several hormones route and asked to bring back the empty boxes , such as TSH, follicle-stimulatin g hormone used for the treatment , at the following sched - (FSH) and insulin 22 . Indeed, in TSH signal cas - uled medical visits . Also, a questionnaire to cade, inositol regulates hydrogen peroxide-medi - evaluate the level of subjective symptomatology ated iodination 23 . (SS), due to the thyroid inflammation process, Based on this clinical evidence and our previ - was filled in by each patient at the beginning ous preliminary data , we decided to further in - and the end of the study.

52 Myo-inositol and selenium restore euthyroid state

Laboratory and Technical Investigations The flow rate was fixed to 1.2 ml/min and results From the 171 patients selected, 1 68 agreed to were analyzed by an MS 5973 Network Series enter the study . Three of them were excluded detector in SIM mode. when they got pregnant during the recruiting pe - At enrolment and after 6 months the SS was riod. evaluated using a questionnaire 25 , which includes Blood samples were drawn from each patient 7 questions ranging from the level of pain to the and serum TSH, fT 3, fT 4, TPOAb, and TgAb lev - degree of discomfort during swallowing, with an els were measured at baseline and the end of the arbitrary scale between 0 = no symptoms and 4 = 6-month period. The concentrations of fT 3, fT 4 very important symptoms . and TSH were measured by an enzyme immuno - metric assay (Byk-Sangtec Dietzenbach, Ger - Statistical Analysis many). Plasma total TPOAb and TgAb concen - Data were processed using Graph Pad Prism, trations were measured by a commercial enzyme version 6.0f (Mac, San Diego, CA, USA) and are luminescence assay (Byk-Sangtec, Dietzenbach, indicated as mean values ± standard deviation Germany). The specificity for AIT in these as - (SD ). The significance of differences between says is greater than 90% when antibody concen - measures in pre- vs. post-treatment in-group A trations are above 350 IU/ml . (§), pre- vs. post-treatment in-group B ( *), post- To provide additional information concerning treatment group A vs. post-treatment group B ( †) thyroid tissue texture, high-resolution ultrasound was compared using one-way ANOVA. A two- scan of the thyroidal area was carried out using tailed p-value ≤ 0. 05 was utilized throughout as Doppler sonography 24 . Particular attention was criterion of statistical significance . paid to evaluate the so-called Systolic Peak Ve - locity (SPV) of the lower thyroid artery because its blood flux generally is altered during the in - Results flammatory process. A single experienced opera - tor, who was unaware of the diagnosis, per - A significant decrease in serum TSH levels formed all the scans. was noted in patients of group B (MI -Se) com - Atomic absorption spectrometry was carried pared prior and after treatment ( p ≤ 0. 001), out to determine plasma selenium. Plasma MI showing at baseline 4 .22 ± 0.6 µIU/ml and 3 .26 was determined using Gas Chromatography- ± 0.89 µIU/ml over 6 months treatment. The Mass Spectrometry (GC-MS) analysis after ex - decrement in controls pre- vs . post-treatment was traction with organic solvents and derivatization. not significant (4 .32 ± 0.86 µIU/ml and 4 .23 ± Injection (1.0 µ l) was performed in splitless 0.89 µIU/ml). However , significance was ob - mode at 270 °C and a capillary column Agilent served comparing TSH values between group A 122-5532 DB-5ms (0.25 mm × 30 m × 0.25 µ m) and B post-treatment ( p ≤ 0.001) ( Table I; Figure was used. Total run time was 15 minutes: oven at I). 70 °C from 0 to 1 min; 20 °C /min to 150 °C; 10 The concentrations of fT 4 significantly in - °C/min to 240 ° C; 4 min at 320 °C in post -run. creased in treated patients, from 0 .93 ± 0.15 ng/dl

Table I. Overall results of laboratory parameters: serum TSH levels, fT4, fT3, TPOAb TgAb, and Subjective Symptomatology (SS) pre- and post-treatment with Se (group A) or with MI plus Se (group B) over a period of 6 months

Group A Group B

Tests Pre-treatment Post-treatment Pre-treament Post-treatment

TSH µIU/ml 4.32 ± 0.86 4.23 ± 0.89 4.22 ± 0.6 3.26 ± 0.89*** ,††† fT4 ng/dl 0.9 ± 0.25 0.95 ± 0.25 0.93 ± 0.15 1.06 ± 0.14 *** ,††† fT3 pg/ml 2.73 ± 0.35 2.81 ± 0.12 2.71 ± 0.44 2.83 ± 0.32 TPOAb IU/ml 820.13 ± 513.99 724.51 ± 524.98 733.7 ± 485.8 614.4 ± 472.0* ,† TgAb IU/ml 415.43 ± 275.89 422.03 ± 256.74 355 ± 220.5 298.8 ± 216.6** SS 4.6 ± 0.63 2.75 ± 0.62 §§§ 4.71 ± 0.83 2.42 ± 0.81*** ,††

Statistical differences: group A pre- vs . post-treatment (§), group B pre- vs . post-treatment (*), group A vs . group B post-treat - ment (†). p-value: §≤ 0.05; §§ ≤ 0.01; §§§ ≤ 0.001. p-value: * ≤ 0.05; **≤ 0.01; ***≤ 0.001. p-value: †≤ 0.05; †† ≤ 0.01; ††† ≤ 0.001.

53 M. Nordio, S. Basciani

Figure 1. TSH levels. Results of TSH values at baseline and after treatment in both groups (Se and MI+Se). A reduction of TSH levels was observed after treatment in MI+Se group. Values are shown as mean ± SD. at baseline to 1 .06 ± 0. 14 ng/dl after six months A significant improvement of SS was reached administration of MI-Se (p ≤ 0.001). Between among all patients . The questionnaire score pre- and post- treatment, controls showed not sta - showed a lowering from 4 .71 ± 0.83 at baseline tistical significance in fT 4 values (0 .9 ± 0.25 ng/dl to 2 .42 ± 0. 81 post-treatment in combined MI -Se and 0 .95 ± 0.25 ng/dl, respectively), whereas sig - patients ( p ≤ 0. 001), and from 4 .6 ± 0. 63 at be - nificance was seen in fT 4 titers inter-groups after ginning to 2 .75 ± 0. 62 at the end of the study in 6 months therapy ( p ≤ 0.001) ( Table I ). Se-patients (p ≤ 0. 001). One-way ANOVA re - The mean fT 3 concentrations were approxi - vealed a significant variance between group A mately identical in both groups and statistical and group B after treatment ( p ≤ 0.01) ( Table I ). significance was not observed in any of the In both groups at baseline plasma selenium analysis of variance within groups , as well as be - levels were not different (132.4 ± 13.5 µg/l group tween groups (group A pre-treatment 2 .73 ± 0. 35 A; 135.2 ± 14.8 µg/l group B). After 6 months pg/ml and post-treatment 2 .81 ± 0. 12 pg/ml; treatment, selenium values were significantly group B pre-treatment 2 .71 ± 0. 44 pg/ml and augmented in each group compared to baseline post-treatment 2 .83 ± 0. 32 pg/ml) (Table I ). (243.8 ± 20.2 µg/l , p ≤ 0.001 and 234.6 ± 17.3 At study entry , group B had a mean TgAb titer µg /l, p ≤ 0.001). At baseline there were no differ - of 355.0 ± 220.5 IU/ml and at the end of the ences between the two groups in the concentra - study 298.8 ± 216.6 IU/ml showing a not signifi - tion of MI, whereas after treatment, a significant cant reduction. A slight, but not significant in - increase of plasma MI levels was observed only crease in TgAb titer was seen in controls after 6 in the combined therapy group (27.3 ± 5.1 months of L-selenomethionine administration , µmol/l vs . 42.2 ± 5.7 µ mol/l , p ≤ 0.01). displaying as basal TgAb levels 415 .43 ± 275.89 The SPV of the inferior thyroid artery was IU/ml and post-L-selenomethionine supplemen - mainly reduced in patients treated with MI-Se, tation 422 .03 ± 256.74 IU/ml. Variance between therefore showing a minimization of the inflam - treated subjects vs . controls resulted significant mation (Data not shown). (p ≤ 0.05) ( Table I). There was a significant de - crease in mean TPOAb concentrations in group B (from 733.7 ± 485.8 IU/ml to 614.4 ± 472.0 Discussion IU/ml, ( p ≤ 0.05). The mean values of serum TPOAb concentrations in group A decreased Our study confirms that oral administration of from 820 .13 ± 513.99 IU/ml to 724 .51 ± 524.98 MI plus Se for over a period of 6 months signifi - IU/ml , but the decrement was not significant. cantly reduces serum TSH levels in Hashimoto’s Significance was observed in the comparison be - patients with subclinical hypothyroidism and tween values obtained after six months adminis - raises thyroid hormones concentration. The tration in treated vs . controls ( p ≤ 0.05) ( Table I ). changes in TPOAb and TgAb have been defined

54 Myo-inositol and selenium restore euthyroid state as secondary outcomes of the study and , as ex - nosis of AIT. These results are in agreement with pected , a lower TPOAb concentration was identi - our previous findings 20 , where, in the group treat - fied in both groups after treatment, whereas only ed with combined MI-Se , TPOAb decreased by in MI-Se group a reduction of TgAb titer was ob - 44% and TgAb by 48% . Reduction of TPOAb served. Besides, a significant SS amelioration and TgAb in the present study was less relevant was observed in all patients of each group. than in the preceding one ; this may be due to the TSH is a very sensitive marker of thyroid extended antibodies range at baseline. function and, in milder forms of hypothyroidism Previous clinical trials 16,30,31 have reported a re - like SH, it moderately increases , whereas thyroid duction of TPOAb levels after 6 months of treat - hormones stay still in the normal range. As a ment with L-selenomethionine demonstrating its matter of fact, the most important finding of this valuable contribution in lowering TPOAb and er - study was the reduction of TSH levels only in go improving clinical conditions in AIT patients . patients treated with combined MI-Se , but not in L-selenomethionine is the most common oral those treated only with Se. This might be inter - form of Se supplementation, along with sodium preted as a crucial role of MI; indeed , its benefi - selenite. Among all mechanisms regulating thy - cial effect can be explained by the inositol bio - roid function , selenium-dependent enzymes exert logical function in the TSH signaling 21,26 , regula - a particular influence 32,33 . It has been demonstrated tion of iodination 23,27 and increased sensitivity of that Se deficiency, leads to glutathione peroxidase thyrocytes to TSH 20 . TSH and its receptor consti - (GPx) inactivity, which may contribute to oxida - tute the main regulatory pathway of thyroid ; its tive harm for thyroid cells and induction of thy - signaling is quite complex involving two-second roid damage and fibrosis 34 . Turker et al 35 have messengers, cyclic AMP and MI. Precisely, in shown that TPOAb suppression in patients with human thyrocytes TSH activates the cAMP cas - AIT requires doses higher than 100 µg of L-se - cade and the Ca 2+ phosphatidyl-inositol phos - lenomethionine per day to maximize GPx activi - 29 phate cascade (PIP 2) . MI, found in the cell ties. These data are basically in agreement with membranes, is implicated in cell growth, lipid ours, obtained by the daily administration of L-se - synthesis, cell cytogenesis and morphogenesis; in lenomethionine, even if we used a lower amount. particular, growth and differentiation of thyroid It has been shown that low Se intake is associ - epithelial cells are mediated by the stimulation of ated with a significantly greater incidence of the cAMP cascade, which requires the receptor negative mood states and depression 36,37 . Al - activation by TSH and also the activation of the though mild thyroid failure is often asympto - Gs alpha subunit complex. Moreover, MI is actu - matic , nearly 30% of patients with this disorder ally known to be involved in one of the first steps may have many debilitating symptoms such as of thyroid hormone production. Therefore, as in - mood-related problems, fatigue and muscle ositol modulates H 2O2-mediated iodination and weakness, correlated to a change in the quality of hypothyroidism can be caused by an impairment life, that suggest a thyroid hormone deficiency. of inositol-depended TSH signaling branch (TSH Therefore, in our study SS was also considered, resistance) 29 , we speculate that , by increasing the including a questionnaire to evaluate changes in amount of MI , the TSH sensitivity can be im - the quality of life and related symptoms over the proved . The increase in thyroid hormones con - trial period. Patients in both groups receiving ei - centration was observed in both groups, but it ther supplementation of Se alone or combined was significantly higher in patients receiving the with MI reported significantly better wellbeing, combined MI plus Se , thereby possibly due to which supports earlier findings 16,38 . This might be the MI effect in regulating H 2O2-mediated iodi - explained by the crucial Se activity in the brain nation. As a secondary outcome of this study the and its association with senility and cognitive de - concentration of the antibodies TPOAb and cline 39,40 . Nevertheless, patients treated with both TgAb was analyzed, and , as expected , a signifi - MI and Se scored a better SS result, inducing an cant decrease of TPOAb in both groups was assumption that the combined elements might be seen. In contrast to TPOAb levels, TgAb concen - more efficacious in improving the quality of life trations decreased in MI-Se-treated group, but in - in hypothyroid patients. In fact, also inositol has creased slightly whilst not significantly in the shown to have therapeutic effects in the spectrum control group. However, plasma TPOAb concen - of illnesses responsive to serotonin selective re- trations are specific for AIT and TgAb are less uptake inhibitors such as depression, panic and relevant for the pathogenesis , as well as the diag - obsessive-compulsive disorder 41-43 .

55 M. Nordio, S. Basciani

Furthermore, inositol has been shown to play a load and oxygen consumption. We might then critical role in the etiology and treatment of poly - suppose that combination of MI-Se can also be a cystic ovary syndrome (PCOS) 44 . Indeed, several valuable aid in preventing cardiac complications studies have reported the effectiveness of inosi - in patients with AIT. tols , mainly the two stereoisomers MI and D-chi - ro-inositol (DCI) , in improving the pathological conditions associated with PCOS 45-48 . In fact, al - Conclusions though they exert different metabolic functions, both molecules are mediators of insulin action In this study, we wanted to highlight the bene - inside the cell 49 . As mentioned above, these two ficial effect of combined MI and Se , in improv - molecules have been shown to be involved in the ing clinical conditions of Hashimoto with sub - signaling-transduction cascade of insulin and clinical hypothyroidism’s patients having TSH they exert important actions in the control of glu - level between 3.0 and 6.0 µIU/ml . Though L-T 4 cose homeostasis 49,50 . It has been established that efficacy is well recognized as a treatment when insulin resistance and the consequent hyperin - the TSH level is above 10 µIU/ml 52-54,59,60 , it is sulinaemia are relevant factors associated with still disputed for patients with serum TSH levels the typical clinical signs and hormonal disorders lower than 10 µIU/ml 13,55,56 . of PCOS. MI and DCI administration, primarily The present trial corroborates our previous re - in the physiological plasma ratio (40:1), has been sults 20 , confirming that the combined treatment, proven to be an optimal approach for the treat - MI plus Se, is effective in significantly reducing ment of PCOS disorders, by improving insulin the TSH and autoantibodies values in AIT, thus resistance, serum androgen levels and many fea - improving the well-being of patients and restor - tures of the metabolic syndrome 45,47 . It has also ing the euthyroid state in Hashimoto’s subjects been shown by Paul et al 51 that MI and/or DCI with SH . work synergically in their metabolic actions and with other insulin sensitizing drugs and/or nu - ––––––––––––––––– –– traceuticals. Moreover, the 2013 Florence Inter - Acknowledgements national Consensus Conference on Myo- and D- We thank LO.LI. Pharma Srl, Rome, Italy, that kindly sup - chiro-inositol in obstetrics and gynecology has plied the formula treatments. drawn attention to the use of inositols, according to their role in oocyte and spermatozoa develop - –––––––––––––––– –-– –– ment, in assisted reproductive technologies Conflict of Interest (ART) 48 . The Authors declare that there are no conflicts of interest. Another hot topic, that lately has been debat - ed, concerns the relationship between AIT and heart and blood vessel diseases. Many studies References consistently highlight the increased risks of coro - nary illnesses and cardiovascular mortality asso - 1) LEE SL . Hashimoto thyroiditis. Medscape website. ciated with SH 55,57 , although the trend of higher http://emedicine.medscape.com/article/ risk is perceived in patients with TSH levels of 2) 120937-overview external link disclaimer. Updat - 52 ed february 25, 2013. Accessed november 14, 10 µIU/ml or greater . Furthermore, thyroid hor - 2013. mones regulate heart rate and metabolism and 3) FATOURECHI V. Demystifying autoimmune thyroid decreased serum fT 3 and fT 4 levels can lead to a disease. Which disorders require treatment? number of complications such as higher blood Postgrad Med 2000; 107: 127-134. pressure, altered endothelial function, low heart 4) WARTOFSKY L, D ICKEY RA. The evidence for a nar - rate, increased the stiffness of blood vessel walls rower thyrotropin reference range is compelling. J and augmented heart strain 58 . Therefore, in our Clin Endocrinol Metab 2005; 90: 5483-5488. study, we have shown not only that administra - 5) DUMONT JE, L AMY F, R OGER P, M AENHAUT C. Physio - tion of combined MI-Se decreases TSH levels logical and pathological regulation of thyroid cell proliferation and differentiation by thy - but also significantly increases serum T 3 and T 4 rotropin and other factors. Physiol Rev 1992; concentration. The role of thyroid hormones in 72: 667-697. patients with coronary heart diseases is not com - 6) PIETRZIK CU, H OFFMANN J, S TÖBER K, C HEN CY, B AUER pletely understood, but they could protect indi - C, O TERO DA, R OCH JM, H ERZOG V. From differenti - rectly the cardiac muscle by reducing the work - ation to proliferation: the secretory amyloid pre -

56 Myo-inositol and selenium restore euthyroid state

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