The results of Levothyroxine therapy on thyroid nodules

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1 712 The results of Levothyroxine therapy on thyroid nodules Clinic of Endocrinology, Kaunas University of Medicine, Lithuania Key words: thyroid nodules, supressive therapy, Levothyroxine. Summary. The aim of this study to investigate the effect of Levothyroxine on thyroid nodules avoiding the growth of nodules. We have compared results with studies, had evaluated this treatment method and discuss about guidelines of endocrinologist s- practitioner s consensus on this subject. Materials and methods. Sixty-two patients (all female) were evaluated. The mean age of the group was 47.89±13.73 year. Plasma thyroid stimulating hormone (TSH) concentration was measured in all patients before therapy initiation and after 6 months, some of them were observed during 24 months (20 (32.3)) and were examined every 6 months. Nodules evaluation was made by ultrasound. Therapy with Levothyroxine was prescribed for 37 (59.68) patients. The data was compared with 25 (40.32) cases of control group not treated with Levothyroxine. Results. There was reached mild TSH suppression in 11 (29.7) cases, moderate in 4 (10.8), strong in 2 (5.4) prescribing 54.39±26.71 µg of Levothyroxine. Thirteen women s TSH significantly decreased, while was >1 miu/l. Seven (18.9) patients failed suppression. Conclusions. The treatment with little moderate doses decreased TSH significantly and TSH suppression mild to strong was achieved in a half of treated investigative; furthermore, the size of thyroid nodules have changed statistically significant after 6 months of therapy and positive effect was reached for 89.2 of treated patients. Introduction Thyroid nodules are such pathologies that generally occur during work of endocrinologist. This at first sight simple contraction of a disease often raises many doubts when selecting a cure. Possibilities of treatment of nodal thyroid are rather sparing surgical ablation of node or nodules, treatment with radioactive iodine, conservative treatment with levothyroxine or just node observation (10). Since operational treatment is rather expensive and related with a particular risk of complications and patients by themselves are tended to treat conservatively as long as possible, at first more often nodule is observed or medication is prescribed. Still, is treatment with levothyroxine considered and adequate in all cases in daily practice? Definitely that thyroid-stimulating hormone (TSH) controls proliferation of thyroid tissue. Thyroxine (T 4 ) reduces TSH secretion by the principle of backward connection and anti- proliferation effect is obtained hypertrophy and hyperplasia of thyrocites are arrested. Though nodules may increase or the new ones may occur (despite TSH suppression) and because of another cells growth factors that are independent of TSH, i.e. paracrine and autocrine factors and immunologycally active agents: IGF 1 ( Insulin like Growth Factor ), epidermal growth factor, immunoglobulins that stimulate growth and concentration of iodine in thyroid (4). The goal of this treatment is to avoid increase of node while prescribing thyroid hormone preparations. It would be applicable in a case of nodal colloidal or proliferating goiter and nodules are small ( 3 cm) (6). The view of different authors about nodules treatment topic is not solid. However, not a few studies were accomplished that proved the use of suppressive therapy (4). Although the goal of treatment with levothyroxine should be suppression of endogenic TSH secretion without invoking iatrogenic thyreotoxicosis or other unwanted phenomenon, still generally insufficient doses are administered. An adequate dose (regarding literature) of levothyroxine is such that allows reducing and maintaining of TSH concentration miu/l. Such therapy is suppressive, contrarily to alternative that s goal is to maintain TSH within the mark (1,4). Correspondence to E.Sakalauskienė, Clinic of Endocrinology, Kaunas University of Medicine, Eivenių 2, 3007 Kaunas, Lithuania. eglesak@takas.lt

2 The results of Levothyroxine therapy on thyroid nodules 713 Thyroid size returns to the previous in one-year after use and termination of levothyroxine (3). That is why it is important not only to reach for non-increase of nodules or goiter, but also and to maintain gained treatment effect. Some authors refer that the less size of nodule the better treatment prognosis and results, but neither TSH, concentration of free thyroxine (f T 4 ) nor thyroglobuline are not related with regression of node (4). In summary of literature finding it could be stated that it is proved by various quantitative methods that suppressive therapy of thyroid nodules with levothyroxine allows clinically with meaning ( 50 ) reducing size of nodules or arrest growth of benign solid nodules. The other positive side is that when reducing of node this treatment reduces and perinodular volume of thyroid. Thus pressure is bypassed into surrounding bodies, cosmetic defect decreases (4). Objective.The evaluation of treatment with levothyroxine prescribed to avoid expansion of thyroid nodules and its effectiveness. Materials and methods Analysis of results of treatment and observation of patients who were consulted and treated at Endocrinology outpatient department of Kaunas University of Medicine during period of year. There were 80 patients whom nodules in thyroid were diagnosed during ultrasound analysis selected for an investigation by a casual way. Doctor radiologist at Radiology department of Kaunas University of Medicine made ultrasound examination of thyroid. Sparing alterations of thyroid tissue that were bigger than 5 mm were considered as nodules. Nodes were examined every 6 months and their structure and size were estimated with ultrasound (the biggest diameter gauge). Nodes were considered as increased if they grew up to 5 and more millimetres in 6 months (6). Investigative contingent was divided into two groups as follows: the first that was prescribed with treatment with levothyroxine in order to avoid expansion of nodules; the second (control group) treatment was not prescribed and patients were only observed. 62 patients finished the investigation: 37 patients in the first group and 25 patients in the second group. Investigated patients were divided in age groups: under 55 years and age over 55 years (1). Quantity of thyroid-stimulating hormone (TSH) in blood serum was analyzed for all patients before treatment by radioimmunology method with RIA reagents (standard miu/l) and was repeated every 6 months at hormonology laboratory of Endocrinology Institute (EI) of Kaunas University of Medicine. Levothyroxine was administered for treatment of nodules. Treatment with levothyroxine was considered as suppressive when during treatment TSH was less than 0.38 miu/l (because adequate limits from 0.1 up to 0.5 miu/l of TSH suppression are presented in literature, though standards of analysis differ in various laboratories, thus TSH was estimated while adapting according to standards of analysis in our laboratory). TSH suppression was estimated in two levels according to recommendations of multicentral examinations and international agreement as follows: strong (TSH 0.1 miu/ L) and moderate ( miu/l) (4). Since according to these recommendations TSH within the range of miu/l was referred as mild suppression (4), though meet the standard of TSH analysis of hormonology laboratory of EI, thus it was estimated as suppression only if a primary TSH analysis was more than 1 miu/l and decreased during treatment. Treatment was considered as effective when nodule increased less than 5 millimetres, did not increase, decreased or disappeared. In order to diagnose malignancy of nodules timely the aspiration biopsy (FNA) was made and aspiration material was citologically investigated for patients whom strong alterations of structure of node or increase of node were observed. Examined female patients were treated or observed for 6 months, the part of them was observed at the maximum for 24 months. Data were analyzed using statistical package SPSS 8. Averages were presented in absolute numbers as M (an average) ±SD (a standard deviation). Correlations were calculated using Pearson and Spearman correlation rate (r). Significance of disparity was controlled using paired and impaired T tests. Disparities of frequencies were estimated using Pearson chi square criterion. Observed differences estimated as significant if p<0.05. Results and discussion Treatment and observation data of 62 female patients (all of them were women) who visited Endocrinology department of Kaunas University of Medicine concerning thyroid nodules were analyzed. Age of female patients ranged from 16 to 74 years (the average 47.89±13.73). There were 40 female patients (64.52 perc.) under 55 years of old and 22 female patients (35.48 perc.) over 55 years of old. Examined female patients distributed according the number of nodules in thyroid as follows: one node was found for 27 female patients (43.55 perc.), multinodular

3 714 goiter (two nodules and more) was found for 35 female patients (56.45 perc.). Small nodules (from 0.5 cm to 1 cm) were diagnosed with ultrasound for 23 female patients (37.1 perc.), nodules of size from 1 cm to 3 cm were diagnosed for 39 female patients (62.9 perc.). When diagnosing thyroid nodules for the first time, endocrinologist meets the problem whether to prescribe treatment with levothyroxine or just observe nodules hoping their spontaneous regression. Although levothyroxine often is administered in the case of nodal goiter or in order to decrease size of diffuse goiter and to avoid relapse after operation, there are controversial views concerning its effectiveness. It is defined in examinations that perc. of cases in the occurrence of solid nodules they decrease in half without any treatment (6). Effectiveness of levothyroxine is proved in the other studies (1, 4). That and reflects complexity of reasons and topicality of problem of this disorder. Since treatment with levothyroxine may invoke the number of unwanted phenomenon and sometimes it is even dangerous, before administering this medication it is necessary to take into account age of patient, probability of assert of heart and vascular diseases and functional activity of thyroid. Particularly it is important in the case of patients who are older than 55 years, the risk and benefit should be weighted (1). The function of thyroid was estimated for all examined female patients before selecting method of treatment as follows: during examination clinic of euthyrosis was found for 48 women (77.42 perc.), hypothyrosis was suspected for 8 women (12.9 perc.), hyperthyrosis - 6 women (9.68 perc.). After performance of TSH laboratory analysis, normal function was found for all women: (TSH 1.99±1.04 miu/l) (the minimal value was 0.49 miu/l, the maximal miu/l). TSH was 1.73±0.99 miu/l in the first group of age and it was 2.48±0.96 miu/l in the second group of age and differed significantly (p=0.005). After making a diagnosis of nodular goiter a more active tactics of nodules treatment was selected as follows: levothyroxine was administered in 37 cases (59.68 perc.) and nodules of 25 women (40.32 perc.) were observed further (p = 0.14). Women were treated or observed for 24 months longest as follows: 19 women (30.6 perc.) were treated or observed for 6 months, 23 women (37.1 perc.) were treated or observed longest - for 12 months, 7 (11.3 perc.) - 18 months, 13 women (20.9 perc.) - for 24 months. In our opinion, the first group of investigative continued treatment under observation of endocrinologists in a living place. There is no one opinion about what dose of levothyroxine should be administered in the case of thyroid nodules: it is proposed to maintain at least mild or moderate TSH suppression. The most often recommended dose of levothyroxine is µg/d and it is supposed that smaller doses ( µg/d) are not sufficient in the case of nodular goiter and should be administered only in the primary stage of treatment (1,4,7,9). A primary average dose of levothyroxine was little 53.04±24.9 µg per day and ranged from 12.5 to 125 µg/d. Mostly at the beginning of treatment dose of 50 µg was administered at once (51.4 perc. of cases), more Levothyroxine, µg Fig.1. Dose of levothyroxine administered at the beginning of treatment

4 The results of Levothyroxine therapy on thyroid nodules 715 rarely dose of 25 µg was administered for 21.6 perc. of investigated patients and 75 µg for 13.5 perc. (1 figure). A little administered dose may be explained with the carefulness of doctors, because treatment with larger doses can cause serious health disorders for patients, such as auricle palpitation, complicated with systematic embolization (7). Although it is indicated in literature that these complications are more typical for people of older age, still it is avoided to administer a larger dose and for young patients fearing to overdose levothyroxine that can appear in a way of tachycardia and/or tachyarrhythmia, increasing of systolic blood pressure, increasing and perturbation of systolic heart functions and decrease of diastolic heart functions, hypertrophy of left ventricle may appear (1). Supposedly, treatment with suppressive doses of levothyroxine can cause osteoporosis, though views about this question differ. The part of scientists states that if treatment is continued not long, this complication will not occur (8), and during recently performed study while examining patients after one-year period of suppressive treatment with levothyroxine to TSH<0.3 miu/l, statistically significant reduction of bone mass density was not found Levothyroxine, µg Fig. 2. Dose of levothyroxine administered after 6 month of treatment Levothyroxine, µg Fig. 3. Dose of levothyroxine administered for the maintaining treatment

5 716 Table 1. TSH changes during study Patients TSH before study, TSH after 6 months, TSH terminal miu/l miu/l miu/l Treated: 2.23± ± ±0.69 <55 years 1.73± ± ± years 2.48± ± ±1.03 Non treated: 1.63± ± ±0.79 <55 years 1.45± ± ± years 2.12± ± ±0.86 Dose of levothyroxine was increased to 58.8±30.97 µg (min 12.5 µg, max 175 µg) after 6 months of treatment, but significantly did not differ from a primary (p=0.38); dose of levothyroxine of 50 µg was administered for 55.6 perc. (2 figure). Average dose of maintaining treatment with levothyroxine was just indistinctly larger that a primary dose 54,39±26,71 µg (p=0.73), because there was a need of reducing it for some investigative due to a lateral impact, mostly for the heart vascular system. Dose of levothyroxine of 50 µg was administered ever after for treatment of nodules in 54.1 perc. of cases (3 figure). Averages of doses among age groups did not significantly differ: 51.7±29.45 µg in the first group, and 58.33±22.49 µg in the second one (p=0.47). Thus statistically significant differences were not found while comparing treatment of female patients of age under 55 years and older. Variation of thyroid-stimulating hormone during study among both groups and age ranges are presented in the 1 st table. A primary TSH (before selecting treatment) of treated and non-treated patients differed (p=0.024). When comparing TSH between only observed and treated women after 6 months, significant difference was not found (p=0.19), though it significantly decreased (p=0.007) for treated women at the end of study. Significant reduction of TSH was found when comparing TSH before treatment with levothyroxine and after 6 months and at the end of investigation, also after 6 months and at the end (p = ; and 0.005). During period of observation TSH did not significantly change in the group of non-treated women (p>0.05). Duration of treatment conversely correlated with TSH (p= 0.001, r= 0.408). It was recommended a strong (TSH 0.1 miu/l) or moderate (TSH from 0.1 to miu/l) suppression subject to an age and a gender in the review of 26 studies where 16 independent experts pronounced. Majority of endocrinologists practitioners who prepared convention about this question, also agreed with the view that it ought to be reached for a strong TSH suppression for healthy young women. More than a half of Patients number ATVEJŲ SKAIČIUS ,9 29, , , ,1 not achieved mild moderate strong TSH significant decrease TSH supression Fig. 4. Distribution of TSH suppression among treated with levothyroxine patients

6 The results of Levothyroxine therapy on thyroid nodules 717 experts pronounced that a level of TSH ought to be reduced and for older patients or younger ones who have heart disease, though a mild or moderate TSH suppression should be maintained (4). Gained TSH suppression or reduction of TSH from a primary level in the group of treated patients is presented in the 4 th picture. Though TSH level of part of women remained over 1 miu/l, it significantly decreased after treatment: at the beginning TSH average was 2.62 miu/l, after 6 months 1.6 miu/l, and at the end of study 1.33 miu/l (p=0.001). TSH was more than 1 miu/l in 14 cases (56 ) before observation in the group of non-treated women, in 7 cases (28 perc.) less than 1 miu/l, in 4 cases (16 perc.) it decreased insignificantly (p=0.5). During period of treatment due to a worse toleration of medication in some cases it was forced to reduce dose of medication and strong TSH suppression progressed to moderate and mild in two patients, moderate TSH progressed to mild and non-suppressive in two female, in one case mild suppression progressed to not suppressed TSH level. A direct dependence was defined between maintaining dose of levothyroxine and TSH difference before and after treatment (r=0.457, p=0.0040) and between a primary and maintaining dose and TSH suppression level (p=0.033 and 0.048, r=0.351 and 0.327). Some authors consider that it is enough to maintain TSH within the range of mild suppression (0.4 1 miu/ L) (4): quite a number of information appeared in a scientific literature recently about that treatment with little doses, but such that warrant reduction of TSH from a primary level, would be effective (3) (9). It was possible to expect shrinkage of nodules or stabilization of process in 30 female patients (48.3 perc.) in this study, because while treating with levothyroxine TSH suppression or significant reduction from a primary level was obtained. Nevertheless due to the many side effects some authors recommend to reach TSH suppression only in cases of small nodules and for patients of younger age (3). Since almost third of investigated patients were women older than 55 years of age, so it was reached for a smaller suppression in this group and this could influence on rates of the whole group. Significant reduction was found for younger (p = 0.01) and older (p = 0.03) examined female patients when comparing dynamics of TSH (before treatment, after 6 months and at the end). Though maximum TSH suppression (the smallest identified TSH) in the group of younger patients did not differ from the older ones: 1.08±0.57 µg and 1.42±0.95 µg (p=0.082). Reduction of serum TSH also did not differ significantly (p=0.07) after 6 months and at the end of study. Recently it was made study which lasted 5 years wherein suppressive therapy was prescribed for a treatment of thyroid nodules: volume of nodules decreased only in the part of patients but therapy effectively protected from formation of new nodules, increase of nodules and thyroid volume (3). New nodules formatted in this study for 5 women (8.06 perc.) (3 of them (4.84 perc.) were not treated and 2 of them (3.23 perc.) were treated with levothyroxine), and disappeared for 8 (12.9 perc.): 2 of them (3.23 perc.) were not treated and 6 of them (9.68 perc.) were treated. Metaanalysis of 28 studies showed that reduction of nodule in 50 perc. and more was more frequent in the groups who got suppressive therapy (23 perc.) than in controls (10 perc.). Additionally suppressive therapy was related with a probability times greater (p=0.008) for decrease a size of node in a half (at least 50 perc.) (4). Shrinkage of nodules in 50 perc. and more after 6 months of treatment was observed in 8 cases (21.62 perc.) in this study and in 1 case (4 perc.) when nontreating. Statistical significance was not gained due to a small number of cases. Alternations of nodules size were observed in a general group, which was treated with levothyroxine, and in controls are presented on the 2 nd table and in 5 th figure. A positive dynamics of nodules variation or stabilization of their growth was observed for general in 89.2 perc. of treated women. Table 2. Changes of size of thyroid nodules Thyroid nodules n () Treatment with levothyroxine not of increased of decreased or increased and changed all all disappeared decreased Administered (n=37) 20 (54.1) (10.8) (35.1) 21 Not administered (n=25) 17 (68) (16) (12) (4) 1.6 Total (n=62)

7 Perc decreased Increased/ decreased Not changed Changes in thyroid nodules size increased treated controls Fig. 5. Comparison of thyroid nodules size between treated and not treated patients Significant differences were not found when comparing frequency of increase of nodules between treated and non-treated female patients (p=0.22), their increase in groups with one node and several nodules (p=0.73), age ranges (p=0.83). While administering levothyroxine size of nodules did not change significantly in the group of small nodules comparing with medium and large ones. Nodes of non-treated patients also did not differ in groups of different size of nodules (p>0.05). Size of nodules statistically significantly decreased already after 6 months of treatment: average of the largest measure of diameter was 1.35±0.73 cm before treatment and decreased to 1.09±0.7 cm after treatment (p=0.024), notwithstanding again increased to 1.36±0.91 cm (p=0.073) though insignificantly. Size of node did not differ among age groups and was as follows: in the group of younger female patients before treatment 1.26±0.78 cm, after 6 months of treatment 0.99±0.63 cm and in the group of older female patients 1.49±0.66 cm and 1.25±0.81 cm (p>0.05), after treatment 1.36±1.01 cm (p>0.05). Reduction of nodules was not significant for younger women when administering levothyroxine (p=0.21). Nodes of non-treated patients did not change in 6 months of observation (p=0.67), but they decreased by themselves at the end of observation (p=0.023). Size of nodules did not differ significantly among the groups of treated and non-treated women at the beginning of study (p=0.15), after 6 months (p=0.76) and at the end of study (p=0.9). Duration of treatment did not influence on changes of nodules size (r=0.15). According to recommendations treatment must be continued for 6 12 months and if while treating with levothyroxine a further increase in nodule size is observed, than it will be terminated and FNA (fine needle aspiration) will be made in order to solve question concerning surgical treatment. FNA was made for 9 female patients due to change of size of nodules or structure in order to specify a structure of nodule: adenoma was found in 4 cases (4.88 perc.), benign goiter, colloid nodule or cystic changes (cystic content or cystic degeneration) were found in 5 cases (6.1 perc.). If size of nodule is stabilizing or its regression is observed, treatment might be terminated for 6 months and again prescribed when notifying increase (1), or if after terminating TSH remains suppressed for 2 months, especially if probability of cardiovascular diseases exists, it is recommended only to observe patient (6). Treatment was not terminated for patients, whom TSH suppression was gained in study; only dose of levothyroxine was reduced. A level of momentary strong TSH suppression was achieved only in one case; moderate TSH suppression was achieved in two cases and mild TSH suppression was achieved in other two cases from 7 cases (12.28 perc.) when dose of medication was reduced; suppression was not gained in the rest two cases. The main reason of dose reduction was not gained strong suppression, but worse toleration of medicament and, maybe, a fear of doctor to overdose medication.

8 The results of Levothyroxine therapy on thyroid nodules 719 Conclusions 1. TSH statistically significantly decreased while treating with small and medium doses of levothyroxine (54.39±26.71 µg). 2. TSH suppression was achieved for 48.3 perc. of female patients who were treated with levothyroxine. 3. A direct dependence was settled between dose of levothyroxine and a level TSH suppression. 4. A positive effect of treatment was gained for 89.2 perc. of examined female patients who were administered with levothyroxine. 5. Size of nodules statistically significantly decreased already after 6 months of treatment with levothyroxine or they did not increase later. 6. Duration of treatment did not influence changes in nodules size. Skydliaukės mazgų gydymo levotiroksinu rezultatai Kauno medicinos universiteto Endokrinologijos klinika Raktažodžiai: skydliaukės mazgai, supresinė terapija, levotiroksinas. Santrauka. Šio darbo tikslas atlikti gydymo levotiroksinu, skiriamo siekiant išvengti skydliaukės mazgų didėjimo, efektyvumo analizę. Duomenys lyginti su studijų, tyrusių šį gydymo metodą, rezultatais. Nagrinėjamos ir tarptautinio endokrinologų praktikų susitarimo gairės supresinio gydymo levotiroksinu klausimais. Stebėtos 62 pacientės. Vidutinis tiriamųjų amžius 47,89±13,73 metų. Prieš paskiriant gydymą ir po 6 mėnesių visoms pacientėms tirtas tireotropinis hormonas serume. Dalis tiriamųjų stebėtos ilgiau (24 mėnesius 20 (32,3 proc.)) ir tirtos kas šeši mėnesiai. Mazgų dydžio pakitimai vertinti ultragarsiniu tyrimu. 37 (59,68 proc.) pacientėms skirtas gydymas levotiroksinu. Duomenys lyginti su 25 (40,32 proc.) kontrolinės grupės tiriamųjų, kurioms levotiroksino neskirta. Skiriant vidutiniškai 54,39±26,71 µg levotiroksino, neryškios tireotropinio hormono supresijos (0,4 1 miu/l) pasiekta 11 (29,7 proc.), vidutinio lygio supresijos 4 (10,8 proc.), o ryškaus tireotropinio hormono sumažėjimo ( 0,1 miu/l) 2 tiriamosioms (5,4 proc.). Trylikai moterų (35,1 proc.), nors tireotropinis hormonas išliko daugiau 1 miu/l, tačiau žymiai sumažėjo. 7 (18,9 proc.) tiriamųjų tireotropinio hormono supresijos nepasiekta. Išvados. Gydant nedidelėmis ir vidutinėmis dozėmis, tireotropinio hormono reikšmingai sumažėjo, o tireotropinio hormono supresija nuo nežymios iki vidutinės pasiekta pusei levotiroksinu gydytų tiriamųjų. Be to, mazgų dydis statistiškai reikšmingai sumažėjo jau po šešių mėnesių gydymo, arba vėliau jie nedidėjo. Teigiamų gydymo rezultatų pasiekta 89,2 proc. gydytų moterų. Adresas susirašinėjimui: E.Sakalauskienė, KMU Endokrinologijos klinika, Eivenių 2, 3007 Kaunas El. paštas: eglesak@takas.lt References 1. Mercuro G, Panzuto M.G, et al. Cardiac function, physical exercise capacity, and quality of life during long term thyrotropin supressive therapy with Levothyroxine: effect of individual dose tailoring. J Clin Endocrinol Metab 2000;85:1. 2. Colin M Dayan, Gilbert H, Daniels. Chronic autoimmune thyroiditis. NEJM 1996;335: Papini E, Petrucci L. Long term changes in nodular goiter: a 5 years prospective randomised trial of levothyroxine suppressive therapy for benign cold thyroid nodules. J Clin Endocrinol Metab 1998;83: Csako G, Byrd D, et al. Assessing the effects of thyroid supression on benign solitary thyroid nodules. A model for using Quantative research synthesis. Lippincot Williams and Vilkins 2000;79(1): Tunbridge W, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Wickham survey. Clin Endocr 1977;7: Gerasimov G, Troškina E. Diferencijalnaja diagnostika i vybor lečenija pri yzlovom zobe. (Differential diagnosis and choise of treatment in nodular goiter.) Problemy endokrinologyi 1998: Toft AD. Thyroid hormone treatment, how and when? Thyroid international 2001;4: Leb G, Waerkross H, Obermayer P. Thyroid hormone excess and osteoporosis. Acta Medica Austriaca 1994;21: Zelmanovitz F, Genro S, Gross JL. Suppressive therapy with levothyroxine for solitary thyroid nodules : A double-blind controlled clinical study and cumulative meta-analyses. J Clin Endocrinol Metab 1998;83: Wesche MFT, Tiel-v Buul MC, Lips P, et al. A randomised trial comparing Levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J Clin Endocrinol Metab 2001;86(3): Received 14 May 2002, accepted 24 June 2002