Refence values of serum TSH in humans:
Confusing data!
Two recent publications report 95% reference values for serum TSH of which the upper-normal level differ considerable.  Thus while the NACB guide lines suggest a limit of  2.5mU/L (see below), Jensen et al. (see below)  find a  value that is not different from the ones that we still use i.e. 4 mU/L.
What is the consequence for clinicians from this confusing situation? Should we change TSH reference values or not? Maybe people should get together to sort out the differences, so that hopefully we soon know where we stand.

NACB guide lines 2002: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. Laurence M. Demers LM and Spencer CA, pp34 
TSH Upper Reference Limits-Over the last two decades, the upper reference limit for TSH has steadily declined from ~10 to approximately ~4.0-4.5 mIU/L. This decrease reflects a number of factors including the improved sensitivity and specificity of current monoclonal antibody based immunometric assays, the recognition that normal TSH values are log-distributed and importantly, improvements in the sensitivity and specificity of the thyroid antibody tests that are used to pre-screen subjects. The recent follow-up study of the Whickham cohort has found that individuals with a serum TSH >2.0 mIU/L at their primary evaluation had an increased odds ratio of developing hypothyroidism over the next 20 years, especially if thyroid antibodies were elevated (35). An increased odds-ratio for hypothyroidism was even seen in antibody-negative subjects. It is likely that such subjects had low levels of thyroid antibodies that could not be detected by the insensitive microsomal antibody agglutination tests used in the initial study (207). Even the current sensitive TPOAb immunoassays may not identify all individuals with occult thyroid insufficiency. In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.
(b) TSH Lower Reference Limits -Before the immunometric assay era, TSH methods were too insensitive to detect values in the lower end of the reference range (209). Current methods however, are capable of measuring TSH at the lower end and now cite lower limits between 0.2 and 0.4 mIU/L (202). As the sensitivity of the methods has improved, there has been an increased interest in defining the true lower limit of normal to better determine the presence of mild (subclinical) hyperthyroidism.  Current studies suggest that TSH values in the 0.1 to 0.4 mIU/L range may represent thyroid hormone excess and in elderly patients might be associated with an increased risk of atrial fibrillation, and cardiovascular mortality (36,37). It is therefore important to carefully exclude subjects with a goiter and any illness or stress in the normal cohort selected for reference range study.

Clinical Chemistry and Laboratory Medicine 42, (7) (2004)
Esther Jensen, Per Hyltoft Petersen, Ole Blaabjerg, Pia Skov Hansen, Thomas H. Brix, Kirsten Ohm Kyvik and Laszlo Hegedüs
Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies 
It has previously been shown that thyroid antibodies affect thyroid stimulating hormone (TSH) concentrations in men and women and that TSH levels are predictive of future thyroid disease. We investigated the validity of the National Academy of Clinical Biochemistry (NACB) guidelines regarding the TSH reference interval by studying 1512 individuals. Two hundred and fifty had at least one thyroid antibody, 121 were taking medications other than estrogens and occasional analgesics, and 105 reported a family history of thyroid disease. Serum TSH, thyroid peroxidase antibodies (TPOab) and thyroglobulin antibodies (Tgab) were determined on AutoDELFIA and TSHRab by a radioreceptor assay (RRA) from Brahms Diagnostica. For individuals without thyroid antibodies and other risk factors, no effect of age and gender was seen for serum TSH. Neither medication nor the presence of Tgab alone had any influence on serum TSH. TPOab alone or in combination with Tgab were associated with an increased serum TSH level. The ‘cumulative percentage distributions’ of subgroups, as well as the combined population, was ln-Gaussian distributed. The central 95% of the population was within the 95% CI in rankit-plots. Consequently, a common reference interval for serum TSH of 0.58–4.07 mIU/l for all adults between 17 and 66 years of age was established. This reference interval is much higher than expected from the NACB guidelines.

TSH response to TRH in bipolar depression

There have been reports in the literature about the hypothalamic-pituitary-thyroid (HPT)-axis in psychiatric patients, suggesting that it may be abnormal. The present study (see below) has the advantage that it is performed in a well defined group of patients, i.e. with bipolar affective disorder, that repeated HPT-axis function tests were done in a prospective manner over a period of no less than 3 years. Tests were done every 3 months and at the same time mood ratings were collected. The authors find an inverse correlation between the TSH response to TRH and the severity of mood derangement. The authors can not rule out an influence of lithium therapy on the results but argue that this is unlikely. The mechanism of this relationship is unknown but could point to a supra-hypothalamic regulation of the HPT-axis. It would be interesting to evaluate if this type of regulation is a general phenomenon, i.e. to test the HPT-axis in non-psychiatric healthy subjects versus changes in mood over a period of time.

Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder Psychoneuroendocrinology. 2004 Aug;29(7):917-924. J. K. Larsen , J. Faber, E. M. Christensen, B. B. Bendsen, K. Solstad, A. Gjerris and K. Siersbæk-Nielsen

Abstract -Moderate to severe depression and mania are associated with a reduced thyroid stimulating hormone (TSH) response to TSH releasing hormone (TRH). Continued reduction of this response after clinical recovery seems indicative of early relapse. The aim of the present study was to test the relationship between mild changes in mood and the TSH response to TRH stimulation in patients with bipolar affective disorder. Nineteen outpatients with bipolar affective disorder were followed prospectively for three years. Every third month, mood symptoms were rated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Bech-Rafaelsen Mania Scale (BRMS). A TRH test was performed in connection with each rating session (IV injection of 200 μg TRH), and serum TSH was measured at 0, 20, and 60 min. The maximum TSH response (D-max TSH) and the temporal change in D-max TSH between succeeding rating sessions (DD-max TSH) were determined. Psychometric rating and TRH data were obtained for a total of 198 examinations. The temporal change in mood symptom rating score was negatively correlated with the temporal change in D-max TSH, thus suggesting that increasing severity of mood symptoms was related to a reduced TSH response to TRH stimulation. The temporal change in TSH response to TRH stimulation correlated with the actual score on an overall index of symptom severity. In conclusion, milder fluctuations in mood in bipolar affective disorder seem to correlate with the TSH response to TRH stimulation: Increasing severity of mood symptoms seems to be associated with reduced TSH response.

Improved cytological differentiation between benign and malignant follicular thyroid tissue, using molecular markers (12 May 2004)
A common problem in clinical practice is the evaluation and management of thyroid tumors with a follicular pattern. Cytology obtained by FNA cannot differentiate between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC).  Therefore most guidelines recommend that a nodule diagnosed as having a follicular pattern should be surgically removed to provide an accurate diagnosis. Overall, only 8–17% of these cytologically suspicious nodules are indeed malignant on histology. A large percentage of patients would, therefore, benefit greatly from improved diagnosis of FNA material. Accurate molecular markers based on genes expressed differentially between FTC and FTA would be one means of improving the accuracy of diagnoses made from FNA.
Janete M. Cerutti, et al, abstract see below, analyzed the gene-expression profile in normal thyroid tissue, follicular adenoma tissue (FTA), and follicular carcinoma tissue (FTC). They selected twelve transcripts that were highly expressed in the FTC library, and five that were expressed only in FTA and normal-thyroid libraries. These marker-transcripts were tested in 23 specimens of FTC, FTA and normal thyroid tissue, in order to evaluate if differences in expression profile could improve cytological differentiation between FTA and FTC.
ABSTRACT  A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression
Janete M. Cerutti,^1,2 Rosana Delcelo,³ Marcelo João Amadei,¹ Claudia Nakabashi,¹ Rui M.B. Maciel,¹ Bercedis Peterson,⁴ Jennifer Shoemaker,⁴ and Gregory J. Riggins⁵
J Clin Invest. 2004 April 15; 113 (8): 1234–1242
Accurate diagnosis of thyroid tumors is challenging. A particular problem is distinguishing between follicular thyroid carcinoma (FTC) and benign follicular thyroid adenoma (FTA), where histology of fine-needle aspirates is not conclusive. It is often necessary to remove healthy thyroid to rule out carcinoma. In order to find markers to improve diagnosis, we quantified gene transcript expression from FTC, FTA, and normal thyroid, revealing 73 differentially expressed transcripts (P ≤ 0.0001). Using an independent set of 23 FTCs, FTAs, and matched normal thyroids, 17 genes with large expression differences were tested by real-time RT-PCR. Four genes (DDIT3, ARG2, ITM1, and C1orf24) differed between the two classes FTC and FTA, and a linear combination of expression levels distinguished FTC from FTA with an estimated predictive accuracy of 0.83. Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]). A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules, allowing better treatment decisions and reducing long-term health costs.

McDermott MT, Woodmansee WW, Haugen BR, Smart A, Ridgway EC Thyroid 13,1133-39,2004
The management of subclinical hyperthyroidism by thyroid specialists ABSTRACT

More experience with recombinant human thyrotropin.

The group from Nijmegen, The Netherlands, who have extensive experience with RAJ treatment of nodular goiter, now show that pre-treatment with a low dose rhTSH allows about 50% reduction of the therapeutic RAJ dose without affecting percentage reduction of thyroid volume, see abstract 1.

The group from Frankfurt, Germany, show that effective half-life of ¹³¹I in patients treated for thyroid carcinoma is shortened when pre-treated with hrTSH. See abstract 2.

WAIT AND SEE FOR PAPILLARY MICROCARCINOMA?

Treatment of thyroid papillary carcinoma's less than 10 mm in diameter (termed papillary microcarcinoma, formerly occult carcinoma) is being debated increasingly. Since the introduction of the ultrasound in medicine, imaging of the thyroid is frequently performed and is sufficiently sensitive to detect nodules of > 3 mm in diameter. It has been known for a long time that in routine autopsy of the thyroid, microcarcinoma's of the papillary type are frequently found. Thus, Fukanga and Yatani (Cancer 36: 1095-9,1975) report a worldwide geographical variation in frequency of these tumours between 5% and 24%. Many of these tumours seem to be biologically inactive and hence the controversy about the treatment if such nodules are "accidentally" detected.

Yashiro et al, (Thyroid 13:381-387, 2003) now report that patients with papillary microcarcinoma's may choose between surgical treatment or observation, even if these tumours are multifocal and/or involve lymph nodes, as they rarely become clinically apparent.

ABSTRACT:

FUTURE USE OF CYTO-GENETICS IN THE DIAGNOSIS OF PAPILLARY THYROID CARCINOMA?
An activating mutation in the BRAF gene has found to be associated with the majority of papillary thyroid cancers (69%), according to a report in the Journal of the National Cancer Institute (abstract see below).The BRAF gene product activates the mitogen-activated protein kinase (MAPK) pathway, resulting in abnormal proliferation and differentiation in many human cancers, the authors explain. BRAF has previously been shown to be activated in 80% of malignant melanoma tumors and in colon carcinoma. The authors screened for the common BRAF T1796A mutation in over 300 cancer specimens -- 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers.
Twenty-four of 35 (69%) papillary thyroid carcinomas contained the BRAF mutation, the authors report. In contrast, no BRAF mutations were identified in samples from 13 patients with follicular thyroid carcinoma, three patients with medullary thyroid carcinoma, three patients with Hurthle cell carcinoma, or 20 patients with benign thyroid conditions.
ABSTRACT
BRAF Mutation in Papillary Thyroid Carcinoma .  Yoram Cohen, Mingzhao Xing, Elizabeth Mambo, Zhongmin Guo, Guogun Wu, Barry Trink, Uziel Beller, William H. Westra, Paul W. Ladenson, David Sidransky , J Natl Cancer Inst 95:625-627,2003.
The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)–restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.

OVEREXPRESIION OF DEIODINASES IN TUMOROUS TISSUES  
B. W. Kim, et al, J Clin Endocrinol Metab, 88,594-598,2003, describe 3 patients with follicular thyroid carcinoma and elevated plasma T₃ to T₄ ratio, due to overexpression of type II deiodinase in carcinomatous tissue, leading to increased T₄ to T₃ conversion ( see abstract below). 
The same group published ( NEJM 343,185-189,2000) overt hypothyroidism in infants with massive haemangiomas due to increased expression of type III deiodinase in these tissues, resulting accelerated inactivation of thyroid hormone for which the infants thyroid could not compensate.
It would be interesting to study plasma T₃/T₄ ratios in patients with different tumors to study further the phenomenon of overexpression of deiodinases affecting the thyroid hormone profile.
Abstract   Thyroid function is normally undisturbed in patients with thyroid carcinoma. We have identified three patients with large or widely metastatic follicular thyroid carcinoma who had a persistently increased ratio of serum T₃ to T₄ in the absence of autonomous production of T₃ by the tumor. To investigate the possibility of tumor-mediated T₄ to T₃ conversion, we assayed types 1 and 2 iodothyronine selenodeiodinase (D1 and D2) activity in a 965-g follicular thyroid carcinoma resected from one of these patients. The V_max for D2 was 8-fold higher than in normal human thyroid tissue. Resection of this tumor, leaving the left thyroid lobe intact, normalized the serum T₃ to T₄ ratio. In two other patients, treatment with sufficient levothyroxine to suppress TSH was associated with a high normal T₃ and a subnormal free T₄ index. In one, concomitant administration of the D1 inhibitors, propylthiouracil and propranolol, did not decrease the elevated serum T₃ to T₄ ratio. These data illustrate that increased T₄ to T₃ conversion in follicular thyroid carcinomas, probably by D2, can cause a significant perturbation in peripheral thyroid hormone concentrations.  

An hitherto  un-recognized  side effect  of ¹³¹I treatment
Nasolacrimal Drainage System Obstruction from Radioactive Iodine Therapy for Thyroid Carcinoma
Richard T. Kloos, Vani Duvuuri, Sissy M. Jhiang, Kenneth V. Cahill, Jill A. Foster and John A. Burns
Abstract-Ophthalmic complications of ¹³¹I therapy, including ocular dryness, have been recently investigated and described. However, nasolacrimal drainage system obstruction (NDSO), complicating ¹³¹I therapy, has not been previously well appreciated or characterized. One of our patients developed bilateral complete nasolacrimal duct obstruction after ¹³¹I therapy that prompted awareness of this potential complication. Over 16 months, 423 patients with epithelial-derived thyroid cancer were provided routine clinical care; 390 of these patients had received ¹³¹I ablation or therapy, and 10 patients subsequently reported epiphora. All had evidence of NDSO disease after a mean cumulative ¹³¹I dose of 17,279 ± 2,923 MBq (467 ± 79 mCi), with a mean individual ¹³¹I dose of 6,660 ± 555 MBq (180 ± 15 mCi). Symptoms appeared 6.5 ± 1.4 (range, 3–16) months after the last ¹³¹I dose, whereas the mean time from symptom onset to correct diagnosis was 18 ± 5 months. A causal relationship between ¹³¹I administration and NDSO is strongly suspected. Patients reporting epiphora should be evaluated promptly by an oculoplastic surgeon.

L-T4 substitution revisited. (1 Nov 02)
There is growing interest if not concern amongst thyroidologists about the way we substitute for thyroid failure. The standard treatment consist of L-T₄ substitution in a dose that normalizes serum TSH. The question however is if this regimen is still correct. In this respect there are several points that have to be discussed.

1. Organs depend differently for T₃-nuclear occupancy on T₃ extracted form the plasma and T₃ that is locally produced from T4. In hypothyroid rats all organs are in a euthyroid state only if the serum T4/T₃ ratio is kept normal by subcutaneous administration of T4/T₃ in an amount and ratio as produced by the intact thyroid (Escobar-Morreale HF, et al. Endocrinology 1996; 137: 2490-2502.) As thyroid hormone metabolism and action in humans and rats is similar in many aspects, this phenomenon may also be true man. Substitution of thyroid function in hypothyroid patients using T₄ only, results in an elevated T4/T₃ serum ratio, because the thyroidal contribution to plasma T₃ is lacking. Bunevicius R, et al (New Engl J Med 1999; 340: 424-29.) reported that in hypothyroid subjects when substituted with a combination of T₄ and T₃, cognitive function was better than when treated with T₄ only. Alevizaki et al, (see: Abstracts ETA, 2002: www.hotthyroidology.com or J Endocrinol Invest, 25, suppl to 7, 77, 2002) demonstrate that substitution with T₄ only, such that serum TSH is normal, results in serum T₃ and SHBG concentrations that are lowered, suggesting hypothyroidism at the level of the liver.  However A Levitt and J Silverberg reported at the American Thyroid Assoc. annual meeting (Program, Annual Meeting, p.112, Oct 10-13, 2002)  that T₄ alone, or T₄ plus T₃ in 15/1 ratio given twice daily, were overall equivalent  in a double blind 3-6 month evaluation.
2. There are recent suggestions that we have to re-define the normal serum TSH 

range. Thus Spencer et al, (see: Abstracts ATA 2002,  www.thyroid.org or Program and Abstracts 74^th Annual Meeting ATA, 2002, p 111.) suggest a range between 0.4 and 2.0 mU/L, as values >2.0 mU/l may represent early hypothyroidism. Others advise an optimal “normal” TSH range of 0.4 to 1.5 mU/L for patients substituted with T₄ only.

In summary the questions are 1) if we should narrow the normal range for serum TSH to 0.4 and 2.0 mU/L and 2) if substitution with L-T₄ only is adequate or should be effected with a combination preparation of T₄ plus T₃? 
     In a sense complementary to the study of Bunevicius R, et al ( see above), Saravan et al abstract see below, report that “ patients on thyroxine replacement even with a normal TSH display significant impairment in psychological well-being compared to controls”. 
      The point seems to be if the apparent cognitive impairments detected in subjects on L-T₄ substitution are due to incorrect adjustment of serum TSH and or absent  T₃ in the substitution preparation.   
ABSTRACT:
Psychological well-being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based questionnaire study.
Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Clin Endocrinol (Oxf) 57:663-586,2002
OBJECTIVE: Over 1% of the UK population is receiving thyroid hormone replacement with l-thyroxine (T4). However, many patients complain of persistent lethargy and related symptoms on T₄ even with normal TSH levels. To date there has been no large study to determine whether this is related to thyroxine replacement or coincidental psychological morbidity. We have therefore attempted to address this issue using a large, community-based study. DESIGN AND PATIENTS: Computerized prescribing records of five general practices were used to identify 961 patients who had been on thyroxine for a minimum of 4 months from a population of 63 000 (1.5%), along with age- and sex-matched controls. All 1922 individuals were sent a two-page questionnaire, made up of the short form of the General Health Questionnaire (GHQ-12), designed to detect minor psychiatric disorders in the community, and a 12-question 'thyroid symptom questionnaire' (TSQ) in the same format. A covering letter explained that we were interested in 'how patients felt on medication' and made no direct reference to thyroxine. MEASUREMENTS: Scores from the GHQ and TSQ were marked for each individual using the GHQ and Likert scoring methods. Patients' latest TSH measurements were obtained from laboratory records. Comparisons were then made on scores for the total GHQ-12, TSQ and individual questions between patients (P) and control (C) groups. Separate analyses were made comparing the patients with a normal TSH (nP) and the control group. RESULTS: Five hundred and ninety-seven (62%) of the patients (P) and 551 (57%) of the controls (C) responded and fully completed at least one of the two questionnaire. Three hundred and ninety-seven responding patients (nP) had a TSH estimation performed in the previous 12 months with the last result being in the local laboratory normal range for TSH (0.1-5.5 or 0.2-6.0 mU/l, according to the assay method used). The responding P, nP and C populations were well matched for age (59.96, 59.73, 59.35 years) and sex (85%, 83%, 87% female). The number of individuals scoring 3 or more on the GHQ-12 (indicating 'caseness') was 21% higher in P than C [185/572 (32.3%) vs. 137/535 (25.6%), P = 0.014] and 26% higher in nP than C [131/381 (34.4%) vs. 137/535 (25.6%), P < 0.005]. Stronger differences were seen with the TSQ scores [C = 187/535 (35.0%), P = 273/583 (46.8%), P < 0.001, P vs. C; and nP = 189/381 (48.6%), P < 0.001, nP vs. C]. Differences existed in chronic drug use and chronic disease prevalence between the control and patient groups, but the differences in GHQ and TSQ scores between the groups remained significant even after correction for these factors as well as age and sex in multiple regression analysis. CONCLUSIONS: This community-based study is the first evidence to indicate that patients on thyroxine replacement even with a normal TSH display significant impairment in psychological well-being compared to controls of similar age and sex. In view of the large numbers of people on thyroxine replacement, we believe that these differences, although not large, could contribute to significant psychological morbidity in a substantial number of individuals.

  September 2002
In 1998, Zelmanovitz et al (JCEM 83,3881,1998) published the results of a cumulative meta-analysis (risk-difference method) of studies assessing the effect of TSH suppression by T₄ on the volume of benign solitary thyroid nodules. Altogether 7 studies were included in this meta-analysis. These studies met the following criteria: prospective, controlled clinical trials with a sufficient dose of T₄ for TSH suppression, minimum follow-up of 6 months, and nodule volume monitored by ultrasonography. They concluded that T₄ treatment would decrease nodule volume by more than 50% in only 17% of patients and inhibit growth in a further 10%.
In a recent study by an other group, abstract see below, a similar analysis was done using the same criteria. In total, 7 studies were included, of which 5 were also included in the analysis mentioned above. From the results of this study the authors could not find a significant reduction in nodule volume.
COMMENT
It seems that it is reasonable to conclude that, although a great many studies have entered the literature that are concerned with the effect of TSH suppression on benign nodule volume, only a few can withstand scientific criteria. From these few studies, in total 9, no important effect could be found from TSH suppression on benign nodule volume. In the opinion of the writer, Dr Georg Henneman, there is no place for routine, TSH suppression in such patients, considering the lack of an important effect and the risks of T₄ suppressive therapy on bones and heart. 
Nevertheless, opinion (L De Groot,MD) remains divided. Many physicians advise treatment to place TSH at the bottom of the normal range, considering 1) that in the first study quoted 27% were found to have a positive effect after as short a time as 6 months, 2) that  long term treatment may help prevent enlargement if not causing shrinkage, 3) the treatment may help prevent development of other nodules, and 4) treatment can be carried out without significant risk to the patient.
Abstract:M. Regina Castro, Pedro J. Caraballo and John C. Morris. Effectiveness of Thyroid Hormone Suppressive Therapy in Benign Solitary Thyroid Nodules: A Meta-Analysis. Journal of Clinical Endocrinology and Metabolism
The effectiveness of thyroid hormone suppressive therapy in reducing the volume of benign thyroid nodules is controversial. It is important to clarify this therapeutic effect of thyroid hormone, because its prolonged use needs to be carefully weighed against its potential deleterious effects in the skeletal and cardiovascular systems. To evaluate the best available evidence, we conducted a systematic review and meta-analysis of the randomized controlled trials that fulfill the following inclusion criteria: single thyroid nodules proven benign by fine needle aspiration, treatment, and follow-up of at least 6 months; documented suppression of TSH; measurement of thyroid nodule volume by ultrasound; and response to therapy defined as more than 50% volume reduction from baseline. Six randomized clinical trials published between 1987 and 1999, with 346 patients, were included in the meta-analysis. Ninety percent of the participants were female. Using a random effects model, the overall effect size showed a relative risk of 1.9 (95% confidence interval, 0.95–3.81) favoring a treatment effect. A sensitivity analysis showed significant changes in the results. 
Suppressive thyroid hormone therapy for longer than 6 months is associated with a trend toward a reduction of more than 50% in volume of benign thyroid nodules, without achieving statistical significance. The results are highly sensitive to changes in the statistical analysis, especially if the method used ignores heterogeneity among the effect sizes. More studies are needed before this therapy can be widely recommended.  

SUPPRESSIVE THERAPY WITH LEVOTHYROXINE FOR SOLITARY THYROID NODULES:  A DOUBLE-BLIND CONTROLLED CLINICAL STUDY AND CUMULATIVE META-ANALYSIS  
Flavio Zelmanovitz, Sandra Genro, and Jorge L. Gross(J. Clin. Endocrinol. Metab. 83:3881-3885, 1998.)     Levothyroxine suppressive treatment of solitary thyroid nodules is controversial.  A one year prospective randomized placebo-controlled trial was conducted to evaluate the effect of T₄ on nodule volume and bone mineral density, and meta-analyses were performed to examine the quantitative synthesis of data from similar designed controlled trials.  Forty-five euthyroid patients (42 females, age range: 19-73 yr) with single, colloid nodules were randomized to T₄   (21 patients, 2.7 " 0.3 Fg/kg, TSH < 0.3 FIU/ml) and placebo.  Ultrasonography and densitometry were performed at baseline and repeated after treatment.  Mean nodule volume or bone mineral density did not change.  Nodule reduction more than 50% was observed in 6 of 21 treated patients and 2 of 24 placebo patients (P = 0.12).  This study and another 6 prospective controlled trials (minimum 6 months, ultrasonographic nodule evaluation) were included in cumulative meta-analyses (risk-difference method).  Nodule volume decreased more than 50% in a significantly higher percentage of patients in the T₄  groups (risk difference, 16.7%; 95% confidence intervals, 5.8 – 27.6%).  Four trials evaluated nodule growth with homogeneous results (Q = 0.42).  Nodule volume increased more than 50% in a significantly smaller percentage of patients treated with T₄  (risk difference, 9.7%; 95% confidence intervals, 2.0-17.4%).  In conclusion, T₄ treatment is associated with decreased nodule volume in 17% of patients and may inhibit growth in another 10%.