Thienpont LM, Van Uytfanghe K, De Grande LAC, Reynders D, Das B, Faix JD, MacKenzie F, Decallonne B, Hishinuma A, Lapauw B, Taelman P, Van Crombrugge P, Van den Bruel A, Velkeniers B, Williams P; IFCC Committee for Standardization of Thyroid Function Tests (C-STFT).
Harmonization of Serum Thyroid-Stimulating Hormone Measurements Paves the Way for the Adoption of a More Uniform Reference Interval.
Clin Chem. 2017 Jul;63(7):1248-1260. doi: 10.1373/clinchem.2016.269456. Epub 2017 May 18.
Abstract/Text
BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests developed a global harmonization approach for thyroid-stimulating hormone measurements. It is based on a multiassay method comparison study with clinical serum samples and target setting with a robust factor analysis method. Here we describe the Phase IV method comparison and reference interval (RI) studies conducted with the objective to recalibrate the participating assays and demonstrate the proof-of-concept.
METHODS: Fourteen manufacturers measured the harmonization and RI panel; 4 of them quantified the harmonization and first follow-up panel in parallel. All recalibrated their assays to the statistically inferred targets. For validation, we used desirable specifications from the biological variation for the bias and total error (TE). The RI measurements were done with the assays' current calibrators, but data were also reported after transformation to the new calibration status. We estimated the pre- and postrecalibration RIs with a nonparametric bootstrap procedure.
RESULTS: After recalibration, 14 of 15 assays met the bias specification with 95% confidence; 8 assays complied with the TE specification. The CV of the assay means for the harmonization panel was reduced from 9.5% to 4.2%. The RI study showed improved uniformity after recalibration: the ranges (i.e., maximum differences) exhibited by the assay-specific 2.5th, 50th, and 97.5th percentile estimates were reduced from 0.27, 0.89, and 2.13 mIU/L to 0.12, 0.29, and 0.77 mIU/L.
CONCLUSIONS: We showed that harmonization increased the agreement of results from the participating immunoassays, and may allow them to adopt a more uniform RI in the future.
© 2017 American Association for Clinical Chemistry.
Refetoff S, DeWind LT, DeGroot LJ.
Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone.
J Clin Endocrinol Metab. 1967 Feb;27(2):279-94. doi: 10.1210/jcem-27-2-279.
Abstract/Text
Tagami T.
An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.
Endocr J. 2021 May 28;68(5):509-517. doi: 10.1507/endocrj.EJ21-0059. Epub 2021 May 6.
Abstract/Text
Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of β type of resistance to thyroid hormone (RTHβ). The differential diagnoses of RTHβ include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHβ, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHβ and TSHoma. The FT3/FT4 values in RTHβ were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.
Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi IS, Gurnell M, Chatterjee K.
A mutation in the thyroid hormone receptor alpha gene.
N Engl J Med. 2012 Jan 19;366(3):243-9. doi: 10.1056/NEJMoa1110296. Epub 2011 Dec 14.
Abstract/Text
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
Muller I, Moran C, Lecumberri B, Decallonne B, Robertson N, Jones J, Dayan CM.
2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy.
Eur Thyroid J. 2019 Jul;8(4):173-185. doi: 10.1159/000500881. Epub 2019 Jul 4.
Abstract/Text
Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves' disease (GD), followed by hypothyroidism and thyroiditis; Graves' orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.
Copyright © 2019 by S. Karger AG, Basel.
Bednarczuk T, Brix TH, Schima W, Zettinig G, Kahaly GJ.
2021 European Thyroid Association Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction.
Eur Thyroid J. 2021 Jul;10(4):269-284. doi: 10.1159/000517175. Epub 2021 Jun 16.
Abstract/Text
Given the fact that a large number of radiological examinations using iodine-based contrast media (ICM) are performed in everyday practice, clinicians should be aware of potential ICM-induced thyroid dysfunction (TD). ICM can induce hyperthyroidism (Hyper) or hypothyroidism (Hypo) due to supraphysiological concentrations of iodine in the contrast solution. The prevalence of ICM-induced TD varies from 1 to 15%. ICM-induced Hyper is predominantly found in regions with iodine deficiency and in patients with underlying nodular goiter or latent Graves' disease. Patients at risk for ICM-induced Hypo include those with autoimmune thyroiditis, living in areas with sufficient iodine supply. Most cases of ICM-induced TD are mild and transient. In the absence of prospective clinical trials on the management of ICM-induced TD, an individualized approach to prevention and treatment, based on patient's age, clinical symptoms, pre-existing thyroid diseases, coexisting morbidities and iodine intake must be advised. Treatment of ICM-induced Hyper with antithyroid drugs (in selected cases in combination with sodium perchlorate) should be considered in patients with severe or prolonged hyperthyroid symptoms or in older patients with underlying heart disease. It is debated whether preventive therapy with methimazole and/or perchlorate prior to ICM administration is justified. In ICM-induced overt Hypo, temporary levothyroxine may be considered in younger patients with symptoms of Hypo, with an underlying autoimmune thyroiditis and in women planning pregnancy. Additional clinical trials with clinically relevant endpoints are warranted to further aid in clinical decision-making in patients with ICM-induced TD.
Copyright © 2021 by European Thyroid Association Published by S. Karger AG, Basel.
Han Y, Wang J, Wang X, Ouyang L, Li Y.
Relationship Between Subclinical Hypothyroidism in Pregnancy and Hypertensive Disorder of Pregnancy: A Systematic Review and Meta-Analysis.
Front Endocrinol (Lausanne). 2022;13:823710. doi: 10.3389/fendo.2022.823710. Epub 2022 Mar 8.
Abstract/Text
OBJECTIVE: Studies have shown a high incidence of subclinical hypothyroidism in pregnancy, but the adverse pregnancy outcomes caused by it are not clear. Therefore, we conducted a systematic review and meta-analysis to evaluate the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy(HDP) to guide clinical practice.
METHOD: We searched the MEDLINE (PubMed), Cochrane Central, EMBASE, Web of Science, and SCOPUS databases and screened all studies evaluating the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy. Two researchers independently evaluated the quality of all eligible original studies using the Newcastle-Ottawa Scale (NOS). We also performed a meta-analysis using STATA15.1. Sensitivity analyses were also performed by examining the effects of individual studies as well as using different effect models and detecting any publication bias using the harbord test.
RESULTS: Twenty-two studies were included in the final meta-analysis. Our results indicated that pregnant women with subclinical hypothyroidism had an increased risk of HDP (OR = 1.54(95% CI: 1.21-1.96) I²=67.1%), compared with euthyroidism. Subclinical hypothyroidism in pregnancy was not associated with hypertensive disorders of pregnancy at TSH diagnostic cut-off of less than 3.0 mIU/L (P = 0.077). Curiously, the risk of HDP increases when the TSH diagnostic cut-off value is higher or lower than 4 mIU/L. Although only 9 studies were above the threshold, the risk of developing HDP was still 1.69 times, which was highest in all subgroup analyses. This is consistent with the newly recommended diagnostic cut-off value of 4 mIU/L for TSH by the ATA. Our results consider that the risk of hypertensive disorder complicating pregnancy is increased regardless of the diagnosis of subclinical hypothyroidism at any stage of pregnancy. Unfortunately, there is insufficient evidence to support that patients can benefit from treatment with levothyroxine.
CONCLUSION: The results of this meta-analysis indicate that subclinical hypothyroidism in pregnancy is associated with an increased risk of developing HDP, and this association exists regardless of the gestational period. However, the available evidence cannot support these patients receiving thyroxine intervention can benefit from it, so routine screening is only recommended for pregnant women with risk factors for hypothyroidism. Further research is needed to validate more scientific and rigorous clinical studies to clarify the relationship between subclinical hypothyroidism and HDP to improve patient prognosis.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42021286405).
Copyright © 2022 Han, Wang, Wang, Ouyang and Li.
Hadgu R, Worede A, Ambachew S.
Prevalence of thyroid dysfunction and associated factors among adult type 2 diabetes mellitus patients, 2000-2022: a systematic review and meta-analysis.
Syst Rev. 2024 Apr 30;13(1):119. doi: 10.1186/s13643-024-02527-y. Epub 2024 Apr 30.
Abstract/Text
BACKGROUND: Thyroid dysfunction (TD) and type 2 diabetes mellitus (T2DM) frequently co-occur and have overlapping pathologies, and their risk increases with age. Thyroid dysfunction along with T2DM will worsen macro- and microvascular complications, morbidity, and mortality.
METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guideline was followed. The databases used were Embase, ScienceDirect, PubMed, and Google Scholar. The Joana Briggs Institute (JBI) scale was used to assess the quality of the included studies. The data was extracted by Microsoft Excel and analyzed through STATA version 14 software. The overall pooled prevalence of TD and its main components were estimated using the random-effects model. The consistency of studies was assessed by I2 test statistics. Pooled meta-logistic regression was used to present the pooled prevalence with a 95% confidence interval (CI). Besides, subgroup and sensitivity analyses were employed.
RESULT: Thirty-eight studies were included. The pooled prevalence of TD was 20.24% (95% CI: 17.85, 22.64). The pooled prevalence of subclinical hypothyroidism, hypothyroidism, subclinical hyperthyroidism, and hyperthyroidism was found to be 11.87% (95% CI: 6.90, 16.84), 7.75% (95% CI: 5.71, 9.79), 2.49% (95% CI: 0.73, 4.25), and 2.51% (95% CI: 1.89, 3.13), respectively. Subgroup analysis based on continent revealed a higher prevalence of TD in Asia and Africa. Factors like being female, HbA1c ≥ 7%, DM duration > 5 years, family history of TD, central obesity, smoking, the presence of retinopathy, and neuropathy were found associated with TD.
CONCLUSION: The current systematic review and meta-analysis showed that the TD's pooled prevalence was relatively higher than the general population. Therefore, regular screening of TD should be done for T2DM patients.
© 2024. The Author(s).
Hashemipour M, Rad AH, Dalili S.
Guideline for the Treatment of Hypothyroidism in Prematurity.
Int J Prev Med. 2021;12:123. doi: 10.4103/ijpvm.IJPVM_424_20. Epub 2021 Sep 29.
Abstract/Text
Congenital hypothyroidism is one of the most common endocrine disorders in infants and children. Thyroid hormone effects the function of most organs of the body. In premature neonates, thyroid abnormalities are very common but transient. There is a significant difference between the appropriate time for screening in premature and term neonates and there are different viewpoints in treating hypothyroidism in prematurity. According to the probable exceptions in this issue, there is no definite guideline. Therefore, regarding this confusion, this guideline aimed to help clinicians for rapid on-time decision making.
Copyright: © 2021 International Journal of Preventive Medicine.
Chen Y, Tai HY.
Levothyroxine in the treatment of overt or subclinical hypothyroidism: a systematic review and meta-analysis.
Endocr J. 2020 Jul 28;67(7):719-732. doi: 10.1507/endocrj.EJ19-0583. Epub 2020 Mar 31.
Abstract/Text
The goal of this study was to review relevant randomized controlled trials in order to determine the clinical efficacy of levothyroxine in the treatment of overt or subclinical hypothyroidism. Using appropriate keywords, we identified relevant studies using PubMed, the Cochrane library, and Embase. Key pertinent sources in the literature were also reviewed, and all articles published through December 2019 were considered for inclusion. For each study, we assessed odds ratios (ORs), mean difference (MD), and 95% confidence interval (95%CI) to assess and synthesize outcomes. We included 25 studies with totally 1,735 patients in the meta-analysis. In the patients with hypothyroidism, compared with L-T4, L-T4 plus L-T3 significantly decreased TSH levels and increased FT3 levels. Compared with placebo, L-T4 significantly increased FT4 levels and decreased TSH levels. In patients with subclinical hypothyroidism, compared with placebo, L-T4 significantly decreased SBP, TSH, T3 and TC and increased FT3 and FT4.
Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, McLaren EH.
Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial.
BMJ. 2001 Oct 20;323(7318):891-5. doi: 10.1136/bmj.323.7318.891.
Abstract/Text
OBJECTIVES: To determine whether thyroxine treatment is effective in patients with symptoms of hypothyroidism but with thyroid function tests within the reference range, and to investigate the effect of thyroxine treatment on psychological and physical wellbeing in healthy participants.
DESIGN: Randomised double blind placebo controlled crossover trial.
SETTING: Outpatient clinic in a general hospital.
PARTICIPANTS: 25 patients with symptoms of hypothyroidism who had thyroid function tests within the reference range, and 19 controls.
METHODS: PARTICIPANTS were given thyroxine 100 microgram or placebo to take once a day for 12 weeks. Washout period was six weeks. They were then given the other to take once a day for 12 weeks. All participants were assessed physiologically and psychologically at baseline and on completion of each phase.
MAIN OUTCOME MEASURES: Thyroid function tests, measures of cognitive function and of psychological and physical wellbeing.
RESULTS: 22 patients and 19 healthy controls completed the study. At baseline, patients' scores on 9 out of 15 psychological measures were impaired when compared with controls. Patients showed a significantly greater response to placebo than controls in 3 out of 15 psychological measures. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo (mean (SD) 60 (17) v 73 (16), P<0.01). However, patients' scores from psychological tests when taking thyroxine were no different from those when taking placebo except for a poorer performance on one visual reproduction test when taking thyroxine. Serum concentrations of free thyroxine increased and those of thyroid stimulating hormone decreased in patients and controls while they were taking thyroxine, confirming compliance with treatment. Although serum concentrations of free triiodothyronine increased in patients and controls taking thyroxine, the difference between the response to placebo and to thyroxine was significant only in the controls.
CONCLUSIONS: Thyroxine was no more effective than placebo in improving cognitive function and psychological wellbeing in patients with symptoms of hypothyroidism but thyroid function tests within the reference range. Thyroxine did not improve cognitive function and psychological wellbeing in healthy participants.
Wang X, Wang H, Li Q, Wang P, Xing Y, Zhang F, Li J, Shan Z.
Effect of Levothyroxine Supplementation on the Cardiac Morphology and Function in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2674-2683. doi: 10.1210/clinem/dgac417.
Abstract/Text
CONTEXT: The impact of abnormal thyroid hormone levels on the cardiovascular system has been explored for decades. Recent emerging evidence suggests that subclinical thyroid dysfunction, especially subclinical hypothyroidism (SCH), significantly affects cardiac indices.
OBJECTIVE: We aimed to determine whether levothyroxine (LT4), commonly used to treat hypothyroidism, affects cardiovascular indices in SCH patients.
METHODS: This is a systematic review and meta-analysis. We searched online databases for studies analyzing cardiac morphology and functional changes in SCH patients before and after LT4 supplementation. A total of 294 SCH patients participated and finished the follow-up. The standard mean difference and 95% CI were calculated in fixed or random-effects models. The clinical outcomes analyzed in this study included 18 indicators, mainly covering cardiac morphology, myocardial performance (including various indicators of systolic and diastolic function), mitral wave flow, and systemic vascular resistance.
RESULTS: A total of 11 studies met our search criteria. All studies explicitly mentioned that serum thyrotropin levels decreased to normal at follow-up. Our results suggest that the cardiac output (CO), left ventricular ejection fraction (LVEF), and the ratio of peak E velocity/peak A velocity were all significantly increased after LT4 supplementation compared with the baseline level. However, we found no clear evidence of significant morphological changes in the heart.
CONCLUSION: Judging from the obvious changes in the CO, LVEF, and E/A ratio, LT4 supplementation can effectively improve the cardiac systolic and diastolic dysfunction prevalent in SCH patients. This study provides evidence of the recommendation for LT4 supplementation in adult SCH patients.
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Perez CL, Araki FS, Graf H, de Carvalho GA.
Serum thyrotropin levels following levothyroxine administration at breakfast.
Thyroid. 2013 Jul;23(7):779-84. doi: 10.1089/thy.2012.0435. Epub 2013 Jun 21.
Abstract/Text
BACKGROUND: Hypothyroidism is treated with oral levothyroxine. Some patients fail to attain adequate control because of poor compliance. Delaying breakfast to take levothyroxine on an empty stomach can decrease adherence to hypothyroidism treatment. The objective of this study was to evaluate whether administering levothyroxine with breakfast can maintain thyrotropin (TSH) levels in the therapeutic range, without major clinical changes.
METHODS: A prospective, randomized, open-label, crossover study was conducted to compare usual levothyroxine administration while in a fasting state with administration during breakfast. From September 2008 to April 2009, 45 patients with primary hypothyroidism who received levothyroxine were recruited. The patients completed 180 days of the protocol and were randomized to 90 days of each levothyroxine administration regimen (while fasting or with breakfast). Clinical and biochemical analyses were performed at baseline and on days 45, 90, 135, and 180. The primary outcome was TSH level.
RESULTS: Forty-two patients completed the protocol. The TSH level was higher for levothyroxine administration with breakfast than while fasting (2.89 vs. 1.9 mIU/L, p=0.028). Uncontrolled hypothyroidism (TSH ≥3.5 mIU/L) occurred regardless of the type of levothyroxine administration (p=0.26). No risk factors were identified for TSH elevation.
CONCLUSIONS: Levothyroxine administration with breakfast could be an alternative regimen for patients who have adherence difficulties due to the need for delaying intake, and is more likely to cause variability in the TSH level, meaning the patient should be followed more closely. For patients in whom a specific serum TSH goal is important, taking levothyroxine while fasting is recommended.
Pang X, Pu T, Xu L, Sun R.
Effect of l-thyroxine administration before breakfast vs at bedtime on hypothyroidism: A meta-analysis.
Clin Endocrinol (Oxf). 2020 May;92(5):475-481. doi: 10.1111/cen.14172. Epub 2020 Feb 16.
Abstract/Text
PURPOSE: To compare the effects of l-thyroxine (L-T4) administration before breakfast and administration at bedtime on hypothyroidism.
METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched to identify relevant articles. All prospective or randomized controlled studies (RCTs) comparing L-T4 administration before breakfast to the administration at bedtime in patients with hypothyroidism were included in the analysis.
RESULTS: Initially, 2884 articles were retrieved from the databases, and 10 articles were included in the quantitative analysis. The effect of L-T4 administration before breakfast compared with administration at bedtime had no statistically significant association with hormone thyrotropin (TSH) (Standardized mean differences [SMD] = 0.09, 95% confidence intervals (CI): -0.12, 0.30; P = .39), or free triiodothyronine (FT3) (SMD=-0.19, 95% CI: -0.53, 0.15; P = .28) in patients with hypothyroidism. However, the result of FT4 level was favourable for L-T4 bedtime administration group (SMD=-0.27, 95% CI: -0.52, -0.02; P = .03).
CONCLUSION: Our meta-analysis revealed that L-T4 administration at bedtime is as effective as administration before breakfast for patients with hypothyroidism. Taking L-T4 at bedtime may be an attractive option for patients with hypothyroidism.
© 2020 John Wiley & Sons Ltd.
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP.
2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism.
Eur Thyroid J. 2012 Jul;1(2):55-71. doi: 10.1159/000339444. Epub 2012 Jun 13.
Abstract/Text
BACKGROUND: Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area.
METHODS: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large.
RESULTS: SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.
CONCLUSION: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.
Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, McAninch EA, Moeller LC, Nygaard B, Sawka AM, Watt T, Dayan CM.
Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.
Eur Thyroid J. 2021 Mar;10(1):10-38. doi: 10.1159/000512970. Epub 2021 Feb 16.
Abstract/Text
BACKGROUND: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies.
METHODS: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members.
RESULTS: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations.
DISCUSSION: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
Copyright © 2021 by European Thyroid Association Published by S. Karger AG, Basel.
Feller M, Snel M, Moutzouri E, Bauer DC, de Montmollin M, Aujesky D, Ford I, Gussekloo J, Kearney PM, Mooijaart S, Quinn T, Stott D, Westendorp R, Rodondi N, Dekkers OM.
Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.
JAMA. 2018 Oct 2;320(13):1349-1359. doi: 10.1001/jama.2018.13770.
Abstract/Text
IMPORTANCE: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.
OBJECTIVE: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.
DATA SOURCES: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.
STUDY SELECTION: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.
DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.
MAIN OUTCOMES AND MEASURES: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.
RESULTS: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.
CONCLUSIONS AND RELEVANCE: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.
Liu G, Ren M, Du Y, Zhao R, Wu Y, Liu Y, Qi L.
Effect of thyroid hormone replacement treatment on cardiac diastolic function in adult patients with subclinical hypothyroidism: a meta-analysis.
Front Endocrinol (Lausanne). 2023;14:1263861. doi: 10.3389/fendo.2023.1263861. Epub 2023 Sep 25.
Abstract/Text
BACKGROUND: Although subclinical hypothyroidism (SCH) is related to abnormalities in left ventricular diastolic function, the use of levothyroxine as a regular treatment remains debatable. This meta-analysis aimed to determine whether thyroid hormone replacement therapy affects cardiac diastolic function in patients with SCH as measured by echocardiography.
METHODS: This meta-analysis included a search of the EMBASE, PubMed, Web of Science, and Cochrane Library databases from their inception to May 18, 2023, for studies analyzing cardiac morphology and functional changes in patients with SCH before and after thyroid hormone replacement. The outcome measures were cardiac morphology and diastolic and overall cardiac function, as assessed using ultrasound parameters (including ventricular wall thickness, chamber size, mitral wave flow, tissue Doppler, and speckle tracking). The quality of the studies was assessed using the Newcastle-Ottawa Scale. The standard mean differences (MDs) and 95% confidence intervals (CI) were calculated using fixed- or random-effects models.
RESULTS: Seventeen studies met the inclusion criteria. A total of 568 patients participated and completed the follow-up. All studies specifically stated that serum thyrotropin levels returned to normal by the end of the study period. Compared with baseline levels, no significant morphological changes were observed in the heart. In terms of diastolic function, we discovered that the ratios of E-velocity to A-velocity (E/A) had greatly improved after thyroid hormone replacement therapy, whereas the ratios of the mitral inflow E wave to the tissue Doppler e' wave (E/e') had not. Global longitudinal strain (GLS) increased significantly after treatment with levothyroxine.
CONCLUSION: In adult patients with SCH, thyroid hormone supplementation can partially but not completely improve parameters of diastolic function during the observation period. This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement, an updated guideline for reporting systematic reviews (11) and was registered with INPLASY (INPLASY202320083).
SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2023-2-0083.
Copyright © 2023 Liu, Ren, Du, Zhao, Wu, Liu and Qi.
Yavuz DG, Yazan CD, Hekimsoy Z, Aydin K, Gokkaya N, Ersoy C, Akalın A, Topaloglu O, Aydogan BI, Dilekci ENA, Alphan Uc Z, Cansu GB, Ozsari L, Iyidir OT, Olgun ME, Keskin L, Mert M, Can B, Gungor K, Galip T, Cantürk Z, Elbuken G, Pekkolay Z, Kutbay NO, Yorulmaz G, Kalkan AT, Unsal YA, Yay A, Karagun B, Bozkur E.
Assesment of attainment of recommended TSH levels and levothyroxine compliance in differentiated thyroid cancer patients.
Clin Endocrinol (Oxf). 2022 Dec;97(6):833-840. doi: 10.1111/cen.14787. Epub 2022 Jun 12.
Abstract/Text
OBJECTIVE: Thyroid-stimulating hormone (TSH) suppression treatment can induce signs and symptoms of hyperthyroidism and hypothyroidism due to inappropriate treatment or poor compliance to the treatment. The current study aimed to investigate TSH levels, frequency of being on target TSH, adherence to levothyroxine (LT4) suppression treatment in differentiated thyroid cancer (DTC) patients after surgery in a multicentric setting.
DESIGN AND PATIENTS: This multicentric cross-sectional study was conducted at 21 medical centres from 12 cities in Turkey. DTC patients followed at least one year in the same center included in the study. Clinical data, serum TSH, free thyroxine (FT4), thyroglobulin (Tg) and anti-Tg levels were recorded during the most recent visit. Body mass index, systolic and diastolic blood pressures, pulse rate were measured. LT4 doses were recorded and doses per kilogram of bodyweight were calculated. Pill ingestion habits recorded and adherence to the therapy were evaluated using the Morisky Medication Adherence Scale and categorized as good, moderate or poor compliant based on their scores. Risk stratification forpredicting the disease persistance and/or reccurence was assessed using the American Joint Committee on Cancer-7th edition thyroid cancer staging calculator. TSH serum concentrations were classified as severe suppression (TSH < 0.01 mU/L), moderate suppression (TSH: 0.01-0.1 mU/L), mild suppression (TSHL 0.1-0.5 mU/L), euthyroid (TSH: 0.5-4 mU/L) and hypothyroid (TSH > 4 mU/L). TSH levels can also be classified as on being on target, under the target, or beyond over the target, according to the American Thyroid Association recommendations.
RESULTS: A group of 1125 patients (F/M: 941/184, 50.7 ± 11.7 years) were included in the study. The mean LT4 daily dosage was 132.4 ± 39.6 mcg/day. TSH levels showed severe suppression in 99 (%8.8) patients, moderate suppression in 277 (%24.6) patients and mild suppression in 315 (%28) patients and euthyroid range in 332 (%29.5) patients and hypothyroid range in 97 (8.6%). TSH levels were in target in 29.2% of the patients 20.4% of the patients were undertreated, 50.4% overtreated. The daily LT4 dose and LT4 dose/kg were significantly higher in the severe suppression group (p < .001, p < .001). According to the Morisky scale, 564 patients (50.1%) were good compliant, 368 patients (32.7%) were moderate compliant, and 193 patients (17.1%) were noncompliant. Patients with poor compliance need a higher dose of LT4 compared to the good compliance group (p < .001). TSH levels of patients with good compliance were 0.67 ± 1.96 mU/L and TSH with poor compliance was 2.74 ± 7.47 mU/L (p < .001). TSH levels were similar in patients on fixed and alternating dosages.
CONCLUSION: In 29.2% of the DTC patients, serum TSH levels were at target levels. Remaining of the study group have TSH levels under or over treatment range, exposing the patient to medication side effects. Majorty of the study group 82.8% have good or moderate adherence to LT4 therapy. Reaching TSH targets requires simplified and applicable guidelines and following the guideline recommendations.
© 2022 John Wiley & Sons Ltd.
Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T.
Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study.
J Clin Endocrinol Metab. 2009 Jan;94(1):151-6. doi: 10.1210/jc.2008-1440. Epub 2008 Nov 4.
Abstract/Text
CONTEXT: In patients with coexisting iron-deficiency anemia and subclinical hypothyroidism, anemia does not adequately respond to oral iron therapy.
OBJECTIVE: We studied whether iron-deficiency anemia might indicate treatment of subclinical hypothyroidism.
DESIGN: PATIENTS were assigned to a control or experimental group: 240 mg/d oral iron alone (iron group) or 240 mg/d oral iron plus 75 microg/d levothyroxine (iron/levothyroxine group). Levels of hemoglobin, hematocrit, red blood cell count, serum iron levels, ferritin, total iron-binding capacity, TSH, and free T(4) were measured before and after treatment.
SETTING: The study was conducted at a university hospital outpatient clinic.
PATIENTS: Fifty-one patients with coexisting iron-deficiency anemia and subclinical hypothyroidism participated in the study.
INTERVENTION: PATIENTS were treated as described above in either the iron group or the iron/levothyroxine group.
MAIN OUTCOME MEASURE: A clinically satisfactory increase in hemoglobin was regarded as successful.
RESULTS: Mean hemoglobin levels increased by 0.4 g/dl in the iron group [95% confidence interval (CI) 0.2-0.7, P = 0.001], whereas it increased by a mean of 1.9 g/dl in the iron/levothyroxine group (95% CI 1.5-2.3, P < 0.0001). The increase in serum iron was greater in the iron/levothyroxine group by a mean of 47.6 microg/dl (95% CI 34.5-60.6, P < 0.0001). Increases in hemoglobin, red blood cells, hematocrit, and serum ferritin levels after treatment were statistically significantly greater in the iron/levothyroxine group (P < 0.0001). Starting hemoglobin and increase in hemoglobin were negatively correlated in the iron/levothyroxine group (r = -0.531, P = 0.006).
CONCLUSIONS: Subclinical hypothyroidism should be treated in iron-deficiency anemia patients when both conditions coexist. This would provide a desired therapeutic response to oral iron replacement and prevent ineffective iron therapy.
Kececi H, Degirmenci Y.
Hormone replacement therapy in hypothyroidism and nerve conduction study.
Neurophysiol Clin. 2006 Mar-Apr;36(2):79-83. doi: 10.1016/j.neucli.2006.04.001. Epub 2006 Apr 25.
Abstract/Text
OBJECTIVES: To evaluate the electrodiagnostic evidence of peripheral nerve dysfunction in patients with hypothyroidism before and after hormone replacement treatment.
MATERIALS AND METHODS: Forty patients aged above 18 years diagnosed with hypothyroidism were included in our study. Patients with FT4 levels below 11.6 pmol/l and TSH levels above 4.2 IU/ml were accepted as hypothyroidic. Electrodiagnostic evaluation was performed at the onset of the study and after 3 months. Electrodiagnostic evaluation included motor and sensory nerve conduction studies, and F wave.
RESULTS: The differences between pre- and post-treatment FT4, FT3 and TSH values were found to be statistically significant. At the onset, electrophysiological evaluation revealed carpal tunnel syndrome in 15 patients and polyneuropathy in seven patients; whereas 18 patients were found normal in these respects. After treatment, the electrodiagnostic evaluation revealed that 35 patients were normal, while only two patients had carpal tunnel syndrome and three patients had polyneuropathy. The differences between before and after treatment values of median motor distal latency and amplitude, median sensorial nerve conduction velocity, tibial motor nerve conduction velocity and sural sensory nerve conduction velocity were found to be statistically significant.
CONCLUSION: The results of the control evaluation after treatment demonstrated that the findings related to entrapment neuropathy and polyneuropathy in hypothyroid patients can be reversible in a period of 3 months if appropriate hormone replacement treatment can be obtained. Especially in the treatment of entrapment neuropathy in hypothyroidism, the chance of medical treatment must be given to patients before considering surgical treatment.
Zhao C, Wang Y, Xiao L, Li L.
Effect of Levothyroxine on Older Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis.
Front Endocrinol (Lausanne). 2022;13:913749. doi: 10.3389/fendo.2022.913749. Epub 2022 Jul 14.
Abstract/Text
BACKGROUND: Subclinical hypothyroidism (SCH) is usually treated with levothyroxine, but there is controversy as to whether SCH should be treated, especially for older patients. The aim of the systematic review and meta-analysis was to evaluate whether levothyroxine has a beneficial or harmful effect on older patients with SCH.
METHODS: Databases including PubMed, Embase, Cochrane Library, Web of Science, Wanfang, Weipu and China National Knowledge Infrastructure were searched from inception until December 21, 2021. Subjects must be diagnosed with SCH, and older than or equal to 60 years of age. Interventions should be thyroid hormone therapy (e.g. levothyroxine). The literature was independently screened by 2 researchers. Statistical analysis was performed using RevMan5.3 software.
RESULTS: A total of 13 articles were included. Meta-analysis results showed that in older SCH patients, levothyroxine can significantly reduce cholesterol (TC) (p < 0.00001), triglyceride (TG) (p < 0.00001), low-density lipoprotein cholesterol (LDL-C) (p = 0.03) and apolipoprotein B (ApoB) (p < 0.00001). In addition, levothyroxine had no significant effect on bone mineral density, fatigue, hypothyroidism symptoms, quality of life, BMI, cognitive function, depression, blood pressure, etc. in older SCH patients, and also did not significantly increase the incidence of adverse events.
CONCLUSIONS: Among older SCH patients, levothyroxine treatment may reduce TC, TG, LDL-C, and ApoB.
Copyright © 2022 Zhao, Wang, Xiao and Li.
Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, Heath C, Sheppard M, Franklyn J, Hobbs FD.
A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study.
J Clin Endocrinol Metab. 2010 Aug;95(8):3623-32. doi: 10.1210/jc.2009-2571. Epub 2010 May 25.
Abstract/Text
CONTEXT: Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit.
OBJECTIVE: Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function.
DESIGN AND SETTING: We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care.
PATIENTS: Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening.
INTERVENTION: T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr).
MAIN OUTCOME MEASURES: Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered.
RESULTS: Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months.
CONCLUSIONS: This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.
Peng CC, Huang HK, Wu BB, Chang RH, Tu YK, Munir KM.
Association of Thyroid Hormone Therapy with Mortality in Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis.
J Clin Endocrinol Metab. 2021 Jan 1;106(1):292-303. doi: 10.1210/clinem/dgaa777.
Abstract/Text
CONTEXT: Benefits of thyroid hormone therapy on mortality in adults with subclinical hypothyroidism remain undetermined.
OBJECTIVE: To summarize the impact of thyroid hormone therapy on mortality in adults with subclinical hypothyroidism.
DATA SOURCES: PubMed, Embase, Scopus, Web of Science, and Clinicaltrials.gov from inception until April 25, 2020.
STUDY SELECTION: Studies comparing the effect of thyroid hormone therapy with that of placebo or no therapy in adults with subclinical hypothyroidism on all-cause and/or cardiovascular mortality.
DATA EXTRACTION: Two reviewers independently extracted data and performed quality assessments. Random-effects models for meta-analyses were used.
DATA SYNTHESIS: Five observational studies and 2 randomized controlled trials with 21 055 adults were included. Overall, thyroid hormone therapy was not significantly associated with all-cause (pooled relative risk [RR] = 0.95, 95% confidence interval [CI]: 0.75-1.22, P = .704) or cardiovascular (pooled RR = 0.99, 95% CI: 0.82-1.20, P = .946) mortality. Subgroup analyses revealed that in younger adults (aged <65-70 years), thyroid hormone therapy was significantly associated with a lower all-cause (pooled RR = 0.50, 95% CI: 0.29-0.85, P = .011) and cardiovascular (pooled RR = 0.54, 95% CI: 0.37-0.80, P = .002) mortality. However, no significant association between thyroid hormone therapy and mortality was observed in older adults (aged ≥65-70 years).
CONCLUSIONS: Use of thyroid hormone therapy does not provide protective effects on mortality in older adults with subclinical hypothyroidism. However, thyroid hormone therapy for subclinical hypothyroidism may show benefits on morality in adults aged <65 to 70 years.
© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Razvi S, Weaver JU, Butler TJ, Pearce SH.
Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality.
Arch Intern Med. 2012 May 28;172(10):811-7. doi: 10.1001/archinternmed.2012.1159.
Abstract/Text
BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic heart disease (IHD); however, it is unknown whether treatment of SCH with levothyroxine sodium will reduce the risk of IHD. The aim of this study was to investigate the association between levothyroxine treatment of SCH with IHD morbidity and mortality. METHODS We used the United Kingdom General Practitioner Research Database to identify individuals with new SCH (serum thyrotropin levels of 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with outcomes analyzed until March 2009. All analyses were performed separately for younger (40-70 years) and older (>70 years) individuals. Hazard ratios (HRs) for IHD events (fatal and nonfatal) were calculated after adjustment for conventional IHD risk factors, baseline serum thyrotropin levels, and initiation of levothyroxine treatment as a time-dependent covariate. RESULTS Subclinical hypothyroidism was identified in 3093 younger and 1642 older individuals. For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39-0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted.
Andersen MN, Olsen AM, Madsen JC, Faber J, Torp-Pedersen C, Gislason GH, Selmer C.
Levothyroxine Substitution in Patients with Subclinical Hypothyroidism and the Risk of Myocardial Infarction and Mortality.
PLoS One. 2015;10(6):e0129793. doi: 10.1371/journal.pone.0129793. Epub 2015 Jun 12.
Abstract/Text
BACKGROUND: Subclinical hypothyroidism is associated with a number of cardiovascular risk factors, yet only limited data exist on long-term outcome of levothyroxine treatment of this condition with respect to hard end-points. The aim of this retrospective cohort study was to determine effects of levothyroxine treatment on myocardial infarction (MI), cardiovascular death and all-cause mortality, in patients with subclinical hypothyroidism.
METHODS AND RESULTS: Primary care patients aged 18 years and older that underwent thyroid function tests between 2000 and 2009 were enrolled. Participants were identified by individual-level linkage of nationwide registers. Patients with subclinical hypothyroidism at baseline were included in the study. Exclusion criteria included a history of thyroid disease, related medication or medication affecting thyroid function. The total cohort comprised 628,953 patients of which 12,212 (1.9%) had subclinical hypothyroidism (mean age 55.2 [SD ± 18.8] years; 79.8% female). Within the first six months 2,483 (20.3%) patients claimed a prescription for levothyroxine. During a median follow-up of 5.0 (IQR: 5.2) years, 358 MI's and 1,566 (12.8%) deaths were observed. Out of these, 766 of the deaths were cardiovascular related. No beneficial effects were found in levothyroxine treated patients on MI (IRR 1.08 [95% CI: 0.81 to 1.44]), cardiovascular death (IRR 1.02 [95% CI: 0.83 to 1.25]) or all-cause mortality (IRR 1.03 [95% CI: 0.90 to 1.19]), except in patients under the age of 65 years (IRR 0.63 [95% CI: 0.40 to 0.99]).
CONCLUSION: Levothyroxine substitution in subclinical hypothyroid patients does not indicate an association with lower mortality or decreased risk of MI.
Andersen MN, Olsen AS, Madsen JC, Kristensen SL, Faber J, Torp-Pedersen C, Gislason GH, Selmer C.
Long-Term Outcome in Levothyroxine Treated Patients With Subclinical Hypothyroidism and Concomitant Heart Disease.
J Clin Endocrinol Metab. 2016 Nov;101(11):4170-4177. doi: 10.1210/jc.2016-2226. Epub 2016 Aug 29.
Abstract/Text
CONTEXT: Subclinical hypothyroidism is a common condition that may lead to impaired cardiac function.
OBJECTIVE: This study sought to examine the effects of levothyroxine treatment in patients with subclinical hypothyroidism and heart disease.
DESIGN: This was a register-based historical cohort study.
SETTING AND PARTICIPANTS: The study was composed of Danish primary care patients and hospital outpatients age 18 years and older with established heart disease who were diagnosed with subclinical hypothyroidism in 1997-2011. Patients were stratified according to whether they claimed a subsequent prescription of levothyroxine. Event rates and incidence rate ratios (IRR) were calculated by use of time-dependent multivariable Poisson regression models.
MAIN OUTCOME MEASURES: Measures included all-cause mortality and major adverse cardiac events (MACEs), defined as cardiovascular death, fatal or nonfatal myocardial infaction and stroke, and all-cause hospital admissions.
RESULTS: Of 61 611 patients with a diagnosis of cardiac disease having their first time thyroid function testing, 1192 patients with subclinical hypothyroidism (mean age 73.6 [SD ± 13.3] y, 63.8% female) were included, of whom 136 (11.4%) were treated with levothyroxine. During a median follow-up time of 5.6 y (interquartile range, 6.5 y), 694 (58.2%) patients died. Patients treated with levothyroxine displayed no significantly increased risk of all-cause mortality (adjusted IRR, 1.17; 95% confidence interval [CI], 0.90-1.52), MACE (adjusted IRR, 1.08; 95% CI, 0.80-1.45), or hospital admission (adjusted IRR, 0.94; 95% CI, 0.71-1.24), when compared with patients not treated with levothyroxine.
CONCLUSION: Levothyroxine treatment in patients with subclinical hypothyroidism and heart disease was not associated with a significant benefit nor risk of all-cause mortality, MACE, or hospital admission in this large real-world cohort study.
Kotwal A, Cortes T, Genere N, Hamidi O, Jasim S, Newman CB, Prokop LJ, Murad MH, Alahdab F.
Treatment of Thyroid Dysfunction and Serum Lipids: A Systematic Review and Meta-analysis.
J Clin Endocrinol Metab. 2020 Dec 1;105(12). doi: 10.1210/clinem/dgaa672.
Abstract/Text
CONTEXT: Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia.
OBJECTIVE: The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids.
DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018.
STUDY SELECTION: Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism.
DATA EXTRACTION: Pairs of independent reviewers extracted data and appraised studies.
DATA SYNTHESIS: Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration.
CONCLUSIONS: Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.
© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Papadopoulou AM, Bakogiannis N, Skrapari I, Moris D, Bakoyiannis C.
Thyroid Dysfunction and Atherosclerosis: A Systematic Review.
In Vivo. 2020 Nov-Dec;34(6):3127-3136. doi: 10.21873/invivo.12147.
Abstract/Text
BACKGROUND/AIM: Thyroid dysfunction, both hypo- and hyperthyroidism, has been associated with cardiovascular disease. The aim of this study was to evaluate the association between thyroid dysfunction and atherosclerosis measured mostly by carotid intima-media thickness, as well as discuss whether L-T4 replacement is able to reverse or slow down the progression of atherosclerosis.
MATERIALS AND METHODS: The review was conducted according the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performed on PubMed a literature search from May 2004 to January 2020, using the search terms 'subclinical hypothyroidism' or 'thyroid disorders' and 'carotid artery', 'carotid intima-media thickness (IMT)', 'levothyroxine', and 'atherosclerosis'.
RESULTS: Twenty-six studies were eligible and included in the analysis. Overall, the studies encompassed a total of 36.434 patients included in this review. Most studies indicated a proportional correlation between IMT and thyroid dysfunction. Levothyroxine (L-T4) replacement led to significant decrease of IMT after 1 year in most studies.
CONCLUSION: Most studies have concluded that thyroid dysfunction is associated with arterial wall remodeling and, thus, with increased cardiovascular risk. However, the exact mechanistic background of pathological structural changes in the arterial wall is still unsettled. Large randomized controlled studies are required to definitively address the extent to which T4 replacement therapy might benefit patients with subclinical thyroid disorders.
Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Paone L, Fleisch AF, Feldman HA, Brown RS, Wassner AJ.
Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone.
J Pediatr. 2016 Aug;175:167-172.e1. doi: 10.1016/j.jpeds.2016.04.022. Epub 2016 May 11.
Abstract/Text
OBJECTIVE: To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital hypothyroidism and central resistance to thyroid hormone.
STUDY DESIGN: We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation.
RESULTS: In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% (P < .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P < .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P < .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly.
CONCLUSION: The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.
Copyright © 2016 Elsevier Inc. All rights reserved.
Reinehr T.
Thyroid function in the nutritionally obese child and adolescent.
Curr Opin Pediatr. 2011 Aug;23(4):415-20. doi: 10.1097/MOP.0b013e328344c393.
Abstract/Text
PURPOSE OF REVIEW: In recent years, there has been an increasing focus on thyroid function in obese children. There is controversy concerning whether the changes in the levels of thyroid hormones and thyroid-stimulating hormone (thyrotropin - TSH) in obesity are causes or consequences of weight status and whether these subtle differences merit treatment with thyroxine. This review aimed to study the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function.
RECENT FINDINGS: In the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid.
SUMMARY: The elevated TSH levels in obesity seem a consequence rather than a cause of obesity. Therefore, treatment of hyperthyrotropinemia with thyroxine seems unnecessary in obese children.
Ding Z, Liu Y, Maraka S, Abdelouahab N, Huang HF, Fraser WD, Fan J.
Pregnancy and Neonatal Outcomes With Levothyroxine Treatment in Women With Subclinical Hypothyroidism Based on New Diagnostic Criteria: A Systematic Review and Meta-Analysis.
Front Endocrinol (Lausanne). 2021;12:797423. doi: 10.3389/fendo.2021.797423. Epub 2021 Dec 10.
Abstract/Text
BACKGROUND: Subclinical hypothyroidism (SCH) during pregnancy has been associated with multiple adverse maternal and neonatal outcomes. However, the potential benefits of levothyroxine (LT4) supplementation remain controversial. Variations across studies in diagnostic criteria for SCH may, in part, explain the divergent findings on the subject. This study aimed to assess the effect of LT4 treatment on pregnancy and neonatal outcomes among pregnant women who were diagnosed as SCH based on the most recent diagnostic criteria.
METHODS: We conducted a systematic review and meta-analysis of the literature published from inception to January 2020. The search strategy targeted the studies on pregnancy and neonatal outcomes following LT4 treatment in women with SCH based on 2017 American Thyroid Association diagnostic criteria. Pooled effect sizes were estimated using fixed and random effect models, according to the absence or presence of heterogeneity which was assessed using the I-squared statistic. Sources of heterogeneity and the stability of results were evaluated through sensitivity analysis.
RESULTS: Of the 2781 identified references, 306 full-text articles were screened for eligibility. Finally, 6 studies including a total of 7955 participants were retained for analysis. Summary effect estimates indicated that pregnant women with SCH treated with LT4 had a lower risk of pregnancy loss [odds ratio (OR) = 0.55, 95% confidence interval (CI): 0.43-0.71], preterm birth (OR=0.63, 95% CI: 0.41-0.98) and gestational hypertension (OR = 0.78, 95% CI: 0.63-0.97) than those in control group.
CONCLUSION: LT4 treatment in pregnant women with SCH may reduce the risk of pregnancy loss, preterm delivery and gestational hypertension.
Copyright © 2021 Ding, Liu, Maraka, Abdelouahab, Huang, Fraser and Fan.
Maraka S, Ospina NM, O'Keeffe DT, Espinosa De Ycaza AE, Gionfriddo MR, Erwin PJ, Coddington CC 3rd, Stan MN, Murad MH, Montori VM.
Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis.
Thyroid. 2016 Apr;26(4):580-90. doi: 10.1089/thy.2015.0418. Epub 2016 Mar 3.
Abstract/Text
BACKGROUND: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients.
METHODS: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score.
CONCLUSIONS: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.
Jiao XF, Zhang M, Chen J, Wei Q, Zeng L, Liu D, Zhang C, Li H, Zou K, Zhang L, Zhang L.
The impact of levothyroxine therapy on the pregnancy, neonatal and childhood outcomes of subclinical hypothyroidism during pregnancy: An updated systematic review, meta-analysis and trial sequential analysis.
Front Endocrinol (Lausanne). 2022;13:964084. doi: 10.3389/fendo.2022.964084. Epub 2022 Aug 5.
Abstract/Text
BACKGROUND: Several systematic reviews and meta-analyses have investigated the effect of levothyroxine (LT4) therapy in pregnant women with subclinical hypothyroidism (SCH). However, all these studies have clinical or methodological problems (such as adopting the old 2011 American Thyroid Association [ATA] diagnostic criteria, directly combining randomized controlled trials [RCTs] and cohort studies for meta-analysis, and so on), and cannot provide accurate and satisfactory results. Thus, we performed this updated systematic review, meta-analysis and trial sequential analysis (TSA) to assess the effect of LT4 therapy in pregnant women with SCH, with the goal of providing more accurate and reliable evidence for clinical practice.
METHODS: We searched nine databases from inception to February 2022. The search strategy targeted the RCTs and cohort studies on pregnancy, neonatal and childhood outcomes following LT4 treatment in pregnant women with SCH based on the new 2017 ATA diagnostic criteria. We performed meta-analyses of RCTs and cohort studies separately, and further performed meta-analyses by excluding studies with high risk of bias. TSA was performed to test whether the current evidence was sufficient, and the quality of evidence was evaluated using the GRADE method.
RESULTS: A total of 9 RCTs and 13 cohort studies comprising 11273 pregnant women with SCH were included. There were no statistically significant differences between LT4 group and control group in all primary and secondary outcomes, such as preterm delivery (RR=0.46, 95%CI: 0.19-1.09, P=0.08, I2 = 65%), miscarriage (RR=0.36, 95%CI: 0.13-1.03, P=0.06, I2 = 38%), gestational hypertension (RR=0.91, 95%CI: 0.58-1.43, P=0.69, I2 = 0%), preeclampsia (RR=1.10, 95%CI: 0.61-1.97, P=0.76, I2 = 0%), gestational diabetes (RR=0.80, 95%CI: 0.51-1.25, P=0.32, I2 = 34%), and so on. TSA showed that the results for all outcomes were insufficient and inconclusive. According to GRADE, the evidences for four outcomes (miscarriage, gestational hypertension, gestational diabetes, and small for gestational age) were rated as moderate quality, while the evidences for the other outcomes were rated as low or very low quality.
CONCLUSION: Unlike previous systematic reviews and meta-analyses, our study found no evidence of benefit of LT4 therapy on pregnancy, neonatal and childhood outcomes in pregnant women with SCH.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022321937, identifier CRD42022321937.
Copyright © 2022 Jiao, Zhang, Chen, Wei, Zeng, Liu, Zhang, Li, Zou, Zhang and Zhang.
Myneni R, Chawla HV, Grewal AS, Vivekanandan G, Ndakotsu A, Abubacker AP, Iqbal A, Khan S.
Thyroxine Replacement for Subfertile Females With Subclinical Hypothyroidism and Autoimmune Thyroiditis: A Systematic Review.
Cureus. 2021 Aug;13(8):e16872. doi: 10.7759/cureus.16872. Epub 2021 Aug 4.
Abstract/Text
The second most prevalent endocrine condition affecting women of reproductive age is thyroid disease. The difference between an increased thyroid-stimulating hormone (TSH) concentration and a normal free thyroxine hormone level is used to identify subclinical hypothyroidism. Thyroid autoantibodies, independent of thyroid hormone levels, are used to diagnose autoimmune thyroid disease (ATD). Thyroxine can help infertile women with these two types of thyroid illnesses have better birth outcomes during fertility treatment. We performed a systematic review using PubMed (Medline) as a major database and some other sources EMBASE, the Cochrane Library, Web of Science, Scopus, and Science Direct. We concentrated on four studies, including 806 patients. Our goal is to investigate the efficacy and risks of levothyroxine therapy in infertile women who are receiving fertility treatments and have subclinical hypothyroidism or adequate thyroid function as well as thyroid autoimmunity (euthyroid autoimmune thyroid disorder). Thyroid activity in hypothyroid women should be tracked at pregnancy confirmation and closely monitored during the pregnancy. Early in pregnancy, the dosage of levothyroxine (LT4) can be raised. To ensure optimum TSH levels during breastfeeding, we recommend that patients who are followed in the primary sector have their LT4 dose increased by their general practitioner before their first referral to an endocrinological outpatient clinic. It's important to pay more attention to and track pregnant women with hypothyroidism, who consider pregnancy, to get the best results. LT4 therapy can help subfertile women with subclinical hypothyroidism who are having in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) since it improves embryo growth, implantation rate, and live birth rate.
Copyright © 2021, Myneni et al.
Yoshioka W, Amino N, Ide A, Kang S, Kudo T, Nishihara E, Ito M, Nakamura H, Miyauchi A.
Thyroxine treatment may be useful for subclinical hypothyroidism in patients with female infertility.
Endocr J. 2015;62(1):87-92. doi: 10.1507/endocrj.EJ14-0300. Epub 2014 Oct 10.
Abstract/Text
Infertile women sometimes associated with subclinical hypothyroidism (SCH). The guidelines of the American Endocrine Society, and American Association of Clinical Endocrinologists and American Thyroid Association recommend treatment with thyroxine (T4) for patients with SCH who want to have children. We examined 69 female infertile patients with SCH and the effects of levothyroxine (l-T4) therapy on pregnancy rates and pregnancy outcomes were observed. Fifty-eight (84.1%) patients successfully conceived during the T4 treatment period (Group A), although 17 patients (29.3%) had miscarriage afterward. The remaining 11 patients continued to be infertile (Group B). The median TSH value in Group A before the T4 treatment was 5.46 μIU/mL (range 3.1-13.3) and this significantly decreased to 1.25 μIU/mL (range 0.02-3.75) during the treatment (p<0.001). The estimated duration of infertility before the T4 treatment was 2.8±1.7 years and the duration until pregnancy after the treatment was significantly shorter at 0.9±0.9 years (p<0.001). Shortening of the infertile period after the T4 therapy was observed not only in patients who were treated with assisted reproductive technology (ART) but also in patients who conceived spontaneously in Group A. Administered T4 dose was 54.3±14.2 μg before pregnancy and 68.5±22.8 μg during pregnancy (p<0.001). Anti-thyroid autoantibodies were identified in 42.0% of all patients and no significant difference was observed in positivity between Group A and Group B. High successful pregnancy rate and shorter duration of infertility until pregnancy after T4 treatment strongly suggest that T4 enhanced fertility in infertile patients with SCH.
Bein M, Yu OHY, Grandi SM, Frati FYE, Kandil I, Filion KB.
Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis.
BMC Endocr Disord. 2021 Feb 27;21(1):34. doi: 10.1186/s12902-021-00699-5. Epub 2021 Feb 27.
Abstract/Text
BACKGROUND: Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.
METHODS: A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.
RESULTS: Seven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age.
CONCLUSION: Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.
Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr, Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network.
Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy.
N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/NEJMoa1606205.
Abstract/Text
BACKGROUND: Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children.
METHODS: We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4 level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years.
RESULTS: A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.
CONCLUSIONS: Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297 .).
Poppe K, Bisschop P, Fugazzola L, Minziori G, Unuane D, Weghofer A.
2021 European Thyroid Association Guideline on Thyroid Disorders prior to and during Assisted Reproduction.
Eur Thyroid J. 2021 Feb;9(6):281-295. doi: 10.1159/000512790. Epub 2021 Jan 21.
Abstract/Text
Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.
Copyright © 2021 by European Thyroid Association Published by S. Karger AG, Basel.
