Chinese herbal medicines for hypothyroidism (Review) Ke LQ, Hu Y, Yang K, Tong N
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2015, Issue 2 http://www.thecochranelibrary.com
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW
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Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Chinese herbal medicines for hypothyroidism Lin-qiu Ke1 , Ying Hu2 , Kun Yang3 , Nanwei Tong1 1 Department
of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China. 2 Department of Obstetrics and Gynecology, West China Second University Hospital, West China Women’s and Children’s Hospital, Chengdu, China. 3 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China Contact address: Nanwei Tong, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. [email protected].
Editorial group: Cochrane Metabolic and Endocrine Disorders Group. Publication status and date: New, published in Issue 2, 2015. Review content assessed as up-to-date: 1 September 2014. Citation: Ke LQ, Hu Y, Yang K, Tong N. Chinese herbal medicines for hypothyroidism. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD008779. DOI: 10.1002/14651858.CD008779.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background The reduced production of thyroid hormones is the main feature of the clinical state termed hypothyroidism. In Chinese philosophical and medical theory, it results from Yang deficiency. Chinese herbal medicines (CHM) are thought to restore Yang and have been used in China to treat hypothyroidism for many years. Objectives To assess the effects of CHM for hypothyroidism. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Chinese Biomedical Literature Database on Disc, and the China National Knowledge Infrastructure for randomised clinical trials (RCTs). The date of the last search was September 2014 for all databases. We also searched for ongoing trials in trial registers. Selection criteria We considered RCTs of CHM alone or combined with thyroid hormone therapy compared with no treatment, placebo or thyroid hormone therapy. We also planned to compare different formulae of CHM with each other, alone or combined with thyroid hormone therapy. Hypothyroid individuals had to be diagnosed by the standard criteria valid at the time of the beginning of the trial regardless of the cause of hypothyroidism. Data collection and analysis Data extraction and risk of bias assessment were not performed because no study could be included. Main results We found no RCTs and therefore could not establish the effects of CHM on hypothyroidism. Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors’ conclusions Currently, there is no evidence available from RCTs on CHM for the treatment of hypothyroidism. We also did not find any ongoing registered trial.
PLAIN LANGUAGE SUMMARY Chinese herbal medicines for hypothyroidism Review question What are the effects of Chinese herbal medicines for the treatment of hypothyroidism? Background Hypothyroidism, also known as underactive or low thyroid, is a condition in which the thyroid gland does not produce sufficient amounts of thyroid hormones which are important for many functions of the body (metabolism). In adults hypothyroidism may cause fatigue and sluggishness, increased sensitivity to cold, constipation, pale and dry skin, brittle fingernails and hair, a puffy face, hoarse voice, unexplained weight gain, muscle aches, tenderness, stiffness and weakness, pain, stiffness or swelling in the joints, heavier than normal menstrual periods, and depression. Hypothyroidism in infants and teenagers may result in poor growth and mental development as well as delayed development of permanent teeth and puberty. In Chinese philosophical and medical theory, Yin and Yang are the essential components of the material universe. When Yang is deficient, it cannot produce the vital energy necessary to keep the body functioning well, and symptoms of hypothyroidism may result. Chinese herbal medicines are thought to restore Yang, but the specific mechanisms are unknown. Results We did not find any randomised clinical trial or ongoing study investigating the effects of Chinese herbal medicines for hypothyroidism and could therefore not establish the effects of this treatment. Currentness of evidence This evidence is up to date as of September 2014.
BACKGROUND
2014).
A reduced production of thyroid hormones is the main feature of the clinical state termed hypothyroidism. The causes of hypothyroidism are various and are usually divided into two categories: firstly, the permanent loss or destruction of the thyroid through processes such as autoimmune diseases or irradiation injury is described as primary hypothyroidism, which is the cause of approximately 99% of cases of hypothyroidism (Kronenberg 2008); secondly, insufficient stimulation of the normal thyroid gland as a result of a hypothalamic or pituitary disease or defects in the thyroid-stimulating hormone (TSH) molecule is called central or secondary hypothyroidism. Congenital hypothyroidism affects 1 per 4000 newborns and causes a substantial immediate health problem as well as social and economic burdens (IAEA 2005; Orlander
Hypothyroidism can affect all organ systems and its clinical presentations vary with the severity of thyroid hormone deficiency and the length of time the body has been deprived of the proper amount of the hormones. Obvious signs and symptoms in adults may include fatigue and sluggishness, increased sensitivity to cold, constipation, pale and dry skin, brittle fingernails and hair, a puffy face, hoarse voice, an elevated blood cholesterol level, unexplained weight gain, muscle aches, tenderness, stiffness and weakness, pain, stiffness or swelling in the joints, heavier than normal menstrual periods, and depression. Hypothyroidism in infants and teenagers may result in poor growth and mental development as well as delayed development of permanent teeth and puberty.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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An appropriate laboratory evaluation is critical to establish the diagnosis and the cause of hypothyroidism. A TSH assay should always be used as the primary test to establish the diagnosis of primary hypothyroidism; free thyroxine (FT4) or total thyroxine (TT4) are more valuable measures than TSH for the diagnosis of secondary hypothyroidism. Additional tests may include thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), thyroid scans and ultrasonography. The standard treatment for hypothyroidism is levothyroxine and its dosage must be tailored to the age, weight, and cardiac status of the individual patient and the severity and duration of the hypothyroidism. Combinations of thyroxine (T4) and triiodothyronine (T3) or natural thyroid preparations are also used by some doctors (AACE 2002).
Criteria for considering studies for this review
Types of studies We planned to include randomised controlled clinical trials (RCTs).
Types of participants People with hypothyroidism, irrespective of cause.
Diagnostic criteria
Description of the intervention In Chinese philosophical and medical theory, Yin and Yang are the essential components of the material universe. Everything that exists is Yin or Yang (generally a combination of both in a characteristic balance). The Yin principle is dark, moist, receptive, female, sinking, and its electrical charge is negative. The Yang principle is light, fiery, active, male, outward-expanding, and its electrical charge is positive. When Yang is deficient, it simply cannot produce the vital energy necessary to keep the body functioning well, and symptoms of hypothyroidism result. The function of Chinese herbal medicines (CHM) is to restore Yang, but the specific mechanisms still remain obscure. Adverse effects of the intervention The great majority of CHM preparations are safe, but allergic reactions as well as nephropathy are reported (Chan 1996; Lampert 2002).
Why it is important to do this review CHM have been used alone or in combination with thyroid hormone therapy in the treatment of hypothyroidism for many years. However, there has been no systematic review to evaluate the efficacy and safety of this therapy. Besides, for people who would like to be treated more naturally, it is important to be informed about potential benefits and harms of CHM in the treatment of hypothyroidism.
To be consistent with changes in classification and diagnostic criteria of hypothyroidism through the years, the diagnosis should have been established using the standard criteria valid at the time of the beginning of the trial. Ideally, diagnostic criteria should have been described. If necessary, we intended to use authors’ definition of hypothyroidism. We planned to subject diagnostic criteria to a sensitivity analysis.
Types of interventions We planned to investigate the following comparisons of intervention versus control/comparator.
Intervention
(a) Chinese herbal medicines (CHM). (b) CHM combined with thyroid hormone therapy.
Comparator
• • • •
No treatment compared with (a) or (b). Placebo compared with (a) or (b). Thyroid hormone therapy compared with (a). Another formula of CHM compared with (a) or (b).
Concomitant therapies had to be the same in the intervention and comparator groups.
Types of outcome measures
OBJECTIVES To assess the effects of Chinese herbal medicines for hypothyroidism.
METHODS
Primary outcomes
• Hypothyroidism-related symptoms. • Serum thyroid hormone levels. • Adverse events.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Secondary outcomes
• All-cause mortality. • Health-related quality of life (using validated instruments). • Hypothyroidism-related laboratory measures (such as thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating hormone (TSH)). • Socioeconomic effects.
Search methods for identification of studies
We planned to identify additional studies by searching the reference lists of included trials and (systematic) reviews, meta-analyses and health technology assessment reports.
Data collection and analysis Because we could not include any study we just report on one main element of our planned methods which actually was performed in this review. All planned methods reflected standard Cochrane methodology and the standards of the Cochrane Metabolic and Endocrine Disorders Group. Selection of studies
Electronic searches We searched the following sources from inception of each database to the specified date. • The Cochrane Library (2014, Issue 9). • MEDLINE (September 2014). • EMBASE (September 2014). For detailed search strategies see Appendix 1. We also searched the Chinese Biomedical Literature Database on Disc and the China National Knowledge Infrastructure for relevant trials and databases of ongoing trials; ClinicalTrials.gov (www.clinicaltrials.gov/); Current Controlled Trials metaRegister (www.controlled-trials.com/); the EU Clinical Trials register (www.clinicaltrialsregister.eu/); and the World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/)). If we had detected additional relevant key words during any of the electronic or other searches we would have modified the electronic search strategies to incorporate these terms and document the changes. We placed no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in potentially relevant publications.
Searching other resources
Two review authors (LK, YH) independently scanned the abstract, title or both sections of every record retrieved to determine the studies to be assessed further. All potentially relevant articles were investigated as full text. A third review author resolved any differences in opinion. If resolving disagreement was not possible, we planned to add the article to those ’awaiting classification’ and would have contacted authors for clarification. We attach a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram of study selection (Liberati 2009).
RESULTS
Description of studies We searched all databases until September 2014 and found 239 citations (see Figure 1). After deduplication, 211 records remained and 206 publications could be clearly excluded after reading the title, the abstract or both. No study fulfilled the inclusion criteria. Five studies (Kuang 1988a; Kuang 1988b; Tao 2008; Yang 2007; Zha 1993) were excluded after two authors (LK, YH) independently read and assessed the full articles (see Characteristics of excluded studies).
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 1. Study flow diagram.
Risk of bias in included studies Since no studies met the inclusion criteria, consideration of risk of bias was not possible.
Effects of interventions Since no studies were included, the effects of interventions could not be evaluated.
Also, researchers noted improved serum thyroid hormone levels and hypothyroidism-related laboratory measures such as increasing T4, FT4, T3 and FT3 levels and decreasing TSH and serum total cholesterol levels (Kuang 1988a; Kuang 1988b; Zha 1993). One study reported CHM combined with thyroid hormones to be more effective than CHM alone (Kuang 1988a). Another study reported that the combined treatment of CHM and thyroid hormones was superior to thyroid hormones alone in treating the condition of goitre with hypothyroidism (Yang 2007). None of the trials reported adverse effects, health-related quality of life or socioeconomic effects.
DISCUSSION We did not find any study that met our inclusion criteria. Among the five studies retrieved by the electronic searches, one was a narrative review reporting how to apply traditional Chinese medicine differential treatment for hypothyroidism (Tao 2008); the other four were non-randomised clinical trials with duration of therapies ranging from two to six months (Kuang 1988a; Kuang 1988b; Yang 2007; Zha 1993). Three trials reported that Chinese herbal medicines (CHM) alone could effectively relieve hypothyroidismrelated symptoms such as weight gain, dry skin and slow heart rate.
AUTHORS’ CONCLUSIONS Implications for practice We found no evidence from randomised controlled trials (RCTs) for or against the efficacy of Chinese herbal medicines (CHM) for treating hypothyroidism and could therefore not establish the effects of this therapy.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Implications for research
ACKNOWLEDGEMENTS
Well-designed adequately-powered RCTs are needed to test the benefits and risks of CHM especially compared to thyroid hormone therapy when used for hypothyroidism. We suggest that these studies should consider patient-important outcomes such as symptom control, health-related quality of life and socioeconomic effects.
The authors acknowledge the editorial base of the Cochrane Metabolic and Endocrine Disorders Group and those who made helpful comments on this review. Special thanks to Gudrun Paletta, Managing Editor Assistant, for her help; and to Karla Bergerhoff, former Trials Search Coordinator, for her assistance with designing the search strategies.
REFERENCES
References to studies excluded from this review
Additional references
Kuang 1988a {published data only} Kuang AK, Ding Y, Chen JL, Xu MY, Zhang DQ, Cai YS, et al. Clinical effect of the treatment of myxedema with traditional Chinese medicine alone and traditional Chinese medicine supplemented by thyroid tablets. Chung Hsi i Chieh Ho Tsa Chih (Chinese Journal of Modern Developments in Traditional Medicine) 1988;8(2):74–6.
AACE 2002 American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the evaluation and treatment of hypothyroidism and hyperthyroidism. Endocrine Practice 2002;8(6):456–69. Chan 1996 Chan TY, Critchley JA. Usage and adverse effects of Chinese herbal medicine. Human and Experimental Toxicology 1996; 15(1):5–12.
Kuang 1988b {published data only} Kuang AK, Ding Y, Chen JL, Xu MY, Zhang DQ, Li DQ, et al. Effect of traditional Chinese medicine on primary hypothyroidism in relation to nuclear T3 receptors of lymphocytes. Chung Hsi i Chieh Ho Tsa Chih (Chinese Journal of Modern Developments in Traditional Medicine) 1988;8(11):650-3, 643.
IAEA 2005 International Atomic Energy Agency. Screening of newborns for congenital hypothyroidism: guidance for developing programmes. IAEA in Austria, 2005.
Tao 2008 {published data only} Tao CX. How to give TCM differential treatment for hypothyroidism?. Journal of Traditional Chinese Medicine 2008;28(3):231–2.
Kronenberg 2008 Kronenberg HM (author), Melmed S (editor), Polonsky KS (editor), Reed Larsen P (editor). Williams Textbook of Endocrinology. 11th Edition. Saunders, 2008.
Yang 2007 {published data only} Yang K, Guo KQ, Wu HY, Ye LX, Xia H. Clinical effect of Prunellae Oral Liquid on goiter with different thyroid function. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 2007; 27(1):37–9.
Lampert 2002 Lampert N, Xu Y. Chinese herbal nephropathy. Lancet 2002;359(9308):796-7.
Zha 1993 {published data only} Zha LL, Shen ZY, Zhang P. Relation of hypothyroidism and deficiency of kidney yang. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 1993;13(4):202–4.
Liberati 2009 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic and meta-analyses of studies that evaluate interventions: explanation and elaboration. PLoS Med 1999;6(7):1–28. [DOI: 10.1371/journal.pmed.1000100] Orlander 2014 Orlander PR. Hypothyroidism. http:// emedicine.medscape.com/article/122393-overview (accessed 9 February 2015). ∗ Indicates the major publication for the study
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CHARACTERISTICS OF STUDIES Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Kuang 1988a
Non-randomised clinical trial
Kuang 1988b
Non-randomised clinical trial
Tao 2008
Narrative review
Yang 2007
Non-randomised clinical trial
Zha 1993
Non-randomised clinical trial
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DATA AND ANALYSES This review has no analyses.
APPENDICES Appendix 1. Search strategies
The Cochrane Library #1 MeSH descriptor Medicine, Traditional explode all trees #2 MeSH descriptor Phytotherapy explode all trees #3 MeSH descriptor Plant extracts explode all trees #4 MeSH descriptor Plants explode all trees #5 (phytodrug* in All Text or phytomedicin* in All Text or phytotherap* in All Text or phytotreatment* in All Text or phytopharmaceutical in All Text) #6 (chinese in All Text near/3 herbal in All Text) #7 (chinese in All Text near/3 drug* in All Text) #8 (chinese in All Text near/3 formul* in All Text) #9 (chinese in All Text near/3 plant* in All Text) #10 (chinese in All Text near/3 prescri* in All Text) #11 (chinese in All Text near/3 therap* in All Text) #12 (chinese in All Text near/3 treatment* in All Text) #13 (herb* in All Text near/3 remed* in All Text) #14 (herb* in All Text near/3 extract* in All Text) #15 (herb* in All Text near/3 medic* in All Text) #16 (herb* in All Text near/3 preparation* in All Text) #17 (herb* in All Text near/3 mixture* in All Text) #18 (herb* in All Text near/3 therap* in All Text) #19 (herb* in All Text near/3 treatment* in All Text) #20 (plant* in All Text near/3 remed* in All Text) #21 (plant* in All Text near/3 extract* in All Text) #22 (plant* in All Text near/3 medicin* in All Text) #23 (plant* in All Text near/3 preparation* in All Text) #24 (plant* in All Text near/3 mixture* in All Text) #25 (plant* in All Text near/3 therap* in All Text) #26 (plant* in All Text near/3 treatment* in All Text) #27 (medicine in All Text near/3 traditional in All Text) #28 (medicine in All Text near/3 chinese in All Text) #29 (medicine in All Text near/3 kampo in All Text) #30 (medicine in All Text near/3 plant* in All Text) #31 (complementary in All Text near/3 medicine in All Text) #32 (complementary in All Text near/3 therap* in All Text) #33 (complementary in All Text near/3 treatment* in All Text) #34 (complementary in All Text near/3 drug* in All Text) #35 (alternative in All Text near/3 medicine in All Text)
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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#36 (alternative in All Text near/3 therap* in All Text) #37 (alternative in All Text near/3 treatment* in All Text) #38 (alternative in All Text near/3 drug* in All Text) #39 TCM in All Text #40 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15) #41 (#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30) #42 (#31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39) #43 (#40 or #41 or #42) #44 MeSH descriptor Hypothyroidism explode all trees #45 (hypothyr* in All Text or hypo-thyr* in All Text) #46 (thyroid in All Text near/3 defic* in All Text) #47 (thyroid in All Text near/3 insuffic* in All Text) #48 (#44 or #45 or #46 or #47) #49 (#43 and #48) MEDLINE 1 exp medicine, traditional/ or exp medicine, african traditional/ or exp medicine, arabic/ or exp medicine, ayurvedic/ or exp medicine, east asian traditional/ or exp medicine, chinese traditional/ or exp medicine, kampo/ or exp medicine, korean traditional/ or exp medicine, tibetan traditional/ 2 exp Phytotherapy/ 3 exp plant extracts/ or exp drugs, chinese herbal/ or exp plant oils/ 4 exp Plants, Medicinal/ 5 exp Plants/ or exp Plants, Medicinal/ 6 (chinese adj3 (medic* or herb* or drug* or formul* or plant* or prescri* or therap* or treatment*)).mp. 7 (phytodrug* or phytomedicin* or phytotherap* or phytotreatment* or phytopharmaceutical*).mp. 8 (herb* adj3 (remed* or extract* or medic* or preparation* or mixture* or therap* or treatment*)).mp. 9 (plant* adj3 (remed* or extract* or medicin* or preparation* or mixture or therap* or treatment*)).mp. 10 (medicine adj3 (traditional or chinese or kampo or plant*)).mp. 11 ((complementary or alternative) adj3 (medicine or therap* or treatment* or drug*)).mp. 12 TCM.tw,ot. 13 or/1-12 14 exp Hypothyroidism/ 15 (thyroid adj3 (defic* or insuffic*)).tw,ot. 16 (hypothyr* or hypo-thyr).mp. 17 or/14-16 18 13 and 17 19 randomized controlled trial.pt. 20 controlled clinical trial.pt. 21 randomi?ed.ab. 22 placebo.ab. 23 drug therapy.fs. 24 randomly.ab. 25 trial.ab. 26 groups.ab. 27 or/19-26 28 Meta-analysis.pt. 29 exp Technology Assessment, Biomedical/ 30 exp Meta-analysis/ Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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31 exp Meta-analysis as topic/ 32 hta.tw,ot. 33 (health technology adj6 assessment$).tw,ot. 34 (meta analy$ or metaanaly$ or meta?analy$).tw,ot. 35 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systemat$)).tw,ot. 36 or/28-35 37 27 or 36 38 (comment or editorial or historical-article).pt. 39 37 not 38 40 (animals not (animals and humans)).sh. 41 39 not 40 42 18 and 41 EMBASE 1 plant extract/ or medicinal plant/ or plant medicinal product/ or herbal medicine/ 2 exp alternative medicine/ 3 exp phytotherapy/ 4 exp herbaceous agent/ 5 exp Chinese drug/ or exp Chinese herb/ or exp Chinese medicine/ or exp traditional medicine/ 6 (chinese adj3 (medic* or herb* or drug* or formul* or plant* or prescri* or therap* or treatment*)).mp. 7 (phytodrug* or phytomedicin* or phytotherap* or phytotreatment* or phytopharmaceutical*).mp. 8 (herb* adj3 (remed* or extract* or medic* or preparation* or mixture* or therap* or treatment*)).mp. 9 (plant* adj3 (remed* or extract* or medicin* or preparation* or mixture* or therap* or treatment*)).mp. 10 (medicine adj3 (traditional or chinese or kampo or plant*)).mp. 11 ((complementary or alternative) adj3 (medicine or therap* or treatment* or drug*)).mp. 12 TCM.tw,ot. 13 or/1-12 14 exp hypothyroidism/ 15 (hypothyr* or hypo-thyr*).tw,ot. 16 (thyroid adj3 (defic* or insuffic*)).tw,ot. 17 or/14-16 18 clinical trial/ 19 exp comparative study/ 20 exp drug comparison/ 21 major clinical study/ 22 exp randomization/ 23 crossover procedure/ 24 double blind procedure/ 25 single blind procedure/ 26 exp placebo/ 27 exp prospective study/ 28 ((clinical or controlled or comparative or placebo or prospective or randomi?ed) adj3 (trial or study)).ti,ab. 29 (random* adj7 (allocat* or allot* or assign* or basis* or divid* or order*)).ti,ab. 30 ((singl* or doubl* or trebl* or tripl*) adj7 (blind* or mask*)).ti,ab. 31 (cross?over* or (cross adj1 over*)).ti,ab. 32 or/18-31 33 exp meta analysis/
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34 (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot. 35 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot. 36 exp Literature/ 37 exp Biomedical Technology Assessment/ 38 hta.tw,ot. 39 (health technology adj6 assessment$).tw,ot. 40 or/33-39 41 32 or 40 42 (comment or editorial or historical-article).pt. 43 41 not 42 44 13 and 17 and 43 45 limit 44 to human
CONTRIBUTIONS OF AUTHORS Lin-qiu Ke (LK): protocol draft, trial selection, data analysis and data interpretation. Ying Hu (YH): search strategy development, acquiring trial reports, trial selection and data extraction. Kun Yang (KY): search strategy development, acquiring trial reports, data extraction, data analysis and data interpretation. Nanwei Tong (NT): data analysis, data interpretation, review draft and future update draft.
DECLARATIONS OF INTEREST LK: none known. YH: none known. KY: none known. NT: none known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW Because we could not include any study we just report on one main element of our planned methods which actually was performed in this review. All planned methods reflected standard Cochrane methodology and the standards of the Cochrane Metabolic and Endocrine Disorders Group.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2015, Issue 2 http://www.thecochranelibrary.com
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW
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[Intervention Review]
Chinese herbal medicines for hypothyroidism Lin-qiu Ke1 , Ying Hu2 , Kun Yang3 , Nanwei Tong1 1 Department
of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China. 2 Department of Obstetrics and Gynecology, West China Second University Hospital, West China Women’s and Children’s Hospital, Chengdu, China. 3 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China Contact address: Nanwei Tong, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. [email protected].
Editorial group: Cochrane Metabolic and Endocrine Disorders Group. Publication status and date: New, published in Issue 2, 2015. Review content assessed as up-to-date: 1 September 2014. Citation: Ke LQ, Hu Y, Yang K, Tong N. Chinese herbal medicines for hypothyroidism. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD008779. DOI: 10.1002/14651858.CD008779.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background The reduced production of thyroid hormones is the main feature of the clinical state termed hypothyroidism. In Chinese philosophical and medical theory, it results from Yang deficiency. Chinese herbal medicines (CHM) are thought to restore Yang and have been used in China to treat hypothyroidism for many years. Objectives To assess the effects of CHM for hypothyroidism. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Chinese Biomedical Literature Database on Disc, and the China National Knowledge Infrastructure for randomised clinical trials (RCTs). The date of the last search was September 2014 for all databases. We also searched for ongoing trials in trial registers. Selection criteria We considered RCTs of CHM alone or combined with thyroid hormone therapy compared with no treatment, placebo or thyroid hormone therapy. We also planned to compare different formulae of CHM with each other, alone or combined with thyroid hormone therapy. Hypothyroid individuals had to be diagnosed by the standard criteria valid at the time of the beginning of the trial regardless of the cause of hypothyroidism. Data collection and analysis Data extraction and risk of bias assessment were not performed because no study could be included. Main results We found no RCTs and therefore could not establish the effects of CHM on hypothyroidism. Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors’ conclusions Currently, there is no evidence available from RCTs on CHM for the treatment of hypothyroidism. We also did not find any ongoing registered trial.
PLAIN LANGUAGE SUMMARY Chinese herbal medicines for hypothyroidism Review question What are the effects of Chinese herbal medicines for the treatment of hypothyroidism? Background Hypothyroidism, also known as underactive or low thyroid, is a condition in which the thyroid gland does not produce sufficient amounts of thyroid hormones which are important for many functions of the body (metabolism). In adults hypothyroidism may cause fatigue and sluggishness, increased sensitivity to cold, constipation, pale and dry skin, brittle fingernails and hair, a puffy face, hoarse voice, unexplained weight gain, muscle aches, tenderness, stiffness and weakness, pain, stiffness or swelling in the joints, heavier than normal menstrual periods, and depression. Hypothyroidism in infants and teenagers may result in poor growth and mental development as well as delayed development of permanent teeth and puberty. In Chinese philosophical and medical theory, Yin and Yang are the essential components of the material universe. When Yang is deficient, it cannot produce the vital energy necessary to keep the body functioning well, and symptoms of hypothyroidism may result. Chinese herbal medicines are thought to restore Yang, but the specific mechanisms are unknown. Results We did not find any randomised clinical trial or ongoing study investigating the effects of Chinese herbal medicines for hypothyroidism and could therefore not establish the effects of this treatment. Currentness of evidence This evidence is up to date as of September 2014.
BACKGROUND
2014).
A reduced production of thyroid hormones is the main feature of the clinical state termed hypothyroidism. The causes of hypothyroidism are various and are usually divided into two categories: firstly, the permanent loss or destruction of the thyroid through processes such as autoimmune diseases or irradiation injury is described as primary hypothyroidism, which is the cause of approximately 99% of cases of hypothyroidism (Kronenberg 2008); secondly, insufficient stimulation of the normal thyroid gland as a result of a hypothalamic or pituitary disease or defects in the thyroid-stimulating hormone (TSH) molecule is called central or secondary hypothyroidism. Congenital hypothyroidism affects 1 per 4000 newborns and causes a substantial immediate health problem as well as social and economic burdens (IAEA 2005; Orlander
Hypothyroidism can affect all organ systems and its clinical presentations vary with the severity of thyroid hormone deficiency and the length of time the body has been deprived of the proper amount of the hormones. Obvious signs and symptoms in adults may include fatigue and sluggishness, increased sensitivity to cold, constipation, pale and dry skin, brittle fingernails and hair, a puffy face, hoarse voice, an elevated blood cholesterol level, unexplained weight gain, muscle aches, tenderness, stiffness and weakness, pain, stiffness or swelling in the joints, heavier than normal menstrual periods, and depression. Hypothyroidism in infants and teenagers may result in poor growth and mental development as well as delayed development of permanent teeth and puberty.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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An appropriate laboratory evaluation is critical to establish the diagnosis and the cause of hypothyroidism. A TSH assay should always be used as the primary test to establish the diagnosis of primary hypothyroidism; free thyroxine (FT4) or total thyroxine (TT4) are more valuable measures than TSH for the diagnosis of secondary hypothyroidism. Additional tests may include thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), thyroid scans and ultrasonography. The standard treatment for hypothyroidism is levothyroxine and its dosage must be tailored to the age, weight, and cardiac status of the individual patient and the severity and duration of the hypothyroidism. Combinations of thyroxine (T4) and triiodothyronine (T3) or natural thyroid preparations are also used by some doctors (AACE 2002).
Criteria for considering studies for this review
Types of studies We planned to include randomised controlled clinical trials (RCTs).
Types of participants People with hypothyroidism, irrespective of cause.
Diagnostic criteria
Description of the intervention In Chinese philosophical and medical theory, Yin and Yang are the essential components of the material universe. Everything that exists is Yin or Yang (generally a combination of both in a characteristic balance). The Yin principle is dark, moist, receptive, female, sinking, and its electrical charge is negative. The Yang principle is light, fiery, active, male, outward-expanding, and its electrical charge is positive. When Yang is deficient, it simply cannot produce the vital energy necessary to keep the body functioning well, and symptoms of hypothyroidism result. The function of Chinese herbal medicines (CHM) is to restore Yang, but the specific mechanisms still remain obscure. Adverse effects of the intervention The great majority of CHM preparations are safe, but allergic reactions as well as nephropathy are reported (Chan 1996; Lampert 2002).
Why it is important to do this review CHM have been used alone or in combination with thyroid hormone therapy in the treatment of hypothyroidism for many years. However, there has been no systematic review to evaluate the efficacy and safety of this therapy. Besides, for people who would like to be treated more naturally, it is important to be informed about potential benefits and harms of CHM in the treatment of hypothyroidism.
To be consistent with changes in classification and diagnostic criteria of hypothyroidism through the years, the diagnosis should have been established using the standard criteria valid at the time of the beginning of the trial. Ideally, diagnostic criteria should have been described. If necessary, we intended to use authors’ definition of hypothyroidism. We planned to subject diagnostic criteria to a sensitivity analysis.
Types of interventions We planned to investigate the following comparisons of intervention versus control/comparator.
Intervention
(a) Chinese herbal medicines (CHM). (b) CHM combined with thyroid hormone therapy.
Comparator
• • • •
No treatment compared with (a) or (b). Placebo compared with (a) or (b). Thyroid hormone therapy compared with (a). Another formula of CHM compared with (a) or (b).
Concomitant therapies had to be the same in the intervention and comparator groups.
Types of outcome measures
OBJECTIVES To assess the effects of Chinese herbal medicines for hypothyroidism.
METHODS
Primary outcomes
• Hypothyroidism-related symptoms. • Serum thyroid hormone levels. • Adverse events.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Secondary outcomes
• All-cause mortality. • Health-related quality of life (using validated instruments). • Hypothyroidism-related laboratory measures (such as thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating hormone (TSH)). • Socioeconomic effects.
Search methods for identification of studies
We planned to identify additional studies by searching the reference lists of included trials and (systematic) reviews, meta-analyses and health technology assessment reports.
Data collection and analysis Because we could not include any study we just report on one main element of our planned methods which actually was performed in this review. All planned methods reflected standard Cochrane methodology and the standards of the Cochrane Metabolic and Endocrine Disorders Group. Selection of studies
Electronic searches We searched the following sources from inception of each database to the specified date. • The Cochrane Library (2014, Issue 9). • MEDLINE (September 2014). • EMBASE (September 2014). For detailed search strategies see Appendix 1. We also searched the Chinese Biomedical Literature Database on Disc and the China National Knowledge Infrastructure for relevant trials and databases of ongoing trials; ClinicalTrials.gov (www.clinicaltrials.gov/); Current Controlled Trials metaRegister (www.controlled-trials.com/); the EU Clinical Trials register (www.clinicaltrialsregister.eu/); and the World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/)). If we had detected additional relevant key words during any of the electronic or other searches we would have modified the electronic search strategies to incorporate these terms and document the changes. We placed no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in potentially relevant publications.
Searching other resources
Two review authors (LK, YH) independently scanned the abstract, title or both sections of every record retrieved to determine the studies to be assessed further. All potentially relevant articles were investigated as full text. A third review author resolved any differences in opinion. If resolving disagreement was not possible, we planned to add the article to those ’awaiting classification’ and would have contacted authors for clarification. We attach a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram of study selection (Liberati 2009).
RESULTS
Description of studies We searched all databases until September 2014 and found 239 citations (see Figure 1). After deduplication, 211 records remained and 206 publications could be clearly excluded after reading the title, the abstract or both. No study fulfilled the inclusion criteria. Five studies (Kuang 1988a; Kuang 1988b; Tao 2008; Yang 2007; Zha 1993) were excluded after two authors (LK, YH) independently read and assessed the full articles (see Characteristics of excluded studies).
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 1. Study flow diagram.
Risk of bias in included studies Since no studies met the inclusion criteria, consideration of risk of bias was not possible.
Effects of interventions Since no studies were included, the effects of interventions could not be evaluated.
Also, researchers noted improved serum thyroid hormone levels and hypothyroidism-related laboratory measures such as increasing T4, FT4, T3 and FT3 levels and decreasing TSH and serum total cholesterol levels (Kuang 1988a; Kuang 1988b; Zha 1993). One study reported CHM combined with thyroid hormones to be more effective than CHM alone (Kuang 1988a). Another study reported that the combined treatment of CHM and thyroid hormones was superior to thyroid hormones alone in treating the condition of goitre with hypothyroidism (Yang 2007). None of the trials reported adverse effects, health-related quality of life or socioeconomic effects.
DISCUSSION We did not find any study that met our inclusion criteria. Among the five studies retrieved by the electronic searches, one was a narrative review reporting how to apply traditional Chinese medicine differential treatment for hypothyroidism (Tao 2008); the other four were non-randomised clinical trials with duration of therapies ranging from two to six months (Kuang 1988a; Kuang 1988b; Yang 2007; Zha 1993). Three trials reported that Chinese herbal medicines (CHM) alone could effectively relieve hypothyroidismrelated symptoms such as weight gain, dry skin and slow heart rate.
AUTHORS’ CONCLUSIONS Implications for practice We found no evidence from randomised controlled trials (RCTs) for or against the efficacy of Chinese herbal medicines (CHM) for treating hypothyroidism and could therefore not establish the effects of this therapy.
Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Implications for research
ACKNOWLEDGEMENTS
Well-designed adequately-powered RCTs are needed to test the benefits and risks of CHM especially compared to thyroid hormone therapy when used for hypothyroidism. We suggest that these studies should consider patient-important outcomes such as symptom control, health-related quality of life and socioeconomic effects.
The authors acknowledge the editorial base of the Cochrane Metabolic and Endocrine Disorders Group and those who made helpful comments on this review. Special thanks to Gudrun Paletta, Managing Editor Assistant, for her help; and to Karla Bergerhoff, former Trials Search Coordinator, for her assistance with designing the search strategies.
REFERENCES
References to studies excluded from this review
Additional references
Kuang 1988a {published data only} Kuang AK, Ding Y, Chen JL, Xu MY, Zhang DQ, Cai YS, et al. Clinical effect of the treatment of myxedema with traditional Chinese medicine alone and traditional Chinese medicine supplemented by thyroid tablets. Chung Hsi i Chieh Ho Tsa Chih (Chinese Journal of Modern Developments in Traditional Medicine) 1988;8(2):74–6.
AACE 2002 American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the evaluation and treatment of hypothyroidism and hyperthyroidism. Endocrine Practice 2002;8(6):456–69. Chan 1996 Chan TY, Critchley JA. Usage and adverse effects of Chinese herbal medicine. Human and Experimental Toxicology 1996; 15(1):5–12.
Kuang 1988b {published data only} Kuang AK, Ding Y, Chen JL, Xu MY, Zhang DQ, Li DQ, et al. Effect of traditional Chinese medicine on primary hypothyroidism in relation to nuclear T3 receptors of lymphocytes. Chung Hsi i Chieh Ho Tsa Chih (Chinese Journal of Modern Developments in Traditional Medicine) 1988;8(11):650-3, 643.
IAEA 2005 International Atomic Energy Agency. Screening of newborns for congenital hypothyroidism: guidance for developing programmes. IAEA in Austria, 2005.
Tao 2008 {published data only} Tao CX. How to give TCM differential treatment for hypothyroidism?. Journal of Traditional Chinese Medicine 2008;28(3):231–2.
Kronenberg 2008 Kronenberg HM (author), Melmed S (editor), Polonsky KS (editor), Reed Larsen P (editor). Williams Textbook of Endocrinology. 11th Edition. Saunders, 2008.
Yang 2007 {published data only} Yang K, Guo KQ, Wu HY, Ye LX, Xia H. Clinical effect of Prunellae Oral Liquid on goiter with different thyroid function. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 2007; 27(1):37–9.
Lampert 2002 Lampert N, Xu Y. Chinese herbal nephropathy. Lancet 2002;359(9308):796-7.
Zha 1993 {published data only} Zha LL, Shen ZY, Zhang P. Relation of hypothyroidism and deficiency of kidney yang. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 1993;13(4):202–4.
Liberati 2009 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic and meta-analyses of studies that evaluate interventions: explanation and elaboration. PLoS Med 1999;6(7):1–28. [DOI: 10.1371/journal.pmed.1000100] Orlander 2014 Orlander PR. Hypothyroidism. http:// emedicine.medscape.com/article/122393-overview (accessed 9 February 2015). ∗ Indicates the major publication for the study
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CHARACTERISTICS OF STUDIES Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Kuang 1988a
Non-randomised clinical trial
Kuang 1988b
Non-randomised clinical trial
Tao 2008
Narrative review
Yang 2007
Non-randomised clinical trial
Zha 1993
Non-randomised clinical trial
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DATA AND ANALYSES This review has no analyses.
APPENDICES Appendix 1. Search strategies
The Cochrane Library #1 MeSH descriptor Medicine, Traditional explode all trees #2 MeSH descriptor Phytotherapy explode all trees #3 MeSH descriptor Plant extracts explode all trees #4 MeSH descriptor Plants explode all trees #5 (phytodrug* in All Text or phytomedicin* in All Text or phytotherap* in All Text or phytotreatment* in All Text or phytopharmaceutical in All Text) #6 (chinese in All Text near/3 herbal in All Text) #7 (chinese in All Text near/3 drug* in All Text) #8 (chinese in All Text near/3 formul* in All Text) #9 (chinese in All Text near/3 plant* in All Text) #10 (chinese in All Text near/3 prescri* in All Text) #11 (chinese in All Text near/3 therap* in All Text) #12 (chinese in All Text near/3 treatment* in All Text) #13 (herb* in All Text near/3 remed* in All Text) #14 (herb* in All Text near/3 extract* in All Text) #15 (herb* in All Text near/3 medic* in All Text) #16 (herb* in All Text near/3 preparation* in All Text) #17 (herb* in All Text near/3 mixture* in All Text) #18 (herb* in All Text near/3 therap* in All Text) #19 (herb* in All Text near/3 treatment* in All Text) #20 (plant* in All Text near/3 remed* in All Text) #21 (plant* in All Text near/3 extract* in All Text) #22 (plant* in All Text near/3 medicin* in All Text) #23 (plant* in All Text near/3 preparation* in All Text) #24 (plant* in All Text near/3 mixture* in All Text) #25 (plant* in All Text near/3 therap* in All Text) #26 (plant* in All Text near/3 treatment* in All Text) #27 (medicine in All Text near/3 traditional in All Text) #28 (medicine in All Text near/3 chinese in All Text) #29 (medicine in All Text near/3 kampo in All Text) #30 (medicine in All Text near/3 plant* in All Text) #31 (complementary in All Text near/3 medicine in All Text) #32 (complementary in All Text near/3 therap* in All Text) #33 (complementary in All Text near/3 treatment* in All Text) #34 (complementary in All Text near/3 drug* in All Text) #35 (alternative in All Text near/3 medicine in All Text)
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#36 (alternative in All Text near/3 therap* in All Text) #37 (alternative in All Text near/3 treatment* in All Text) #38 (alternative in All Text near/3 drug* in All Text) #39 TCM in All Text #40 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15) #41 (#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30) #42 (#31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39) #43 (#40 or #41 or #42) #44 MeSH descriptor Hypothyroidism explode all trees #45 (hypothyr* in All Text or hypo-thyr* in All Text) #46 (thyroid in All Text near/3 defic* in All Text) #47 (thyroid in All Text near/3 insuffic* in All Text) #48 (#44 or #45 or #46 or #47) #49 (#43 and #48) MEDLINE 1 exp medicine, traditional/ or exp medicine, african traditional/ or exp medicine, arabic/ or exp medicine, ayurvedic/ or exp medicine, east asian traditional/ or exp medicine, chinese traditional/ or exp medicine, kampo/ or exp medicine, korean traditional/ or exp medicine, tibetan traditional/ 2 exp Phytotherapy/ 3 exp plant extracts/ or exp drugs, chinese herbal/ or exp plant oils/ 4 exp Plants, Medicinal/ 5 exp Plants/ or exp Plants, Medicinal/ 6 (chinese adj3 (medic* or herb* or drug* or formul* or plant* or prescri* or therap* or treatment*)).mp. 7 (phytodrug* or phytomedicin* or phytotherap* or phytotreatment* or phytopharmaceutical*).mp. 8 (herb* adj3 (remed* or extract* or medic* or preparation* or mixture* or therap* or treatment*)).mp. 9 (plant* adj3 (remed* or extract* or medicin* or preparation* or mixture or therap* or treatment*)).mp. 10 (medicine adj3 (traditional or chinese or kampo or plant*)).mp. 11 ((complementary or alternative) adj3 (medicine or therap* or treatment* or drug*)).mp. 12 TCM.tw,ot. 13 or/1-12 14 exp Hypothyroidism/ 15 (thyroid adj3 (defic* or insuffic*)).tw,ot. 16 (hypothyr* or hypo-thyr).mp. 17 or/14-16 18 13 and 17 19 randomized controlled trial.pt. 20 controlled clinical trial.pt. 21 randomi?ed.ab. 22 placebo.ab. 23 drug therapy.fs. 24 randomly.ab. 25 trial.ab. 26 groups.ab. 27 or/19-26 28 Meta-analysis.pt. 29 exp Technology Assessment, Biomedical/ 30 exp Meta-analysis/ Chinese herbal medicines for hypothyroidism (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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31 exp Meta-analysis as topic/ 32 hta.tw,ot. 33 (health technology adj6 assessment$).tw,ot. 34 (meta analy$ or metaanaly$ or meta?analy$).tw,ot. 35 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systemat$)).tw,ot. 36 or/28-35 37 27 or 36 38 (comment or editorial or historical-article).pt. 39 37 not 38 40 (animals not (animals and humans)).sh. 41 39 not 40 42 18 and 41 EMBASE 1 plant extract/ or medicinal plant/ or plant medicinal product/ or herbal medicine/ 2 exp alternative medicine/ 3 exp phytotherapy/ 4 exp herbaceous agent/ 5 exp Chinese drug/ or exp Chinese herb/ or exp Chinese medicine/ or exp traditional medicine/ 6 (chinese adj3 (medic* or herb* or drug* or formul* or plant* or prescri* or therap* or treatment*)).mp. 7 (phytodrug* or phytomedicin* or phytotherap* or phytotreatment* or phytopharmaceutical*).mp. 8 (herb* adj3 (remed* or extract* or medic* or preparation* or mixture* or therap* or treatment*)).mp. 9 (plant* adj3 (remed* or extract* or medicin* or preparation* or mixture* or therap* or treatment*)).mp. 10 (medicine adj3 (traditional or chinese or kampo or plant*)).mp. 11 ((complementary or alternative) adj3 (medicine or therap* or treatment* or drug*)).mp. 12 TCM.tw,ot. 13 or/1-12 14 exp hypothyroidism/ 15 (hypothyr* or hypo-thyr*).tw,ot. 16 (thyroid adj3 (defic* or insuffic*)).tw,ot. 17 or/14-16 18 clinical trial/ 19 exp comparative study/ 20 exp drug comparison/ 21 major clinical study/ 22 exp randomization/ 23 crossover procedure/ 24 double blind procedure/ 25 single blind procedure/ 26 exp placebo/ 27 exp prospective study/ 28 ((clinical or controlled or comparative or placebo or prospective or randomi?ed) adj3 (trial or study)).ti,ab. 29 (random* adj7 (allocat* or allot* or assign* or basis* or divid* or order*)).ti,ab. 30 ((singl* or doubl* or trebl* or tripl*) adj7 (blind* or mask*)).ti,ab. 31 (cross?over* or (cross adj1 over*)).ti,ab. 32 or/18-31 33 exp meta analysis/
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34 (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot. 35 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot. 36 exp Literature/ 37 exp Biomedical Technology Assessment/ 38 hta.tw,ot. 39 (health technology adj6 assessment$).tw,ot. 40 or/33-39 41 32 or 40 42 (comment or editorial or historical-article).pt. 43 41 not 42 44 13 and 17 and 43 45 limit 44 to human
CONTRIBUTIONS OF AUTHORS Lin-qiu Ke (LK): protocol draft, trial selection, data analysis and data interpretation. Ying Hu (YH): search strategy development, acquiring trial reports, trial selection and data extraction. Kun Yang (KY): search strategy development, acquiring trial reports, data extraction, data analysis and data interpretation. Nanwei Tong (NT): data analysis, data interpretation, review draft and future update draft.
DECLARATIONS OF INTEREST LK: none known. YH: none known. KY: none known. NT: none known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW Because we could not include any study we just report on one main element of our planned methods which actually was performed in this review. All planned methods reflected standard Cochrane methodology and the standards of the Cochrane Metabolic and Endocrine Disorders Group.
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