Use of thyroid hormones in euthyroid patients with unexplained fatigue: analyses of aggregate data from European national surveys of professional endocrine society members

Background: Managing patients with fatigue is a clinical challenge. Because fatigue is often reported in hypothyroidism, thyroid hormone (TH) therapy may sometimes be incorrectly considered for biochemically euthyroid individuals. This study aimed to evaluate the prevalence and determinants of this practice in different European countries.

Methods: We analyzed aggregate data from the THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) online survey. We analyzed responses from 5,695 members of 28 national endocrine/thyroid societies’ specialists to the statement: “Thyroid hormones may be indicated in biochemically euthyroid patients with unexplained fatigue”.

Results: Overall, 7.5% (426/5695) of respondents indicated that TH therapy might be considered for euthyroid patients with unexplained fatigue. The proportion of positive responses varied widely across different countries (between 1.1% in Switzerland and 29.3% in Serbia; p=2 ×10^-16) and regions (between 4.7% in Western Europe and 8.7% in Western Asia or 8.8% in Eastern Europe; p=0.004). TH were more frequently prescribed for unexplained fatigue by male respondents (Odds Ratio, OR 1.45, 95% CI 1.18-1.78) and physicians practicing in private practice (OR 1.27, 95% CI 1.02-1.58), and less frequently by endocrinologists (OR 0.62, 95% CI 0.46-0.83).

Conclusion: A small, yet not negligible percentage of European thyroid-focused physicians consider using TH for euthyroid patients with unexplained fatigue, with significant variations based on geographic, demographic, and practice-related factors. Using levothyroxine and/or liothyronine in such cases lacks evidence and may partially contribute to the concerning overuse of TH therapy.

1 Introduction

Fatigue is among the most frequently reported symptoms of overt hypothyroidism, potentially causing significant impairment in daily activities and severely impacting patients’ quality of life (QoL) (1–4). Fatigue is reported across all age groups in hypothyroid patients, with a prevalence reaching 95% in individuals under 50 years old and its severity correlates with the decrease in serum thyroxine (T4) levels (5, 6). Although thyroid hormones play a pivotal role in maintaining neuronal integrity and function in the adult brain, the pathophysiology underlying hypothyroidism-related fatigue remains largely unknown (7, 8). It is speculated that: (i) fatigue results from a substantial decrease in the basal metabolic rate; (ii) TH exert a modulatory effect on the brain’s serotonergic system, (iii) general autoimmune/inflammatory mechanisms may contribute to fatigue, and (iv) fatigue may be associated with various comorbidities, including mental disorders, which are more prevalent among hypothyroid patients (9–16).

The association between fatigue and subclinical hypothyroidism remains controversial. Although fatigue is a predominant symptom in subclinical hypothyroidism, its prevalence does not differ significantly from euthyroid individuals and is strongly associated with concomitant diseases (17). Furthermore, several randomized controlled trials indicate that levothyroxine (LT4) treatment for subclinical hypothyroidism in adults does not improve general QoL or alleviate thyroid-related symptoms, including fatigue (18). Therefore, the treatment of subclinical hypothyroidism with TH warrants careful consideration, especially in those individuals with mild elevations of thyroid-stimulating hormone (TSH).

A recent and concerning trend is the lowering of the TSH threshold for initiating thyroid hormone therapy, with as many as 20-30% of patients started on LT4 despite having normal TSH levels (19). One reason behind the tendency to treat euthyroid individuals is the mistaken belief that symptoms commonly linked to hypothyroidism are more dependable for diagnosis than thyroid function tests (20–24). Therefore, exploring the influence of patient-reported fatigue on physicians’ decisions to prescribe TH may be important in understanding the escalating overuse of LT4. The aim of this survey was to explore the impact of patient-reported unexplained fatigue on thyroid specialists’ decisions regarding the prescription of TH.

2 Materials and methods

2.1 Design

The study is a part of an aggregate data analysis from all national THESIS surveys (Treatment of Hypothyroidism in Europe by Specialists: an International Survey). The THESIS study design and survey details have been previously described in detail (25–29). The project was supervised by a Steering Committee (LH, EVN, EP, PP, RA, RN). Briefly, 26 European countries, each with a population over 4 million, a national endocrine or thyroid professional society, and a national medical journal, participated in the project. Additionally, two Western Asian countries, Turkey and Israel, were included. Participating countries were grouped by geographic region according to the United Nations Statistics Division definition (https://data.un.org/en/index.html): Western Europe (Austria, Belgium, France, Germany, Netherlands, Switzerland), Northern Europe (Denmark, Finland, Ireland, Sweden, United Kingdom), Southern Europe (Croatia, Greece, Italy, Portugal, Serbia, Spain), Eastern Europe (Belarus, Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Ukraine), and Western Asia (Israel, Turkey).

The survey targeted practicing specialists, who were members of their respective national endocrine/thyroid societies and managed patients with hypothyroidism. Participants anonymously answered 8 questions regarding their demographics and 23 questions or statements concerning the use of TH in diverse clinical scenarios. The relevant statement regarding fatigue was: “Thyroid hormones may be indicated in biochemically euthyroid patients with unexplained fatigue”. Respondents were asked to select either “yes” or “no.” To further characterize respondents endorsing TH use in euthyroid patients with unexplained fatigue, an additional survey question was re-analyzed regarding potential causes of persistent symptoms in LT4-treated hypothyroid patients achieving normal serum TSH. Respondents expressed their opinion (strongly disagree/disagree/neutral/agree/strongly agree) about potential causes: (i) inability of levothyroxine to restore normal physiology, (ii) psychosocial factors, (iii) comorbidities, (iv) chronic fatigue syndrome, (v) unrealistic patient expectations, (vi) underlying inflammation due to autoimmunity, (vii) burden of chronic disease, and (viii) burden of medication adherence.

2.2 Statistics

Data analysis was performed using ‘R’ software. Survey results were not weighted. Categorical (qualitative) variables were presented as frequencies and percentages, while quantitative variables were presented as mean and standard deviation or median and range. Associations between categorical variables were evaluated using Pearson’s chi-square test. Cramer’s V test was used to determine effect size, independent of sample size and p-value. Cramer’s V (ϕc​) values were interpreted according to Rea and Parker: <0.1 (negligible), 0.1-0.2 (weak), 0.2-0.4 (moderate), 0.4-0.6 (relatively strong) and >0.6 (strong association). Multivariate analysis was conducted using logistic regression. Statistical significance was set at p <0.05.

3 Results

3.1 Baseline characteristics of respondents

Respondent characteristics have been previously described in detail (29). Briefly, survey invitations were distributed to 17,232 members of national thyroid or endocrine societies, with 5695 (33.0%) physicians completing the survey. The majority of respondents were specialists in endocrinology (5132/5695, 90.1%), aged over 40 years (4038/5695, 70.9%), with over 10 years of clinical practice (4487/5693, 78.8%). Most respondents managed more than 100 hypothyroid patients per year (3526/5677, 62.1%), whereas only 2.8% (158/5677) infrequently treated such patients (less than 10 patients per year). Females comprised 65% (3700/5695) of physicians (Table 1).

Table 1

Table 1. Characteristics of respondents.

3.2 Univariate analysis: characteristics of respondents who considered the use of TH in unexplained fatigue

Of all respondents, 7.5% (426/5695) indicated that TH use may be considered in biochemically euthyroid patients with unexplained fatigue. The likelihood of prescribing TH for unexplained fatigue was significantly higher among respondents who were: (i) male compared to female (9.1% vs. 6.6%, p=0.0008, Cramer’s V 0.04, 95% CI: 0.018-0.07), (ii) non-endocrinologists compared to endocrinologists (10.8% vs. 7.1%, p=0.001, Cramer’s V 0.04, 95% CI: 0.016-0.07), (iii) members of international thyroid associations compared to non-members (10.7% vs. 7.1%, p=0.003, Cramer’s V 0.04, 95% CI: 0.016-0.06) and (iv) specialists working in private practice compared to specialists in public or academic service (9.1% vs. 6.8%, p=0.003, Cramer’s V 0.04, 95% CI: 0.019- 0.07). Respondents who infrequently managed hypothyroid patients showed a trend towards affirmative responses, although this difference did not reach statistical significance (Table 1).

The proportion of physicians considering the use of TH in unexplained fatigue varied significantly among geographic regions and countries (p=0.004, Cramer V 0.05, 95% CI: 0.02-0.07, and p=2×10^-16, Cramer V 0.16, 95% CI: 0.12–0.18, respectively). The lowest percentage of affirmative responses were observed in Western Europe (44/938, 4.7%), while the highest percentages were in Western Asia (27/312, 8.7%) and Eastern Europe (147/1679, 8.8%) (Table 2). Fewer than 5% of respondents in Switzerland (1.1%), France (2.8%), Spain (4.1%), Portugal (4.6%), Russia (4.6%), and Italy (4.7%) indicated that TH might be appropriate for unexplained fatigue. Conversely, over 10% of respondents in Ukraine (10.3%), Germany (11.2%), Finland (11.4%), Poland (12.0%), Greece (12.7%), and Serbia (29.3%) considered TH for this indication (Table 2, Figure 1).

Table 2

Table 2. Number of responders who considered the use of thyroid hormones (TH) in euthyroid patients with unexplained fatigue by region and country.

Figure 1

Figure 1. Proportion of respondents considering thyroid hormone (TH) use in biochemically euthyroid patients with unexplained fatigue by country. Color-coding corresponds to percentages of affirmative responses: <5%, 5% - 7.5%, 7.6% - 10% and >10%. Created with MapChart.

3.3 Multivariate analysis: characteristics of respondents who considered the use of TH in unexplained fatigue

Multivariate analysis confirmed positive associations between male gender (p=0.0004, OR: 1.45, 95% CI: 1.18-1.78), practicing in private clinics (p=0.03, OR: 1.27, CI: 1.02-1.58), and practicing outside Western Europe (p=0.006) with more frequent consideration of TH for unexplained fatigue in euthyroid patients. Endocrinologists were less inclined to prescribe TH for this indication than non-endocrinologists (p=0.001, OR: 0.62, 95% CI: 0.46-0.83) (Table 3).

Table 3

Table 3. Propensity to prescribe TH in biochemically euthyroid patients with unexplained fatigue (multivariate analysis).

3.4 Association between respondents’ view on TH indication for unexplained fatigue and their opinion on potential causes of persistent symptoms

Participants attributing persistent symptoms to the inability of LT4 to restore normal physiology or underlying autoimmune inflammation were significantly more likely to consider TH for euthyroid patients with unexplained fatigue (p<0.001; Cramer’s V 0.072, 95% CI: 0.045–0.103 and Cramer’s V 0.102, 95% CI: 0.074–0.133, respectively). Respondents attributing persistent symptoms to psychosocial factors were less likely to suggest TH therapy for unexplained fatigue (p<0.001, Cramer’s V 0.067, 95% CI: 0.04–0.098) (Figure 2; Supplementary Table S1).

Figure 2

Figure 2. Association between respondent willingness to prescribe thyroid hormones (TH) for euthyroid patients with fatigue, and respondent perceptions about causes of persistent symptoms in hypothyroid patients treated with levothyroxine who have achieved serum TSH levels within the reference range. The horizontal axis shows respondent perceptions for possible causes (A–D) of persistent symptoms in hypothyroid patients treated with LT4 who achieve a normal TSH. For each cause (A–D), responses were grouped into three categories: “agree”, “neutral” or disagree. The vertical axis shows the percentage of respondents identified as TH-prescribers for unexplained fatigue. Pearson’s chi-square test: p<0.001.

4 Discussion

To our knowledge, this is the first survey investigating TH use for fatigue of unknown etiology in euthyroid patients. Respondents were predominantly experienced, thyroid-focused physicians from nearly all European countries. A key finding is that a small, yet not negligible percentage of respondents (7.5%) would consider prescribing TH for biochemically euthyroid patients with unexplained fatigue. Considering the high prevalence of fatigue in the general population, such inappropriate use of LT4 therapy may be one of the factors contributing to the escalating overuse of TH in euthyroid individuals (19).

Fatigue is a complex symptom that is reported by healthy individuals and patients with both acute and chronic diseases (30). An estimated 5% to 10% of primary care consultations pertain to fatigue and its highly non-specific nature presents a diagnostic and therapeutic challenge. A systematic review of 26 studies examining the causes of fatigue identified depression as the most frequent diagnosis (18.5%), while underlying somatic diseases (e.g., anemia, diabetes, hypothyroidism, malignancies) accounted for only 4.3% of cases. Myalgic encephalomyelitis/chronic fatigue syndrome was diagnosed in less than 2% of patients (31). Ultimately, an underlying etiology cannot be identified in approximately one-third of cases with fatigue, a situation referred to as medically not yet explained symptoms (MNYES). The management of these patients is a clinical challenge and may lead to inappropriate TH therapy (32–34).

Although the vast majority of respondents follow evidence-based recommendations, it is noteworthy that this survey found that approximately 1 out of 13 European thyroid specialists would consider prescribing TH to biochemically euthyroid patients with unexplained fatigue. Consistent with prior THESIS reports, this management approach exhibits significant variations across geographic regions and countries. Generally, TH use for fatigue was lowest in Western Europe, particularly Switzerland and France (less than 1 out of 30 respondents). Conversely, more than 1 out of 10 respondents in Ukraine, Germany, Finland, Poland, Greece, and Serbia may consider prescribing TH for unexplained fatigue (35–40). In comparison to most European countries, the use of TH in this setting was considered less frequently by specialists in Australia (3%, 2 out of 80), Latin America (2.5%, 2 out of 81), Canada (2.9%, 2 out of 68) and in Japan (2.9%, 6 out of 207) (41–44). The reasons for this discrepancy are at present unknown. It can be speculated that variations in clinical practices across countries or regions may arise from differences in guideline availability, healthcare systems structures, resource allocation and accessibility, patient advocacy, misinformation, training and education standards, as well as cultural influences (23).

Furthermore, the practice of considering TH therapy for fatigue was associated with physician gender (male), specialty (non-endocrinologist), and work setting (private practice). Since the questionnaire did not investigate the rationale for treating these patients, definitive explanations for the observed variations across respondent characteristics cannot be established (26–28, 45, 46). The differences in TH use observed between endocrinologists and non-endocrinologists may reflect greater awareness of the limitations and possible side effects of TH treatment. Further exploration of THESIS data yielded an interesting observation. Respondents’ views on potential causes of persistent symptoms in LT4 treated hypothyroid patients despite normal serum TSH have been previously described in detail (25). Briefly, respondents considered psychosocial factors the primary cause of persistent symptoms. Conversely, underlying inflammation due to autoimmunity and the inability of LT4 to restore normal physiology were considered the least important factors. Respondents attributing persistent symptoms to inability of LT4 to restore normal physiology or underlying autoimmune inflammation were significantly more likely to recommend TH for euthyroid patients with unexplained fatigue. These physicians might wrongly perceive symptoms commonly associated with hypothyroidism as more reliable diagnostic indicators than thyroid function tests. Attributing unexplained fatigue to “clinical hypothyroidism in biochemically euthyroid individuals” may lead to thinking traps and fallacies, including: misdiagnosis, false association, somatic fixation, premature attribution to chronic illness and ultimately in offering an ineffective treatment (47). A randomized double-blind placebo-controlled crossover trial of LT4 in euthyroid patients with symptoms of hypothyroidism demonstrated that TH are no more effective than placebo in improving psychological and physical well-being in such patients (48). Clinicians should instead consider MNYES and adopt a ‘two-track approach” to patient management by giving equal attention to both physical and psychosocial aspects, and, if needed, consulting other health professionals (21, 49, 50).

Several important limitations of this survey warrant discussion. The survey explored TH use for unexplained fatigue via a single statement, lacking any clinical context (e.g., fatigue duration, comorbidities, longitudinal TSH concentrations and anti-thyroid antibody levels). It remains speculative whether TH prescription for fatigue is more common in patients with increasing, “high-normal” TSH levels over time, or very high thyroid peroxidase antibodies levels (51). Although many associations in this study are highly significant, the low Cramer V-values (most often below 0.1) implies that other important drivers for considering TH for euthyroid patients with unexplained fatigue remain to be identified. The strength of this study lie in its large cohort of respondents who regularly manage hypothyroid patients across a wide range of settings (academic centers, public hospitals/clinics, and private practice) and represents nearly all eligible European countries with national endocrine or thyroid societies. Thus, this provides a novel insight into the (mis)use of LT4 and clinical practice in managing fatigue across Europe.

In conclusion, the use of TH in patients with unexplained fatigue may be one of the factors contributing to the escalating overuse of TH. If fatigue relief is the goal of TH treatment in euthyroid subjects, then this approach is likely to result in therapeutic failure, a delay in reaching an appropriate diagnosis and potential harm of overtreatment (including increased risk of cardiovascular morbidity and osteoporosis) (21, 52–54). The results of this study should prompt national endocrine and thyroid associations in countries where TH is frequently recommended for fatigue to validate these findings, explore the underlying drivers, and provide education on the appropriate use of LT4 therapy.

Data availability statement

The datasets presented in this article are not readily available because Data is the property of the THESIS sub-committee. Requests to access the datasets should be directed to TB, dG9tYXN6LmJlZG5hcmN6dWtAd3VtLmVkdS5wbA==.

Ethics statement

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

Author contributions

TB: Methodology, Formal analysis, Writing – review & editing, Writing – original draft. ASu: Formal analysis, Writing – review & editing, Writing – original draft. RA: Writing – review & editing, Formal analysis, Methodology, Supervision. EN: Writing – review & editing, Supervision, Methodology, Conceptualization, Formal analysis. RN: Methodology, Supervision, Writing – review & editing, Formal analysis. EP: Formal analysis, Writing – review & editing, Conceptualization, Methodology, Supervision. MŽ: Writing – review & editing, Formal analysis, Methodology, Supervision. EA: Writing – review & editing. MA: Writing – review & editing. GA: Writing – review & editing. BN: Writing – review & editing. EB: Writing – review & editing. MkB: Writing – review & editing. AB: Writing – review & editing. MhB: Writing – review & editing. CB: Writing – review & editing. M-CB: Writing – review & editing. CC: Writing – review & editing. JĆ: Writing – review & editing. JD: Writing – review & editing. HD: Writing – review & editing. VF: Writing – review & editing. BF: Writing – review & editing. EF: Writing – review & editing. DF-S: Writing – review & editing. JF: Writing – review & editing. JG: Writing – review & editing. TH: Writing – review & editing. JJ: Writing – review & editing. PK: Writing – review & editing. MKr: Writing – review & editing. MKš: Writing – review & editing. MKu: Writing – review & editing. IL: Writing – review & editing. LL: Writing – review & editing. SL: Writing – review & editing. VL: Writing – review & editing. AM: Writing – review & editing. MM: Writing – review & editing. SM: Writing – review & editing. CM: Writing – review & editing. TM: Writing – review & editing. DN: Writing – review & editing. BP: Writing – review & editing. TP: Writing – review & editing. CP: Writing – review & editing. FP: Writing – review & editing. ER: Writing – review & editing. PR: Writing – review & editing. MR: Writing – review & editing. KR: Writing – review & editing. ASh: Writing – review & editing. MT: Writing – review & editing. DU: Writing – review & editing. IV: Writing – review & editing. WV: Writing – review & editing. AV: Writing – review & editing. YY: Writing – review & editing. EY: Writing – review & editing. PP: Formal analysis, Methodology, Writing – review & editing, Supervision, Conceptualization. LH: Writing – review & editing, Supervision, Formal analysis, Methodology, Conceptualization.

Funding

The author(s) declare that no financial support was received for the research, and/or publication of this article.

Acknowledgments

We gratefully thank the leadership of the 28 countries’ Endocrine Societies, as well as all the members generously answering the questionnaire.

Conflict of interest

LH, PP, EP, EN received consultancy fees from IBSA Biochimique SA. Author IV was employed by the company Klinikum Vest GmbH Knappschaftskrankenhaus Recklinghausen.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be perceived as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2025.1713814/full#supplementary-material

Supplementary Table 1 | Association between respondents’ view that thyroid hormones may be indicated in biochemically euthyroid subjects with unexplained fatigue (TH prescribers) and potential causes of persistent symptoms in LT4-treated patients with hypothyroidism who achieve normal serum TSH. ¹ Not all respondents answered the question concerning the cause of persistence of hypothyroid symptoms despite normal serum TSH. ² “TH prescribers” vs “TH non-prescribers” were analysed using Pearson’s chi-square test. P values <0.05 are in bold. Cramér’s V is an effect size measurement for the chi-square test of independence. ³ The causes of persistent symptoms are ranked from most to least important. ⁴ Answers agree/strongly agree and disagree/strongly disagree were analyzed together.

References

1. Hegedüs L, Bianco AC, Jonklaas J, Pearce SH, Weetman AP, and Perros P. Primary hypothyroidism and quality of life. Nat Rev Endocrinol. (2022) 18:230–42. doi: 10.1038/s41574-021-00625-8

PubMed Abstract | Crossref Full Text | Google Scholar

2. Taylor PN, Medici MM, Hubalewska-Dydejczyk A, and Boelaert K. Hypothyroidism. Lancet. (2024) 404:1347–64. doi: 10.1016/S0140-6736(24)01614-3

PubMed Abstract | Crossref Full Text | Google Scholar

3. Grixti L, Fisher H, Priestley J, McMullan C, Woollven A, Perros P, et al. Prevalence and severity of fatigue in treated hypothyroidism: results of a UK survey. Eur Thyroid J. (2025) 14:e250044. doi: 10.1530/ETJ-25-0044

PubMed Abstract | Crossref Full Text | Google Scholar

4. Chaker L, Razvi S, Bensenor IM, Azizi F, Pearce EN, and Peeters RP. Hypothyroidism. Nat Rev Dis Primer. (2022) 8. doi: 10.1038/s41572-022-00357-7

PubMed Abstract | Crossref Full Text | Google Scholar

5. Carlé A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Andersen S, et al. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: A population-based case-control study. Am J Med. (2016) 129:1082–92. doi: 10.1016/j.amjmed.2016.06.013

PubMed Abstract | Crossref Full Text | Google Scholar

6. Larsen CB, Winther KH, Cramon PK, Rasmussen ÅK, Feldt-Rasmussen U, Groenvold M, et al. Severity of hypothyroidism is inversely associated with impaired quality of life in patients referred to an endocrine clinic. Thyroid Res. (2023) 16:37. doi: 10.1186/s13044-023-00178-0

PubMed Abstract | Crossref Full Text | Google Scholar

7. de Souza JS. Thyroid hormone biosynthesis and its role in brain development and maintenance. Adv Protein Chem Struct Biol. (2024) 142:329–65. doi: 10.1016/bs.apcsb.2023.12.024

PubMed Abstract | Crossref Full Text | Google Scholar

8. Sinkó R, Salas-Lucia F, Mohácsik P, Halmos E, Wittmann G, Egri P, et al. Variable transduction of thyroid hormone signaling in structures of the mouse brain. Proc Natl Acad Sci U.S.A. (2025) 122:e2415970122. doi: 10.1073/pnas.2415970122

PubMed Abstract | Crossref Full Text | Google Scholar

9. Bauer M, Heinz A, and Whybrow PC. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry. (2002) 7:140–56. doi: 10.1038/sj.mp.4000963

PubMed Abstract | Crossref Full Text | Google Scholar

10. Louwerens M, Appelhof BC, Verloop H, Medici M, Peeters RP, Visser TJ, et al. Fatigue and fatigue-related symptoms in patients treated for different causes of hypothyroidism. Eur J Endocrinol. (2012) 167:809–15. doi: 10.1530/EJE-12-0501

PubMed Abstract | Crossref Full Text | Google Scholar

11. Martin JV and Sarkar PK. Nongenomic roles of thyroid hormones and their derivatives in adult brain: are these compounds putative neurotransmitters? Front Endocrinol. (2023) 14:1210540. doi: 10.3389/fendo.2023.1210540

PubMed Abstract | Crossref Full Text | Google Scholar

12. Raij T and Raij K. Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome. Front Endocrinol. (2024) 15:1358404. doi: 10.3389/fendo.2024.1358404

PubMed Abstract | Crossref Full Text | Google Scholar

13. Finsterer J and Mahjoub SZ. Fatigue in healthy and diseased individuals. Am J Hosp Palliat Med. (2014) 31:562–75. doi: 10.1177/1049909113494748

PubMed Abstract | Crossref Full Text | Google Scholar

14. Brenta G and Gottwald-Hostalek U. Comorbidities of hypothyroidism. Curr Med Res Opin. (2025) 41:421–9. doi: 10.1080/03007995.2025.2476075

PubMed Abstract | Crossref Full Text | Google Scholar

15. Thvilum M, Brandt F, Almind D, Christensen K, Brix TH, and Hegedüs L. Increased psychiatric morbidity before and after the diagnosis of hypothyroidism: A nationwide register study. Thyroid. (2014) 24:802–8. doi: 10.1089/thy.2013.0555

PubMed Abstract | Crossref Full Text | Google Scholar

16. Thvilum M, Brandt F, Almind D, Christensen K, Brix TH, and Hegedüs L. Type and Extent of Somatic Morbidity before and after the Diagnosis of Hypothyroidism. A Nationwide Register Study. PloS One. (2013) 8:e75789. doi: 10.1371/journal.pone.0075789

PubMed Abstract | Crossref Full Text | Google Scholar

17. Carlé A, Karmisholt JS, Knudsen N, Perrild H, Thuesen BH, Ovesen L, et al. Does subclinical hypothyroidism add any symptoms? Evidence from a danish population-based study. Am J Med. (2021) 134:1115–1126.e1. doi: 10.1016/j.amjmed.2021.03.009

PubMed Abstract | Crossref Full Text | Google Scholar

18. Feller M, Snel M, Moutzouri E, Bauer DC, De Montmollin M, Aujesky D, et al. 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) 320:1349. doi: 10.1001/jama.2018.13770

PubMed Abstract | Crossref Full Text | Google Scholar

19. Brito JP, Ross JS, El Kawkgi OM, Maraka S, Deng Y, Shah ND, et al. Levothyroxine use in the United States, 2008-2018. JAMA Intern Med. (2021) 181:1402. doi: 10.1001/jamainternmed.2021.2686

PubMed Abstract | Crossref Full Text | Google Scholar

20. Dzurec LC. Experiences of fatigue and depression before and after low-dose 1-thyroxine supplementation in essentially euthyroid individuals. Res Nurs Health. (1997) 20:389–98. doi: 10.1002/(sici)1098-240x(199710)20:5%3C389::aid-nur3%3E3.0.co;2-k

PubMed Abstract | Crossref Full Text | Google Scholar

21. Hegedüs L, Nagy EV, Papini E, and Perros P. Limiting the use and misuse of liothyronine in hypothyroidism. Nat Rev Endocrinol. (2025) 21:3–4. doi: 10.1038/s41574-024-01055-y

PubMed Abstract | Crossref Full Text | Google Scholar

22. Weetman AP. Thyroxine treatment in biochemically euthyroid but clinically hypothyroid individuals. Clin Endocrinol (Oxf). (2002) 57:25–7. doi: 10.1046/j.1365-2265.2002.01561.x

PubMed Abstract | Crossref Full Text | Google Scholar

23. Perros P, Poots A, Nagy EV, Papini E, Hay H, Abad-Madroñero J, et al. Knowledge gaps about the diagnosis and treatment of hypothyroidism: an international patient survey. Front Endocrinol. (2025) 16:1663497. doi: 10.3389/fendo.2025.1663497

PubMed Abstract | Crossref Full Text | Google Scholar

24. Laryea EA. Subclinical hypothyroidism. To treat or not to treat. Can Fam Physician Med Fam Can. (1993) 39:1997–8.

Google Scholar

25. Attanasio R, Žarković M, Papini E, Nagy EV, Negro R, Perros P, et al. Patients’ persistent symptoms, clinician demographics and geo-economic factors are associated with choice of therapy for hypothyroidism by European thyroid specialists: The “THESIS”* collaboration (*Treatment of Hypothyroidism in Europe by Specialists, an International Survey). Thyroid. (2024) 34(4):429–441. doi: 10.1089/thy.2023.0580

PubMed Abstract | Crossref Full Text | Google Scholar

26. Galofré JC, Díez JJ, Attanasio R, Nagy EV, Negro R, Papini E, et al. Treatment of obesity with thyroid hormones in europe. Data from the THESIS* Collaboration. J Endocrinol Invest. (2024) 48:201–12. doi: 10.1007/s40618-024-02409-z

PubMed Abstract | Crossref Full Text | Google Scholar

27. Negro R, Žarković M, Attanasio R, Hegedüs L, Nagy EV, Papini E, et al. Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey). Clin Endocrinol (Oxf). (2024) 101:180–90. doi: 10.1111/cen.15099

PubMed Abstract | Crossref Full Text | Google Scholar

28. Papini E, Attanasio R, Žarković M, Nagy EV, Negro R, Perros P, et al. Thyroid hormones for euthyroid patients with simple goiter growing over time: a survey of European thyroid specialists. Endocrine. (2024) 87:262–72. doi: 10.1007/s12020-024-04002-z

PubMed Abstract | Crossref Full Text | Google Scholar

29. Žarković M, Attanasio R, Nagy EV, Negro R, Papini E, Perros P, et al. Characteristics of specialists treating hypothyroid patients: the “THESIS” collaborative. Front Endocrinol. (2023) 14:1225202. doi: 10.3389/fendo.2023.1225202

PubMed Abstract | Crossref Full Text | Google Scholar

30. Dukes JC, Chakan M, Mills A, and Marcaurd M. Approach to fatigue. Med Clin North Am. (2021) 105:137–48. doi: 10.1016/j.mcna.2020.09.007

PubMed Abstract | Crossref Full Text | Google Scholar

31. Stadje R, Dornieden K, Baum E, Becker A, Biroga T, Bösner S, et al. The differential diagnosis of tiredness: a systematic review. BMC Fam Pract. (2016) 17:147. doi: 10.1186/s12875-016-0545-5

PubMed Abstract | Crossref Full Text | Google Scholar

32. Hegedüs L, van der Feltz-Cornelis CM, Papini E, Nagy EV, Weetman AP, and Perros P. Medically not yet explained symptoms in hypothyroidism. Nat Rev Endocrinol. (2024) 20:685–93. doi: 10.1038/s41574-024-01022-7

PubMed Abstract | Crossref Full Text | Google Scholar

33. Perros P, van der Feltz-Cornelis C, Papini E, Nagy EV, Weetman AP, and Hegedüs L. The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review. Clin Endocrinol (Oxf). (2023) 98:461–8. doi: 10.1111/cen.14473

PubMed Abstract | Crossref Full Text | Google Scholar

34. Van Der Feltz-Cornelis CM, Sweetman J, Edwards M, Gall N, Gilligan J, Hayle S, et al. Identifying the top research priorities in medically not yet explained symptoms (MNYES): a James Lind Alliance priority setting partnership. BMJ Open. (2022) 12:e061263. doi: 10.1136/bmjopen-2022-061263

PubMed Abstract | Crossref Full Text | Google Scholar

35. Bednarczuk T, Attanasio R, Hegedüs L, Nagy EV, Negro R, Papini E, et al. Use of thyroid hormones in hypothyroid and euthyroid patients: a THESIS* questionnaire survey of Polish physicians. *THESIS: Treatment of hypothyroidism in Europe by specialists: an international survey. Endokrynol Pol. (2021) 72:357–65. doi: 10.5603/EP.a2021.0048

PubMed Abstract | Crossref Full Text | Google Scholar

36. Metso S, Hakala T, Attanasio R, Nagy E, Negro R, Papini E, et al. Use of thyroid hormones in the treatment of hypothyroidism: ­Thesis questionnaire survey for Finnish specialists. Finnish Med J. (2021) 48:2885–9.

Google Scholar

37. Buffet C, Belin L, Attanasio R, Negro R, Hegedüs L, Nagy EV, et al. Real-life practice of thyroid hormone use in hypothyroid and euthyroid patients: A detailed view from the THESIS questionnaire survey in France. Ann Endocrinol. (2022) 83:27–34. doi: 10.1016/j.ando.2021.11.002

PubMed Abstract | Crossref Full Text | Google Scholar

38. Paschou SA, Alevizaki M, Attanasio R, Hegedüs L, Nagy EV, Papini E, et al. Use of thyroid hormones in hypothyroid and euthyroid patients: a 2020 THESIS questionnaire survey of members of the Hellenic Endocrine Society. Hormones. (2022) 21:103–11. doi: 10.1007/s42000-021-00335-w

PubMed Abstract | Crossref Full Text | Google Scholar

39. Nedeljkovic-Beleslin B, Attanasio R, Hegedüs L, Nagy E, Negro R, Papini E, et al. Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of Serbian physicians. Srp Arh Celok Lek. (2022) 150:667–74. doi: 10.2298/SARH211221110N

PubMed Abstract | Crossref Full Text | Google Scholar

40. Vardarli I, Brandenburg T, Hegedüs L, Attanasio R, EndreV N, Papini E, et al. A questionnaire survey of german thyroidologists on the use of thyroid hormones in hypothyroid and euthyroid patients: the THESIS (Treatment of hypothyroidism in europe by specialists: an international survey) collaborative. Exp Clin Endocrinol Diabetes. (2022) 130:577–86. doi: 10.1055/a-1832-0644

PubMed Abstract | Crossref Full Text | Google Scholar

41. Cassemiro JF, Ilera V, Batalles S, Reyes A, Nagy EV, Papini E, et al. Use of thyroid hormones in hypothyroid and euthyroid patients: a 2022 THESIS questionnaire survey of members of the Latin American Thyroid Society (LATS). Thyroid Res. (2023) 16:40. doi: 10.1186/s13044-023-00182-4

PubMed Abstract | Crossref Full Text | Google Scholar

42. Lafontaine N, Brown SJ, Perros P, Papini E, Nagy EV, Attanasio R, et al. Use of thyroid hormones in hypothyroid and euthyroid patients: A survey of members of the Endocrine Society of Australia. Clin Endocrinol (Oxf). (2024) 100:477–85. doi: 10.1111/cen.15049

PubMed Abstract | Crossref Full Text | Google Scholar

43. Liu A, Morrison D, Hegedüs L, Nagy EV, Papini E, Perros P, et al. Canadian endocrinologists′ Perspectives on treatment with thyroid hormone substitutions in euthyroid and hypothyroid patients: A 2023 THESIS questionnaire survey. Clin Endocrinol (Oxf). (2025) 103(5):739–748. doi: 10.1111/cen.70009

PubMed Abstract | Crossref Full Text | Google Scholar

44. Nagayama Y, Tajiri J, Murakami T, Watanabe N, Sato S, Shindo H, et al. A questionnaire survey of thyroid specialists in Japan on the use of thyroid hormones in hypothyroid and euthyroid patients. Endocr J. (2025) 72(8):911–923. doi: 10.1507/endocrj.ej25-0106

PubMed Abstract | Crossref Full Text | Google Scholar

45. Galofré JC, Díez JJ, Attanasio R, Nagy EV, Bednarczuk T, Papini E, et al. Thyroid hormone treatment for hypercholesterolemia in euthyroid patients: results from a european survey of thyroid specialists. Clin Endocrinol (Oxf). (2025) 103(5):749–756. doi: 10.1111/cen.70014

PubMed Abstract | Crossref Full Text | Google Scholar

46. Ludgate S, McGowan A, Moran C, Attanasio R, Žarković M, Nagy EV, et al. The use of thyroid hormones in the treatment of euthyroid patients with treatment-resistant depression. Data from a survey of 5695 European national endocrine professional organization members. Front Endocrinol. (2025) 16:1665720. doi: 10.3389/fendo.2025.1665720

PubMed Abstract | Crossref Full Text | Google Scholar

47. Maisel P, Baum E, and Donner-Banzhoff N. Fatigue as the chief complaint. Dtsch Ärztebl Int. (2021) 118(33-34):556–576. doi: 10.3238/arztebl.m2021.0192

PubMed Abstract | Crossref Full Text | Google Scholar

48. Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJG, McMahon AD, et al. 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) 323:891–5. doi: 10.1136/bmj.323.7318.891

PubMed Abstract | Crossref Full Text | Google Scholar

49. Burton C, Mooney C, Sutton L, White D, Dawson J, Neilson AR, et al. Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial. Lancet. (2024) 403:2619–29. doi: 10.1016/S0140-6736(24)00700-1

PubMed Abstract | Crossref Full Text | Google Scholar

50. Perros P, Nagy EV, Papini E, Abad-Madroñero J, Lakwijk P, Poots AJ, et al. Hypothyroidism and type D personality: results from E-MPATHY, a cross-sectional international online patient survey. J Clin Endocrinol Metab. (2024) 110:e97–e108. doi: 10.1210/clinem/dgae140

PubMed Abstract | Crossref Full Text | Google Scholar

51. Guldvog I, Reitsma LC, Johnsen L, Lauzike A, Gibbs C, Carlsen E, et al. Thyroidectomy versus medical management for euthyroid patients with hashimoto disease and persisting symptoms: A randomized trial. Ann Intern Med. (2019) 170:453–64. doi: 10.7326/M18-0284

PubMed Abstract | Crossref Full Text | Google Scholar

52. Abrahamsen B, Jørgensen HL, Laulund AS, Nybo M, Bauer DC, Brix TH, et al. The excess risk of major osteoporotic fractures in hypothyroidism is driven by cumulative hyperthyroid as opposed to hypothyroid time: an observational register-based time-resolved cohort analysis. J Bone Miner Res. (2015) 30:898–905. doi: 10.1002/jbmr.2416

PubMed Abstract | Crossref Full Text | Google Scholar

53. Centanni M, Duntas L, Feldt-Rasmussen U, Koehrle J, Peeters RP, Razvi S, et al. ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism. Eur Thyroid J. (2025) 14(4):e250123. doi: 10.1530/etj-25-0123

PubMed Abstract | Crossref Full Text | Google Scholar

54. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, and Hegedüs L. Duration of over- and under-treatment of hypothyroidism is associated with increased cardiovascular risk. Eur J Endocrinol. (2019) 180:407–16. doi: 10.1530/EJE-19-0006

PubMed Abstract | Crossref Full Text | Google Scholar