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Psychological well‐being in patients on ‘adequate’ doses of l‐thyroxine: results of a large, controlled community‐based questionnaire study
Abstract
Summary: objective Over 1% of the UK population is receiving thyroid hormone replacement with l‐thyroxine (T4). However, many patients complain of persistent lethargy and related symptoms on T4 even with normal TSH levels. To date there has been no large study to determine whether this is related to thyroxine replacement or coincidental psychological morbidity. We have therefore attempted to address this issue using a large, community‐based study. design and patients Computerized prescribing records of five general practices were used to identify 961 patients who had been on thyroxine for a minimum of 4 months from a population of 63 000 (1·5%), along with age‐ and sex‐matched controls. All 1922 individuals were sent a two‐page questionnaire, made up of the short form of the General Health Questionnaire (GHQ‐12), designed to detect minor psychiatric disorders in the community, and a 12‐question ‘thyroid symptom questionnaire’ (TSQ) in the same format. A covering letter explained that we were interested in ‘how patients felt on medication’ and made no direct reference to thyroxine. measurements Scores from the GHQ and TSQ were marked for each individual using the GHQ and Likert scoring methods. Patients’ latest TSH measurements were obtained from laboratory records. Comparisons were then made on scores for the total GHQ‐12, TSQ and individual questions between patients (P) and control (C) groups. Separate analyses were made comparing the patients with a normal TSH (nP) and the control group. results Five hundred and ninety‐seven (62%) of the patients (P) and 551 (57%) of the controls (C) responded and fully completed at least one of the two questionnaire. Three hundred and ninety‐seven responding patients (nP) had a TSH estimation performed in the previous 12 months with the last result being in the local laboratory normal range for TSH (0·1–5·5 or 0·2–6·0 mU/l, according to the assay method used). The responding P, nP and C populations were well matched for age (59·96, 59·73, 59·35 years) and sex (85%, 83%, 87% female). The number of individuals scoring 3 or more on the GHQ‐12 (indicating ‘caseness’) was 21% higher in P than C [185/572 (32·3%) vs. 137/535 (25·6%), P = 0·014] and 26% higher in nP than C [131/381 (34·4%) vs. 137/535 (25·6%), P < 0·005]. Stronger differences were seen with the TSQ scores [C = 187/535 (35·0%), P = 273/583 (46·8%), P < 0·001, P vs. C; and nP = 189/381 (48·6%), P < 0·001, nP vs. C]. Differences existed in chronic drug use and chronic disease prevalence between the control and patient groups, but the differences in GHQ and TSQ scores between the groups remained significant even after correction for these factors as well as age and sex in multiple regression analysis. conclusions This community‐based study is the first evidence to indicate that patients on thyroxine replacement even with a normal TSH display significant impairment in psychological well‐being compared to controls of similar age and sex. In view of the large numbers of people on thyroxine replacement, we believe that these differences, although not large, could contribute to significant psychological morbidity in a substantial number of individuals.
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In the citing paper
“Patients on levothyroxine display ongoing substantial impairment of psychological wellbeing compared with controls of similar age and sex.165”
From Hypothyroidism (2024) · cites this paper as [165]
In the citing paper
“Persistent symptoms in patients treated for hypothyroidism are common.”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [4]
In the citing paper
“a proportion of individuals have significant dissatisfaction with it, including ongoing significant impairment in psychological well -being compared to controls of similar age and sex. 4 -8”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [4]
In the citing paper
“There is now a consensus that a fraction of the LT4-treated hypothyroid patients with normal serum TSH levels remains symptomatic ( 6 , 7 , 23 , 24 ).”
From Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism (2021) · cites this paper as [6]
In the citing paper
“For some patients, however, the success story was limited by the persistence of residual cognitive symptoms and decrements in the quality of life (5–7).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [5]
In the citing paper
“However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [5]
In the citing paper
“Limiting the analysis to patients with serum TSH in a narrow normal range (0.4-4.0 mU/l) gave similar outcomes: caseness was 35.1% in GHQ-12 and 48.5% in TSQ.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [11]
In the citing paper
“After correction for age, sex, chronic diseases and chronic medication, the proportion of caseness was higher in patients than in controls, both in the GHQ-12 (34.4 vs. 25.6%,p = 0.012, odds ratio (OR) 1.48 [1.09-2.00])and in the TSQ (48.6 vs. 35.0%,p ! 0.001, OR 1.71 [1.29-2.25]).”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [11]
In the citing paper
“After correction for age, sex, chronic diseases and chronic medication, the proportion of caseness was higher in patients than in controls, both in the GHQ-12 (34.4 vs. 25.6%,p = 0.012, odds ratio (OR) 1.48 [1.09-2.00])and in the TSQ (48.6 vs. 35.0%,p ! 0.001, OR 1.71 [1.29-2.25]).”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [11]
In the citing paper
“The study provided evidence that patients on L-T4 replacement even with a normal serum TSH display significant impairment of psychological well-being compared to controls of similar age and sex.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [11]
In the citing paper
“However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction.”
From Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee (2016) · cites this paper as [22]
In the citing paper
“Approximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL).”
In the citing paper
“Hypothyroid subjects on long-term LT4 alone have (a) a 15% excess of psychological caseness (5)”
In the citing paper
“We observed that in individuals on LT4 alone (n = 573), homozygosity for the Thr92Ala polymorphism was associated with reduced QoL (5).”
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Self-citationBrain disorders in euthyroid Hashimoto’s thyroiditis patients
Strzałkowska, B., Strzelczyk, J., Dawidowicz, M., Kula, A., Mielcarska, S., Szarek, R., & Świętochowska, E. (2024) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2024.108519 · Cited by 4
“A study by Saravanan and others confirmed previous studies as they found that patients on thyroxine replacement with normal TSH levels had worse General Health Questionnaire (GHQ-12) and 12-question ’ thyroid symptom questionnaire ’ (TSQ) scores compared to controls [11].”
Calcium and magnesium levels in patients with primary hypothyroidism
Turanjanin, D., Mijović, R., Starčević, I., & Tatalović, V. (2024) · Medicinski pregled · doi:10.2298/mpns2404106t · Cited by 4
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Bablis, P., Day, R. R., Bablis, S., & Pollard, H. P. (2024) · Cureus · doi:10.7759/cureus.58231 · Cited by 6
“…to moderate effect sizes up to six months after commencing treatment with LT4 [113]; however, studies report impaired psychological well-being [112,114] and cognitive functioning [115] in euthyroid patients on LT4, revealing that patient QoL does not always correlate with improvements in TSH…”
BackgroundDiagnosis and Treatment of Hypothyroidism
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“Social disorders, along with motor and cognitive impairments, have been reported in children with congenital hypothyroidism, even with early diagnosis and thyroid hormone replacement therapy 169 .”
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“However, in a subgroup of thyroidectomized subjects [3,4], typical symptoms of hypothyroidism persist with a reduced quality of life (QoL) despite normalization of serum TSH levels.”
BackgroundFree triiodothyronine/free thyroxine ratio in children with congenital hypothyroidism
Sydlik, C., Dubinski, I., Bechtold, S. M., & Schmidt, H. (2022) · Endocrine Connections · doi:10.1530/ec-22-0032 · Cited by 3
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“Levothyroxine replacement may cause disruption in psychological condition, lower resting energy expenditure, lower T3:T4 ratio, higher body mass index (BMI) and increased levels of serum cholesterol and LDL compared with normal controls (13-17).”
BackgroundPsychosocial Factors in Patients with Thyroid Disease
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“There are studies which prove that despite the treatment of hypothyroidism with hormone T4 substitution, a lot of patients quote more or less vague complaints and feel worsened quality of life (Mc Millan et al., 2004, 2005, 2008; Saravanan et al., 2002; Wekking et al., 2005).”
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Quality of life in patients with overt hypothyroidism: a systematic review
Thvilum, M., Lind, S. M., Ebbehøj, E., Gregersen, S., & Grove‐Laugesen, D. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf179 · Cited by 4
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“Many patients do not feel well on standard LT4 [16– 19] and may benefit from experimental treatment with combined LT3 + LT4 preparations [13]; however, combination therapy with LT4/LT3 did not show any significant improvement in related parameters compared to LT4 monotherapy [20].”
A Clinical Debate: What Is the Therapeutic Choice for Recurrent Graves’ Hyperthyroidism?
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“derangements, lower resting energy expenditure, and impairment of psychological well-being compared to normal controls or euthyroid Graves’ patients (53-57).”
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Metadata
- Authors
- Saravanan, P., Chau, W. ‐., Roberts, N., Vedhara, K., Greenwood, R., & Dayan, C. M.
- Affiliations
- Weston General Hospital (GB)
- Bristol Royal Infirmary (GB)
- University of Bristol (GB)
- Corresponding author
- Dayan, C. M.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2002-10-22
- Volume
- 57
- Issue
- 5
- Pages
- 577-585
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W1888479777
- Cited by
- 514
- References
- 33
- Citations by year
- 2026: 12 · 2025: 27 · 2024: 26 · 2023: 30 · 2022: 45 · 2021: 33 · 2020: 37 · 2019: 33 · 2018: 27 · 2017: 26 · 2016: 31 · 2015: 21 · 2014: 25 · 2013: 15 · 2012: 16
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- levothyroxine, thyroid hormone replacement, psychological well-being, thyroid symptoms, thyroid-stimulating hormone, psychiatric morbidity, lethargy, General Health Questionnaire, community-based study, adverse drug reactions, quality of life
- MeSH terms
- Adolescent, Adult, Aged, Drug Administration Schedule, Female, Humans, Hypothyroidism, Male, Middle Aged, Psychiatric Status Rating Scales, Surveys and Questionnaires, Regression Analysis, Thyrotropin, Thyroxine, Chi-Square Distribution, Case-Control Studies
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