THE OCCURRENCE OF various abnormalities in brain

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1 X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(9): Printed in U.S.A. Copyright 2006 by The Endocrine Society doi: /jc Psychological Well-Being Correlates with Free Thyroxine But Not Free 3,5,3 -Triiodothyronine Levels in Patients on Thyroid Hormone Replacement Ponnusamy Saravanan, Theo J. Visser, and Colin M. Dayan Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (P.S., C.M.D.), University of Bristol, Bristol BS1 3NY, United Kingdom; and Department of Internal Medicine (T.J.V.), Erasmus University Medical Centre, 3000 DR Rotterdam, The Netherlands Context and Objective: An association between mood disorders and overt thyroid dysfunction is well established, but there are few data on the potential for thyroid hormone levels closer to the reference range to correlate with psychological well-being. Design, Setting, and Patients: We analyzed the relationship between psychological well-being and free T 4 (ft4), free T 3 (ft3), TSH, and total rt 3 in 697 patients on thyroid hormone replacement therapy at entry to a randomized, controlled trial of combined T 4 and T 3 replacement therapy. were on 100 g or more T 4. Interventions and Main Outcome Measures: Psychological wellbeing was assessed with General Health Questionnaire-12 (GHQ-12), Thyroid Symptom Questionnaire, and Hospital Anxiety and Depression Scale. First Published Online June 27, 2006 Abbreviations: b, Coefficient beta; ft3, free T 3 ; ft4, free T 4 ; GHQ, General Health Questionnaire; HADS, Hospital Anxiety and Depression Scale; NR, normal range; OR, odds ratio; TPO, thyroid peroxidase; TSQ, Thyroid Symptom Questionnaire; WATTS, Weston Area T 3 /T 4 Study. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community Results: ft 4 and TSH showed a strong correlation with GHQ-12 scores (ft4 b: 0.16, P 0.005; TSH b: 0.663, P 0.04). No correlations were seen between the GHQ scores and ft3 (b: 0.318, P 0.275), rt 3 (b: 0.095, P 0.95), rt 3 to ft4 ratio (b: 71.83, P 0.09) or ft3 to rt 3 ratio (b: 0.05, P 0.32). The correlations remained when the data set was limited to patients with TSH in the range miu/liter. Similar correlations were seen with the Thyroid Symptom Questionnaire, although not with the Hospital Anxiety and Depression Scale scores. Conclusions: Differences in ft4 and TSH concentration, even within the reference range, may be a determinant of psychological well-being in treated hypothyroid patients although not necessarily with symptoms typical of anxiety or depression. (J Clin Endocrinol Metab 91: , 2006) THE OCCURRENCE OF various abnormalities in brain function including cognitive and memory impairment in patients with overt hypothyroidism is now well established. Reduced levels of thyroid hormone appear to slow serotonergic neurotransmission in the brain (1), an effect associated with low mood. In addition, thyroid hormones are widely used to augment antidepressant treatment (2), although the trial evidence underlying this is controversial (3). Evidence for lesser variation in thyroid hormone levels affecting mood and psychological well-being remains more controversial. Some cross-sectional studies suggested that subclinical thyroid dysfunction is associated with depression, cognitive impairment, and memory loss (reviewed in Ref. 4), and Carr et al. (5) reported that patients receiving thyroid hormone replacement appeared more content on higher doses of T 4. The large HUNT (Nørd-Trondelag Health Study) community-based study failed to find an association, but the correlations were made with categories of TSH level rather than using T 4 and TSH, as continuous variables. Interestingly, in the subgroup of patients on T 4, a link with depression was reported (6). Recently several studies of thyroid hormone replacement therapy reported that the combination of T 4 and T 3 is not superior to T 4 alone (7, 8). However, where thyroid hormone levels were raised, psychological well-being appeared to have improved (9). In view of the large body of circumstantial evidence linking thyroid hormone levels and mood and the relative stability of endogenous thyroid hormone levels within a given individual over time (10, 11), we hypothesized that variation in thyroid hormone levels, even within the laboratory reference range, might represent an independent risk factor for low mood and depression. To test this hypothesis, we examined the relationship between thyroid hormone parameters and psychological well-being across a large cohort of patients treated with T 4 who were about to take part in a randomized, controlled trial of different forms of thyroid hormone treatment (12). Subjects and Methods Baseline data were obtained from subjects recruited to a randomized, controlled trial studying the effects of combined T 3 /T 4 therapy vs. T 4 alone for treating hypothyroidism [Weston Area T 3 /T 4 Study (WATTS)] (12). The study was approved by the local research ethics committee. All patients provided written, informed consent. Data from 697 patients in WATTS were available for analysis. Entry criteria for the WATTS have previously been published (12) and included age between 18 and 75 yr and T 4 replacement at a dose of 100 g/d or more, unchanged for a minimum of 3 months and with a TSH level reported to be in the laboratory reference range in the preceding 15 months. At study entry to WATTS, blood was drawn (untimed in relation to dose) and stored for measurement of thyroid hormones at the end of the study: serum TSH [normal range (NR) miu/ml], free

2 3390 J Clin Endocrinol Metab, September 2006, 91(9): Saravanan et al. Correlation of Thyroid Hormones and Well-Being T 4 (ft4) [NR ng/dl ( pmol/liter)], and anti-thyroid peroxidase (TPO) antibodies (positive if titer is 100) were measured by RIA (Diagnostic Product Corp., Los Angeles, CA). Serum free T 3 (ft3) [NR ng/dl ( pmol/liter)] was measured by chemiluminescence assay (Elecsys system 1010; Roche Diagnostics, Mannheim, Germany). Serum rt 3 was measured by an in-house RIA [NR 9 22 ng/dl ( nmol/liter)] (13). All the samples were analyzed as a single batch at the end of the study. Serum from 637 patients was available for the rt 3 assays. Psychological assessment Patients well-being was assessed at study entry by the General Health Questionnaire (GHQ)-12, which is a well-validated tool in predicting psychiatric morbidity when compared with complex psychometric tests and detailed psychiatric interview (14). The GHQ-12 has four responses for each question: better than usual, same as usual, less than usual, and much less than usual. In addition to the GHQ- 12, all subjects completed the Hospital Anxiety and Depression Scale (HADS) (15) and an unvalidated questionnaire, the Thyroid Symptom Questionnaire (TSQ) based on symptoms frequently reported by patients on thyroid hormone (16). The TSQ responses were developed in a similar way to the GHQ-12. The GHQ-12 and TSQ were scored by both the Likert method [0 3 per question, maximum score 36 (most dissatisfied), linear method] and the GHQ scoring method [0, 0, 1, 1, maximum score 12 (most dissatisfied), categorical method]. A score of 3 or greater by the GHQ scoring method is taken to indicate caseness, as when the GHQ was compared with complex psychiatric interview; such scores have been found to be strongly predictive of a psychiatric diagnosis being confirmed at interview (14). The HADS questionnaire was also scored by both the linear and categorical scoring method (15). Statistical analyses All the analyses were conducted in Stata version 8.0 (17). The relationships between psychological questionnaire scores and serum thyroid hormone measurements were ascertained using linear and logistic regression analyses for continuous and binary versions of the questionnaires, respectively. Multiple regression analysis was used when adjusting for age, sex, and anti-tpo antibody positivity. The results of the linear regression analyses were reported as correlation coefficient beta (b) and results of logistic regression analyses as odds ratio (OR). All correlations were reported with the whole data set and again with the restricted data set of subjects with TSH levels in the range of miu/liter at the time of psychological testing (n 473). 2 test and ANOVA were used to ascertain the relationship between ft4 levels (high and normal) and the binary and continuous versions of the questionnaires, respectively. Results The mean age of the patients was 57.3 yr. Eighty-four percent of patients were women (n 586). The original causes of hypothyroidism were autoimmune hypothyroidism (73.45%), Graves disease (17.07%), toxic multinodular goiter (2.58%), and nontoxic goiter (6.89%). The current diagnoses were autoimmune hypothyroidism (73.45%), postradioactive iodine (9.33%), postthyroidectomy (15.78%), and postthyroidectomy postradioactive iodine (1.44%). Forty-four percent of the patients (n 307) had a strongly positive titer for anti-tpo antibodies (titer 100). Baseline thyroid function at the time of initial psychological testing in all subjects is shown in Table 1, and the distribution of TSH, ft4, ft3, and rt 3 values is shown in Fig. 1. Nearly 43% of patients scored 3 or more on the GHQ-12 categorical score, demonstrating increased psychiatric morbidity. This is approximately 18% higher than reported in the general population (18) and 10% higher than seen in our crosssectional study (16) and may reflect selection bias in subjects volunteering for an intervention trial. Ten of the subjects (1.4%) had undetectable levels of TSH ( 0.01 miu/liter) and 171 (24.5%) had TSH levels less than 0.3 miu/liter. Fifty-three (7.6%) of the subjects had TSH levels more than 4.0 miu/liter; the highest TSH level was 12.9 miu/liter. Although all subjects had a TSH level within their local laboratory reference range in the 15 months before recruitment, when remeasured at study entry, 32% of subjects had TSH levels outside the range miu/liter in the study laboratory. A more sensitive TSH assay and a narrower reference range used for the study might be a contributing factor. Baseline ft4 showed a strong negative correlation to the GHQ-12 scores (correlation coefficient b: 0.155, P 0.005). The relationship persisted even after correcting for age, sex, and anti-tpo antibody positivity (b: 0.14, P 0.015) and was also present in the subset of patients with TSH between 0.3 and 4.0 miu/liter (b: 0.159, P 0.038, n 473). The same correlations were observed when the GHQ was scored as a categorical parameter (GHQ scoring) (Table 2). The relationship was in the expected direction (higher ft4 associated with lower GHQ scores implying improved well-being), and the slope indicated an improvement of 1 GHQ point for a 0.51 ng/dl (6.5 pmol/ liter) rise in ft4. A positive correlation was seen with log TSH and GHQ [b: 0.66, P 0.04; no change after controlling for age, sex, and anti-tpo antibody positivity (b: 0.68, P 0.04)]. This correlation was preserved in the subset of patients with TSH in the range miu/liter (b: 2.3, P 0.006). In contrast, no correlation was seen among ft3, rt 3,rT 3 to T 4 and T 3 to rt 3 ratios, and anti-tpo positivity and GHQ scores in either the full data set or the subset. A significant relationship was seen with ft3/ft4 ratio, but this was due to the contribution of ft4 and not an independent effect (Table 2). Similar results were observed with the TSQ. ft4 showed significant correlation with both the linear (correlation coefficient b: 0.11, P 0.03) and categorical scores of TSQ, and this persisted in the TSH miu/liter subset (Table 3). Whereas no correlation was seen between linear TSQ and log TSH (b: 0.09, P 0.41), a relationship was seen between the categorical TSQ and log TSH (OR 1.4, P 0.007) but was lost in the miu/liter subset. Similar to GHQ, no other correlation was seen between TSQ and any other thyroid hormone parameters. No correlation was seen among any of the TABLE 1. Baseline thyroid function tests Variable Mean SD Range NR Age (yr) (n 697) n/a TSH (miu/liter) (n 697) (geometric mean/median) 0.86 (0.948) ft4 (ng/dl) (n 697) ft3 (ng/dl) (n 697) rt 3 (ng/dl) (n 637) For SI units, multiply by for T 4, for T 3, and for rt 3.

3 Saravanan et al. Correlation of Thyroid Hormones and Well-Being J Clin Endocrinol Metab, September 2006, 91(9): thyroid hormone parameters and the anxiety and depression scales of the HADS (data not shown) with the exception of log TSH and HADS depression as a continuous variable (b: 0.562, P 0.004). However, this relationship was not seen when HADS depression score was used as a categorical variable (OR 1.2, P 0.54). Further post hoc analyses of the subgroup of patients with a TABLE 2. Correlations between GHQ scores and thyroid functions Variable FIG. 1. Histograms of log TSH (A), ft4 (B), ft3 (C), and total rt 3 (D). (n 697) GHQ linear scores b(p value) ft4 level above the reference range did not show any correlation between psychological well-being and the ft4 levels in this group using the regression model (GHQ Likert vs. ft 4 :b,0.08, P 0.70; GHQ Likert vs. log TSH: b, 0.08, P 0.90; TSQ Likert vs. ft 4 :b,0.21,p 0.26; TSQ Likert vs. log TSH: b, 0.99, P 0.08; data with categorical scores were not shown). However, the mean GHQ scores are significantly lower (improved well- (n 473) (n 693) GHQ categorical scores OR (P value) (n 470) ft (0.005) a (0.038) a 0.95 (0.014) a 0.94 (0.037) a ft (0.28) (0.86) 1.06 (0.58) 1.03 (0.82) ft3/ft (0.003) a 9.09 (0.098) 58.7 (0.016) a (0.10) Log TSH (0.038) a 2.3 (0.006) a 1.31 (0.027) a 2.47 (0.005) a rt (0.95) 0.89 (0.69) (0.17) (0.09) rt 3 to ft4 ratio (0.09) (0.12) 0.69 (0.98) 14.0 (0.81) ft3 to rt 3 ratio 0.05 (0.32) 0.01 (0.84) 1.03 (0.07) 1.03 (0.28) Anti-TPO (titer 100) (0.32) (0.21) 1.0 (0.37) 1.0 (0.41) Regression coefficient (beta-linear scores) and ORs (categorical scores) for the relationship between GHQ scores and thyroid function parameters. a Significant values (P 0.05).

4 3392 J Clin Endocrinol Metab, September 2006, 91(9): Saravanan et al. Correlation of Thyroid Hormones and Well-Being TABLE 3. Correlations between TSQ scores and thyroid functions Variable (n 696) TSQ linear scores b(p value) being) in this group as a whole, compared with the subgroup of patients with levels of thyroid hormones in the reference range (high ft4 vs. normal ft4: vs , P 0.007). By the categorical scoring method, the percentage of caseness was also less in patients with high ft4 levels (35.1 vs. 45.3%, P 0.03). Similar results were seen in TSQ scores (linear TSQ scores: high ft4 vs. normal ft4: vs , P 0.04; percent caseness: high ft4 vs. normal ft4: 56.1 vs. 66.0%, P 0.03) Similar post hoc analysis of patients according to anti-tpo antibody status did not show any significant difference in GHQ between anti-tpo-positive and negative patients (anti-tpo positive vs. anti-tpo negative: vs , P 0.147). Similar results were obtained when antibody status was used as an interaction factor in the regression model. (n 472) (n 691) TSQ categorical scores OR (P value) (n 469) ft (0.03) a (0.007) a 0.95 (0.028) a 0.94 (0.058) ft (0.098) 0.21 (0.52) 0.88 (0.27) 0.92 (0.58) ft3/ft (0.003) a (0.02) a 4.86 (0.37) 5.75 (0.42) Log TSH 0.23 (0.44) 1.49 (0.04) a 1.4 (0.007) a 1.8 (0.07) rt (0.52) 1.26 (0.53) 0.92 (0.90) 1.74 (0.53) rt 3 to ft4 ratio (0.04) a (0.049) a 4.31 (0.24) 8.79e 13 (0.12) ft3 to rt 3 ratio 0.02 (0.69) 0.02 (0.72) 0.99 (0.50) 0.97 (0.22) Anti-TPO (titer 100) (0.19) (0.21) 1.0 (0.06) 1.0 (0.17) Regression coefficient (beta-linear scores) and ORs (categorical scores) for the relationship between TSQ scores and thyroid function parameters. a Significant values (P 0.05). Discussion This is the first large data set to explore the relationship between ft4, ft3, and rt 3 and psychological well-being in subjects on thyroid hormone replacement. Improved psychological well-being was found to correlate with higher ft4 levels. The significance of the observation is supported by the finding of a relationship between psychological well-being and TSH with the opposite slope (higher TSH with reduced well-being as might be expected). A similar relationship with ft4 was found with an unvalidated score of symptoms that relates more directly to thyroid status (TSQ) making an artifactual association due to multiple testing less likely, although still possible. These relationships also persisted in the subset of patients with TSH values in the reference range ( miu/liter). Interestingly, no clear association was seen with the HADS scale, which may suggest that the thyroid function influences parameters of psychological well-being not typical of anxiety or depression. The GHQ-12 refers more generally to psychological well-being comparing current status with how patients would usually expect to feel (14). A previous Norwegian study (the HUNT study) also showed no relationship between thyroid function and HADS ratings except in individuals who are already on T 4 replacement (6). It should be noted, however, that the subjects in the HUNT study were grouped according to TSH, and T 4 was measured only when the TSH was outside of the range miu/liter. TSH is often considered the most sensitive measure of thyroid function. However, it appears that the relationship between well-being and ft4 was as much if not more pronounced as with TSH (Table 2), especially when studied across the whole cohort. TSH levels reflect hypothalamopituitary sensing of circulating thyroid hormone levels, which may be different from thyroid hormone status in other tissues and the importance of ft4 measurement in addition to or distinct from serum TSH estimation to assess thyroid status has been emphasized in recent studies of pregnancy. Maternal hypothyroxinemia in the first trimester and not raised TSH was associated with impaired psychomotor development in offspring (19, 20), and a recent study from the northeast of England showed that ft4 but not TSH at 9 wk of pregnancy is directly proportional to the birth weight of the offspring (Vaidya B., personal communication). An association between ft4 but not TSH at booking visit (mean gestation wk) and fetal birth length and head circumference has also been reported (21). Very recently Wekking et al. (22) failed to find a correlation between TSH and either cognitive function or psychological well-being in patients on T 4, but this data set was relatively small (n 141). TSH was only correlated as greater than or less than 2.0 miu/liter (not as a continuous variable), and the relationship with ft4 was not reported. It should be noted that thyroid function testing was not timed with T 4 dosing in our study. Although this is a limitation, if anything, this would be expected to reduce rather than augment the significance of any correlations with thyroid function. The failure to find a relationship between serum ft3 and GHQ/TSQ scores is also of interest. Many thyroidologists consider the T 3 assay to be less technically reliable and less reflective of thyroid status, particularly in the hypothyroid range (23). Although T 3 is the active hormone, free concentrations of T 4 are five times higher, and many tissues obtain 30% or more of their intracellular T 3 directly from circulating T 4 (24). Hence, circulating T 3 levels may not be directly reflective of intracellular levels. We measured serum rt 3 levels as a possible measure of intracellular deiodinase activity (24, 25). The failure of rt 3 levels or ratios with thyroid hormones to correlate with psychological well-being might relate to serum levels being more indicative of hepatic type 1 (D1) and 2 (D2) iodothyronine deiodinase activity, whereas intracellular levels are strongly influenced by local levels of membrane-bound deiodinases including type 2 and 3 (D3) iodothyronine deiodinase (24, 26). Our findings provide some support for the view that serum ft4 levels as well as TSH levels should be taken into account

5 Saravanan et al. Correlation of Thyroid Hormones and Well-Being J Clin Endocrinol Metab, September 2006, 91(9): when adjusting dosages and that TSH may not be a perfect indicator of the adequacy of replacement, particularly with regard to psychological well-being (27). In support of this, data from Carr et al. (5) as well as recent data from Appelhof et al. (9) suggest that patients prefer dosages of thyroid hormone that result in suppression of TSH. In addition, it is possible that the increased levels of psychological morbidity reported in patients on doses of T 4 adjusted to normal TSH values might also relate to this (16). However, this is a complex area because there is increasing evidence that suppressive doses of T 4 can be associated with adverse effects on both bone metabolism and the heart (reviewed in Ref. 25), and the current recommendation remains to titrate T 4 dosages to TSH levels in the reference range where possible (23, 28). Our data relate only to patients on thyroid hormone replacement. Additional adequately powered independent studies with appropriate questionnaires and large populations of patients on T 4 (and preferably not just patients selected to take part in an intervention trial) are required to confirm our findings. It is possible that in the general population without thyroid dysfunction, variation in thyroid hormone levels across the reference range is also a determinant of psychological well-being. Such a consequence of interindividual variation in normal levels of a hormone would be similar to the relationship observed between IGF-I levels and the risk of cancer across the reference range for IGF-I (29). Large population-based studies of thyroid function parameters including ft4 and psychological wellbeing will be required to explore this. Acknowledgments The authors thank Dr. B. Vaidya for the use of his unpublished data. Received February 22, Accepted June 19, Address all correspondence and requests for reprints to: Dr. Colin M. Dayan, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom. colin.dayan@bris.ac.uk. This work was supported by Southwest National Health Service Research and Development, United Kingdom, and Goldshield Pharmaceuticals PLC, United Kingdom. References 1. Bauer M, Heinz A, Whybrow PC 2002 Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry 7: Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC 2001 Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. 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Less intervention to avoid cancer? More intervention to prevent cancer? J Endocrinol 162: JCEM is published monthly by The Endocrine Society ( the foremost professional society serving the endocrine community.