Health Status, Psychological Symptoms, Mood, and Cognition in L-Thyroxine-Treated Hypothyroid Subjects

Division of Endocrinology, Diabetes & Clinical Nutrition, Oregon Health and Science University, Portland, Oregon, United States
Thyroid (Impact Factor: 4.49). 04/2007; 17(3):249-58. DOI: 10.1089/thy.2006.0252
Source: PubMed


Many hypothyroid subjects receiving L-thyroxine (L-T4) complain of psychological symptoms or cognitive dysfunction. However, there is limited validated information on these self-reports.
Cross-sectional comparison of 20 euthyroid and 34 treated hypothyroid subjects, aged 20-45 years, with normal thyroid-stimulating hormone (TSH) levels. Subjects underwent the following validated measures: Short Form 36 (SF-36); Symptom Checklist 90-Revised (SCL-90-R); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor).
L-T4-treated subjects had higher mean TSH and free T4 levels, but free triiodothyronine (T3) levels were comparable to controls. L-T4-treated subjects had decrements on SF-36 and SCL-90-R summary scales and subscales. These subjects performed slightly worse on N-Back and Pursuit Rotor tests. Neither TSH nor thyroid hormone levels were associated with performance on psychological or cognitive measures.
This group of L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls. Higher mean TSH levels suggest this may be related to suboptimal treatment, although there were no correlations between TSH levels and outcomes. These findings are limited by potential selection bias, and randomized studies targeting different TSH levels and memory subdomains would clarify these issues.

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    • "Studies also show that thyroid hormones continue to modulate the function of the adult brain, which explains the tight regulation of thyroid hormone transport into the brain, regionspecific T 4 to T 3 conversion as well as T 3 receptor levels (Ceballos et al., 2009). Epidemiological studies indicated that thyroid dysfunction whether hypothyroidism or hyperthyroidism (overt or subclinical) increases the risk of cognitive impairment, (Beydoun et al., 2013; Bono et al., 2004; Correia et al., 2009; Miller et al., 2006; Munte et al., 2001) although the evidence is still sparse (Almeida et al., 2007; Ceresini et al., 2009; de Jongh et al., 2011; Formiga et al., 2014; Joffe et al., 2013; Kramer et al., 2009; Parle et al., 2010; Samuels et al., 2007; Wijsman et al., 2013). It is less well-known how thyroid hormone fluctuations within normal ranges can affect cognitive outcomes in the general population, particularly when studies have examined cognitive performance among middle-aged adults (Beydoun et al., 2012, 2013; Grigorova and Sherwin, 2012; van Boxtel et al., 2004). "
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    ABSTRACT: Recent evidence indicates that thyroid hormones may be closely linked to cognition among adults. We investigated associations between thyroid hormones and longitudinal cognitive change, within and outside of reference ranges, stratifying by sex and race. This longitudinal study used data from the Healthy Aging in Neighborhoods of Diversity Across the Lifespan study, set in Baltimore City, MD, 2004-2013, on adults aged 30-64 years at baseline visit, with a length of follow-up between visits 1 and 2 ranging from <1 to 8 years; mean ± standard deviation: 4.64 ± 0.93. The final analytic sample sizes ranged from 1486 to 1602 participants with 1.6-1.7 visits per participant (total visits: 2496-2757), depending on the cognitive test. Eleven cognitive test scores spanning domains of learning or memory, language or verbal, attention, visuospatial and/or visuoconstruction, psychomotor speed, executive function, and mental status were used. Mixed-effects regression models were conducted, interacting time of follow-up with several thyroid exposures. Whites performed better than African Americans, with only 4 cognitive test scores of 11 declining significantly over time. Importantly, above reference range thyroid stimulating hormone (vs. reference range, thyroid stimulating hormone, above reference range [TSHarr]) was linked to faster rates of decline on the digits span backwards test, reflecting working memory (TSHarr × time γ ± standard error: -0.14 ± 0.05, p = 0.006) and clock-command, at test of visuospatial and/or visuoconstruction abilities (TSHarr × Time γ ± standard error: -0.10 ± 0.04, p = 0.004). The latter finding was replicated when comparing normal thyroid function to "subclinical hypothyroidism". Within-reference ranges, a higher thyroid stimulating hormone was related to faster decline on the clock-command test scores in women. In sum, higher baseline thyroid stimulating hormone was associated with faster cognitive decline over-time among urban US adults, specifically in domains of working memory and visuospatial and/or visuoconstruction abilities. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Neurobiology of aging
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    • "Groups were additionally matched for handedness (one left per group), smoking status (three smokers per group) and use of estrogen containing contraceptives (five patients, six control subjects). All subsequent analyses were controlled for age, sex, TSH, fT3 and fT4 to ensure ideal matching for biochemical thyroid status (Samuels et al., 2007). Analyses were repeated with control for age and sex alone to investigate group differences under the influence of differences in biochemical status between treated and healthy participants. "
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    ABSTRACT: The current study investigated neuropsychological and underlying structural and functional brain alterations in long-term adequately treated patients with Hashimoto's thyroiditis in order to examine much discussed residual complaints in patients in relation to possible long-term neural alterations with a specific interest in the underlying autoimmune process. Eighteen patients with treated hypothyroidism due to Hashimoto's thyroiditis (mean age 32, range 18–54 years; two males; mean treatment duration 4.4 years) and 18 healthy matched control subjects underwent 3-Tesla magnetic resonance imaging (MRI). Voxel-based morphometry was used to investigate grey matter density, resting-state functional MRI to analyse the brain connectivity of areas known to be altered in hypothyroidism and event-related functional MRI to examine brain activity during associative memory encoding. Neuropsychological assessment included memory, working memory, psychomotor speed and attention. We previously reported subclinically reduced mood in this study population and investigated its neural correlates here. Thyroid stimulating hormone, free triiodthyronine, free thyroxine and thyroid peroxidase antibodies were measured in serum. We did not find cognitive deficits or alterations in grey matter density, functional connectivity or associative memory-related brain activity in comparison to the control group and cognition was unrelated to thyroid serum measures in the patient group. Thyroid peroxidase antibodies in the patient group correlated with increased grey matter density in right amygdala and enhanced connectivity between subcallosal and parahippocampal areas. Treatment duration was associated with brain structure in frontal and occipital cortex and connectivity between left amygdala and frontal cortex. Mood correlated with brain areas associated with distinct functional networks, but not with those most prominently affected in depression. In conclusion, no cognitive or neural alterations were detected in this young and otherwise healthy cohort of patients in comparison to a healthy control group and current mood status could not be related to depression-related networks. However, autoimmune activity and treatment duration showed a relationship with depression and hypothyroidism-related brain structure and function. They are thus promising factors to further investigate residual complaints despite biochemically adequate treatment in patients with Hashimoto's thyroiditis. Given the small sample size, all findings require replication.
    Full-text · Article · Apr 2014 · Psychoneuroendocrinology
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    • "Levothyroxin (thyroxin) replacement therapy improves memory in subclinical hypothyroid subjects (Osterweil et al., 1992; Monzani et al., 1993; Baldini et al., 1997; Jensovsky et al., 2002). However, clinical reports show variable results as to whether the thyroid hormone replacement therapy fully restores the hypothyroidism-induced impaired learning and memory (Treadway et al., 1967; Jaeschke et al., 1996; Capet et al., 2000; Miller et al., 2006; but see Mennemeier et al., 1993; Leentjens and Kappers, 1995; Wekking et al., 2005; Samuels et al., 2007b). While a large body of literature is available on the effect of thyroid hormone deficiency during the developmental stage (e.g. "
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    ABSTRACT: Cyclic-AMP response element binding protein (CREB) is a transcription factor crucial for late phase long-term potentiation (L-LTP) induction and maintenance. Upon Multiple high frequency stimulation (MHFS), large Ca(2+) influx activates adenylyl cyclase. This, in turn, activates PKA, which by itself or through MAPK p42/p44 can activate (phosphorylate) CREB. Upon phosphorylation, P-CREB activates multiple genes essential for L-LTP generation. Calcium calmodulin kinase IV (CaMKIV) is also activated by calcium and can directly activate CREB. We have shown previously that hypothyroidism impairs L-LTP and reduces the basal protein levels of CREB, MAPK p42/p44, and CaMKIV in area CA1 of the hippocampus. In the present study, levels of these signaling molecules were determined in area CA1 during the induction and maintenance phases of L-LTP. Standard MHFS was used to evoke L-LTP in the CA1 area of hypothyroid, levothyroxin treated hypothyroid and sham control anaesthetized adult rats. Chronic levothyroxin treatment reversed hypothyroidism-induced L-LTP impairment. Five minutes after MHFS, western blotting showed an increase in the levels of P-CREB, and P-MAPK p42/p44 in sham-operated control, and levothyroxin treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/p44, BDNF and CaMKIV were not altered in all groups five minutes after MHFS. Four hours after MHFS, the levels of P-CREB, and P-MAPK p42/p44 remained unchanged in hypothyroid animals, while they were elevated in sham-operated control, and levothyroxin treated hypothyroid animals. We conclude that normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/p44 may account for restoration of normal L-LTP induction and maintenance in the CA1 area of levothyroxin-treated hypothyroid animals.
    Full-text · Article · Nov 2013 · Brain research bulletin
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