The effects of stress exposure on the hypothalamic-pituitary-adrenal axis,thymus, thyroid hormones and glucose levels

In the present study, an attempt was made to compare three stress models and their effects on the hypothalamic-pituitary-adrenal (HPA) axis, the thymus, the thyroid hormones and the glucose levels. The three different stress models were the chronic mild stress (CMS), the 14-day and the 1-day cold swim stress model. The CMS procedure caused a decrease in thymus weight and rendered no changes on glucose, the adrenocorticotropin hormone (ACTH) or the adrenals. Administration of imipramine (IMI) after the third week of CMS did not reverse the decrease in thymus weight. The 14-day cold swim stress doubled ACTH levels and the adrenal weight and reduced thymus weight, while total thyroxine (tT4), total triiodothyronine (tT3) and glucose levels were unaffected. IMI treatment restored the weights of the adrenal and thymus glands. One-day cold swim stress did not induce any statistically significant effect on the tested physiological parameters. The above findings indicate a distinct effect of the 14-day cold swim stress on HPA axis. Relative to CMS or the 14-day cold swim stress, no effect was induced by the 1-day cold swim stress. The IMI restoring effect, especially in the case of the 14-day cold swim stress, also suggests an association of antidepressant effect with the duration of drug treatment.     

Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains

Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in rats that resembles some of the symptoms of endogenous depression in humans. In the present study, CMS-induced behavioural responses along with neurochemical alterations in dopaminergic and serotonergic function in prefrontal cortex, striatum, hypothalamus and hippocampus were examined following treatment with imipramine in Wistar and Sprague-Dawley rats. The CMS procedure lasted 7 weeks in total. Once per week, a 1-h preference test for 1% sucrose solution was conducted. Treatment with imipramine (10mg/kg i.p., once daily) commenced after experimental week 3. CMS induced significant reductions in absolute and relative sucrose intake and sucrose preference in both rat strains but their temporal pattern was different especially during the weeks 0-3. These effects were reversed by IMI. An increase in the dopaminergic and a decrease in the serotonergic activity were observed in the prefrontal cortex in both rat strains following CMS. A decrease in the striatal dopaminergic activity and an increased hippocampal serotonergic activity were also seen in both rat strains following CMS. In Wistar rats, dopaminergic and serotonergic activities were enhanced in the hypothalamus whereas in Sprague-Dawley rats no such stress-induced changes were observed. Notably, the clear decrease in sucrose consumption observed in stressed Wistar rats could be directly associated with a respective increase in the dopaminergic hypothalamic activity. Chronic treatment with imipramine normalized all neurochemical alterations induced by CMS. Our results suggest that a specific and regionally differentiated serotonin-dopamine interaction is directly related to the observed stress-induced anhedonia.     

Thyroid hormones in children on antiepileptic therapy

The aim of this study was to evaluate the thyroid function alterations in a group of epileptic children taking antiepileptic drugs (AEDs). Patients demographic data and the free throxine (fT4) and thyroid-stimulating hormone (TSH) levels at the beginning of the treatment and at the third, sixth and ninth months of AED treatment were recorded retrospectively. A total of 106 children, 59 males and 47 females, were enrolled in the study. Mean patient age was 3.7 years, ranging between 3 months and 14 years. In total, 54% of patients were on valproic acid (VPA), 16% phenobarbital (PB), 14% were on carbamazepine (CBZ), 6% were on oxcarbazepine (OXC), 5% were on levetiracetam, and 5% were on topiramate therapy. There were no significant differences in average fT4 values between the drug groups. But the mean fT4 levels of the patients on VPA therapy showed a clear decrease within the observation period. No significant difference in average TSH values between the groups was detected in the beginning and in the third and sixth month. However, in the ninth month, a significant increase in TSH values was found in the VPA group (p = 0.007). In the patients taking VPA, average TSH values rose progressively while staying within normal limits. During follow-up, thyroid dysfunction were found in 21 patients (19.6%). A statistically significant relationship was found between severe electroencephalography (EEG) findings and thyroid dysfunction (p = 0.041). It was concluded that epileptic children with severe EEG findings and using VPA could have thyroid dysfunction. These patients should be followed up closely by thyroid function tests during treatment.     

Altered Thyroid Hormones and Behavioural Change in a Sub‐Population of Rats Following Chronic Constriction Injury

Hypothyroidism is associated with a disturbance of behaviour and mood. There are also individuals, not classified as hypothyroid, with low to ‘low normal’ thyroid hormone levels and normal thyroid‐stimulating hormone (TSH) levels who have mood and behavioural changes. As the peripheral thyroid hormones decrease, TSH is expected to increase. However, there are a number of physiological mechanisms known to suppress TSH. In the present study, we report on thyroid hormone regulation in a rat model of neuropathic pain and altered social behaviour that is usually transient, but is persistent in a sub‐group of the population. Following ligation of the sciatic nerve, male Sprague‐Dawley rats were assessed for social dominance towards an intruder: 20% showed persistently decreased social dominance. Plasma levels of thyroid hormones, TSH and corticosterone were measured before and on days 2, 3, 4, 5 and 6 after injury in 21 rats. The mean plasma thyroxine (T4), free thyroxine (fT4) and triiodothyronine (T3) levels decreased significantly post‐injury in rats with persistently changed behaviour compared to rats with unchanged behaviour (P ≤ 0.002). There was no significant difference between groups for mean change in free triiodothyronine (fT3) or TSH. There was a correlation between decreased dominance behaviour and decrease in both T4 (r = 0.62, P = 0.009) and fT4 (r = 0.71, P = 0.001), but no correlation with TSH. In a sub‐population of rats, decreased thyroid hormones did not result in the expected increased levels of TSH to restore pre‐injury levels, nor did they show increased hypothalamic thyrotrophin‐releasing hormone mRNA expression, indicating altered hypothalamic‐pituitary‐thyroid axis regulation. Because T3 availability to the brain is dependent on both circulating T3 and T4, decreased peripheral thyroid hormones may result in changed neural function, as expressed in altered complex behaviours in this sub‐population of rats.     

Thyroid function in patients with Alzheimer disease: implications on response to anticholinesterase treatment

Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in Alzheimer disease (AD). The aim of the present study was to explore thyroid function in patients with AD before and after acetylcholinesterase inhibition treatment to possibly identify variances in response. Thyroid function tests were evaluated in 28 AD patients and 24 age and sex-matched controls. Nineteen of the patients were reevaluated after (4 mo) treatment with donepezil. Serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), the free fractions (fT3, fT4) and thyroid autoantibodies were determined using standard methods. All subjects were clinically euthyroid. Patients presented with higher fT4 and anti-thyroperoxidase levels, as compared with the controls. Significant reduction in T4, fT3, fT4, and anti-thyroperoxidase levels were observed 4 months after treatment. Responders had higher T4 and fT4, than nonresponders, followed by significant reductions after treatment. The above, within the normal range alterations, may represent a direct effect on hormone release from the thyroid gland and/or increased conversion of T4 to T3 within the brain. Higher T4 and fT4 levels before treatment might predict a favorable response to donepezil treatment.     

The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate

PURPOSE: The aim of this study was to evaluate the effects of short-term oxcarbazepine (OXC) and valproate (VPA) monotherapy on thyroid functions in children. METHODS: Fifty-five newly diagnosed epileptic children with normal thyroid functions (confirmed with the thyrotropin releasing hormone stimulation test) participated in this study. VPA treatment was started in 30 patients and OXC in 25 patients. Serum thyroxine (T(4)), free thyroxine (fT(4)), triiodothyronine (T(3)), free triiodothyronine (fT(3)), reverse T3 (rT(3)), thyroid peroxidase antibodies (TPO-ab), and urine iodine levels were evaluated at baseline and at the third and sixth months of therapy. RESULTS: In the OXC group, serum T(4), fT(4), T(3), fT(3), and rT(3) levels were found to be decreased at the third and sixth months, the differences were significant compared to the baseline values except for fT(3) levels at the third month and fT(4) and rT(3) levels at the sixth month (p < 0.05). At the sixth month, serum T(4) level dropped below the normal reference value in 8 (32%), fT(4) in 5 (20%), T(3) in 4 (16%), and fT(3) in 3 (12%) patients. In the VPA group, mean T(4), fT(4), T(3), fT(3), and rT(3) levels at 3 and 6 months remained similar compared to the baseline values (p > 0.05). Mean serum thyroid stimulating hormone levels increased significantly at the sixth month compared to the baseline values in the VPA group (p < 0.05) while it remained unchanged in the OXC group (p > 0.05). There was no effect of either drug on urinary iodine excretion and serum TPO-ab levels remained in normal ranges throughout the study. CONCLUSIONS: In this prospective study, it is documented that children under short-term OXC or VPA therapy showed altered thyroid functions similar to the changes observed after long-term treatment. Although, the clinical significance of these results need to be evaluated with future studies, this observation of altered thyroid functions points out that thyroid functions may need to be monitored closely in children receiving antiepileptic treatment, even in the short-time interval.     

The effect of antiepileptic drugs on thyroid function in children

BackgroundLimited and conflicting data exist for the influence of antiepileptic drugs on thyroid function in children.ObjectiveThe aim of this study was to investigate the effects of phenobarbital, valproate, carbamazepine, oxcarbazepine, and levetiracetam monotherapy on thyroid function in daily clinical practice during a 12-month treatment period.MethodA total of 223 children (103 females and 120 males) with new onset and controlled epilepsy treated with valproate (n = 129), phenobarbital (n = 33), carbamazepine (n = 36), oxcarbazepine (n = 14), levetiracetam (n = 11) were enrolled in the study. Serum free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels were measured before and at first, sixth and twelfth months of therapy.ResultsAt baseline, average fT4 and TSH concentrations were not different between the drug groups. Valproate-treated patients had decreased fT4 and increased TSH levels at months 1, 6, and 12. Carbamazepine-treated patients had decreased fT4 levels at months 1, 6, and 12 and increased TSH levels at months 1, and 6. Phenobarbital-treated patients had decreased fT4 levels at months 1, and 6, and increased TSH levels at months 6 and 12. Oxcarbazepine-treated patients had decreased fT4 levels at month 1. Levetiracetam-treated patients showed no significant change of fT4 and TSH at any times. The frequency of subclinical hypothyroidism at month 12 was 28% in valproate, 21.4% in oxcarbazepine, 18.2% in phenobarbital, 13.9% in carbamazepine, and 0% in levetiracetam groups.ConclusionOur data suggest that all antiepileptic drugs studied except levetiracetam had varying degrees of deleterious effects on thyroid function.     

The Effect of Chronic Mild Stress and Imipramine on the Markers of Oxidative Stress and Antioxidant System in Rat Liver

Liver abnormalities have been reported to occur in up to 20 % of patients on a long-term therapy with the tricyclic antidepressant drug imipramine (IMI). The mechanism involved in this IMI-induced process is unknown but a contribution of oxidative stress is highly likely. Chronic mild stress (CMS) is widely used for modeling depressive-like behavior in rats. In the present study, we examined the effects of CMS and chronic IMI treatment, applied alone or in combination, on the levels of oxidative stress markers, such as reactive oxygen species (ROS), malondialdehyde (MDA), non-protein sulfhydryl groups, and sulfane sulfur as well as on activities of key antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase in the rat liver. Administration of IMI for 5 weeks to rats subjected to CMS resulted in a gradual significant reduction of anhedonia measured by sucrose intake, in a majority of animals (CMS IMI-reactive, CMS IMI-R), although about 20 % of rats did not respond to the IMI treatment (CMS IMI non-reactive, CMS IMI-NR). CMS-induced hepatic oxidative stress, estimated by increased ROS and MDA concentrations, was not prevented by the IMI administration, moreover, in CMS IMI-NR animals, the level of the marker of lipid peroxidation, i.e., MDA was increased in comparison to CMS-subjected rats and activity of antioxidant enzymes (GPx and CAT) was decreased compared to IMI-treated rats. The clinical significance of this observation remains to be established.     

Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors

OBJECTIVE: To examine the relation between baseline measurements of thyroid function and response to selective serotonin reuptake inhibitors (SSRIs) and to consider the effect of these antidepressants on thyroid hormone levels. METHODS: Nineteen subjects with major depression, but without a history of thyroid treatment or lithium treatment, were treated openly with either sertraline or fluoxetine in a university- affiliated tertiary care hospital. Hamilton Depression Rating Scale (Ham-D) scores were measured before and after treatment. Clinical Global Impressions (CGI) scores were measured at study end. Thyroid data, consisting of values for thyroid-stimulating hormone (TSH), triiodothyronine (T(3), measured by radioimmunoassay [RIA]), thyroxine (T(4), measured by RIA) and free T(4), were collected before and after treatment. Complete thyroid data were available for 17 subjects. Data were collected during 1997-1999. RESULTS: Baseline TSH correlated strongly with response to treatment as measured by change in Ham-D scores (r = 0.64, p = 0.003). Low TSH values correlated with greater improvement in depressive symptoms. Thyroid hormone levels decreased with treatment, but these decreases did not correlate with clinical improvement. CONCLUSION: Baseline thyroid function, as measured by serum TSH, may predict a patient's response to antidepressant treatment with SSRIs. Optimal thyroid function, beyond simply being within the normal laboratory values, may be necessary for an optimal response to antidepressants.     

Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine

BACKGROUND: Thyroid dysfunction is relatively common in patients with schizophrenia, possibly related to a genetic linkage of the disorders and to antipsychotic treatment. Quetiapine has been implicated as causing some degree of thyroid function changes, yet it remains unclear as to what extent or why these changes may occur. Furthermore, the need for thyroid function monitoring in patients taking this medication is not definitive. METHOD: Thyroid function was assessed in 38 adult DSM-IV-diagnosed schizophrenia patients after 6 weeks of prospective, double-blind, randomized treatment with quetiapine (400 mg/day), risperidone (4 mg/day), or fluphenazine (12.5 mg/day). Data were collected from 1997 to 2002. RESULTS: At baseline, the percentages of randomized patients with abnormal values were 18% (4/22) for serum T(3) resin uptake, 13% (4/30) for thyroid-stimulating hormone (TSH), and 9% (2/22) for total serum thyroxine (TT(4)), representing fairly widespread thyroid abnormalities independent of treatment group. Little change was noted in thyroid function during the 6 weeks of treatment, except for a significant decrease in TT(4) values for those taking quetiapine (p = .01). Clinically, however, no patients demonstrated any signs or symptoms of hypothyroidism during the study, nor were any significant changes in the free thyroxine index or TSH levels noted. CONCLUSIONS: It is expected that TT(4) levels will decrease during quetiapine treatment, and this may possibly be related to competitive metabolism of thyroid hormones and quetiapine by UDP-glucuronosyltransferase. Routine monitoring of thyroid function in quetiapine-treated patients without a history of thyroid disease is not recommended.     

Early inhibition and changes in diurnal rhythmicity of the pituitary-thyroid axis after superior cervical ganglionectomy of rats

The effect of superior cervical ganglionectomy (SCGx) on the pituitary-thyroid axis was examined in rats. SCGx decreased serum thyrotropin (TSH) and thyroxine (T4) levels for up to 4 days after surgery, during and immediately after completion of anterograde degeneration of regional sympathetic terminals. At later times TSH levels in control and SCGx rats did not differ, but a significant increase of serum T4 was found two weeks after SCGx. A diurnal rhythm in serum TSH and T4 levels with maxima at 11.00 h (TSH) and at 14.00 and 22.00 h (T4) was found in sham-operated rats 3 days after surgery. At this time SCGx evoked a general depression of TSH levels as well as a shift of 3 h in their maximum. A similar shift of the afternoon peak and abolition of the nocturnal peak in serum T4 were detectable in SCGx rats. In SCGx animals examined during anterograde nerve degeneration, i.e. 14 h after surgery, injection of the alpha 1-adrenoceptor blocker phenoxybenzamine negated denervation-induced changes of TSH and counteracted partially T4 effects. The beta-adrenergic blocker propranolol did not modify serum TSH levels in SCGx rats but further decreased serum T4 concentration. Treatment with both drugs simultaneously did no affect TSH release compared to SCGx, phenoxybenzamine-treated rats but effectively decreased serum T4. These results further support the involvement of superior cervical ganglion neurons in the control of thyroid function.     

Chronic mild stress induces widespread decreases in thyroid hormone alpha1 receptor mRNA levels in brain--reversal by imipramine

While considerable clinical evidence implicates thyroid hormones (THs) in depressive illness, the specific nature of this involvement remains unclear. The alpha1 subtype (TR-alpha1) is the most abundant TH receptor in brain. Here we investigated changes in TR-alpha1 mRNA in the chronic mild stress (CMS) model of depression. Rats were exposed to a CMS schedule for 3 weeks, which resulted in a progressive decreases in sucrose preference (an index of anhedonia). They were then treated daily with either imipramine (IMI, 10mg/kg) or vehicle (VEH) for 2 weeks before being sacrificed for quantitative in situ hybridization analyses of TR-alpha1 mRNA throughout the brain. Results indicated that CMS followed by VEH induced widespread decreases in TR-alpha1 mRNA in brain. In contrast, CMS-exposed rats receiving IMI for the last 2 weeks prior to sacrifice showed full recovery of sucrose preference. Furthermore, brain TR-alpha1 mRNA levels in these animals were similar to those of non-stressed controls receiving either SAL or IMI. These results reveal that TR-alpha1 mRNA brain levels are very sensitive to CMS effects. The reversal of both anhedonic and TR-alpha1 effects of CMS by IMI suggests that TR-alpha1 may play a role both in stress-induced depressive symptoms and in their reversal by antidepressant interventions.     

Sinemet and thyroid function in Parkinson disease

Patients on chronic carbidopa-levodopa (Sinemet) therapy underwent thyroid function testing that included measurement of serum thyroxine (T4), triiodothyronine (t3), thyrotropin (TSH), T3 uptake (T3U), free T4 index (FT4I), and free T3 index (FT3I). The subjects were studied both in a random sampling and in a controlled manner, fasting and 2 hours after receiving the drug. All subjects were euthyroid by testing, and there was no significant difference in thyroid hormone levels of patients and controls or in fasting values and values 2 hours after the drug. However, there was a small but significant reduction in serum TSH levels after Sinemet. Therapeutic doses of Sinemet have no significant effect on thyroid function in euthyroid patients with Parkinson disease.     

Neuroendocrinological investigations during sleep deprivation in depression. II. Longitudinal measurement of thyrotropin, TH, cortisol, prolactin, GH, and LH during sleep and sleep deprivation

Thyrotropin (TSH), thyroxin (T4), triiodothyronine (T3), free T3 (fT3), cortisol, prolactin, and human growth hormone (HGH) were measured every 2 hr during a night of sleep, the following day, and a night of sleep deprivation (SD) in 14 patients with major depressive disorder. In subgroups fT4 (n = 5), reverse T3 (rT3), and luteinizing hormone (LH) (n = 6) were also investigated. Significant increases in TSH, T4, fT4, T3, fT3, rT3, and cortisol and decreases in prolactin levels occurred during the night of SD, compared to the pattern during the night of sleep. The pre-SD T4 and T3 levels of the responders to SD were already higher than in the nonresponders, and increased less during SD. The cortisol and HGH concentrations of the responders rose higher during SD than those of the nonresponders. Changes in TSH and prolactin were not correlated to clinical response. Analysis of possible neurochemical mechanisms underlying this "pattern" of changes in different endocrine profiles suggests that enhanced noradrenergic activity might play a role in the changes in TSH, cortisol, thyroid hormones, and possibly HGH secretion during SD, and increased dopaminergic tone probably induced the decline in prolactin levels. Additional effects of the serotonergic system cannot be excluded at present. In conclusion, the data suggest that enhanced noradrenergic activity of the locus coeruleus stimulates alpha and/or beta adrenergic receptors in depressed patients during SD. This mechanism could well be involved in the antidepressant effect of this therapy.     

血管性痴呆患者血脂及甲状腺激素变化的临床观察

目的 探讨血管性痴呆（VaD）与血清胆固醇、甘油三酯、甲状腺激素的关系。方法 对35例VaD和16例健康对照组血清胆固醇、甘油三酯、甲状腺激素进行测定,并进行组间对比研究。结果 VaD组血清胆固醇、甘油三酯明显高于对照组（P〈0．05）,并且VaD组甘油三酯水平与对照组相比差异更明显（P〈0．01）,VaD组血清总T4（TT4）水平明显高于健康对照组（P〈0．01）,而总T3（TT3）及TSH两组之间无显著性差异。结论 甲状腺激素代谢异常可能与VaD发病有关;血清胆固醇和甘油三醌增高与VaD有明显的关系,降低胆固醇及血脂可能对VaD预防和治疗有益。     

Changes in hypothalamic–pituitary–thyroid axis following successful treatment with low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression

Hypothalamic-pituitary-thyroid (HPT) axis abnormalities have been reported in some patients with major depression. To knowledge, however, the effects of low-frequency right prefrontal transcranial magnetic stimulation (TMS) on the HPT axis have not yet been elucidated. The goal of this study was to evaluate alterations in the HPT axis associated with the therapeutic efficacy of TMS treatments. Twenty patients with treatment-resistant depression received five 60-s 1-Hz trains over the right dorsolateral prefrontal cortex. Twelve treatment sessions were administered within a 3-week period (total pulses, 3600). Responders were defined as a ≥ 50% decrease in the Hamilton Depression Rating Scale (HDRS) score. Serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) were measured, respectively, at pre- and post-treatment. There were no significant changes in fT3 and fT4 levels measured at either pre- or post-treatment in either responders or nonresponders; however, TSH levels of responders elevated significantly after TMS treatments. In addition, there was a significant negative correlation between TSH levels at pretreatment and decrease (%) in the HDRS score. These findings suggest that the HPT axis is associated with antidepressant effects of low-frequency right prefrontal TMS, and indicate that lower TSH levels at pre-treatment are correlated with better therapeutic efficacy.     

难治性抑郁症患者甲状腺激素水平的分析

目的 探讨难治性抑郁症患者的甲状腺激素水平。方法 按性别、年龄1：1匹配选取难治性抑郁症患者和健康对照各30例,采用放射免疫法测定患者组治疗前和对照组血清TSH、T3、T4、FT3、FT4水平。结果 患者组异常者17例,占56．7％,对照组异常者2例,占6．7％,两组比较,患者组甲状腺激素水平出现异常的比率明显高于对照组,主要表现为TSH升高、T3降低、FT4降低,差异均有统计学意义（P〈0．05）。结论 难治性抑郁症患者中有56．7％的患者存在亚临床型甲状腺功能的减退。     

T3 level may be a helpful marker to predict disease prognosis of acute central nervous system viral infections

Aim of the study: Acute central nervous system viral infections are progressive and inflammatory diseases with inflammatory cells infiltrating into the central nervous system (CNS), and thyroid hormone (TH) level is associated with the oxidative and antioxidant status. Variations in oxidative stress and antioxidant status are related to the pathogenesis of inflammatory diseases. Our study aimed to investigate the possible correlation between viral infections in CNS and TH levels of thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3).

Materials and methods: We measured serum concentrations of TSH, fT4, and fT3 in 206 individuals, including 59 viral meningitis (VM) patients, 60 viral encephalitis (VE) patients, and 87 healthy controls.

Results: Our findings showed that VE and VM patients had lower levels of fT3 and higher levels of fT4 compared with healthy controls, whether male or female. Moreover, levels of TSH and fT3 in patients with viral infections in CNS were inversely correlated with disease prognosis measured by the Glasgow Outcome Scale.

Conclusions: Variations in TH level may represent the oxidative status and are surrogate biomarkers for disease prognosis of acute central nervous system viral infections.     

Migraine and thyroid dysfunction: Co-occurrence,shared genes and biological mechanisms

Background and purpose

Migraine and thyroid dysfunction, particularly hypothyroidism, are common medical conditions and are known to have high heritability. Thyroid function measures, thyroid stimulating hormone (TSH) and free thyroxine (fT4), are also known to be genetically influenced. Although observational epidemiological studies report an increased co-occurrence of migraine and thyroid dysfunction, a clear and combined interpretation of the findings is currently lacking. A narrative review is provided of the epidemiological and genetic association evidence linking migraine, hypothyroidism, hyperthyroidism and thyroid hormones TSH and fT4.

Methods

An extensive literature search was conducted in the PubMed database for epidemiological, candidate gene and genome-wide association studies using the terms migraine, headache, thyroid hormones, TSH, fT4, thyroid function, hypothyroidism and hyperthyroidism.

Results

Epidemiological studies suggest a bidirectional relationship between migraine and thyroid dysfunction. However, the nature of the relationship remains unclear, with some studies suggesting migraine increases the risk for thyroid dysfunction whilst other studies suggest the reverse. Early candidate gene studies have provided nominal evidence for MTHFR and APOE, whilst more recently genome-wide association studies have provided robust evidence for THADA and ITPK1 being associated with both migraine and thyroid dysfunction.

Conclusions

These genetic associations improve our understanding of the genetic relationship between migraine and thyroid dysfunction, provide an opportunity to develop biomarkers to identify migraine patients most likely to benefit from thyroid hormone therapy, and indicate that further cross-trait genetic studies have excellent potential to provide biological insight into their relationship and inform clinical interventions.     

Thyroid function in Down syndrome.

The thyroid function of 181 patients with Down syndrome was investigated. When compared with a control group of 163 children we found T4 and FT4 levels to be significantly lower and T3 and TSH levels to be significantly higher in the Down syndrome population. Of the 181 patients with Down syndrome, 29 (16%) showed evidence of either uncompensated or compensated hypothyroidism: 11 (6%) had both low T4 and high TSH levels, 14 (8%) had only high TSH values, and 4 (2%) had only low T4 values. One of the patients with Down syndrome had a significantly elevated T4 level. Studying different age groups, we observed a decline of the mean T4, FT4, T3, FT3, and TBG values with advancing age. T4, T3, and TSH blood levels obtained in 1988 were slightly but not significantly lower when compared with values from 1985. Because thyroid dysfunctions in patients with Down syndrome are more common than in the general population, periodic thyroid hormone function tests should be performed in persons with Down syndrome in particular as they advance in age. Thus, individuals with significantly abnormal results can be identified early before clinical symptoms become manifest. If patients with Down syndrome are found to have a thyroid hormone disorder, appropriate treatment should be forthcoming, which in turn will enhance their quality of life.