Tinnitus refers to the perception of hearing sounds with no identifiable external acoustic source. Affected individuals self-report that tinnitus disturbs thoughts and emotions, interferes with hearing, and interrupts sleep and concentration, although many still consider it to be harmless (1, 2). A cross-sectional study using data from the US National Health and Nutrition Survey (NHANES) found that prevalence of frequent tinnitus was highest (14.3%) among older adults and the odds of frequent tinnitus increased when associated with low-mid and high frequency hearing loss, loud noise exposure, smoking, hypertension and general anxiety disorder (3). However, although tinnitus is prevalent in both genders and all ages, its true global prevalence is not known. A recent systematic review of global tinnitus-related studies from 1980 to 2015 emphasized the difficulty in finding studies with consistent definitions of tinnitus, particularly given the absence of standard diagnostic criteria or methods, and that tinnitus is typically self-reported and may go unrecorded (4). Prevalence among 515 studies ranged widely from 5.1%-42.7%, with agreement between studies shown only for prevalence increasing with age.

Previous studies have reported associations between tinnitus and aging, gender, noise exposure, insomnia, bilateral hearing loss and various diseases and syndromes, including cardiovascular disease, epilepsy, anxiety syndrome and others (5–8). Among patients with chronic tinnitus, the presence of lifetime and current psychiatric disorders was 60% and 55%, respectively, and the majority were depressive and anxiety disorders (9). Frequent tinnitus was also associated with anxiety syndrome in patients undergoing mental health evaluation (3). A population-based study examining risk factors associated with tinnitus found increased odds of developing tinnitus in those with history of hyperlipidemia, osteoarthritis, rheumatoid arthritis and thyroid disease (2). In that cross-sectional study, a history of thyroid disease was significantly associated with tinnitus (OR 1.59).

Tinnitus has been found in patients with hyperthyroidism, hypothyroidism and autoimmune thyroiditis (10). However, although the association between hyperthyroidism and tinnitus has been reported previously in cross-sectional studies, in-depth studies of the causal-relationship are lacking, particularly longitudinal cohort population-based studies, which may yield more definitive results for prevalence of tinnitus as well as confirming the association. We believe that the association between hyperthyroidism and tinnitus has been understudied, and more attention is deserved. This study aimed to investigate the incidence of tinnitus in a national sample of hyperthyroidism patients and to identify level of risk and associated factors for tinnitus in patients with hyperthyroidism.

This is the first longitudinal cohort study to demonstrate a positive association between hyperthyroidism and tinnitus, as well as an increased risk of developing tinnitus in hyperthyroid patients. Results have shown that, relative to individuals without hyperthyroidism, patients with diagnosed hyperthyroidism was more prone to develop tinnitus. Our study found higher risk of tinnitus occurred during the first 3 years of the follow-up period, and that the cumulative incidence of tinnitus was still higher in the hyperthyroidism cohort than that in the non-hyperthyroidism cohort during up to 12 years of follow-up. Additionally, patients with hyperthyroidism who had comorbid vertigo, insomnia, anxiety and/or hearing loss were at significantly higher risk of developing tinnitus than those without these comorbidities.

Previous studies have reported a positive association between tinnitus and thyroid disease history (2). As in the present study, associations with comorbidities were also noted, including gender, smoking, stress, sleep, hearing loss, hyperlipidemia, osteoarthritis, rheumatoid arthritis, asthma, and depression (2). Indirect evidence of the relationship between hyperthyroidism and tinnitus may lie in the link between hyperthyroidism and hearing loss. A statistically significant higher hearing threshold was found among patients with Grave’ s disease than that in the normal population, including significant hearing loss at high frequencies in the hyperthyroidism group (12).

Gender differences have been reported repeatedly in previous studies, including Basso et al. (13), who identified gender-specific risk factors, stating that women with bothersome tinnitus had higher rates of cardiovascular disease and thyroid disease; anxiety was also associated with tinnitus and levels were higher in women than in men. Our study also found a significantly higher incidence of tinnitus in hyperthyroid women than in hyperthyroid men, with women having a 1.10-fold increased risk of developing tinnitus than men. However, a study of older adult patients with persistent tinnitus found no significant differences between genders; the most prominent association with tinnitus was hearing impairment, regardless of age or gender (14). A systematic review of tinnitus-related studies found inconsistent results for gender between the included studies, with half of studies noting higher prevalence of tinnitus severity in males and the other half in females, although the prevalence of tinnitus itself was most often higher in males when age was more widely distributed (4). Study samples with older adults, however, mostly reported higher prevalence among women, which is more in line with other reports.

In the present study, the incidence of tinnitus increased with age, comparable to results of a previous study examining differences in age at tinnitus onset (15). Earlier onset was found associated with less distressing tinnitus while onset at older ages was distressing from the very beginning. It was suggested that an age-related decline in brain plasticity may account for the age-dependent severity. However, in our present study, while stratifying subjects by age (≤ 40 years vs. > 40 years) or by follow-up time to tinnitus after hyperthyroidism diagnosis (≤ 3 years vs. > 3 years), hyperthyroid patients were found to develop tinnitus at an earlier age or within the 3-year follow-up time after hyperthyroidism diagnosis than non-hyperthyroidism patients. Results of a study by Kim et al., 2015, showed that the prevalence of tinnitus was 16.0%–20.5% in those 20 to 54 years old and increased sharply after age 55 years, continuing to increase by 30% after 70 years (2). In another cross-sectional study by McCormack et al., 2016, reported that prevalence of frequent tinnitus increased as age increased, with a peak at 14.3% after age 60 years (3). In a recent study, Kim et al. (16), reported that a low thyroid-stimulating hormone level was associated with 2.78-fold higher odds of annoying tinnitus, in subgroup analyses, this association was apparent only in the female subgroup. However, in their study only patients > 40 years were included for analysis.

While associations between thyroid function and tinnitus have been suggested, the neuropathologic mechanism of tinnitus resulting from thyrotoxicosis has not been elucidated in detail. Whether it is a direct result of neurologic modulation by thyroid hormone or synergistic effects of catecholamine on auditory or non-auditory pathways still needs to be investigated. For example, establishing an animal model of thyrotoxicosis and tinnitus may help to further investigate the role of thyroid hormone in the development of tinnitus. In recent decades, however, the view of the tinnitus mechanism has focused more on centrally mediated consequences, that is, central gain followed by decreased sensory input may induce tinnitus (17–19).

Thyroid hormone has long been known to increase adrenaline sensitivity (20, 21). Hyperthyroid status produces variable changes in the number of adrenergic receptors or an affinity for catecholamines in different tissue, which may affect physiological function (22, 23). The synergistic effect of norepinephrine and thyroid hormone has also been suggested (24). Reduced vascular contractility has been observed in hyperthyroid rats (25). Further examination in humans demonstrated that thyroid hormone may influence peripheral blood flow (26).

Evidence from previous experimental studies reveal close interaction between the autonomic system, cochlear blood flow and cochlear function. Spoendlin and Lichtensteiger (1967) first demonstrated the presence of adrenergic fibers in the inner ear and described the direct influence of the sympathetic nervous system on cochlear receptor via the independent vascular system (27). Hozawa and Kimura used immunohistochemical examination to demonstrate the adrenergic neurotransmitter in the inner ears (28). Another early study observed that abnormal endolymph production may lead to cochlear dysfunction and autonomic imbalance will result in inner ear disorders (29). The concentration of catecholamines in the cochlea was found to change dramatically after superior cervical ganglionectomy (30). Cochlear blood flow also decreased by stimulating the sympathetic stellate ganglion in guinea pigs (31), as well as after cervical sympathetic stimulation (32). Further examination revealed an association between sympathetic nerves in the cochlea and the diameter of the feeding vessel (33), suggesting that cochlear blood flow is controlled by the sympathetic nervous system. The sympathetic fibers in the cerebral cortex cause vessel constriction and may ultimately influence cochlear, vestibular nuclei and cortex functions (34). Therefore, taken together, we suggest that cochlear pathology may result from autonomic imbalance related to excessive thyroid hormone and sympathetic over-activity. Central gain followed by reduced sensory input may then induce tinnitus. However, the neuropathological mechanism of tinnitus resulting from thyrotoxicosis remains to be examined in future experimental studies.

It is known from animal studies that thyroid hormone increases neuronal excitability in the brain, suggesting that not only hypothyroid insufficiency but thyrotoxicosis may produce adverse effects (35). Meanwhile, it is interesting that tinnitus and psychiatric conditions may share overlapped modulating pathways based on the role of the limbic system. Thyroid hormone receptor is widely distributed in limbic structures of the brain, and hyperthyroidism is associated with psychiatric disorders, which may arise from action of thyroid hormone on the limbic system (36–40). The influence of non-auditory pathways on tinnitus, such as the influence of the limbic system, has been addressed but without definitive results (41, 42).

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Institutional Review Board of China Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

T-YC had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: T-CW. Acquisition of data: T-CW, C-JC, P-CC, and C-LL. Analysis and interpretation of data: All authors. Drafting of the manuscript: T-CW, C-JC, P-CC, T-YC, RT, and C-LL. Critical revision of the manuscript: T-CW, C-JC, P-CC, T-YC, RT, E-RR, CC, PM, C-DL, and M-HT. Statistical analysis: T-CW, C-JC, P-CC, T-YC, RT, and C-LL. Definition of intellectual content: T-CW, C-JC, P-CC, T-YC, RT, E-RR, CC, and PM. Clinical and experimental studies: T-CW, C-JC, and P-CC.

Administrative, technical, or material support: T-YC, C-DL, and M-HT. Obtaining Funding: T-CW, C-DL, and M-HT. Supervision: T-YC and RT. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the China Medical University in Taiwan (CMU107-N-30). This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004) and China Medical University Hospital (DMR-110-222), Tseng-Lien Lin Foundation, Taichung, Taiwan.

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

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