The incidence of thyroid diseases has been increasing in recent years. Thyroid-stimulating hormone (TSH), the most sensitive indicator reflecting thyroid function, is produced by the adenohypophysis and regulated by the hypothalamic-adenohypophysis-thyroid axis. As a stimulator of thyroid growth, TSH is closely associated with the occurrence of various thyroid disorders.

Thyroid nodules (TN) are common thyroid conditions, with a reported prevalence of 4%–7% through palpation, and a prevalence of 13%–67% by high-resolution ultrasonography (1). The American Association of Clinical Endocrinologists recommends that TSH should be reevaluated within 12–24 months based on clinical characteristics and changes in nodules following the initial TSH assessment (2). A study involving 1990 adults in Korea found that TSH level was negatively associated with TN, with patients with TN having significantly higher TSH levels than those without TN (3). In addition, high TSH levels within the normal range may be an early indicator of hypothyroidism and are linked to an increased risk of autoimmune thyroid disease (4). Previous studies have found that thyroid peroxidase antibody (TPOAb) and/or thyroglobulin autoantibody (TgAb) levels significantly increase with increasing TSH levels (5, 6). In China, a study aimed at establishing new reference values for thyroid volume (Tvol) showed that Tvol was negatively correlated with TSH levels. Some studies have also reported that serum TSH levels in adults with goiter (GR) were significantly lower than those in individuals without GR (7). These findings highlight the impact of TSH level fluctuations on the occurrence of thyroid diseases.

TSH levels play a significant role in the development of thyroid diseases through various mechanisms. Clarifying the relationship between TSH levels and thyroid diseases is helpful to the diagnosis of thyroid diseases in clinic. In addition, whether the TSH levels in the normal range can predict the future risk of thyroid diseases is also a topic worthy of attention. This study aims to investigate whether serum TSH levels, especially within the normal range, are associated with common thyroid disorders, including TN, GR, and thyroid antibody positivity.

Thyroid diseases represent the most prevalent group of disorders within the endocrine system. TSH levels play a significant role in the development of thyroid diseases through various mechanisms. The main cause of GR remains iodine deficiency (8). When dietary iodine intake is insufficient to synthesize thyroid hormones, serum thyroxine reduces, leading to increased TSH release by the pituitary gland. Elevated TSH stimulates the growth and metabolism of thyroid follicular cells, potentially causing GR. In addition, TSH binds to the TSH receptor on thyroid follicular epithelial cells, activates G proteins, and stimulates thyroid hyperplasia through the GS-AC-cAMP signaling system; the development of TN may increase as TSH levels increase. Additional studies have reported higher rates of TPOAb alone, TgAb alone, or at least one antibody positivity in both the low TSH and high TSH values groups than in euthyroid individuals (9). As demonstrated in our study, abnormal TSH levels were associated with an increased risk of GR and antibody positivity in adults. As the primary hormone regulating thyroid function, TSH is the most important indicator for the laboratory diagnosis of thyroid diseases. Therefore, it would also be particularly interesting to explore the future risk of thyroid disease in subjects with currently normal TSH levels. This study focused on the relationship between normal TSH levels and common thyroid diseases.

In this study, the prevalence of TN was 26.1% in women and 22.4% in men, consistent with a report by Chen et al. (10), in which the prevalence rate of TN in Hangzhou in 2013 was 24.1% for men and 34.7% for women (11, 12). In addition, it is well known that women are more likely than men to develop TN, which is consistent with our findings. TSH significantly regulates the growth and differentiation of thyroid cells and may play a direct role in nodule formation (13). Currently, numerous studies have examined the relationship between thyroid function and TN, yet a definitive conclusion remains elusive. For instance, one study on the elderly concluded that TN in this age group had no correlation with laboratory thyroid function indicators (14). Polyps et al. pointed out that within the normal range, an increase in TSH levels is associated with an elevated risk of malignant tumors in TN (15). Wu et al. reported the same conclusion (16). In contrast, some studies have reported that TSH levels were negatively correlated with TN (3, 17). In this study, TSH levels and the prevalence of TN were analyzed in individuals with normal thyroid function, which revealed that TN prevalence was significantly higher in the TSH-Q1 group (0.27–1.41 IU/mL) than in other groups. This observation was consistent with the findings of Wu et al. (18), which found a correlation between the prevalence of TN and declining TSH levels, even after accounting for factors such as age, sex, smoking, alcohol consumption, and medication use. Moreover, we discovered that a TSH level of 0.27–1.41 IU/mL (low TSH level) was a risk factor for TN. A study on TN in Cyprus women showed that the median serum TSH level was lower in women with nodules than in those without nodules (1.4 mIU/L and 1.7 mIU/L, respectively), and the median serum TSH remained within the normal range (17). In addition, our study indicated that the prevalence of TN increased significantly only in the women’s group among those with low TSH levels, which is consistent with the findings of a Beijing adult study, indicating that women are independent risk factors for TN (19). Estrogen may play a role in the formation of TN, as it can influence thyroid tissue and stimulate the production of TSH. Estrogen receptors are expressed in both normal and tumor thyroid tissue, suggesting that estrogen may contribute to thyroid cell growth and nodule formation (19). We made a stratified analysis of men and women, with age of 50 as the cutoff point for stratification. Similar to the above results, the risk of TN only increased in women ( Supplementary Tables 1 , 2 ). In addition, we found that in populations with low TSH levels, the risk of TN was notably higher in adults aged >60 years than in those aged <60 years. However, regarding the prevalence of TN, there was no significant interaction between age and low TSH levels. This indicates that TSH is valuable in predicting the nature of TN, but further investigation is needed. Furthermore, we found that Tvol decreased with increasing TSH levels in both men and women, even within the normal TSH range. While some studies have demonstrated a clear correlation between TSH and Tvol (20, 21), others have not observed this correlation (22). In a cross-sectional and longitudinal analysis of obese children, GR was not associated with thyroid function parameters (23). In contrast, our study revealed that in addition to the negative correlation between TSH and Tvol, the risk of GR increased when TSH levels within the normal range were <1.41 IU/mL, with a higher risk in men than in women and in the young than in the elderly. A Lithuanian study reported a negative association between Tvol and TSH, regardless of the presence of TN, with patients with GR having lower TSH levels than those without GR (24). Other studies have also found a negative association between TSH levels and GR, with a reduced risk of GR at higher TSH levels (25, 26). These findings are consistent with the findings of our study. Available data suggest that women are more prone to developing GR than men, especially in iodine-deficient areas (27, 28). This difference may be attributed to the hormonal status of women, wherein estrogen downregulates the sodium/iodine symporter (29). Some authors have reported that sex-related differences become apparent after puberty, which indicated that sex hormones may play a role in Tvol (30). After stratified analysis of men and women with age of 50 as the cutoff point for stratification, it was found that the risk of GR was obviously increased when TSH was at a low level (0.27-1.41 IU/mL) for women over 50 years old ( Supplementary Tables 1 , 2 ). Advanced age has been identified as an independent risk factor for GR (31), with one study on factors related to the prevalence of GR in Turkish populations revealing that the prevalence of GR increased with age and reached its peak (38.4%) in those aged >70 years (25). A Danish study showed that the prevalence of GR increased with age but plateaued at 40–45 years old (29).

The presence of thyroid antibodies may serve as an early indicator of thyroid disease, particularly autoimmune thyroid disease (4). TPOAb and/or TgAb have been shown to significantly increase with increasing TSH levels and have been associated with an elevated risk of hypothyroidism (5, 6). Another study found that there was a positive correlation between TPOAb levels and TSH, suggesting that TPOAb and TSH levels may predict hypothyroidism risk, even when TSH levels fall within the normal laboratory reference range (32). In this study, TSH > 2.55 IU/mL within the normal range were associated with an increased risk of antibody positivity. Earlier studies by Jensen et al. (33) and Hollowell et al. (34) linked the presence of TPOAbs not only to a higher frequency of elevated TSH levels outside the normal range but also to a trend toward higher TSH levels within the normal range. This indicates that the presence of TPOAbs necessitate a compensatory increase in TSH levels to maintain normal thyroid function (32). Our study further revealed that while the incidence of thyroid antibody positivity was higher in women than in men, logistic regression analysis showed that men with high TSH levels were at a greater risk of antibody positivity than women. Furthermore, our results demonstrated that high TSH levels in young adults increased the risk of antibody positivity. A Dutch study reported that the risk of positive TPOAb levels decreased with increasing age (35). Several studies have reported that various subsets of T and B lymphocytes decrease with age (36–39), which may lead to a decrease in thyroid lymphocyte infiltration, subsequently lowering the production of TPOAb in older individuals.

We conducted an analysis based on a large-scale epidemiological survey to analyze the association of abnormal and normal TSH levels with common thyroid diseases. This study shows that abnormal TSH levels may increase the risk of GR and thyroid antibody positivity. In addition, our research results show that the normal TSH levels can also predict the future risk of thyroid diseases. This also suggests that adults with TSH at higher or lower levels within the normal range, especially those at upper or lower limits of the normal range, should be reviewed regularly. Nevertheless, several limitations need to be acknowledged. First, not all subjects underwent laboratory testing for FT4 and FT3; only adults with abnormal TSH levels were tested. Second, comorbidities and concomitant medications are common among the elderly. Certain drugs, such as estrogen, aspirin, non-steroidal anti-inflammatory drugs, and glucocorticoids, can impact thyroid hormones. Finally, this study was cross-sectional and did not account for time. Therefore, we cannot infer a causal relationship between TSH and TN, GR, and antibody positivity in the euthyroid population. More longitudinal cohort studies are needed to further investigate these associations.

In summary, our study suggests that lower TSH levels (0.27-1.41 IU/mL) were associated with an increased risk of TN and GR, while higher TSH levels (2.55-4.20 IU/mL) were associated with thyroid antibody positivity. A larger sample size cohort study is needed to investigate the relationship between normal TSH levels and thyroid diseases. In addition, the research also suggests that adults whose TSH levels at upper or lower limits of the normal range should be reviewed regularly.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Ethics Committee of the China Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

FJ, LT and WZ designed the research. SL, WG and QM conducted the research and collected the data. MZ and HW performed the laboratory analysis. SL and WG performed the statistical analysis. SL and WG wrote the paper. All authors have read and approved the final manuscript.