GO is known to have a higher prevalence in women than in men. In this study, GD was 2.4 times more common in women than in men, but the incidence of GO in GD patients was similar in both sexes—6.2% in men, and 5.8% in women. The higher incidence of GO in women may be attributed to the higher prevalence of GD in women and the shared pathogenesis of both diseases. Although there have been studies on the effects of sex hormones on thyroid function and sex-related differences in iodine intake in thyroid disease [17, 18], such sex-related differences have not been studied as risk factors for developing GO. Therefore, we tried to identify sex-specific risk factors for GO through a large population-based cohort study. As a result, our regression model showed that younger age, low income, and heavy drinking were associated with GO development in men. In women, younger age, high serum total cholesterol, and lower BMI at the time of GD diagnosis, and hyperlipidemia after GD diagnosis were associated with GO development. In addition, higher statin doses in women statin users after GD diagnosis were significantly associated with a reduced risk of GO development. Interestingly, in women, factors related to metabolic disorder, such as hyperlipidemia, hypercholesterolemia, and statin use, were identified as the primary risk factors, while in men, sociobehavioral factors were associated with GO development.
Previous studies have reported that high levels of total and LDL-cholesterol correlated with the presence of GO and the clinical activity score [8, 9]. Our results also indicated that the comorbidity of hyperlipidemia and serum total cholesterol were significantly associated with GO development in women. Both were found to be insignificant or even to reduce GO risk in a simple comparison, but the combination in a cox regression model revealed that there was a significant association with GO development in women. These conflicting results between the simple comparison and the regression model may be due to longer follow-up in patients without GO than in patients with GO whose follow-up was discontinued after the occurrence of GO according to our study protocol. Usually, the incidence of hyperlipidemia gradually increases with age, which may be the case in patients without GO who had a longer follow-up period in our study. The confounding effect of the simultaneous use of statins to treat hyperlipidemia may also be another reason. Statins were negatively correlated with GO development in our study. Hyperlipidemia and statin use in men did not show any significant association with GO risk in the regression model, despite their association in a simple comparison. Total cholesterol can also have a positive correlation with age. In this study, the characteristics of women patients with GO with younger age and lower BMI may have influenced the reverse result in simple comparison compared to the regression model with a significant relationship between total cholesterol levels and GO development. The mechanism by which hypercholesterolemia or hyperlipidemia induces GO development is not clear, but it may be associated with systemic, chronic inflammation caused by impaired lipid metabolism.
As hypercholesterolemia emerges as a risk factor for GO, there is growing interests in determining whether GO development can be reduced by statin use. Statins have anti-inflammatory effects and are expected to inhibit the cascade of inflammatory cell and cytokine activation in GO [19, 20]. Moreover, the inhibition of adipogenesis by statins may suppress GO symptoms. In this study, after confirming the preventive effect of statins on GO development, the equivalent statin dose was calculated to determine the differences in dose-response according to sex. Higher doses of statins were associated with a higher GO risk in men (p = 0.05) but a significantly lower GO risk in women (p < 0.001). Considering that statin dose tended to increase over time in GD patients without GO and in women GO patients (Fig. 2), women GD patients with good adherence to statin use seemed to have a much lower risk of developing GO than statin non-users, suggesting the protective effect of statin use. However, it is difficult to explain the relationship between statin dose and the risk of GO in men, although compliance may be one of the reasons, considering that statin dose decreases with time in male GO patients. Therefore, the apparent sex-related differences in statin doses observed in the Forest plots may reflect differences in physiological response or may be due to differences in drug compliance between the sexes.
In men, low income and heavy drinking were found to be associated with the occurrence of GO. A previous study revealed that low social grade and higher social deprivation were associated with more severe GO [21]. People with low socioeconomic status may have fewer opportunities to seek appropriate treatment in hospitals or may be more reluctant to receive treatments. Our study did not perform the thyroid function test for these subjects, but it is likely that GD may not be well controlled in these patients, causing an acceleration in GO occurrence. As is widely known, uncontrolled GD is an important risk factor for GO development. Diet may also be important. Oxidative stress is known to result in the production of free radicals, leading to the proliferation and inflammation of orbital fibroblasts in GO [22]. Patients with lower incomes may have lower intakes of antioxidants in the food they consume [21]. Heavy drinking is also estimated to worsen this lack of antioxidants [23]. It is difficult to explain why these socioeconomic factors are particularly related to the occurrence of GO in men rather than women. Our findings highlight the importance of improving access to high-quality care for these patients.
Smoking is the risk factor most consistently associated with the onset and severity of GO [24]. However, our study did not find a significant association between smoking and GO development in both men and women. In men, 76.4% of GO patients were past or current smokers with high smoking rates, but it did not reach the statistical significance (p = 0.077). Presumably, high proportion (68.3%) of smokers in GD patients contributed to the failure of deriving statistical significance. In contrast, in women, only 6.2% of the GD patients were smokers, so it is estimated that the number was insufficient to analyze the effect of smoking on GO development. The social environment in which smoking is more widespread in men than women seems to have influenced the results. Alternatively, these results could be because only the smoking status, but not the amount or period of smoking, was analyzed.
RAI treatment is a well-known risk factor for GO deterioration [25] and is therefore, administered more cautiously to GD patients with prophylactic oral corticosteroids. Our study did not show any significant association between RAI treatment and GO development. Change in clinical practice and the fact that RAI treatment was administered only to < 7% of the subjects are presumed to be the reasons for the lack of statistical significance. Thyroidectomy was also not associated with GO development in GD patients. Several studies have reported that thyroidectomy is neutral to the natural course of GO [26, 27]
Only older age in both sexes and statin use in men were associated with the progression to active GO in this study, but it was difficult to perform regression analysis due to the small numbers of relevant risk factors and patients with active GO. Previous studies have reported that older age, male sex, and smoking can affect the severity of GO [11, 28]. Although smoking did not show any statistical significance, our results demonstrated that the older age was related to the progression of active GO in both men and women.
This study has several limitations. First, this was a retrospective cohort study, where our data could only suggest the risk factors associated with GO development: the causative relationship could not be predicted. Second, since our study used insurance data consisting of diagnostic codes, there might be a possibility of misdiagnosis. In our study, GO occurred in ~ 6% of GD patients, which was lower than in previous studies [29]. Patients with mild GO may have been excluded as GO was defined using only the diagnostic code, and it is possible that the incidence of GO was underestimated. Finally, as our subjects consisted mostly of Koreans, our results might not be applicable to other ethnicities. However, the present study was a population-based, nationwide, large-scale cohort study with many advantages to offset its limitations. Moreover, time-dependent analyses for time-varying variables such as statin use and comorbidities were performed to minimize guarantee-time bias.
In conclusion, this is the first study to consider sex-related characteristics as risk factors for GO development. We found that younger age, low income, and heavy drinking were associated with GO development in men, while younger age, lower BMI, high total cholesterol, hyperlipidemia, and lower statin doses in statin users among women were associated with GO development. Further studies are necessary to determine the causal relationship between these risks and GO development and to evaluate whether management of these risks modifies GO progression.