Thyroid function in opium users: A Cross-Sectional Study on PERSIAN Cohort of Fasa, 2017

Thyroid function in opium users: A Cross-Sectional Study on PERSIAN Cohort of Fasa, 2017 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Thyroid function in opium users: A Cross-Sectional Study on PERSIAN Cohort of Fasa, 2017 Babak Pezeshki, Hossein Pourmontaseri, Reza Homayounfar, Maryam Talebi Moghaddam, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2338887/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Nov, 2023 Read the published version in BMC Endocrine Disorders → Version 1 posted 10 You are reading this latest preprint version Abstract Background Addiction increases the risk of different lifelong disorders. However, there are limited studies evaluating the effects of opium use on thyroid. The present study aimed to compare the thyroid function of opium users and non-users. Methods This cross-sectional study was conducted on 700 participants of the Persian Cohort of Fasa, Iran. Pregnant women and participants with false or missing data were excluded from the study. Frozen plasma samples of the cohort bank were used to determine the levels of T3, T4, and thyroid-stimulating hormone (TSH). The thyroid function was compared between the two groups using Mann-Whitney test (P < 0.05). Results The mean age of the study population (n = 648) was 54.0 ± 9.8 years, including 336 men (49.1%) and 197 opium users (28.8%). The median levels of TSH, T4, and T3 were 2.91 ± 4.61, 9.26 ± 3.65, and 1.22 ± 0.49, respectively. The opium users had significantly higher TSH (3.72 ± 6.2 vs. 2.58 ± 3.75) and lower T4 (8 ± 3.6 vs. 9.8 ± 3.5) levels (P < 0.001). Also, T3 was slightly lower in opium users (1.1 ± 0.5 vs. 1.3 ± 0.5; P = 0.369), although this association was only significant in female opium users (P < 0.001). Conclusions The present findings revealed that opium use causes a reduction in T4, while increasing TSH. Therefore, opium use may lead to the development of primary hypothyroidism, which needs to be investigated in future studies. Addiction Thyroid hormones Opioids Risk factors Introduction Thyroid hormones (THs) play several important roles in the development of metabolism and growth [ 1 , 2 ]. TH dysregulation causes a group of disorders, including hypothyroidism and hyperthyroidism [ 3 ]. Over the past decades, several tools and therapies have been developed to control thyroid disorders worldwide [ 4 , 5 ]. Although TH disorders can be diagnosed and treated effectively, global reports suggest that more reliable approaches to the addictions and individual habits of patients are needed [ 6 , 7 ]. Besides, the prevalence of TH disorders is growing worldwide (0.2–1.3% in some regions) [ 8 , 9 ], and Iranian reports of iodization have indicated the concerning incidence of hypothyroidism (328 per 100,000) and hyperthyroidism (88 per 100,000) in various regions [ 10 ]. For many years, the hypothalamic-pituitary (HP) axis has been known to regulate the level of THs by releasing thyroid-stimulating hormone (TSH); this axis has a close relationship with TH functions in different types of metabolism [ 11 ]. According to numerous trials, addiction to various substances results in the HP axis dysfunction and causes multiple disorders [ 12 – 14 ]. While some studies have emphasized the role of HP axis downregulation in substance abuse, others have reported unremarkable differences [ 15 – 17 ]. In the past decades, abuse of narcotic substances has globally increased [ 18 ]. Recently, the World Health Organization (WHO) reported that among Islamic countries, Iran has the highest rate of opium abuse [ 19 ]. Studies on rodent models suggest that consumption of narcotics (opium and morphine) results in the dysregulation of THs [ 20 , 21 ]. Besides, in some trials, diminished T3 uptake has been shown in opium abusers [ 22 ]. Overall, opium seems to play a destructive role in thyroid function tests, leading to significant misdiagnosis in the treatment of patients with TH disorders or shift them to hypothyroidism [ 23 ]. With this background in mind, since no similar study has been conducted in Fasa University of Medical Sciences (Fars Province, Iran), the present study aimed to investigate the association between opium addiction and TH levels (T3, T4, and TSH). Materials And Methods Study design This cross-sectional study was conducted on the participants of the Persian Cohort of Fasa. In line with a study by Shahsavar et al., the minimum sample size was estimated at 90 people per group; the participants were randomly recruited in the study [ 22 ]. Initially, 700 participants were randomly selected, including 206 opium users (based on self-reports). The participants with incomplete data or missing samples were excluded. Also, participants with false data (if the urine test result did not match the patient's self-report) were eliminated from the study. Measurements The procedure of data collection is described comprehensively in the protocol of the Persian Cohort of Fasa [ 24 ]. The plasma samples of the selected participants were used to measure the levels of THs using the ELISA technique. The normal ranges of T3, T4, and TSH were as follows: 0.52–1.85 ng/mL, 4.8–14.8 ug/dL, and 0.3–6.1 mIU/L, respectively. Ethical Considerations The present results were extracted from a research project, approved by Fasa University of Medical Sciences, with an ethics code of IR.FUMS.REC.1399.094. In line with ethical and confidentiality principles, the objectives and principles of the research, confidentiality of data, and anonymity of the questionnaire were explained to all the participants. They were also free to refuse participation in the study at any time. Statistical analysis Descriptive data were reported as mean ± standard deviation (SD) and frequency. Data were analyzed in SPSS version 16, using t-test and Mann-Whitney U test. Kolmogorov-Smirnov test was also applied to evaluate the normal distribution of variables. The level of each hormone was compared between the user and non-user groups. The participants were also divided into three groups, based on the normal range of each hormone. To investigate the association of opium use with the level of each hormone, multinomial logistic regression was performed. The significance level was set at P < 0.05. Results A total of 684 participants were evaluated in the present study. The mean age of the population, including 336 (49.1%) men, was 54.0 ± 9.8 years. Overall, 28.8% of the participants (n = 197) were opium users. In this population, there were 25 female opium users, which is significantly lower than the number of men (P < 0.001). Based on the results, the rate of obesity was significantly lower in opium users (P = 0.006). On the other hand, myocardial infarction was more frequent in opium users (P = 0.002). There was no significant difference between the groups regarding age, diabetes, cardiovascular disease, and thyroid disorders (Table 1 ). Table 1 Characteristics and comparison of demographic features between opium users and non-users. variable subgroup User (N = 197) Mean ± SD or frequency (percent) Nonuser (n = 487) Mean ± SD or frequency (percent) p-value* gender men 162(82.2) 174(35.7) 0.001 women 35(17.8) 313(64.3) age 53.61 ± 9.33 54.12 ± 10.0 0.539 BMI normal 98(49.7) 178(36.6) 0.006 Over weight 67(34) 212(43.5) obese 32(16.2) 97(19.9) Diabetes yes 57(28.9) 145(29.8) 0.827 no 140(71.1) 342(70.2) Cardiac yes 89(45.2) 197(40.5) 0.256 no 108(54.8) 290(59.5) MI yes 56(28.4) 87(17.9) .002 no 141(71.6) 400(82.1) * The significant level of independent T-test and Chi-square test was considered P-value < 0.05. The level of TSH was dramatically higher in opium users (P < 0.001). The subgroup analysis showed that this difference was insignificant in men (P = 0.462) and significant in women (P = 0.019). However, all other classifications (shown in Table 2 ) revealed no remarkable differences, except obese participants (P = 0.011). Table 2 Comparision of thyroid related hormones between opium users and non-users. Variable Subgroup TSH T3 T4 User (n = 197) Mean ± SD Nonuser (n = 487) Mean ± SD p-value* User (n = 197) Mean ± SD Nonuser (n = 487) Mean ± SD p-value User (n = 197) Mean ± SD Nonuser (n = 487) Mean ± SD p-value Total 3.72 ± 6.2 2.58 ± 3.75 0.001 1.1 ± 0.5 1.3 ± 0.5 0.369 8 ± 3.6 9.8 ± 3.5 0.001 Gender men 3.31 ± 5.85 2.56 ± 3.81 0.462 1.15 ± 0.46 1.27 ± 0.45 0.068 8.62 ± 3.61 9.65 ± 3.68 0.018 women 5.6 ± 7.41 2.60 ± 3.72 0.019 0.72 ± 0.46 1.27 ± 0.50 0.001 5.36 ± 2.41 9.82 ± 3.45 0.001 Age Q1 3.59 ± 5.75 2.90 ± 5.11 0.179 1.10 ± 0.51 1.38 ± 0.57 0.003 7.93 ± 3.72 10.13 ± 3.85 0.001 Q2 3.16 ± 4.69 2.15 ± 1.55 0.957 1.04 ± 0.44 1.23 ± 0.45 0.034 8.21 ± 3.55 9.50 ± 3.32 0.024 Q3 4.14 ± 7.16 2.59 ± 3.57 0.369 1.08 ± 0.48 1.18 ± 0.42 0.169 8.27 ± 3.26 9.60 ± 3.65 0.063 Q4 4.01 ± 7.11 2.56 ± 3.29 0.453 1.07 ± 0.54 1.27 ± 0.45 0.053 7.7 ± 4.17 9.69 ± 3.19 0.001 Body mass index normal 3.35 ± 4.91 2.46 ± 3.37 0.092 1.17 ± 0.47 1.30 ± 0.51 0.156 8.36 ± 3.74 9.97 ± 3.73 0.002 Over weight 4.71 ± 8.14 2.51 ± 4.42 0.106 0.93 ± 0.49 1.27 ± 0.48 0.001 7.4 ± 3.61 9.63 ± 3.48 0.001 obese 2.78 ± 4.82 2.96 ± 2.66 0.011 1.07 ± 0.47 1.23 ± 0.43 0.116 8.40 ± 3.29 9.64 ± 3.28 0.108 Diabetes yes 4.58 ± 7.36 2.29 ± 2.09 0.915 1.04 ± 0.53 1.28 ± 0.46 0.003 8.10 ± 4.14 9.28 ± 2.99 0.023 no 3.37 ± 5.65 2.71 ± 4.26 0.321 1.08 ± 0.47 1.26 ± 0.49 0.001 8.01 ± 3.43 9.96 ± 3.73 0.001 Cardiac yes 3.64 ± 5.66 2.61 ± 4.40 0.718 1.1 ± 0.49 1.31 ± 0.52 0.012 8.29 ± 3.72 10.14 ± 3.65 0.001 no 3.78 ± 6.64 2.56 ± 3.24 0.409 1.04 ± 0.49 1.25 ± 0.46 0.001 7.83 ± 3.58 9.49 ± 3.44 0.001 Myocardial infarction yes 2.66 ± 3.98 2.15 ± 1.78 0.483 1.2 ± 0.44 1.20 ± 0.45 0.511 8.52 ± 3.33 9.69 ± 3.05 0.035 no 4.14 ± 6.85 2.67 ± 4.05 0.149 1.02 ± 0.50 1.29 ± 0.49 0.001 7.85 ± 3.75 9.77 ± 3.63 0.001 * The significant difference of thyroid related hormones between users and non-users was considered P-value < 0.05 (Mann-Whitney U tests). The level of T4 was significantly lower in opium users compared to non-users (P < 0.001), and the difference remained significant in both sexes, body mass index subgroups, and all age quartiles. Also, after dividing the participants into healthy and patient groups, the difference remained significant (Table 2 ). Conversely, the difference in T3 level between opium users and non-users was insignificant, although users had slightly lower levels of T3 (P = 0.369). However, the difference was significant in women (P < 0.001) and nearly significant in men (P = 0.068); this association became significant in the age subgroups. Although T3 was dramatically lower in overweight participants, the difference remained insignificant in other subgroups. The level of T3 was statistically equal in individuals with a history of myocardial infarction, whereas participants with or without diabetes and cardiac disease showed significant differences‌ (Table 2 ). Table 3 presents the frequency of opium users and non-users in each group of thyroid function, based on the normal ranges of TSH, T4, and T3. Importantly, the present findings revealed that all participants with low levels of T3 and T4 were opium users. Also, less than 20% of participants with high levels of T3 and T4 were opium users. Table 3 indicates that opium users had significantly lower levels of T3 and T4. The multinomial regression analysis showed that opium users had a significantly lower risk of high T4 levels (OR, 0.74; 95% CI: 0.33–1.68); this association was insignificant regarding T3 levels (OR, 0.71; 95% CI: 0.31–1.60). Table 3 The association of opium consumption with different level of thyroid related hormones. Group Non-user User Chi-square P value* crude model OR (95%CI) ** Adjusted model OR (95%CI) *** low-TSH 30 8 0.012 0.69 (0.31, 1.55) 0.67 (0.26, 1.71) Normal-TSH 427 164 1 (ref) 1 (ref) High-TSH 30 25 2.17 (1.24, 3.80) 3.21 (1.66, 6.22) low_T4 0 55 < 0.001 ERROR ERROR Normal_T4 431 130 1 (ref) 1 (ref) high_T4 56 12 0.71 (0.37, 1.37) 0.74 (0.33, 1.68) low_T3 0 38 < 0.001 ERROR ERROR Normal_T3 436 146 1 (ref) 1 (ref) high_T3 51 13 0.76 (0.40, 1.44) 0.71 (0.31, 1.60) * The significant difference of thyroid related hormones between users and non-users was considered P-value < 0.05 (Chi-square). ** The crude model was performed adjusted for no covariates. *** The adjusted model was performed adjusted for gender + age + body mass index + educational status + smoking + alcohol consumption + diabetes + myocardial infarction + cardiac disease + hypertension + fatty liver disease. Regarding TSH levels, a reverse association was observed. Opium users only accounted for 21.1% of cases with low TSH levels, while 45% of them had high levels of TSH; this finding suggests that opium use is associated with higher TSH levels. The unadjusted regression model showed that opium users had a significantly greater risk of high TSH levels (OR, 2.17; 95% CI: 1.24–3.80); this association became more prominent after adjustment (OR, 3.21; 95% CI: 1.66–6.22). Therefore, according to this model, opium use had a close independent association with high TSH levels. In other words, opium users had a lower chance of low TSH levels (OR, 0.67; 95% CI: 0.26–1.71). Discussion This study aimed to evaluate the association between opium use and TH levels (T3, T4, and TSH). The findings showed that T3 and T4 levels decreased in opium users, which might suggest hypothyroidism. On the other hand, opium use was associated with higher TSH levels. Overall, it is speculated that opium use is associated with primary hypothyroidism. Some studies have shown that alcohol, cocaine, and heroin addiction have no significant effects on the secretion of pituitary hormones and possibly, T3 and T4 levels. However, others have indicated changes in T3 and T4 levels, mostly due to the direct effects of these substances on the thyroid gland [ 25 , 26 ]. A study by Dogar et al. reported controversial results regarding the inhibitory effects of opium on TH levels. This observation showed that addicts had higher T3 levels compared to healthy individuals [ 27 ]. Rasheed et al. also found that heroin abuse increased T3 levels compared to the control group. Additionally, the level of T4 was not significantly different between addict and non-addict groups [ 15 ]. In another study by Brambilla et al., the results showed that addictive substances had no effects on T3 and T4 levels [ 28 ]. Although some studies have emphasized the effects of these addictive substances on lowering THs, some studies show no TSH-lowering effects. It should be noted that differences in sample size, type of addictive substances, and studied populations might result in these controversies. Nonetheless, it can be concluded that these substances have some suppressive or destructive effects on the pituitary gland, which are associated with secondary hypothyroidism pathogenesis. The hypothalamic-pituitary-thyroid axis is a continuous longitudinal pathway, which involves several biological mechanisms. Negative feedback increases the level of TSH, followed by a reduction in T4 and T3 levels [ 29 ]. The present study revealed that opium simultaneously suppressed the thyroid gland function and induced the activity of pituitary hormones. Theoretically, it can be concluded that opium use is associated with hypothyroidism (probably primary hypothyroidism), which is followed by a rise in TSH levels. In a study by Gozashti et al., comparing the thyroid function of 50 addict and 50 non-addict participants, similar findings were reported, although our study concentrated on the distribution of THs that influenced the reliability of results [ 23 ]. Basically, THs are not normally distributed, even in large sample sizes [ 30 ]. Therefore, it is important to apply nonparametric tests to investigate different aspects of THs. The present study showed that TSH, T3, and T4 levels had a significant non-normal distribution. Consequently, Mann-Whitney U test was applied to compare the levels of these hormones between opium users and non-users. Nonetheless, normal distribution is an important assumption in linear regressions; therefore, we could not perform this analysis. In the current study, the participants were divided into low, normal, and high hormone levels, based on the normal range of each hormone. Next, multinomial regression analysis was performed to investigate the risk of each pathological condition in opium users. Finally, our findings supported that opium users had a significantly higher chance of lower T4 and T3 levels and higher TSH. The results of studies by Zhang et al. [ 31 ] and Bhoir et al. [ 32 ] are consistent with ours. Although the correlation of opium use with hypothyroidism was significant in some previous studies, no significant difference was found relative to the control group. According to previous observations, lower TH levels are correlated with the level of thyroxine-binding globulin (TBG) in the liver tissue. Generally, the T3 resin uptake (T3RU) assay is the most commonly applied tool for determining TBG levels [ 33 ]. Accordingly, the overall profile of T3 and T4 hormones should be evaluated to make more accurate inferences from the results. A study by Shenkman et al. reported that TSH levels were normal in addicts compared to the control group [ 34 ]. Also, Brambilla et al. showed that heroin abuse did not affect TSH levels [ 28 ]. Some studies have not examined TSH levels alongside other hormones [ 27 ]. In line with the present study, Pende et al. documented increased TSH levels following buprenorphine and heroin abuse [ 35 ]. Different theories have hypothesized the downregulation of T4 and T3 in opium users. Since our results suggest the significant risk of primary hypothyroidism, opium use can induce cellular death or suppression in the thyroid glands. A review study by Mirzaei et al. emphasized that opium and its derivatives induce apoptosis in different cells, especially in the liver, brain, and immune system [ 36 ]. Remarkably, opium upregulated both extrinsic and intrinsic pathways of apoptosis through activation of caspase 9, caspase 8, and caspase 3 [ 37 – 39 ]. The probable destructive effects of chronic opium abuse on thyroid cells should be investigated in future studies. The present study had some limitations. Regarding the common characteristics of cross-sectional studies, our findings showed no cause-and-effect association between opium use and TH levels. On the other hand, for legal and ethical reasons, it was not possible to conduct interventional studies to determine the effect of opium on thyroid function; therefore, further retrospective and prospective cohort studies are required to overcome this limitation. Besides, there are still some controversies about TSH levels in opium users. The current findings support the possibility of primary hypothyroidism and the indirect effect of opium use on the pituitary gland, based on negative feedback. Nevertheless, further studies are required to investigate the molecular and cellular mechanisms of this condition. The present study had several strengths. First, the large sample size of the Persian Cohort of Fasa, which was used in the present study for the first time, provided some new information. Second, our clinical approach of dividing the participants into low, normal, and high levels of each hormone provided more reliable results. Third, the patients were classified into different categories of thyroid function, and their findings were compared with those of a normal population (separately for each hormone). However, future studies with a larger sample size are required to investigate the odds ratio of each pathological condition in opium users. Conclusion According to the findings of the current study, opium abuse can influence the thyroid function by affecting the levels of T3 and T4 hormones. The results also suggested that opium use led to primary hypothyroidism through destruction or suppression of the thyroid gland. Future studies are suggested on a larger sample size with sex-related adjustments and free TH measurements. Declarations Ethics approval and consent to participate The present study was conducted based on Helsinki Declaration. The results of this study have been adapted from a research project approved by Fasa University of Medical Sciences with a code of ethics of IR.FUMS.REC.1399.094 In line with the principles of ethics and confidentiality, all participants in the study were explained about the principles and objectives of the research, the confidentiality of the data and the anonymity of the questionnaire. In addition, they were free to refuse to participate. Also, the certification of ethics approval is uploaded as related file. The Ethics committee of Fasa university of medical science had the high standard observation and validation of informed consent of all eligible individuals which were participated in the present study. The PERSIAN Cohort of Fasa had an approved protocol which were confirmed by Ethics committee of Fasa university of medical science and published in PubMed [40]. Consent for publication Not Applicable. Availability of data and material The data which was analyzed in the present study will be available for the researchers who ask the corresponding author to share them the dataset with ethical approval. In contrast, the Noncommunicable Diseases Research Center of Fasa University of Medical Sciences asked all researchers to respect data confidentiality. As a result, the permission to make the database available depends on having the permission of the Ethics Committee of Fasa University of Medical Sciences. Competing interests The researchers of present study had no competing interest or conflict of interest. Funding None. Authors' contributions Babak Pezeshki: data collection, study design, primary and secondary manuscript Hossein Pourmontaseri: study design, corresponding, data analysis, primary manuscript Reza Homayounfar: study design, primary manuscript Maryam Talebi Moghadam: data analysis, primary manuscript Azizallah Dehghan: data analysis, primary manuscript, study design Acknowledgements The researchers of present study thanks Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran and Clinical Research Development Unit of Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran. References Mughal, B.B., J.B. Fini, and B.A. Demeneix, Thyroid-disrupting chemicals and brain development: an update. Endocr Connect, 2018. 7 (4): p. R160-r186. Sharma, M.A.S.M.A.A.S. Physiology, Thyroid Hormone . 2021; Available from: https://www.ncbi.nlm.nih.gov/books/NBK500006/. Persani, L., Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. 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Cite Share Download PDF Status: Published Journal Publication published 30 Nov, 2023 Read the published version in BMC Endocrine Disorders → Version 1 posted Editorial decision: Major revision 16 Jun, 2023 Reviews received at journal 27 May, 2023 Reviews received at journal 25 Mar, 2023 Reviewers agreed at journal 25 Mar, 2023 Reviewers agreed at journal 24 Mar, 2023 Reviewers invited by journal 24 Mar, 2023 Editor assigned by journal 24 Mar, 2023 Editor invited by journal 23 Dec, 2022 Submission checks completed at journal 23 Dec, 2022 First submitted to journal 02 Dec, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2338887","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":162462531,"identity":"f87642d1-2b32-441b-817e-09a213d5dcc9","order_by":0,"name":"Babak Pezeshki","email":"","orcid":"","institution":"Fasa University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Babak","middleName":"","lastName":"Pezeshki","suffix":""},{"id":162462533,"identity":"a044a0a8-376c-434b-8b6b-05b3e792b732","order_by":1,"name":"Hossein Pourmontaseri","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYBACAySS8UGCgYQciHXgAZFamA0+VNgYg7UkENQCAWySM86kJTaAmPi0mLO3P/7woeAOg7n06QRp3rbD6fPDDj8E2mInp9uAXYtlzxkzyRkGzxgs+3I3GAO15G68nWYA1JJsbHYAh8Nu5LAx8xgcZjA4w7shGaxldgJIy4HEbTi1pD/+/Aeq5TDIYYaz0z8Q0JJgIM0A0bKxEej9BHnpHAK2nAH6pcfgMI9lD+9mBmAgG26Qzik4kGCAxy/HgSH2489hOXMe3u0/gFEpLz87ffOHDxV2cri0wAAPPIIMwCoNcKpEsg7GkG8gQvUoGAWjYBSMKAAAFjRmjjTeHCsAAAAASUVORK5CYII=","orcid":"","institution":"Fasa University of Medical Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hossein","middleName":"","lastName":"Pourmontaseri","suffix":""},{"id":162462534,"identity":"ba962ba1-f724-4a1c-b0de-821aaec7143d","order_by":2,"name":"Reza Homayounfar","email":"","orcid":"","institution":"Fasa University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Reza","middleName":"","lastName":"Homayounfar","suffix":""},{"id":162462535,"identity":"90d84d34-ec14-4dd7-b1f8-ec2a3a577476","order_by":3,"name":"Maryam Talebi Moghaddam","email":"","orcid":"","institution":"Fasa University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"Talebi","lastName":"Moghaddam","suffix":""},{"id":162462536,"identity":"a45b6acb-4f15-4cdf-a751-0ba57d54e20c","order_by":4,"name":"Azizallah Dehghan","email":"","orcid":"","institution":"Fasa University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Azizallah","middleName":"","lastName":"Dehghan","suffix":""}],"badges":[],"createdAt":"2022-12-02 21:29:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2338887/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2338887/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12902-023-01467-3","type":"published","date":"2023-11-30T15:01:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":47561096,"identity":"30abcf33-8b04-498f-8c90-d70a71e01c4f","added_by":"auto","created_at":"2023-12-04 15:09:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":467295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2338887/v1/aeba50cf-2245-4ce1-9de2-4a72af0e0828.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Thyroid function in opium users: A Cross-Sectional Study on PERSIAN Cohort of Fasa, 2017","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThyroid hormones (THs) play several important roles in the development of metabolism and growth [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. TH dysregulation causes a group of disorders, including hypothyroidism and hyperthyroidism [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Over the past decades, several tools and therapies have been developed to control thyroid disorders worldwide [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although TH disorders can be diagnosed and treated effectively, global reports suggest that more reliable approaches to the addictions and individual habits of patients are needed [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Besides, the prevalence of TH disorders is growing worldwide (0.2\u0026ndash;1.3% in some regions) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and Iranian reports of iodization have indicated the concerning incidence of hypothyroidism (328 per 100,000) and hyperthyroidism (88 per 100,000) in various regions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor many years, the hypothalamic-pituitary (HP) axis has been known to regulate the level of THs by releasing thyroid-stimulating hormone (TSH); this axis has a close relationship with TH functions in different types of metabolism [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. According to numerous trials, addiction to various substances results in the HP axis dysfunction and causes multiple disorders [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. While some studies have emphasized the role of HP axis downregulation in substance abuse, others have reported unremarkable differences [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the past decades, abuse of narcotic substances has globally increased [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Recently, the World Health Organization (WHO) reported that among Islamic countries, Iran has the highest rate of opium abuse [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Studies on rodent models suggest that consumption of narcotics (opium and morphine) results in the dysregulation of THs [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Besides, in some trials, diminished T3 uptake has been shown in opium abusers [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Overall, opium seems to play a destructive role in thyroid function tests, leading to significant misdiagnosis in the treatment of patients with TH disorders or shift them to hypothyroidism [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith this background in mind, since no similar study has been conducted in Fasa University of Medical Sciences (Fars Province, Iran), the present study aimed to investigate the association between opium addiction and TH levels (T3, T4, and TSH).\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design\u003c/h2\u003e\n\u003cp\u003eThis cross-sectional study was conducted on the participants of the Persian Cohort of Fasa. In line with a study by Shahsavar et al., the minimum sample size was estimated at 90 people per group; the participants were randomly recruited in the study [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Initially, 700 participants were randomly selected, including 206 opium users (based on self-reports). The participants with incomplete data or missing samples were excluded. Also, participants with false data (if the urine test result did not match the patient's self-report) were eliminated from the study.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eMeasurements\u003c/h2\u003e\n\u003cp\u003eThe procedure of data collection is described comprehensively in the protocol of the Persian Cohort of Fasa [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. The plasma samples of the selected participants were used to measure the levels of THs using the ELISA technique. The normal ranges of T3, T4, and TSH were as follows: 0.52\u0026ndash;1.85 ng/mL, 4.8\u0026ndash;14.8 ug/dL, and 0.3\u0026ndash;6.1 mIU/L, respectively.\u003c/p\u003e\n\u003ch2\u003eEthical Considerations\u003c/h2\u003e\n\u003cp\u003eThe present results were extracted from a research project, approved by Fasa University of Medical Sciences, with an ethics code of IR.FUMS.REC.1399.094. In line with ethical and confidentiality principles, the objectives and principles of the research, confidentiality of data, and anonymity of the questionnaire were explained to all the participants. They were also free to refuse participation in the study at any time.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eDescriptive data were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and frequency. Data were analyzed in SPSS version 16, using t-test and Mann-Whitney U test. Kolmogorov-Smirnov test was also applied to evaluate the normal distribution of variables. The level of each hormone was compared between the user and non-user groups. The participants were also divided into three groups, based on the normal range of each hormone. To investigate the association of opium use with the level of each hormone, multinomial logistic regression was performed. The significance level was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 684 participants were evaluated in the present study. The mean age of the population, including 336 (49.1%) men, was 54.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 years. Overall, 28.8% of the participants (n\u0026thinsp;=\u0026thinsp;197) were opium users. In this population, there were 25 female opium users, which is significantly lower than the number of men (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Based on the results, the rate of obesity was significantly lower in opium users (P\u0026thinsp;=\u0026thinsp;0.006). On the other hand, myocardial infarction was more frequent in opium users (P\u0026thinsp;=\u0026thinsp;0.002). There was no significant difference between the groups regarding age, diabetes, cardiovascular disease, and thyroid disorders (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics and comparison of demographic features between opium users and non-users.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003evariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003esubgroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUser\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;197)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or frequency (percent)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNonuser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;487)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or frequency (percent)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value*\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003egender\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003emen\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e162(82.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e174(35.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ewomen\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35(17.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e313(64.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eage\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.61\u0026thinsp;\u0026plusmn;\u0026thinsp;9.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.12\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.539\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003enormal\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98(49.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e178(36.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOver weight\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67(34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e212(43.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eobese\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32(16.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e97(19.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiabetes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57(28.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e145(29.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.827\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e140(71.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e342(70.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiac\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89(45.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e197(40.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.256\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e108(54.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e290(59.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMI\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56(28.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e87(17.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e141(71.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e400(82.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003cstrong\u003e* The significant level of independent T-test and Chi-square test was considered P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/strong\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe level of TSH was dramatically higher in opium users (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The subgroup analysis showed that this difference was insignificant in men (P\u0026thinsp;=\u0026thinsp;0.462) and significant in women (P\u0026thinsp;=\u0026thinsp;0.019). However, all other classifications (shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) revealed no remarkable differences, except obese participants (P\u0026thinsp;=\u0026thinsp;0.011).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparision of thyroid related hormones between opium users and non-users.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSubgroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTSH\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eT3\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eT4\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;197)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNonuser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;487)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;197)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNonuser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;487)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;197)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNonuser\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;487)\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.72\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.369\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.31\u0026thinsp;\u0026plusmn;\u0026thinsp;5.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.462\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.068\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.62\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.65\u0026thinsp;\u0026plusmn;\u0026thinsp;3.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ewomen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.019\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.36\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.82\u0026thinsp;\u0026plusmn;\u0026thinsp;3.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQ1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.59\u0026thinsp;\u0026plusmn;\u0026thinsp;5.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;5.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.179\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.93\u0026thinsp;\u0026plusmn;\u0026thinsp;3.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.13\u0026thinsp;\u0026plusmn;\u0026thinsp;3.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQ2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.16\u0026thinsp;\u0026plusmn;\u0026thinsp;4.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.957\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.21\u0026thinsp;\u0026plusmn;\u0026thinsp;3.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.50\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQ3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.14\u0026thinsp;\u0026plusmn;\u0026thinsp;7.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.59\u0026thinsp;\u0026plusmn;\u0026thinsp;3.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.369\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.169\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.063\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQ4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.01\u0026thinsp;\u0026plusmn;\u0026thinsp;7.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.453\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.053\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.69\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBody mass index\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.35\u0026thinsp;\u0026plusmn;\u0026thinsp;4.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.46\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.092\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.156\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.36\u0026thinsp;\u0026plusmn;\u0026thinsp;3.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.97\u0026thinsp;\u0026plusmn;\u0026thinsp;3.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOver weight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.71\u0026thinsp;\u0026plusmn;\u0026thinsp;8.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.51\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.106\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.63\u0026thinsp;\u0026plusmn;\u0026thinsp;3.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eobese\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.78\u0026thinsp;\u0026plusmn;\u0026thinsp;4.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.96\u0026thinsp;\u0026plusmn;\u0026thinsp;2.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.116\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.108\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiabetes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eyes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.58\u0026thinsp;\u0026plusmn;\u0026thinsp;7.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.915\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.10\u0026thinsp;\u0026plusmn;\u0026thinsp;4.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.28\u0026thinsp;\u0026plusmn;\u0026thinsp;2.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.023\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eno\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.37\u0026thinsp;\u0026plusmn;\u0026thinsp;5.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.321\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.96\u0026thinsp;\u0026plusmn;\u0026thinsp;3.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiac\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eyes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.64\u0026thinsp;\u0026plusmn;\u0026thinsp;5.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;4.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.718\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.14\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eno\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.78\u0026thinsp;\u0026plusmn;\u0026thinsp;6.64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.409\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.83\u0026thinsp;\u0026plusmn;\u0026thinsp;3.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.49\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMyocardial infarction\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eyes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.66\u0026thinsp;\u0026plusmn;\u0026thinsp;3.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.483\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.511\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.52\u0026thinsp;\u0026plusmn;\u0026thinsp;3.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.69\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.035\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eno\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.14\u0026thinsp;\u0026plusmn;\u0026thinsp;6.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.149\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.85\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.77\u0026thinsp;\u0026plusmn;\u0026thinsp;3.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"11\"\u003e* The significant difference of thyroid related hormones between users and non-users was considered P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (Mann-Whitney U tests).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe level of T4 was significantly lower in opium users compared to non-users (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the difference remained significant in both sexes, body mass index subgroups, and all age quartiles. Also, after dividing the participants into healthy and patient groups, the difference remained significant (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Conversely, the difference in T3 level between opium users and non-users was insignificant, although users had slightly lower levels of T3 (P\u0026thinsp;=\u0026thinsp;0.369). However, the difference was significant in women (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and nearly significant in men (P\u0026thinsp;=\u0026thinsp;0.068); this association became significant in the age subgroups. Although T3 was dramatically lower in overweight participants, the difference remained insignificant in other subgroups. The level of T3 was statistically equal in individuals with a history of myocardial infarction, whereas participants with or without diabetes and cardiac disease showed significant differences\u0026zwnj; (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e presents the frequency of opium users and non-users in each group of thyroid function, based on the normal ranges of TSH, T4, and T3. Importantly, the present findings revealed that all participants with low levels of T3 and T4 were opium users. Also, less than 20% of participants with high levels of T3 and T4 were opium users. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e indicates that opium users had significantly lower levels of T3 and T4. The multinomial regression analysis showed that opium users had a significantly lower risk of high T4 levels (OR, 0.74; 95% CI: 0.33\u0026ndash;1.68); this association was insignificant regarding T3 levels (OR, 0.71; 95% CI: 0.31\u0026ndash;1.60).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe association of opium consumption with different level of thyroid related hormones.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNon-user\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUser\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eChi-square\u003c/p\u003e\n\u003cp\u003eP value*\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ecrude model\u003c/p\u003e\n\u003cp\u003eOR (95%CI) **\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdjusted model\u003c/p\u003e\n\u003cp\u003eOR (95%CI) ***\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003elow-TSH\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.012\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.69 (0.31, 1.55)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67 (0.26, 1.71)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNormal-TSH\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e427\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e164\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHigh-TSH\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.17 (1.24, 3.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.21 (1.66, 6.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003elow_T4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eERROR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eERROR\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNormal_T4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e431\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e130\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ehigh_T4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71 (0.37, 1.37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.74 (0.33, 1.68)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003elow_T3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eERROR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eERROR\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNormal_T3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e436\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e146\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (ref)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ehigh_T3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76 (0.40, 1.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71 (0.31, 1.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e* The significant difference of thyroid related hormones between users and non-users was considered P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (Chi-square).\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e** The crude model was performed adjusted for no covariates.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e*** The adjusted model was performed adjusted for gender\u0026thinsp;+\u0026thinsp;age\u0026thinsp;+\u0026thinsp;body mass index\u0026thinsp;+\u0026thinsp;educational status\u0026thinsp;+\u0026thinsp;smoking\u0026thinsp;+\u0026thinsp;alcohol consumption\u0026thinsp;+\u0026thinsp;diabetes\u0026thinsp;+\u0026thinsp;myocardial infarction\u0026thinsp;+\u0026thinsp;cardiac disease\u0026thinsp;+\u0026thinsp;hypertension\u0026thinsp;+\u0026thinsp;fatty liver disease.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding TSH levels, a reverse association was observed. Opium users only accounted for 21.1% of cases with low TSH levels, while 45% of them had high levels of TSH; this finding suggests that opium use is associated with higher TSH levels. The unadjusted regression model showed that opium users had a significantly greater risk of high TSH levels (OR, 2.17; 95% CI: 1.24\u0026ndash;3.80); this association became more prominent after adjustment (OR, 3.21; 95% CI: 1.66\u0026ndash;6.22). Therefore, according to this model, opium use had a close independent association with high TSH levels. In other words, opium users had a lower chance of low TSH levels (OR, 0.67; 95% CI: 0.26\u0026ndash;1.71).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to evaluate the association between opium use and TH levels (T3, T4, and TSH). The findings showed that T3 and T4 levels decreased in opium users, which might suggest hypothyroidism. On the other hand, opium use was associated with higher TSH levels. Overall, it is speculated that opium use is associated with primary hypothyroidism.\u003c/p\u003e \u003cp\u003eSome studies have shown that alcohol, cocaine, and heroin addiction have no significant effects on the secretion of pituitary hormones and possibly, T3 and T4 levels. However, others have indicated changes in T3 and T4 levels, mostly due to the direct effects of these substances on the thyroid gland [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. A study by Dogar et al. reported controversial results regarding the inhibitory effects of opium on TH levels. This observation showed that addicts had higher T3 levels compared to healthy individuals [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Rasheed et al. also found that heroin abuse increased T3 levels compared to the control group. Additionally, the level of T4 was not significantly different between addict and non-addict groups [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn another study by Brambilla et al., the results showed that addictive substances had no effects on T3 and T4 levels [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Although some studies have emphasized the effects of these addictive substances on lowering THs, some studies show no TSH-lowering effects. It should be noted that differences in sample size, type of addictive substances, and studied populations might result in these controversies. Nonetheless, it can be concluded that these substances have some suppressive or destructive effects on the pituitary gland, which are associated with secondary hypothyroidism pathogenesis.\u003c/p\u003e \u003cp\u003eThe hypothalamic-pituitary-thyroid axis is a continuous longitudinal pathway, which involves several biological mechanisms. Negative feedback increases the level of TSH, followed by a reduction in T4 and T3 levels [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The present study revealed that opium simultaneously suppressed the thyroid gland function and induced the activity of pituitary hormones. Theoretically, it can be concluded that opium use is associated with hypothyroidism (probably primary hypothyroidism), which is followed by a rise in TSH levels. In a study by Gozashti et al., comparing the thyroid function of 50 addict and 50 non-addict participants, similar findings were reported, although our study concentrated on the distribution of THs that influenced the reliability of results [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Basically, THs are not normally distributed, even in large sample sizes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, it is important to apply nonparametric tests to investigate different aspects of THs.\u003c/p\u003e \u003cp\u003eThe present study showed that TSH, T3, and T4 levels had a significant non-normal distribution. Consequently, Mann-Whitney U test was applied to compare the levels of these hormones between opium users and non-users. Nonetheless, normal distribution is an important assumption in linear regressions; therefore, we could not perform this analysis. In the current study, the participants were divided into low, normal, and high hormone levels, based on the normal range of each hormone. Next, multinomial regression analysis was performed to investigate the risk of each pathological condition in opium users. Finally, our findings supported that opium users had a significantly higher chance of lower T4 and T3 levels and higher TSH.\u003c/p\u003e \u003cp\u003eThe results of studies by Zhang et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and Bhoir et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] are consistent with ours. Although the correlation of opium use with hypothyroidism was significant in some previous studies, no significant difference was found relative to the control group. According to previous observations, lower TH levels are correlated with the level of thyroxine-binding globulin (TBG) in the liver tissue. Generally, the T3 resin uptake (T3RU) assay is the most commonly applied tool for determining TBG levels [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Accordingly, the overall profile of T3 and T4 hormones should be evaluated to make more accurate inferences from the results.\u003c/p\u003e \u003cp\u003eA study by Shenkman et al. reported that TSH levels were normal in addicts compared to the control group [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Also, Brambilla et al. showed that heroin abuse did not affect TSH levels [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Some studies have not examined TSH levels alongside other hormones [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In line with the present study, Pende et al. documented increased TSH levels following buprenorphine and heroin abuse [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDifferent theories have hypothesized the downregulation of T4 and T3 in opium users. Since our results suggest the significant risk of primary hypothyroidism, opium use can induce cellular death or suppression in the thyroid glands. A review study by Mirzaei et al. emphasized that opium and its derivatives induce apoptosis in different cells, especially in the liver, brain, and immune system [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Remarkably, opium upregulated both extrinsic and intrinsic pathways of apoptosis through activation of caspase 9, caspase 8, and caspase 3 [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The probable destructive effects of chronic opium abuse on thyroid cells should be investigated in future studies.\u003c/p\u003e \u003cp\u003eThe present study had some limitations. Regarding the common characteristics of cross-sectional studies, our findings showed no cause-and-effect association between opium use and TH levels. On the other hand, for legal and ethical reasons, it was not possible to conduct interventional studies to determine the effect of opium on thyroid function; therefore, further retrospective and prospective cohort studies are required to overcome this limitation. Besides, there are still some controversies about TSH levels in opium users. The current findings support the possibility of primary hypothyroidism and the indirect effect of opium use on the pituitary gland, based on negative feedback. Nevertheless, further studies are required to investigate the molecular and cellular mechanisms of this condition.\u003c/p\u003e \u003cp\u003eThe present study had several strengths. First, the large sample size of the Persian Cohort of Fasa, which was used in the present study for the first time, provided some new information. Second, our clinical approach of dividing the participants into low, normal, and high levels of each hormone provided more reliable results. Third, the patients were classified into different categories of thyroid function, and their findings were compared with those of a normal population (separately for each hormone). However, future studies with a larger sample size are required to investigate the odds ratio of each pathological condition in opium users.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAccording to the findings of the current study, opium abuse can influence the thyroid function by affecting the levels of T3 and T4 hormones. The results also suggested that opium use led to primary hypothyroidism through destruction or suppression of the thyroid gland. Future studies are suggested on a larger sample size with sex-related adjustments and free TH measurements.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was conducted based on Helsinki Declaration. The results of this study have been adapted from a research project approved by Fasa University of Medical Sciences with a code of ethics of IR.FUMS.REC.1399.094 In line with the principles of ethics and confidentiality, all participants in the study were explained about the principles and objectives of the research, the confidentiality of the data and the anonymity of the questionnaire. In addition, they were free to refuse to participate. Also, the certification of ethics approval is uploaded as related file. The Ethics committee of Fasa university of medical science had the high standard observation and validation of informed consent of all eligible individuals which were participated in the present study. The PERSIAN Cohort of Fasa had an approved protocol which were confirmed by Ethics committee of Fasa university of medical science and published in PubMed [40].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data which was analyzed in the present study will be available for the researchers who ask the corresponding author to share them the dataset with ethical approval. In contrast, the Noncommunicable Diseases Research Center of Fasa University of Medical Sciences asked all researchers to respect data confidentiality. As a result, the permission to make the database available depends on having the permission of the Ethics Committee of Fasa University of Medical Sciences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researchers of present study had no competing interest or conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBabak Pezeshki: data collection, study design, primary and secondary manuscript\u003c/p\u003e\n\u003cp\u003eHossein Pourmontaseri: study design, corresponding, data analysis, primary manuscript\u003c/p\u003e\n\u003cp\u003eReza Homayounfar: study design, primary manuscript\u003c/p\u003e\n\u003cp\u003eMaryam Talebi Moghadam: data analysis, primary manuscript\u003c/p\u003e\n\u003cp\u003eAzizallah Dehghan: data analysis, primary manuscript, study design\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researchers of present study thanks Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran and Clinical Research Development Unit of Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMughal, B.B., J.B. Fini, and B.A. Demeneix, \u003cem\u003eThyroid-disrupting chemicals and brain development: an update.\u003c/em\u003e Endocr Connect, 2018. \u003cstrong\u003e7\u003c/strong\u003e(4): p. 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Chen, and L.-C. Yu, \u003cem\u003eMorphine: a protective or destructive role in neurons?\u003c/em\u003e The Neuroscientist, 2008. \u003cstrong\u003e14\u003c/strong\u003e(6): p. 561-570.\u003c/li\u003e\n\u003cli\u003eWang, J.Y., \u003cem\u003eThe capable ABL: what is its biological function?\u003c/em\u003e Molecular and cellular biology, 2014. \u003cstrong\u003e34\u003c/strong\u003e(7): p. 1188-1197.\u003c/li\u003e\n\u003cli\u003eMohammad Gholi Mezerji, N., et al., \u003cem\u003eThe reliability and validity of the Persian version of Pittsburgh sleep quality index in Iranian people.\u003c/em\u003e Avicenna Journal of Neuro Psycho Physiology, 2017. \u003cstrong\u003e4\u003c/strong\u003e(3): p. 95-102.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Addiction, Thyroid hormones, Opioids, Risk factors","lastPublishedDoi":"10.21203/rs.3.rs-2338887/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2338887/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAddiction increases the risk of different lifelong disorders. However, there are limited studies evaluating the effects of opium use on thyroid. The present study aimed to compare the thyroid function of opium users and non-users.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis cross-sectional study was conducted on 700 participants of the Persian Cohort of Fasa, Iran. Pregnant women and participants with false or missing data were excluded from the study. Frozen plasma samples of the cohort bank were used to determine the levels of T3, T4, and thyroid-stimulating hormone (TSH). The thyroid function was compared between the two groups using Mann-Whitney test (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe mean age of the study population (n\u0026thinsp;=\u0026thinsp;648) was 54.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 years, including 336 men (49.1%) and 197 opium users (28.8%). The median levels of TSH, T4, and T3 were 2.91\u0026thinsp;\u0026plusmn;\u0026thinsp;4.61, 9.26\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65, and 1.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49, respectively. The opium users had significantly higher TSH (3.72\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2 vs. 2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75) and lower T4 (8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 vs. 9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5) levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Also, T3 was slightly lower in opium users (1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 vs. 1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5; P\u0026thinsp;=\u0026thinsp;0.369), although this association was only significant in female opium users (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe present findings revealed that opium use causes a reduction in T4, while increasing TSH. Therefore, opium use may lead to the development of primary hypothyroidism, which needs to be investigated in future studies.\u003c/p\u003e","manuscriptTitle":"Thyroid function in opium users: A Cross-Sectional Study on PERSIAN Cohort of Fasa, 2017","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-29 16:18:30","doi":"10.21203/rs.3.rs-2338887/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-06-16T10:11:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-05-27T18:13:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-25T12:05:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"dbb3fd8e-81eb-4542-aa47-5953fa43e1b3","date":"2023-03-25T04:04:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0df68dbd-547b-4a64-a4dd-8a39460ae9e7","date":"2023-03-24T21:01:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-03-24T16:59:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-03-24T16:31:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-12-23T11:24:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-12-23T11:21:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2022-12-02T21:22:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bfe5e017-c388-4582-be99-1411afc8423b","owner":[],"postedDate":"December 29th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-12-04T15:04:06+00:00","versionOfRecord":{"articleIdentity":"rs-2338887","link":"https://doi.org/10.1186/s12902-023-01467-3","journal":{"identity":"bmc-endocrine-disorders","isVorOnly":false,"title":"BMC Endocrine Disorders"},"publishedOn":"2023-11-30 15:01:22","publishedOnDateReadable":"November 30th, 2023"},"versionCreatedAt":"2022-12-29 16:18:30","video":"","vorDoi":"10.1186/s12902-023-01467-3","vorDoiUrl":"https://doi.org/10.1186/s12902-023-01467-3","workflowStages":[]},"version":"v1","identity":"rs-2338887","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2338887","identity":"rs-2338887","version":["v1"]},"buildId":"wLkW0s4AflPzk-lpfg-fK","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}