JOURNAL OF WOMEN’S HEALTH Volume 28, Number 10, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/jwh.2018.7648

Increased Risk of Polycystic Ovary Syndrome in Taiwanese Women with : A Nationwide Population-Based Retrospective Cohort Study

Ching Tong, MSD,1,2 Yu-Hsun Wang, MS,3 Hui-Chieh Yu, PhD,1 and Yu-Chao Chang, PhD1,4

Abstract

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. Both hormonal and inflammatory influences are assumed to affect periodontal tissues. Previous studies have shown that PCOS patients could have higher prevalence of gingival inflammation. However, the relationship between PCOS and chronic periodontitis (CP) is not clear. Materials and Methods: In this study, we evaluated the risk of PCOS from CP exposure in a nationwide population-based retrospective cohort study in Taiwan. We studied the claims data of Taiwanese population from 2001 to 2012. The 24,410 female patients with CP were identified from the National Health Insurance Database. The 24,410 controls were selected with randomly frequency matched by age, sex, and index year from the general population. The risk of PCOS was analyzed by Cox proportional hazards regression models, including sex, age, and comorbidities. Results: In this study, 24,410 female patients with CP (mean age: 35.14 – 8.81 years) and 24,410 controls (mean age: 35.14 – 8.8 years) were observed for 8.89 and 8.85 years, respectively. A total of 441 cases of PCOS were identified in CP cohort and 304 cases in non-CP cohort. Multivariate Cox regression analysis indicated that the incidence rate of PCOS was significantly higher in CP cohort than those in non-CP cohort (adjusted hazard ratio: 1.44, 95% confidence interval: 1.24–1.67). Conclusions: Taken together, this nationwide retrospective cohort study demonstrated that the risk of PCOS was significantly higher in female patients with CP than those without CP in Taiwan.

Keywords: polycystic ovary syndrome, chronic periodontitis, women, nationwide population, cohort study, Taiwan

Introduction Polycystic ovary syndrome (PCOS) is a complex endo- crine disorder among women and affects about 5%–14% of eriodontal disease, an infectious disease, is triggered women in reproductive age.8 PCOS is characterized by by bacterial products exaggerated gingival inflammation, menstrual irregularity, obesity, infertility, excessive amounts

Downloaded by TAICHUNG VETERANS GENERAL HOSP from www.liebertpub.com at 12/06/19. For personal use only. P recognized as in the initial phase. Gingivitis could of androgenic hormones, and polycystic ovaries.9 Recently, further destroy the , leading to alveolar bone de- PCOS was reported to link with an increased risk for car- struction and even tooth loss, which is diagnosed as period- diovascular diseases,10 diabetes,11 and psychiatric disor- ontitis.1 Female sex steroid hormones also play important ders.12 Therefore, PCOS could be recognized not only as a accelerator factors in the pathogenesis of periodontal diseases.2 reproductive problem but also a crucial systemic condition in Inflammatory markers were found to be highly expressed in affected women. periodontal tissues, blood, and salivary or gingival crevice From the literature review, studies had clearly demon- fluid.3,4 Low-grade inflammation of chronic periodontitis (CP) strated that PCOS was associated with gingival inflamma- is emerging as a conceivable etiologic mechanism correlated by tion. Higher levels of oxidative stress and systemic many systemic diseases such as cardiovascular diseases,5 dia- inflammatory markers were found in both gingivitis and betes,6 and chronic pulmonary disease.7 PCOS.13–18 However, gingival inflammation is just one of the

1School of Dentistry, Chung Shan Medical University, Taichung, Taiwan. 2Division of Endodontics and , Department of Stomatology, Taichung Veterans General Hospital, Taichung, Taiwan. Departments of 3Medical Research and 4Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.

1436 INCREASED RISK OF PCOS WITH CP 1437

symptoms/signs of periodontitis. The definition of period- Exposure of CP ontitis should be resulting in alveolar bone loss. The associ- After approval by the Chung Shan Medical University ation between PCOS and CP still remains to be elucidated. In Hospital institutional review board (CS2-15071), we identified previous cross-section studies, women with newly diagnosed the ambulatory patients for dental visit with newly diagnosed PCOS had higher prevalence of periodontitis with increased 19,20 CP (ICD-9-CM code: 523.4) from 2001 to 2012 as a newly . However, the association be- onset CP cohort. The first-time CP diagnosis served as the tween CP and PCOS needs further investigation such as co- index date. In Taiwan, NHI has established the strict guideline hort design and relatively large sample size. that only board-registered dentists can execute the periodontal In this study, we hypothesized that CP may have a higher treatment according to the strict NHI therapeutic guidelines. risk for developing subsequent PCOS in affected women. To ensure the accuracy of CP diagnosis, only patients with at Therefore, a nationwide population-based retrospective co- least three outpatient service claims were recruited. hort study was conducted to investigate the possible link Subjects without periodontitis were randomly selected from between CP and PCOS from Taiwanese National Health In- the data set and identified as healthy controls. The comparison surance Research Database (NHIRD). group included the participations who were never diagnosed with CP from 2000 to 2013. To reduce the confounding bias, Materials and Methods we used propensity score matching to select controls. Pro- Data source pensity score of participants, which predicted the probability of CP exposure for participants, was estimated by logistic re- In 2014, up to 99.9% Taiwanese population was enrolled gression modeling. The predictors involved birth year, sex, and in this compulsory National Health Insurance (NHI) pro- 21 comorbidities at baseline. The 1:1 matched comparisons were gram. The Longitudinal Health Insurance Database 2010 selected with the same propensity score as exposure subjects. (LHID 2010) was used for this cohort study. LHID 2010 Patients diagnosed with any type of periodontal diseases before collected the registration information and dental and medical 2001 were excluded. The flow chart of case selection and ex- data, which contain 1 million beneficiaries randomly sampled clusion is shown in Figure 1. from the 2010 registry of beneficiaries in NHIRD. This da- tabase provides scrambled patient identification number, date PCOS event of birth, sex, diagnostic codes in the format of the Interna- tional Classification of Disease, Revision 9, Clinical Mod- The patients with newly diagnosed PCOS (ICD-9-CM code: ification (ICD-9-CM) code, and the date of visit to medical 256.4X) from January 2001 to December 2012 were selected. institutes as described previously.22,23 In addition to clinical diagnosis, the changes of blood hormones

FIG. 1. The flowchart of case selection and exclusion of cases from NHIRD. Downloaded by TAICHUNG VETERANS GENERAL HOSP from www.liebertpub.com at 12/06/19. For personal use only. NHIRD, National Health Insurance Research Database. 1438 TONG ET AL.

of LH, FSH, or testosterone (NHI codes: 09078B2, 09126B, no age and urbanization variations ( p > 0.05). The percentage 09126C, 09078B1, 09125B, 09125C, 09064B2, 09121B, and of comorbidities also showed no significant difference be- 09121C) and the findings on gynecologic ultrasonography tween female patients with CP and the healthy controls (NHI code: 19003C) were reviewed to ensure the accuracy of ( p > 0.05). PCOS diagnosis. We also excluded patients with a history of The newly diagnosed PCOS female patients were 441 in CP endocrine disorders, which could have a clinical presentation group and 304 female individuals in non-CP group. The inci- similar to PCOS. ICD9-CM codes for these possible con- dence density (ID) rates of PCOS in non-CP group was only founding factors were listed as follows: Cushing syndrome 1.4 per 1,000 person-years (Table 2), but the ID rates were (255.0), nonclassic congenital adrenal hyperplasia (255.2), about 1.429-fold higher in CP group than in non-CP group. hyperprolactinemia, (253.1), thyroid dysfunction (242, 244), Figure 2 shows the cumulative curve of PCOS incidence and androgen-secreting tumors (227.0, 194.0). All partici- and reveals that the curve of CP patients was significantly pants were followed up from index date to the date of the higher than the curve of control subjects (log rank test, primary outcome, withdrawal from the NHI program, or the p < 0.001). After adjustment of age, urbanization, and co- end of 2013, whichever came first. morbidities, PCOS female patients showed a 1.44-fold in- creased risk of PCOS compared with non-CP female patients Comorbidities (95% confidence interval; CI 1.24–1.67). The age group 30– 39 years old (0.26, 95% CI 0.11–0.58) and 40–50-year olds Potential comorbidities such as chronic pulmonary disease (0.03, 95% CI 0.01–0.07) had lower risk compared with <20- (ICD-9: 490, 491, 492, 494, and 496), diabetes (ICD-9: 250), year-old group, respectively. However, there was no signif- hypertension (ICD-9: 401–405), hyperlipidemia (ICD-9: icant risk for PCOS with comorbidities in the adjusted model. 272), insomnia (ICD-9: 780.52), and major depressive dis- The mean follow-up duration and time to PCOS between order (ICD-9: 296.2, 296.3) were included in this study. To CP and non-CP group is shown in Table 3. The mean follow- improve the validity of confounders, these comorbidities up duration of PCOS was 8.89 and 8.85 years for CP and non- were identified as ‡2 outpatient visits or at least 1 admission CP group, respectively. The mean time to PCOS was 4.35 and within 1 year before index date. 4.40 years for CP and non-CP group, respectively.

Statistical analysis Discussion The Student’s t-test and chi-square test were used to ana- lyze the difference of continuous and categorical variables, To the best of our knowledge, this is the first nationwide respectively. The Cox proportional hazard models were ap- population-based cohort study to evaluate the association be- plied to estimate the hazard ratios of CP. All statistical ana- tween CP exposure and PCOS risk. The risk of PCOS in female patients with CP exposure was higher than non-CP group. lyses were performed with the SPSS version 18 (SPSS, 19 Chicago, IL), and the significant level was 0.05. Similar results were found by Porwal et al. whoreportedthat PCOS (41 women) had 2.88 times moderate periodontitis than systemically healthy controls (40 women). Consistently, 30 Results women with PCOS and CP after treatment with scaling and As shown in Table 1, we enrolled 24,410 female patients root planning combined medication with myoinositol were with CP and 24,410 female subjects without CP. There were significantly improved in periodontal status.24 Taken together,

Table 1. Demographic Data of Matched Study Cohorts Control (N = 24,410) CP (N = 24,410) n % n % p Age 0.998 <20 63 0.3 64 0.3

Downloaded by TAICHUNG VETERANS GENERAL HOSP from www.liebertpub.com at 12/06/19. For personal use only. 20–30 8,123 33.3 8,107 33.2 30–40 7,764 31.8 7,761 31.8 40–50 8,460 34.7 8,478 34.7 Mean – SD 35.14 – 8.81 35.14 – 8.8 0.961 Urbanization 0.985 Urban 16,692 68.4 16,707 68.4 Suburban 6,447 26.4 6,430 26.3 Rural 1,271 5.2 1,273 5.2 Hypertension 559 2.3 573 2.3 0.674 Hyperlipidemia 334 1.4 329 1.3 0.845 Diabetes 311 1.3 314 1.3 0.904 Chronic obstructive pulmonary disease 539 2.2 540 2.2 0.975 Insomnia 324 1.3 319 1.3 0.843 Major depressive disorder 73 0.3 74 0.3 0.934

The Student’s t test and chi-squared test were used to test the difference of continuous and categorical variables, respectively. CP, chronic periodontitis; SD, standard deviation. INCREASED RISK OF PCOS WITH CP 1439

Table 2. Risk Factor Analysis of Polycystic Ovary Syndrome Development No. of Observed event person-years ID Crude HR 95% CI Adjusted HRa 95% CI CP No 304 216,060 1.4 1 1 Yes 441 216,984 2.0 1.45 1.25–1.67 1.44 1.24–1.67 Age <20 6 1,152 5.2 1 1 20–30 530 141,276 3.8 0.72 0.32–1.60 0.72 0.32–1.61 30–40 187 139,450 1.3 0.26 0.11–0.58 0.26 0.11–0.58 40–50 22 151,165 0.1 0.03 0.01–0.07 0.03 0.01–0.07 Urbanization Urban 538 295,860 1.8 1 1 Suburban 167 114,516 1.5 0.80 0.67–0.95 0.78 0.66–0.93 Rural 40 22,668 1.8 0.97 0.70–1.34 0.92 0.67–1.26 Hypertension 6 9,658 0.6 0.35 0.16–0.79 1.34 0.56–3.19 Hyperlipidemia 6 5,509 1.1 0.62 0.28–1.39 1.82 0.76–4.37 Diabetes 6 5,459 1.1 0.63 0.28–1.41 1.50 0.64–3.54 Chronic obstructive 7 9,803 0.7 0.41 0.20–0.87 0.60 0.28–1.26 pulmonary disease Insomnia 9 5,145 1.7 0.99 0.52–1.92 1.61 0.83–3.12 Major depressive 2 1,226 1.6 0.93 0.23–3.73 1.08 0.27–4.33 disorder

Bold font represents statistical significance ( p < 0.05). ID, per 1,000 person-years. aAdjusted for age, urbanization, hypertension, hyperlipidemia, diabetes, chronic obstructive pulmonary disease, insomnia, and major depressive disorder. CI, confidence interval; HR, hazard ratio; ID, incidence density.

these studies implied the positive association between PCOS Taken together, these findings indicate that the regular oral and periodontitis. examination may be necessary for women with PCOS. Our study first evaluated the risk of PCOS stratified by The possible mechanism of the increased risk of CP in follow-up years in multivariable Cox proportional hazard PCOS patients may be associated with chronic inflammation regression. The risk of PCOS was significantly higher in CP of CP. Women with PCOS have been reported to be at greater group compared with the periodontal healthy control group. risk for chronic subclinical inflammation25 and potentially under oxidative stress environment.26 Previous studies also have shown a possible relationship that PCOS could impact gingival inflammation by elevating the concentrations of tumor necrosis factor-a,14 interleukin (IL)-6,14 IL-17,15 ma- trix metalloproteinase-9,18 and local oxidant status-like myeloperoxidase18 and nitric oxide.13 In addition to systemic inflammation, both CP and PCOS are associated with insulin resistance27; these two disorders may be linked through a common pathophysiologic pathway. The other biological mechanism that CP may associate with PCOS is presumed to the possibility that oral microbiota Downloaded by TAICHUNG VETERANS GENERAL HOSP from www.liebertpub.com at 12/06/19. For personal use only. could trigger systemic antibody responses in patients with .28 The chronic inflammation might be

Table 3. Track Time of Chronic Periodontitis and Control Cohort

CP Control (N = 24,410) (N = 24,410) p Follow-up duration 8.89 – 3.01 8.85 – 3.03 0.167 (years) Time to event (years), 4.35 – 3.01 4.40 – 2.96 0.804 N = 745 FIG. 2. Adjusted Kaplan–Meier curve of PCOS between CP and non-CP control group. CP, chronic periodontitis; The Student’s t-test was used to test the difference of continuous PCOS, polycystic ovary syndrome. variables. 1440 TONG ET AL.

evoked by direct invasion of periodontal pathogen and their Author Disclosure Statement inflammatory products into the reproductive system. Akcali No competing financial interests exist. et al.29 have shown significant higher periodontal pathogen , , and levels in women with PCOS, particu- References larly in the case of gingivitis. The presence of P. gingivalis 1. Moutsopoulos NM, Madianos PN. Low-grade inflammation and F. nucleatum in saliva also exhibited a strong positive in chronic infectious diseases: Paradigm of periodontal correlation with the corresponding serum antibody levels. infections. Ann N Y Acad Sci 2006;1088:251–264. Taken together, periodontal pathogens could cause systemic 2. Mascarenhas P, Gapski R, Al-Shammari K, Wang HL. antibody responses to influence the pathogenesis of PCOS. Influence of sex hormones on the periodontium. J Clin Steroid sex hormones are known to affect periodontal Periodontol 2003;30:671–681. health. Gingival tissues exhibit various receptors for these 3. Barros SP, Williams R, Offenbacher S, Morelli T. Gingival hormones.30 A case study has revealed expression of estrogen crevicular fluid as a source of biomarkers for periodontitis. receptor in gingival tissue by immunohistochemistry in a Periodontol 2000 2016;70:53–64. female patient with PCOS.31 This report indicated that the CP 4. Korte DL, Kinney J. Personalized medicine: An update of and PCOS might have direct interaction through the dysre- salivary biomarkers for periodontal diseases. Periodontol gulation of sex hormones. However, it still needs further 2000 2016;70:26–37. studies to identify this pathway. 5. Sytkowski PA, D’Agostino RB, Belanger AJ, Kannel WB. Secular trends in long-term sustained hypertension, long-term The strength of this study was the use of a registered da- treatment, and cardiovascular mortality. The Framingham tabase composed of nationwide population and a matched Heart Study 1950 to 1990. Circulation 1996;93:697–703. control group. The cohort study design could confer a higher 6. Polak D, Shapira L. An update on the evidence for patho- level of evidence to suggest a causal relationship rather than genic mechanisms that may link periodontitis and diabetes. the case–control design. All bias resulting from the samples, J Clin Periodontol 2018;45:150–166. the investigator, the selection, and the measuring process was 7. Scannapieco FA, Cantos A. Oral inflammation and infec- minimized. tion, and chronic medical diseases: Implications for the Some potential limitations should be noted of the use of elderly. Periodontol 2000 2016;72:153–175. claims databases. First, according to Rotterdam criteria, 8. Hart R. Polycystic ovarian syndrome: Prognosis and treatment PCOS is recognized as a syndrome with no uniform pheno- outcomes. Curr Opin Obstet Gynecol 2007;19:529–535. typical criteria for making the diagnosis.32 In this study, pa- 9. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on tients who were coded with ICD-9-CM 256.4x might be not women’s health aspects of polycystic ovary syndrome (PCOS): only having polycystic ovaries but possibly also having other The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Con- variable symptoms such as menstrual disorders, infertility, sensus Workshop Group. Fertil Steril 2012;97:28–38. and signs of androgen excess. However, we have added the 10. Legro RS. Polycystic ovary syndrome and cardiovascular dis- blood hormones test and gynecologic ultrasonography and ease: A premature association? Endocr Rev 2003;24:302–312. excluded patients with a history of endocrine disorders to 11. Bentley-Lewis R, Seely E, Dunaif A. Ovarian hyperten- ensure the accuracy of PCOS diagnosis in this study. Second, sion: Polycystic ovary syndrome. Endocrinol Metab Clin obesity is the risk both for PCOS33 and CP.34 However, the North Am 2011;40:433–449. definitive code of obesity is lack in ICD-9. In addition, the 12. Hung JH, Hu LY, Tsai SJ, et al. Risk of psychiatric dis- severity of PCOS, body weight, smoking habits, alcohol use, orders following polycystic ovary syndrome: A nationwide population-based cohort study. PLoS One 2014;9:97041. family history, or nutrition status was unable to investigate 13. Dursun E, Akalın FA, Gu¨ncu¨ GN, et al. Periodontal disease the contributions of these factors in NHIRD. Third, the se- in polycystic ovary syndrome. Fertil Steril 2011;95:320– verity of CP could not truly be interpreted by ICD-9 codes 323. recorded in the NHIRD. Therefore, the severity of CP for 14. O¨ zcxaka O, Ceyhan BO, Akcali A, Bicxakci N, Lappin DF, developing PCOS could not be obtained. Fourth, the unrec- Buduneli N. Is there an interaction between polycystic ognized periodontitis, which did not have any dental claims, ovary syndrome and gingival inflammation? J Periodontol might be included in the healthy controls. However, the use 2012;83:1529–1537.

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