Association between menopause, postmenopausal hormone therapy and peptic ulcer disease in Taiwanese population

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However, limited information is available on the relationship between perimenopause and hormone replacement therapy with the occurrence of digestive ulcers. Therefore, we conducted this population-based study of over 17,000 participants in the Taiwan Biobank to examine the association between menopause and peptic ulcer disease (PUD). In addition, we also examined associations between the types of menopause and postmenopausal hormone therapy with PUD. Menopausal status, hormone replacement therapy during menopause, and the presence of PUD were determined using self-reported questionnaires. The participants were grouped according to whether or not they had entered menopause. The participants were further categorized based on the cause of menopause: natural or surgical. Binary logistic regression was utilized for correlation analysis. Of the 17,460 individuals enrolled for analysis, 9620 (55%) were classified into the postmenopausal group and 7840 (45%) into the premenopausal group. After adjusting for various factors, the postmenopausal group had a 1.19 times higher risk of developing PUD compared to the premenopausal group (odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.03 to 1.38, p = 0.022). Moreover, surgical menopause was significantly associated with PUD (OR, 1.38; 95% CI, 1.16 to 1.63; p < 0.001), but natural menopause was not (OR, 1.128; 95% CI, 0.96 to 1.30; p = 0.153). In addition, the women with natural menopause who received postmenopausal hormone therapy had a significantly higher prevalence of PUD than those who did not (OR, 1.37; 95% CI, 1.11 to 1.70; p = 0.004). However, no significant association was found between postmenopausal hormone therapy and PUD among the women with surgical menopause ( p = 0.622). Menopause was significantly associated with PUD. Furthermore, surgical menopause ( vs. pre-menopause) was associated with a 1.38 times higher risk of PUD, and postmenopausal hormone therapy in women with natural menopause was associated with a 1.37 times higher risk of PUD. Further research is warranted to identify the mechanisms and potential interventions to reduce susceptibility to digestive ulcers in menopausal women. Health sciences/Gastroenterology Health sciences/Medical research menopause postmenopausal hormone therapy peptic ulcer disease Taiwan biobank Figures Figure 1 Introduction Peptic ulcers are a common clinical presentation associated with high medical costs 1 , and peptic ulcer disease (PUD) continues to be a source of significant morbidity and mortality worldwide. Although approximately two-thirds of patients found to have PUD are asymptomatic 2 , peptic ulcers can still cause early satiety, abdominal fullness, dyspepsia, bloating and nausea 2-4 . They most commonly develop in the stomach and proximal duodenum 5 , and the predominant causes in the US have traditionally been Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) treatment 6 . However, with the increasing use of anti-secretory drugs and decreasing prevalence of H. pylori infection in recent decades, NSAID treatment and H. pylori have gradually become less prominent causes of PUD 7,8 . This trend has also been seen in Taiwan, where a prior history of PUD, low education level, high body mass index (BMI), and currently smoking have been shown to be independent risk factors for asymptomatic PUD 9 . Menopause is a normal part of aging, and accounts for the last third of a woman’s lifetime after their reproductive years 10 . Perimenopause is associated with many symptoms, including hot flashes, night sweats, mental illness, and neurological transition 11-13 . After menopause, genitourinary symptoms including vulvovaginal atrophy and dryness predominate, along with lower urinary tract symptoms such as urinary frequency, urgency, and nocturia, all of which can negatively affect the quality of life 14-18 . Hormone treatment can address these issues, however the effects of such treatment on cardiovascular disease, cognitive dysfunction, and depression are still uncertain 19 . Recent research has focused on H. pylori eradication, proton pump inhibitor use and judicious use of NSAIDs to reduce the incidence of PUD 8,20 . However, several studies suggested a correlation between sex hormones and PUD 21,22 . The first of these studies demonstrated that major male (testosterone) and female (progesterone) sex hormones had opposite effects on preexisting ulcer healing in the oral cavity and stomach 22 . The second study showed that that pregnancy itself could relieve the symptoms of ulcers 21 . Some research has shown that female sex has a protective effect against duodenal ulcers, and many studies have suggested that male sex may be an independent risk factor for PUD 23-25 . A study conducted several decades previously reported that menstruation did not have a considerable effect on ulcer symptoms 21 . These findings may suggest that sex is not associated with peptic ulcers, however more recent research has shown a correlation between menopause and PUD. A retrospective Chinese study published in 2016 reported that late menopause may have a protective effect against chronic PUD 26 . However, little research has investigated the association between menopause status and the prevalence of PUD, and the effect of postmenopausal hormone therapy on PUD is also unclear. Therefore, we conducted this population-based study of over 17,000 participants in the Taiwan Biobank (TWB) to examine the association between menopause and PUD. In addition, we also examined associations between the types of menopause and postmenopausal hormone therapy with PUD. Materials and methods Ethics statement The TWB (https://www.twbiobank.org.tw) was approved by the Institutional Review Board of Biomedical Science Research at Academia Sinica and the Ethics and Governance Council of Taiwan Biobank. The current study received approval from the Research Ethics Committee of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20210058). Study population We obtained data from the TWB on women enrolled between 2012 and 2018. All participants in the TWB are aged 30 to 70 years without a prior cancer history, and they are all required to sign informed consent forms before data are collected through self-reported questionnaires, physical and laboratory examinations 27 . Subsequently, we excluded women without data on menopausal status and obstetric history. Finally, we analyzed data from 17,460 women and divided them into premenopausal and postmenopausal groups (Figure 1). The following data were collected at baseline: fluid intake, age, BMI (kg/m 2 ), educational status, whether the participants were current/never smokers, and whether or not they drank alcohol, lived alone, participated in regular physical activity, and were married. Data on gravidity, parity, breastfeeding, hormone therapy, etiology of menopause and whether or not they undergone an induced abortion were also recorded, along with the presence of hypertension, dyslipidemia, diabetes mellitus, gout, and chronic kidney disease (CKD). Systolic blood pressure and diastolic blood pressure measurements were also recorded. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m 2 (using the 4-variable MDRD equation 28 ). Premenopausal, postmenopausal, type of menopause, postmenopausal hormone therapy, and PUD assessments We obtained information on the presence of PUD (yes/no), premenopausal/postmenopausal status (yes/no), the type of menopause (natural/surgical/others), and postmenopausal hormone therapy (never used/ever used) based on the participants’ responses on questionnaires. Postmenopausal women were defined as those who reported no periods for more than 1 year. Statistical Analysis We divided the participants into two groups, premenopausal women and menopausal women. Categorical variables are shown as number and percentage, while continuous variables are shown as mean and standard deviation. The chi-square test was used to compare categorical variables between two groups, and an independent t-test was used to compare continuous variables between two groups. Association analysis was conducted using binary logistic regression, and the results are expressed as odd ratio (OR) and 95% confidence interval (95% CI). A p value < 0.05 was considered significant. We used R (v3.6.2, R Foundation for Statistical Computing, Vienna, Austria) and SPSS (v20.0, IBM Inc., Armonk, NY) as the statistical tools. Results Clinical characteristics of the study participants Of the 17,460 included women, 7840 (44.9%) were premenopausal and 9620 (55.1%) were postmenopausal. Table 1 presents the clinical characteristics of the study participants. The postmenopausal women tended to be older and have higher rates of CKD, arrhythmia, hyperlipidemia, hypertension, diabetes, depression, Parkinson’s disease, dependency, smoking, pregnancy, births, abortion, being married, and physical activity, and lower educational status than the premenopausal women. In addition, compared to the premenopausal women, the postmenopausal women had higher BMI, higher systolic and diastolic blood pressures, lower white blood cell count, lower platelet count, and higher levels of hemoglobin, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase, blood urea nitrogen (BUN) and creatinine. Association between menopause status and PUD The postmenopausal women had a higher prevalence of PUD (16.8%) than the premenopausal women (11.5%), with an unadjusted OR of 1.55 (95% CI, 1.42 to 1.69, p < 0.001) (Table 2). After adjusting for age, postmenopausal status was still associated with PUD (OR, 1.23; 95% CI, 1.07 to 1.42; p = 0.004). Further, after multivariable adjustments for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson’s disease, age, dependency, smoking status, physical activity, pregnancy, births, abortion, systolic and diastolic pressures, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever being married, educational status, BMI, CKD and menstruation status, postmenopausal status was still significantly associated with PUD (OR, 1.19; 95% CI, 1.03 to 1.38; p = 0.022). Association between the types of menopause and PUD Both natural menopause (OR, 1.16; 95% CI 1.00 to 1.35; p = 0.049) and surgical menopause (OR, 1.42; 95% CI, 1.20 to 1.68; p < 0.001) were significantly associated with an increased prevalence of PUD in the age-adjusted model (Table 3). After further adjustments for multivariable analysis, we found that surgical menopause was significantly associated with PUD (OR, 1.38; 95% CI, 1.16 to 1.63; p < 0.001), but natural menopause was not (OR, 1.128; 95% CI, 0.96 to 1.30; p = 0.153). Association between postmenopausal hormone therapy and PUD in the postmenopausal women We further explored the association between postmenopausal hormone therapy and the prevalence of PUD in the women with menopause (Table 4). The results showed that the women with natural menopause who received postmenopausal hormone therapy had a significantly higher prevalence of PUD than those who did not receive postmenopausal hormone therapy (age-adjusted OR, 1.49; 95% CI, 1.21 to 1.83; p < 0.001, and multivariable OR, 1.37; 95% CI, 1.11 to 1.70; p = 0.004). However, no significant association was found between postmenopausal hormone therapy and PUD among the women with surgical menopause (age-adjusted OR, 1.18; 95% CI, 0.82 to 1.71; p = 0.369, and multivariable OR, 1.10; 95% CI, 0.75 to 1.61; p = 0.622). Discussion In this study, we demonstrated that postmenopausal women were significantly associated with PUD compared to premenopausal women, particularly those who underwent surgical menopause. In addition, we found that in women with natural menopause, postmenopausal hormone therapy was associated with an increased rate of PUD. Our finding that menopause was associated with PUD suggests that the relationship between menopause and PUD is multifaceted, involving hormonal fluctuations, changes in immune response, and potentially even alterations in gastrointestinal function 29 . Postmenopausal women are generally thought to be more prone to developing peptic ulcers, possibly due to the dramatic changes in hormone levels during this stage of life 26 . For example, Kim hypothesized that the female sex hormone estrogen increases the expression of tight junction proteins, sealing the gap between cells, reducing mucosal permeability, and stimulating the excretion of bicarbonate ions in the duodenal mucosa 30 . These mechanisms are thought to enhance mucosal defense against acidic environments in the stomach and duodenum, thus preventing ulcer formation. In the absence of estrogen, particularly post-menopause, this protective mechanism may be weakened, leading to increased susceptibility to ulcers. In addition, older females have been shown to be at higher risk of mucosal injury, possibly as a consequence of menopause-induced hormonal alterations, including decreased levels of both estrogen and progesterone 31,32 . This is particularly relevant because aging is a known risk factor for gastrointestinal conditions, and menopause can exacerbate this risk due to the significant hormonal shifts that occur. Immunosenescence, defined as gradual weakening of the immune system with age, has also been implicated in this increased susceptibility 33,34 . Several studies have shown that the major effects of estradiol are mediated through two receptors, namely alpha and beta estrogen receptors, both of which are expressed on a variety of cell types including immune cells, epithelial cells and muscle cells 33,35,36 . These receptors help regulate immune responses, and the decline in estrogen during menopause may impair their function, leading to reduced immune defense against gastrointestinal pathogens and increased mucosal vulnerability 37,38 . Moreover, estrogen has been shown to regulate many facets of the immune response such as immune cell differentiation, cytokine production, regulation of calcium ion mobilization and release of inducible nitric oxide synthase in leukocytes 39,40 . These immunomodulatory effects of estrogen are thought to help protect against mucosal damage in the gastrointestinal tract, and their loss may contribute to the higher rates of PUD observed in postmenopausal women. Furthermore, previous studies have also shown that patients with persistent symptoms of ulcers often have a high rate of gastrointestinal abnormalities, such as hyperemesis and ulcer recurrence after parturition, particularly within the first 6 months 10 . This finding is intriguing because it suggests a connection between reproductive hormone levels and gastrointestinal health, supporting the hypothesis that hormonal fluctuations, particularly those involving estrogen and progesterone, may play a significant role in ulcer pathogenesis and healing. In addition, Grossman reported that 88.2% of cases were associated with remission of ulcer symptoms during pregnancy, suggesting that hormonal changes may influence PUD risk and recurrence 8,32 . These findings support the hypothesis that hormones, particularly estrogen and progesterone, play a role in ulcer pathogenesis and healing. Another interesting finding of this study is that the women who underwent surgical menopause were 1.38 times more likely to develop PUD compared to premenopausal women. Pillay and Manyonda reported that surgical menopause (iatrogenic menopause) occurs when both ovaries are removed before ovarian function is naturally “switched off”, and that this could cause premature ovarian insufficiency leading to menopause in women before the age of 40 41 . This can then lead to a sudden and dramatic reduction in ovarian sex steroid production, particularly estrogen and progesterone 42 . Natural menopause begins 4 to 6 years before the cessation of menses, and middle-aged women experience a progressive change in ovarian activity and a physiologic deterioration of hypothalamic-pituitary-ovarian axis function associated with fluctuating hormone levels 43 . This indicates that the abrupt loss of ovarian hormones due to surgical menopause can have wide-ranging effects on various physiological systems, including the gastrointestinal system. For example, surgical menopause has been associated with more severe and prolonged menopausal symptoms, including hot flashes, mood change, and sleep disturbance, which may contribute to overall physiological stress and potentially influence gastrointestinal function 44 . This may further influence other systems such as cardiovascular, neurologic, bone, and connective tissue, and affect the quality of life due to vasomotor symptoms, mood, sleep, and sexual function 45,46 . The gastrointestinal system is known to be highly responsive to stress, and chronic stress has been linked to increased gastric acid secretion, reduced mucosal blood flow, and impaired mucosal healing, all of which can contribute to the development of peptic ulcers. Some studies have demonstrated surgical menopause-induced physiological and behavioral changes in relation to estradiol-linked compositional changes in the intestinal microbiota 29,47-49 . However, the exact mechanisms by which estrogen deficiency and hormone therapy affect the gut microbial community are not yet well understood 47 . To date, no strong direct evidence has linked surgical menopause specifically to PUD. In this study, we also found that postmenopausal hormone therapy in the women with natural menopause was associated with an increased rate of PUD. Previous studies have reported associations between postmenopausal hormone therapy and increased rates of gastroesophageal reflux disease and PUD 31,50 . In addition, postmenopausal hormone therapy has also been associated with other gastrointestinal diseases such as esophageal cancer, gastric cancer, inflammatory bowel disease, irritable bowel syndrome and colon cancer 51-53 . Close et al. reported that the relationship between hormone therapy and gastrointestinal conditions appears to be multifactorial 50 , involving both direct effects of hormones on the gastrointestinal tract and their systemic effects on metabolism, immune function, and inflammatory responses. Coquoz et al. performed a comprehensive literature review, and found that progesterone had dose-dependent and sex-dependent effects on gastric emptying, and that it slowed gastrointestinal motility 54 . This reduced motility can lead to delayed gastric emptying, which is known to contribute to symptoms of gastroesophageal reflux disease and may also increase the risk of peptic ulcer formation by prolonging exposure of the gastric mucosa to acidic contents. In addition to its effects on gastrointestinal motility, the effects of hormone replacement therapy can vary according to the regimen used, and complications associated with hormone replacement therapy may depend on the specific hormones administered, their dosage, and the duration of therapy 10,19 . For example, studies on different animal species and humans have suggested that sex hormones influence gastric acid secretion and contribute to the integrity of the oral and gastroduodenal mucosa 32,54 . Several studies investigated female rats with intact or removed ovaries (ovariectomy) 22,36 , and gastric acid secretion was determined in rats with gastric ulcers equipped with chronic gastric fistula. The results showed that treatment with progesterone significantly accelerated ulcer healing and increased gastric blood flow at the margins of these ulcers, emphasizing that sex hormones had opposite effects on healing of preexisting ulcers in the stomach 1,22 . Our study showed that postmenopausal hormone therapy was associated with an increased rate of PUD, which is contrary to the expected protective effects of hormone replacement therapy 55,56 , as many previous studies have suggested such therapy should mitigate gastrointestinal issues. The contradictory findings suggest that there may be more complex interactions between hormone replacement therapy and gastrointestinal health than previously thought 22,25 . Thus, there is still no clear explanation for how menopause increases the risk of developing peptic ulcers or delays the healing process in women with preexisting ulcers. This study is the largest population-based investigation to investigate the associations among menopausal status, type of menopause (surgical or natural), and postmenopausal hormone therapy with PUD risk in Taiwanese women. This extensive dataset offers valuable insights into the potential link between menopause and gastrointestinal health in women, providing evidence for further studies on the topic. Nevertheless, there are also several limitations. First, this was a cross-sectional study, and we did not evaluate the duration of PUD. Therefore, we could not evaluate causal relationships between these factors with PUD. Further longitudinal studies are warranted to investigate the risk of incident PUD. Second, the presence of PUD was obtained through questionnaires without endoscopic verification, and the type and severity of PUD could not be ascertained. Nevertheless, a previous study in Taiwan using claims records reported moderate concordance between such data and self-reported renal disease 57 . Finally, participants in the TWB are of Chinese ethnicity, which may limit the broader application of our findings to other groups. In conclusion, the study found that menopause was significantly associated with PUD. Furthermore, surgical menopause ( vs. pre-menopause) was associated with a 1.38 times higher risk of PUD, and that postmenopausal hormone therapy in women with natural menopause was associated with a 1.37 times higher risk of PUD. This study is the largest population-based investigation to explore the associations among menopausal status and hormone therapy with PUD in Taiwanese women. Further research should seek to identify the mechanisms and potential interventions to reduce susceptibility to peptic ulcers in menopausal women. Declarations Ethical Approval: The study was conducted according to the Declaration of Helsinki, and it was granted approval by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20210058), and the TWB was granted approval by the IRB on Biomedical Science Research, Academia Sinica, Taiwan and the Ethics and Governance Council of the TWB. Consent to Participate: Not applicable Consent to Publish: Not applicable Authors Contributions: Conceptualization, methodology, validation, formal analysis, writing—review and editing, and supervision: K-CC, J-HG, C-HK and S-CC. Software and investigation: J-HG, C-HK and S-CC. Resources, project administration, and funding acquisition: S-CC. Data curation: K-CC, C-YK, W-LT, Y-JW, J-HG, C-HK and S-CC. Writing—original draft preparation: K-CC and S-CC. Visualization: J-HG, C-HK and S-CC. All authors have read and agreed to the published version of the manuscript. Funding: no funding. Conflicts of Interest: The authors declare that they have no known competing financial interests. Availability of data and materials: The data underlying this study are from the Taiwan Biobank. Due to restrictions placed on the data by the Personal Information Protection Act of Taiwan, the minimal data set cannot be made publicly available. Data may be available upon request to interested researchers. 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BMC Gastroenterol 12 , 56, doi:10.1186/1471-230x-12-56 (2012). Chen, C. et al. The roles of estrogen and estrogen receptors in gastrointestinal disease. Oncol Lett 18 , 5673-5680, doi:10.3892/ol.2019.10983 (2019). Jacobson, B. C., Moy, B., Colditz, G. A. & Fuchs, C. S. Postmenopausal hormone use and symptoms of gastroesophageal reflux. Arch Intern Med 168 , 1798-1804, doi:10.1001/archinte.168.16.1798 (2008). Nilsson, M., Johnsen, R., Ye, W., Hveem, K. & Lagergren, J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. Jama 290 , 66-72, doi:10.1001/jama.290.1.66 (2003). Coquoz, A., Regli, D. & Stute, P. Impact of progesterone on the gastrointestinal tract: a comprehensive literature review. Climacteric 25 , 337-361, doi:10.1080/13697137.2022.2033203 (2022). Vigneswaran, K. & Hamoda, H. Hormone replacement therapy - Current recommendations. Best Pract Res Clin Obstet Gynaecol 81 , 8-21, doi:10.1016/j.bpobgyn.2021.12.001 (2022). Hodis, H. N. & Mack, W. J. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It Is About Time and Timing. Cancer J 28 , 208-223, doi:10.1097/ppo.0000000000000591 (2022). Wu, C. S., Lai, M. S., Gau, S. S., Wang, S. C. & Tsai, H. J. Concordance between patient self-reports and claims data on clinical diagnoses, medication use, and health system utilization in Taiwan. PLoS One 9 , e112257, doi:10.1371/journal.pone.0112257 (2014). Tables Table 1. Clinical characteristics of the study participants Characteristics Premenopausal ( n = 7840) Postmenopausal ( n = 9620) p value Age, yr 42.16 ± 6.78 58.27 ± 5.49 < 0.001 History of chronic kidney disease, n (%) 16 (0.2) 150 (1.6) < 0.001 History of arrhythmia, n (%) 235 (3.0) 592 (6.2) < 0.001 History of hyperlipidemia, n (%) 167 (2.1) 978 (10.1) < 0.001 History of hypertension, n (%) 288 (3.7) 1553 (16.1) < 0.001 History of diabetes, n (%) 107 (1.4) 647 (6.7) < 0.001 History of depression, n (%) 270 (3.4) 405 (4.2) 0.009 History of manic depression, n (%) 40 (0.5) 59 (0.6) 0.417 History of Parkinson, n (%) 1 (0.0) 12 (0.1) 0.009 History of dependency, n (%) 474 (6.0) 851 (8.8) < 0.001 History of smoke experience, n (%) 776 (9.9) 438 (4.6) < 0.001 History of pregnancy, n (%) 6561 (83.7) 9081 (94.4) < 0.001 History of birth, n (%) 6324 (80.7) 8972 (93.3) < 0.001 History of abortion, n (%) 3978 (50.7) 5966 (62.0) < 0.001 History of getting married, n (%) 6696 (85.4) 9225 (95.9) < 0.001 Education, n (%) < 0.001 ≤ Elementary 115 (1.5) 1465 (15.2) Middle to High school 3271 (41.7) 5288 (55.0) ≥ Collage 4454 (56.8) 2867 (29.8) Sport habit, yes, n (%) 2239 (28.6) 5632 (58.6) < 0.001 BMI, kg/m 2 23.24 ± 3.74 23.79 ± 3.45 < 0.001 Systolic blood pressure, mm Hg 108.75 ± 15.51 121.21 ± 18.49 < 0.001 Diastolic blood pressure, mm Hg 68.15 ± 10.37 72.06 ± 10.40 < 0.001 White blood cell, 10 3 /uL 6.04 ± 1.64 5.67 ± 1.46 < 0.001 Platelet, 10 3 /uL 266.80 ± 61.56 236.77 ± 54.20 < 0.001 Hemoglobin, g/dL 12.68 ± 1.42 13.31 ± 1.0 < 0.001 Fasting glucose, mg/dL 90.47 ± 15.54 97.31 ± 20.14 < 0.001 Total cholesterol, mg/dL 186.02 ± 32.75 207.07 ± 35.29 < 0.001 Triglyceride, mg/dL 89.54 ± 61.05 114.47 ± 73.95 < 0.001 HDL-cholesterol, mg/dL 57.70 ± 12.80 57.73 ± 13.25 0.909 LDL-cholesterol, mg/dL 113.68 ± 29.57 127.75 ± 32.09 < 0.001 SGOT, IU/L 21.16 ± 10.23 25.86 ± 11.61 < 0.001 SGPT, IU/L 18.56 ± 17.50 23.08 ± 16.61 < 0.001 BUN, mg/dL 11.38 ± 2.97 13.89 ± 3.63 < 0.001 Creatinine, mg/dL 0.60 ± 0.18 0.63 ± 0.20 < 0.001 BMI = Body mass index; HDL = High-Density Lipoprotein; LDL = Low-Density Lipoprotein; BUN = Blood Urea Nitrogen; SGOT = Serum Glutamic Oxaloacetic Transaminase; SGPT = Serum Glutamic Pyruvic Transaminase Table 2. Odds ratios for self-reported peptic ulcer disease by menopausal status Premenopausal ( n = 7840) Postmenopausal ( n = 9620) p value Presence of peptic ulcer disease, n (%) 905 (11.5) 1616 (16.8) Unadjusted OR (95% CI) 1.0 (reference) 1.55 (1.42-1.69) < 0.001 Age-adjusted OR (95% CI) 1.0 (reference) 1.23 (1.07-1.42) 0.004 Multivariable OR (95% CI) 1.0 (reference) 1.19 (1.03-1.38) 0.022 OR = odds ratio; CI = Confidence interval. Multivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation. Table 3. Odds ratios for self-reported peptic ulcer disease by the type of menopause Type of menopause Presence of peptic ulcer disease, n (%) Age-adjusted OR (95% CI) p value Multivariable OR (95% CI) p value Pre-menopause 905 (11.5) 1.0 (reference) - 1.0 (reference) - Natural menopause 1269 (16.3) 1.16 (1.00-1.35) 0.049 1.12 (0.96-1.30) 0.153 Surgical menopause 347 (18.7) 1.42 (1.20-1.68) < 0.001 1.38 (1.16-1.63) < 0.001 OR = odds ratio; CI = Confidence interval. Multivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation. Table 4. Age, and multivariable-adjusted odds ratios for self-reported peptic ulcer disease by postmenopausal hormone use in women with menopause Postmenopausal hormone use Age-adjusted OR (95% CI) p value Multivariable OR (95% CI) p value Women with natural menopause Never-users 1.00 (reference) 1.00 (reference) Ever-users 1.49 (1.21-1.83) < 0.001 1.37 (1.11-1.70) 0.004 Women with surgical menopause Never-users 1.00 (reference) 1.00 (reference) Ever-users 1.18 (0.82-1.71) 0.369 1.10 (0.75-1.61) 0.622 OR = odds ratio; CI = Confidence interval. Multivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-5457012","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":388901612,"identity":"ac89ad05-33ff-48a7-b4fd-ce0919da2d14","order_by":0,"name":"Kuan-Chih Chen","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kuan-Chih","middleName":"","lastName":"Chen","suffix":""},{"id":388901613,"identity":"3a048f52-63e0-40c4-b3b7-8eeb6e27db6f","order_by":1,"name":"Chia-Yu Kuo","email":"","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chia-Yu","middleName":"","lastName":"Kuo","suffix":""},{"id":388901614,"identity":"23b5e674-4c74-49e3-95e0-bbf7033c1b8c","order_by":2,"name":"Wan-Ling Tsai","email":"","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wan-Ling","middleName":"","lastName":"Tsai","suffix":""},{"id":388901615,"identity":"426f404c-2280-4945-b2aa-c45755554e9a","order_by":3,"name":"Ying-Jhen Wu","email":"","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ying-Jhen","middleName":"","lastName":"Wu","suffix":""},{"id":388901616,"identity":"d87601b8-19bc-4033-b906-65462f19214d","order_by":4,"name":"Jiun-Hung Geng","email":"","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiun-Hung","middleName":"","lastName":"Geng","suffix":""},{"id":388901617,"identity":"c608416f-53ca-45ad-8dd7-667a5e86d2d9","order_by":5,"name":"Chao-Hung Kuo","email":"","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chao-Hung","middleName":"","lastName":"Kuo","suffix":""},{"id":388901618,"identity":"9d5725b8-a14e-4562-b7a8-8e7be4fc51fd","order_by":6,"name":"Szu-Chia Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYLACxgYI9YCB4QBpWpgNkLQYEKWFTYIoLfLth599+LnDJo9fuvlYNU/NHTl+BuaHj24w/ElswKHF4Eya8czeM2nFknOOpd3mOfbMWLKBzdg4h8EAtxYJBmNmxrbDiRtu5Jjd5mEDMg7wsEkDteTi0iI/g/0zUMt/oJb8b8U8/4jQwnCDB2TLAZAtbMy8bURoMTiTU8zY25acOHNGmrHk3L7DxpLNIL8YGNfjdFj78c0MP9vsEvslkh9+ePPtsBw/e/PDxzkVcsa43IUCmHhAJDPYdqI0AKP0B5EKR8EoGAWjYGQBAMX8Vx0zkD7bAAAAAElFTkSuQmCC","orcid":"","institution":"Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University","correspondingAuthor":true,"prefix":"","firstName":"Szu-Chia","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-11-15 02:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5457012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5457012/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-08072-5","type":"published","date":"2025-07-07T15:57:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71747186,"identity":"926fa9c3-edac-4a5a-bc5e-2a6c21fc89cd","added_by":"auto","created_at":"2024-12-18 08:56:48","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65411,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of study population\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5457012/v1/441b3203acefa291ca7a5177.jpg"},{"id":86700267,"identity":"1ae2bc07-1c41-441b-8897-bdd81deea1b0","added_by":"auto","created_at":"2025-07-14 16:12:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":772217,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5457012/v1/c557e8b2-c9a8-4119-a03f-625cd3f162ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between menopause, postmenopausal hormone therapy and peptic ulcer disease in Taiwanese population","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePeptic ulcers are a common clinical presentation associated with high medical costs \u0026nbsp;\u003csup\u003e1\u003c/sup\u003e, and peptic ulcer disease (PUD) continues to be a source of significant morbidity and mortality worldwide. Although approximately two-thirds of patients found to have PUD are asymptomatic \u003csup\u003e2\u003c/sup\u003e, peptic ulcers can still cause early satiety, abdominal fullness, dyspepsia, bloating and nausea \u003csup\u003e2-4\u003c/sup\u003e. They most commonly develop in the stomach and proximal duodenum \u003csup\u003e5\u003c/sup\u003e, and the predominant causes in the US have traditionally been Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) treatment \u003csup\u003e6\u003c/sup\u003e. However, with the increasing use of anti-secretory drugs and decreasing prevalence of H. pylori infection in recent decades, NSAID treatment and H. pylori have gradually become less prominent causes of PUD \u003csup\u003e7,8\u003c/sup\u003e. This trend has also been seen in Taiwan, where a prior history of PUD, low education level, high body mass index (BMI), and currently smoking have been shown to be independent risk factors for asymptomatic PUD \u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMenopause is a normal part of aging, and accounts for\u0026nbsp;the last third of a woman\u0026rsquo;s lifetime after their reproductive years \u003csup\u003e10\u003c/sup\u003e. Perimenopause is associated with many symptoms, including hot flashes, night sweats, mental illness, and neurological transition \u003csup\u003e11-13\u003c/sup\u003e. After menopause, genitourinary symptoms including vulvovaginal atrophy and dryness predominate, along with lower urinary tract symptoms such as urinary frequency, urgency, and nocturia, all of which can negatively affect the quality of life \u003csup\u003e14-18\u003c/sup\u003e. Hormone treatment can address these issues, however the effects of such treatment on cardiovascular disease, cognitive dysfunction, and depression are still uncertain \u003csup\u003e19\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecent research has focused on H. pylori eradication, proton pump inhibitor use and judicious use of NSAIDs to reduce the incidence of PUD \u003csup\u003e8,20\u003c/sup\u003e. However, several studies suggested a correlation between sex hormones and PUD \u003csup\u003e21,22\u003c/sup\u003e. The first of these studies demonstrated that major male (testosterone) and female (progesterone) sex hormones had opposite effects on preexisting ulcer healing in the oral cavity and stomach \u003csup\u003e22\u003c/sup\u003e. The second study showed that that pregnancy itself could relieve the symptoms of ulcers \u003csup\u003e21\u003c/sup\u003e. Some research has shown that female sex has a protective effect against duodenal ulcers, and many studies have suggested that male sex may be an independent risk factor for PUD \u003csup\u003e23-25\u003c/sup\u003e. A study conducted several decades previously reported that menstruation did not have a considerable effect on ulcer symptoms \u003csup\u003e21\u003c/sup\u003e. These findings may suggest that sex is not associated with peptic ulcers, however more recent research has shown a correlation between menopause and PUD. A retrospective Chinese study published in 2016 reported that late menopause may have a protective effect against chronic PUD\u0026nbsp;\u003csup\u003e26\u003c/sup\u003e. However, little research has investigated the association between menopause status and the prevalence of PUD, and the effect of postmenopausal hormone therapy on PUD is also unclear. Therefore, we conducted this population-based study of over 17,000 participants in the Taiwan Biobank (TWB) to examine the association between menopause and PUD. In addition, we also examined associations between the types of menopause and postmenopausal hormone therapy with PUD.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cem\u003eEthics statement\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe TWB (https://www.twbiobank.org.tw) was approved by the Institutional Review Board of Biomedical Science Research at Academia Sinica and the Ethics and Governance Council of Taiwan Biobank. The current study received approval from the Research Ethics Committee of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20210058).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained data from the TWB on women enrolled between 2012 and 2018. All participants in the TWB are aged 30 to 70 years without a prior cancer history, and they are all required to sign informed consent forms before data are collected through self-reported questionnaires, physical and laboratory examinations\u0026nbsp;\u003csup\u003e27\u003c/sup\u003e. Subsequently, we excluded women without data on menopausal status and obstetric history. Finally, we analyzed data from 17,460 women and divided them into premenopausal and postmenopausal groups (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following data were collected at baseline: fluid intake, age, BMI (kg/m\u003csup\u003e2\u003c/sup\u003e), educational status, whether the participants were current/never smokers, and whether or not they drank alcohol, lived alone, participated in regular physical activity, and were married. Data on gravidity, parity, breastfeeding, hormone therapy, etiology of menopause and whether or not they undergone an induced abortion were also recorded, along with the presence of hypertension, dyslipidemia, diabetes mellitus, gout, and chronic kidney disease (CKD). Systolic blood pressure and diastolic blood pressure measurements were also recorded. CKD was defined as an estimated glomerular filtration rate \u0026lt; 60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e (using the 4-variable MDRD equation\u0026nbsp;\u003csup\u003e28\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePremenopausal, postmenopausal, type of menopause, postmenopausal hormone therapy, and PUD assessments\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained information on the presence of PUD (yes/no), premenopausal/postmenopausal status (yes/no), the type of menopause (natural/surgical/others), and postmenopausal hormone therapy (never used/ever used) based on the participants\u0026rsquo; responses on questionnaires. Postmenopausal women were defined as those who reported no periods for more than 1 year.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe divided the participants into two groups, premenopausal women and menopausal women. Categorical variables are shown as number and percentage, while continuous variables are shown as mean and standard deviation. The chi-square test was used to compare categorical variables between two groups, and an independent t-test was used to compare continuous variables \u0026nbsp;between two groups. Association analysis was conducted using binary logistic regression, and the results are expressed as odd ratio (OR) and 95% confidence interval (95% CI). A \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05 was considered significant. We used R (v3.6.2, R Foundation for Statistical Computing, Vienna, Austria) and SPSS (v20.0, IBM Inc., Armonk, NY) as the statistical tools.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eClinical characteristics of the study participants\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOf the 17,460 included women, 7840 (44.9%) were premenopausal and 9620 (55.1%) were postmenopausal. Table 1 presents the clinical characteristics of the study participants. The postmenopausal women tended to be older and have higher rates of CKD, arrhythmia, hyperlipidemia, hypertension, diabetes, depression, Parkinson\u0026rsquo;s disease, dependency, smoking, pregnancy, births, abortion, being married, and physical activity, and lower educational status than the premenopausal women. In addition, compared to the premenopausal women, the postmenopausal women had higher BMI, higher systolic and diastolic blood pressures, lower white blood cell count, lower platelet count, and higher levels of hemoglobin, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase, blood urea nitrogen (BUN) and creatinine.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssociation between menopause status and PUD\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe postmenopausal women had a higher prevalence of PUD (16.8%) than the premenopausal women (11.5%), with an unadjusted OR of 1.55 (95% CI, 1.42 to 1.69, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) (Table 2). After adjusting for age, postmenopausal status was still associated with PUD (OR, 1.23; 95% CI, 1.07 to 1.42; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.004). Further, after multivariable adjustments for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson\u0026rsquo;s disease, age, dependency, smoking status, physical activity, pregnancy, births, abortion, systolic and diastolic pressures, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever being married, educational status, BMI, CKD and menstruation status, postmenopausal status was still significantly associated with PUD (OR, 1.19; 95% CI, 1.03 to 1.38; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.022).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssociation between the types of menopause and PUD\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBoth natural menopause (OR, 1.16; 95% CI 1.00 to 1.35; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.049) and surgical menopause (OR, 1.42; 95% CI, 1.20 to 1.68; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001) were significantly associated with an increased prevalence of PUD in the age-adjusted model (Table 3). After further adjustments for multivariable analysis, we found that surgical menopause was significantly associated with PUD (OR, 1.38; 95% CI, 1.16 to 1.63; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001), but natural menopause was not (OR, 1.128; 95% CI, 0.96 to 1.30; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.153).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssociation between postmenopausal hormone therapy and PUD in the postmenopausal women\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe further explored the association between postmenopausal hormone therapy and the prevalence of PUD in the women with menopause (Table 4). The results showed that the women with natural menopause who received postmenopausal hormone therapy had a significantly higher prevalence of PUD than those who did not receive postmenopausal hormone therapy (age-adjusted OR, 1.49; 95% CI, 1.21 to 1.83; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, and multivariable OR, 1.37; 95% CI, 1.11 to 1.70; \u003cem\u003ep\u003c/em\u003e = 0.004). However, no significant association was found between postmenopausal hormone therapy and PUD among the women with surgical menopause (age-adjusted OR, 1.18; 95% CI, 0.82 to 1.71;\u003cem\u003e\u0026nbsp;p\u003c/em\u003e = 0.369, and multivariable OR, 1.10; 95% CI, 0.75 to 1.61; \u003cem\u003ep\u003c/em\u003e = 0.622).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we demonstrated that postmenopausal women were significantly associated with PUD compared to premenopausal women, particularly those who underwent surgical menopause.\u0026nbsp;In addition, we found that in women with natural menopause, postmenopausal hormone therapy was associated with an increased rate of PUD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur finding that menopause was associated with PUD suggests that the relationship between menopause and PUD is multifaceted, involving hormonal fluctuations, changes in immune response, and potentially even alterations in gastrointestinal function \u003csup\u003e29\u003c/sup\u003e.\u0026nbsp;Postmenopausal women are generally thought to be more prone to developing peptic ulcers, possibly due to the dramatic changes in hormone levels during this stage of life \u003csup\u003e26\u003c/sup\u003e. For example, Kim hypothesized that the female sex hormone estrogen increases the expression of tight junction proteins, sealing the gap between cells, reducing mucosal permeability, and stimulating the excretion of bicarbonate ions in the duodenal mucosa \u003csup\u003e30\u003c/sup\u003e. These mechanisms are thought to enhance mucosal defense against acidic environments in the stomach and duodenum, thus preventing ulcer formation. In the absence of estrogen, particularly post-menopause, this protective mechanism may be weakened, leading to increased susceptibility to ulcers. In addition, older females have been shown to be at higher risk of mucosal injury, possibly as a consequence of menopause-induced hormonal alterations, including decreased levels of both estrogen and progesterone \u003csup\u003e31,32\u003c/sup\u003e. This is particularly relevant because aging is a known risk factor for gastrointestinal conditions, and menopause can exacerbate this risk due to the significant hormonal shifts that occur. Immunosenescence, defined as gradual weakening of the immune system with age, has also been implicated in this increased susceptibility \u003csup\u003e33,34\u003c/sup\u003e. Several studies have shown that the major effects of estradiol are mediated through two receptors, namely alpha and beta estrogen receptors, both of which are expressed on a variety of cell types including immune cells, epithelial cells and muscle cells \u003csup\u003e33,35,36\u003c/sup\u003e. These receptors help regulate immune responses, and the decline in estrogen during menopause may impair their function, leading to reduced immune defense against gastrointestinal pathogens and increased mucosal vulnerability \u003csup\u003e37,38\u003c/sup\u003e. Moreover, estrogen has been shown to regulate many facets of the immune response such as immune cell differentiation, cytokine production, regulation of calcium ion mobilization and release of inducible nitric oxide synthase in leukocytes \u003csup\u003e39,40\u003c/sup\u003e. These immunomodulatory effects of estrogen are thought to help protect against mucosal damage in the gastrointestinal tract, and their loss may contribute to the higher rates of PUD observed in postmenopausal women. Furthermore, previous studies have also shown that patients with persistent symptoms of ulcers often have a high rate of gastrointestinal abnormalities, such as hyperemesis and ulcer recurrence after parturition, particularly within the first 6 months \u003csup\u003e10\u003c/sup\u003e. This finding is intriguing because it suggests a connection between reproductive hormone levels and gastrointestinal health, supporting the hypothesis that hormonal fluctuations, particularly those involving estrogen and progesterone, may play a significant role in ulcer pathogenesis and healing. In addition, Grossman reported that 88.2% of cases were associated with remission of ulcer symptoms during pregnancy, suggesting that hormonal changes may influence PUD risk and recurrence \u003csup\u003e8,32\u003c/sup\u003e. These findings support the hypothesis that hormones, particularly estrogen and progesterone, play a role in ulcer pathogenesis and healing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;Another interesting finding of this study is that the women who underwent surgical menopause were 1.38 times more likely to develop PUD compared to premenopausal women.\u0026nbsp;Pillay and Manyonda reported that\u0026nbsp;surgical menopause (iatrogenic menopause) occurs when both ovaries are removed before ovarian function is naturally \u0026ldquo;switched off\u0026rdquo;, and that this could cause premature ovarian insufficiency leading to menopause in women before the age of 40 \u003csup\u003e41\u003c/sup\u003e. This can then lead to a sudden and dramatic reduction in ovarian sex steroid production, particularly estrogen and progesterone \u003csup\u003e42\u003c/sup\u003e. Natural menopause begins 4 to 6 years before the cessation of menses, and middle-aged women experience a progressive change in ovarian activity and a physiologic deterioration of hypothalamic-pituitary-ovarian axis function associated with fluctuating hormone levels \u003csup\u003e43\u003c/sup\u003e. This indicates that the abrupt loss of ovarian hormones due to surgical menopause can have wide-ranging effects on various physiological systems, including the gastrointestinal system. For example, surgical menopause has been associated with more severe and prolonged menopausal symptoms, including hot flashes, mood change, and sleep disturbance, which may contribute to overall physiological stress and potentially influence gastrointestinal function \u003csup\u003e44\u003c/sup\u003e. This may further influence other systems such as cardiovascular, neurologic, bone, and connective tissue, and affect the quality of life due to vasomotor symptoms, mood, sleep, and sexual function \u003csup\u003e45,46\u003c/sup\u003e. The gastrointestinal system is known to be highly responsive to stress, and chronic stress has been linked to increased gastric acid secretion, reduced mucosal blood flow, and impaired mucosal healing, all of which can contribute to the development of peptic ulcers. Some studies have demonstrated surgical menopause-induced physiological and behavioral changes in relation to\u0026nbsp;estradiol-linked compositional changes in the intestinal microbiota\u0026nbsp;\u003csup\u003e29,47-49\u003c/sup\u003e. However, the exact mechanisms by which estrogen deficiency and hormone therapy affect the gut microbial community are not yet well understood\u0026nbsp;\u003csup\u003e47\u003c/sup\u003e. To date, no strong direct evidence has linked surgical menopause specifically to PUD.\u003c/p\u003e\n\u003cp\u003eIn this study, we also found that postmenopausal hormone therapy in the women with natural menopause was associated with an increased rate of PUD. Previous studies have reported associations between postmenopausal hormone therapy and increased rates of gastroesophageal reflux disease and PUD \u003csup\u003e31,50\u003c/sup\u003e.\u0026nbsp;In addition, postmenopausal hormone therapy has also been associated with other gastrointestinal diseases such as esophageal cancer, gastric cancer, inflammatory bowel disease, irritable bowel syndrome and colon cancer\u0026nbsp;\u003csup\u003e51-53\u003c/sup\u003e. Close et al. reported that\u0026nbsp;the relationship between hormone therapy and gastrointestinal conditions appears to be multifactorial \u003csup\u003e50\u003c/sup\u003e, involving both direct effects of hormones on the gastrointestinal tract and their systemic effects on metabolism, immune function, and inflammatory responses. Coquoz et al. performed a comprehensive literature review, and found that progesterone had dose-dependent and sex-dependent effects on gastric emptying, and that it slowed gastrointestinal motility \u003csup\u003e54\u003c/sup\u003e. This reduced motility can lead to delayed gastric emptying, which is known to contribute to symptoms of gastroesophageal reflux disease and may also increase the risk of peptic ulcer formation by prolonging exposure of the gastric mucosa to acidic contents. In addition to its effects on gastrointestinal motility, the effects of hormone replacement therapy can vary according to the regimen used, and complications associated with hormone replacement therapy may depend on the specific hormones administered, their dosage, and the duration of therapy \u003csup\u003e10,19\u003c/sup\u003e. For example, studies on different animal species and humans have suggested that sex hormones influence gastric acid secretion and contribute to the integrity of the oral and gastroduodenal mucosa \u003csup\u003e32,54\u003c/sup\u003e. Several studies investigated female rats with intact or removed ovaries (ovariectomy) \u003csup\u003e22,36\u003c/sup\u003e, and gastric acid secretion was determined in rats with gastric ulcers equipped with chronic gastric fistula. The results showed that treatment with progesterone significantly accelerated ulcer healing and increased gastric blood flow at the margins of these ulcers, emphasizing that sex hormones had opposite effects on healing of preexisting ulcers in the stomach \u003csup\u003e1,22\u003c/sup\u003e. Our study showed that postmenopausal hormone therapy was associated with an increased rate of PUD, which is contrary to the expected protective effects of hormone replacement therapy\u0026nbsp;\u003csup\u003e55,56\u003c/sup\u003e, as many previous studies have suggested such therapy should mitigate gastrointestinal issues. The contradictory findings suggest that there may be more complex interactions between hormone replacement therapy and gastrointestinal health than previously thought\u0026nbsp;\u003csup\u003e22,25\u003c/sup\u003e. Thus, there is still no clear explanation for how menopause increases the risk of developing peptic ulcers or delays the healing process in women with preexisting ulcers.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; This study is the largest population-based investigation to investigate the associations among menopausal status, type of menopause (surgical or natural), and postmenopausal hormone therapy with PUD risk in Taiwanese women. This extensive dataset offers valuable insights into the potential link between menopause and gastrointestinal health in women, providing evidence for further studies on the topic. Nevertheless, there are also several limitations. First, this was a cross-sectional study, and we did not evaluate the duration of PUD. Therefore, we could not evaluate causal relationships between these factors with PUD. Further longitudinal studies are warranted to investigate the risk of incident PUD. Second, the presence of PUD was obtained through questionnaires without endoscopic verification, and the type and severity of PUD could not be ascertained. Nevertheless, a previous study in Taiwan using claims records reported moderate concordance between such data and self-reported renal disease \u003csup\u003e57\u003c/sup\u003e. Finally, participants in the TWB are of Chinese ethnicity, which may limit the broader application of our findings to other groups.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the study found that menopause was significantly associated with PUD. Furthermore, surgical menopause (\u003cem\u003evs.\u003c/em\u003e pre-menopause) was associated with a 1.38 times higher risk of PUD, and that postmenopausal hormone therapy in women with natural menopause was associated with a 1.37 times higher risk of PUD. This study is the largest population-based investigation to explore the associations among menopausal status and hormone therapy with PUD in Taiwanese women. Further research should seek to identify the mechanisms and potential interventions to reduce susceptibility to peptic ulcers in menopausal women.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e The study was conducted according to the Declaration of Helsinki, and it was granted approval by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20210058), and the TWB was granted approval by the IRB on Biomedical Science Research, Academia Sinica, Taiwan and the Ethics and Governance Council of the TWB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions:\u0026nbsp;\u003c/strong\u003eConceptualization, methodology, validation, formal analysis, writing\u0026mdash;review and editing, and supervision: K-CC, J-HG, C-HK and S-CC. Software and investigation: J-HG, C-HK and S-CC. Resources, project administration, and funding acquisition: S-CC. Data curation: K-CC, C-YK, W-LT, Y-JW, J-HG, C-HK and S-CC. Writing\u0026mdash;original draft preparation: K-CC and S-CC. Visualization: J-HG, C-HK and S-CC. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare that they have no known competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe data underlying this study are from the Taiwan Biobank. Due to restrictions placed on the data by the Personal Information Protection Act of Taiwan, the minimal data set cannot be made publicly available. Data may be available upon request to interested researchers. Please send data requests to: Szu-Chia Chen, PhD, MD. Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWoolf, A. \u0026amp; Rose, R. in \u003cem\u003eStatPearls\u003c/em\u003e (StatPearls Publishing Copyright \u0026copy; 2024, StatPearls Publishing LLC., 2024).\u003c/li\u003e\n\u003cli\u003eKavitt, R. T., Lipowska, A. M., Anyane-Yeboa, A. \u0026amp; Gralnek, I. M. Diagnosis and Treatment of Peptic Ulcer Disease. \u003cem\u003eAm J Med\u003c/em\u003e \u003cstrong\u003e132\u003c/strong\u003e, 447-456, doi:10.1016/j.amjmed.2018.12.009 (2019).\u003c/li\u003e\n\u003cli\u003eKuo, C. 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Postmenopausal hormone use and symptoms of gastroesophageal reflux. \u003cem\u003eArch Intern Med\u003c/em\u003e \u003cstrong\u003e168\u003c/strong\u003e, 1798-1804, doi:10.1001/archinte.168.16.1798 (2008).\u003c/li\u003e\n\u003cli\u003eNilsson, M., Johnsen, R., Ye, W., Hveem, K. \u0026amp; Lagergren, J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. \u003cem\u003eJama\u003c/em\u003e \u003cstrong\u003e290\u003c/strong\u003e, 66-72, doi:10.1001/jama.290.1.66 (2003).\u003c/li\u003e\n\u003cli\u003eCoquoz, A., Regli, D. \u0026amp; Stute, P. Impact of progesterone on the gastrointestinal tract: a comprehensive literature review. \u003cem\u003eClimacteric\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 337-361, doi:10.1080/13697137.2022.2033203 (2022).\u003c/li\u003e\n\u003cli\u003eVigneswaran, K. \u0026amp; Hamoda, H. Hormone replacement therapy - Current recommendations. \u003cem\u003eBest Pract Res Clin Obstet Gynaecol\u003c/em\u003e \u003cstrong\u003e81\u003c/strong\u003e, 8-21, doi:10.1016/j.bpobgyn.2021.12.001 (2022).\u003c/li\u003e\n\u003cli\u003eHodis, H. N. \u0026amp; Mack, W. J. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It Is About Time and Timing. \u003cem\u003eCancer J\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, 208-223, doi:10.1097/ppo.0000000000000591 (2022).\u003c/li\u003e\n\u003cli\u003eWu, C. S., Lai, M. S., Gau, S. S., Wang, S. C. \u0026amp; Tsai, H. J. Concordance between patient self-reports and claims data on clinical diagnoses, medication use, and health system utilization in Taiwan. \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, e112257, doi:10.1371/journal.pone.0112257 (2014).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Clinical characteristics of the study participants\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePremenopausal (\u003cem\u003en\u003c/em\u003e = 7840)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ePostmenopausal (\u003cem\u003en\u003c/em\u003e = 9620)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eAge, yr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e42.16 \u0026plusmn; 6.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e58.27 \u0026plusmn; 5.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of chronic kidney disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e16 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e150 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of arrhythmia, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e235 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e592 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of hyperlipidemia, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e167 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e978 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of hypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e288 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e1553 (16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of diabetes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e107 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e647 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of depression, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e270 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e405 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of manic depression, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e40 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e59 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.417\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of Parkinson, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e12 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of dependency, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e474 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e851 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of smoke experience, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e776 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e438 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of\u0026nbsp;pregnancy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6561 (83.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e9081 (94.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of birth, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6324 (80.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e8972 (93.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of abortion, n (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e3978 (50.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e5966 (62.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHistory of getting married, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6696 (85.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e9225 (95.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eEducation, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;Elementary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e115 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e1465 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eMiddle to High school\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e3271 (41.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e5288 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u0026ge;\u0026nbsp;Collage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e4454 (56.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e2867 (29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSport habit, yes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2239 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e5632 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e23.24 \u0026plusmn; 3.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e23.79 \u0026plusmn; 3.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSystolic blood pressure, mm Hg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e108.75 \u0026plusmn; 15.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e121.21 \u0026plusmn; 18.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eDiastolic blood pressure, mm Hg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e68.15 \u0026plusmn; 10.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e72.06 \u0026plusmn; 10.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eWhite blood cell, 10\u003csup\u003e3\u003c/sup\u003e/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6.04 \u0026plusmn; 1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e5.67 \u0026plusmn; 1.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003ePlatelet, 10\u003csup\u003e3\u003c/sup\u003e/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e266.80 \u0026plusmn; 61.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e236.77 \u0026plusmn; 54.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHemoglobin, g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e12.68 \u0026plusmn; 1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e13.31 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eFasting glucose, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e90.47 \u0026plusmn; 15.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e97.31 \u0026plusmn; 20.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eTotal cholesterol, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e186.02 \u0026plusmn; 32.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e207.07 \u0026plusmn; 35.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eTriglyceride, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e89.54 \u0026plusmn; 61.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e114.47 \u0026plusmn; 73.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eHDL-cholesterol, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e57.70 \u0026plusmn; 12.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e57.73 \u0026plusmn; 13.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.909\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eLDL-cholesterol, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e113.68 \u0026plusmn; 29.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e127.75 \u0026plusmn; 32.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSGOT, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e21.16 \u0026plusmn; 10.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e25.86 \u0026plusmn; 11.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eSGPT, IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e18.56 \u0026plusmn; 17.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e23.08 \u0026plusmn; 16.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eBUN, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e11.38 \u0026plusmn; 2.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e13.89 \u0026plusmn; 3.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eCreatinine, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0.60 \u0026plusmn; 0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e0.63 \u0026plusmn; 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBMI = Body mass index; HDL = High-Density Lipoprotein; LDL = Low-Density Lipoprotein; BUN = Blood Urea Nitrogen; SGOT = Serum Glutamic Oxaloacetic Transaminase; SGPT = Serum Glutamic Pyruvic Transaminase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Odds ratios for self-reported peptic ulcer disease by menopausal status\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePremenopausal (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 7840)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003ePostmenopausal (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 9620)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003ePresence of peptic ulcer disease, n\u0026nbsp;(%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e905 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1616 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003eUnadjusted OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1.0 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.55 (1.42-1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003eAge-adjusted OR (95% CI)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1.0 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.23 (1.07-1.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003eMultivariable OR (95% CI)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1.0 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.19 (1.03-1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR = odds ratio; CI = Confidence interval.\u003c/p\u003e\n\u003cp\u003eMultivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Odds ratios for self-reported peptic ulcer disease by the type of menopause\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eType of menopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePresence of peptic ulcer disease,\u0026nbsp;\u003cem\u003en\u0026nbsp;\u003c/em\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge-adjusted OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMultivariable OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePre-menopause\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e905 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.0 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.0 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNatural menopause\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1269 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.16 (1.00-1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.12 (0.96-1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSurgical menopause\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e347 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.42 (1.20-1.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.38 (1.16-1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR = odds ratio; CI = Confidence interval.\u003c/p\u003e\n\u003cp\u003eMultivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Age, and multivariable-adjusted odds ratios for self-reported peptic ulcer disease by postmenopausal hormone use in women with menopause\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ePostmenopausal hormone use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eAge-adjusted OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMultivariable OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eWomen with natural menopause\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eNever-users\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eEver-users\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.49 (1.21-1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.37 (1.11-1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eWomen with surgical menopause\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eNever-users\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eEver-users\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.18 (0.82-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1.10 (0.75-1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.622\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR = odds ratio; CI = Confidence interval.\u003c/p\u003e\n\u003cp\u003eMultivariable analysis adjusts for arrhythmia, hyperlipidemia, hypertension, depression, manic depression, Parkinson, age, dependency, smoking experience, sport habit, pregnancy, birth, abortion, systolic and diastolic pressure, white blood cell count, platelet count, hemoglobin level, SGOT, BUN, ever married, educational status, BMI, chronic kidney disease and menstruation.\u003c/p\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"menopause, postmenopausal hormone therapy, peptic ulcer disease, Taiwan biobank","lastPublishedDoi":"10.21203/rs.3.rs-5457012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5457012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMenopause is associated with various health conditions such as osteoporosis, obesity, cardiovascular and psychological disorders. However, limited information is available on the relationship between perimenopause and hormone replacement therapy with the occurrence of digestive ulcers. Therefore, we conducted this population-based study of over 17,000 participants in the Taiwan Biobank to examine the association between menopause and peptic ulcer disease (PUD). In addition, we also examined associations between the types of menopause and postmenopausal hormone therapy with PUD.\u003cstrong\u003e \u003c/strong\u003eMenopausal status, hormone replacement therapy during menopause, and the presence of PUD were determined using self-reported questionnaires. The participants were grouped according to whether or not they had entered menopause. The participants were further categorized based on the cause of menopause: natural or surgical. Binary logistic regression was utilized for correlation analysis.\u003cstrong\u003e \u003c/strong\u003eOf the 17,460 individuals enrolled for analysis, 9620 (55%) were classified into the postmenopausal group and 7840 (45%) into the premenopausal group. After adjusting for various factors, the postmenopausal group had a 1.19 times higher risk of developing PUD compared to the premenopausal group (odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.03 to 1.38, \u003cem\u003ep\u003c/em\u003e = 0.022). Moreover, surgical menopause was significantly associated with PUD (OR, 1.38; 95% CI, 1.16 to 1.63; \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001), but natural menopause was not (OR, 1.128; 95% CI, 0.96 to 1.30; \u003cem\u003ep \u003c/em\u003e= 0.153). In addition, the women with natural menopause who received postmenopausal hormone therapy had a significantly higher prevalence of PUD than those who did not (OR, 1.37; 95% CI, 1.11 to 1.70; \u003cem\u003ep\u003c/em\u003e = 0.004). However, no significant association was found between postmenopausal hormone therapy and PUD among the women with surgical menopause (\u003cem\u003ep\u003c/em\u003e = 0.622).\u003cstrong\u003e \u003c/strong\u003eMenopause was significantly associated with PUD. Furthermore, surgical menopause (\u003cem\u003evs.\u003c/em\u003e pre-menopause) was associated with a 1.38 times higher risk of PUD, and postmenopausal hormone therapy in women with natural menopause was associated with a 1.37 times higher risk of PUD. Further research is warranted to identify the mechanisms and potential interventions to reduce susceptibility to digestive ulcers in menopausal women.\u003c/p\u003e","manuscriptTitle":"Association between menopause, postmenopausal hormone therapy and peptic ulcer disease in Taiwanese population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 08:56:41","doi":"10.21203/rs.3.rs-5457012/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-07T10:30:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-06T07:00:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193690261176276548305640059653015989984","date":"2025-01-27T01:15:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227552094068361805651429452261977663606","date":"2024-12-14T01:54:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-10T15:16:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73865033540674221827362704562495865289","date":"2024-11-29T08:17:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-26T13:42:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-18T13:09:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-15T13:04:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-15T04:39:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-11-15T02:21:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d47fc8e-0f5c-41bf-9c5a-a02a7ab69ebb","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":41447117,"name":"Health sciences/Gastroenterology"},{"id":41447118,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-07-14T16:10:50+00:00","versionOfRecord":{"articleIdentity":"rs-5457012","link":"https://doi.org/10.1038/s41598-025-08072-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-07 15:57:57","publishedOnDateReadable":"July 7th, 2025"},"versionCreatedAt":"2024-12-18 08:56:41","video":"","vorDoi":"10.1038/s41598-025-08072-5","vorDoiUrl":"https://doi.org/10.1038/s41598-025-08072-5","workflowStages":[]},"version":"v1","identity":"rs-5457012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5457012","identity":"rs-5457012","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}