Sex-Specific Differences in <i>Helicobacter pylori</i> Eradication Outcomes: Treatment Success and Adverse Events in a Single Tertiary Center in South Korea

Yonghoon Choi; Nayoung Kim; Moon Chul Lee; Seung Teak Lee; June Young Lim; Jung Hyun Noh; Wootaek Seo; Hee-Eon Lim; So Young Jo; Jongchan Lee; Cheol Min Shin; Seulgi Kim

doi:10.7704/kjhugr.2025.0094

Korean J Helicobacter Up Gastrointest Res > Volume 26(2); 2026 > Article

Choi, Kim, Lee, Lee, Lim, Noh, Seo, Lim, Jo, Lee, Shin, and Kim: Sex-Specific Differences in Helicobacter pylori Eradication Outcomes: Treatment Success and Adverse Events in a Single Tertiary Center in South Korea

Original Article

The Korean Journal of Helicobacter and Upper Gastrointestinal Research 2026;26(2):196-203.

Published online: March 31, 2026

DOI: https://doi.org/10.7704/kjhugr.2025.0094

Sex-Specific Differences in Helicobacter pylori Eradication Outcomes: Treatment Success and Adverse Events in a Single Tertiary Center in South Korea

Yonghoon Choi¹

, Nayoung Kim^1,^2,³

, Moon Chul Lee¹

, Seung Teak Lee¹

, June Young Lim¹

, Jung Hyun Noh¹

, Wootaek Seo¹

, Hee-Eon Lim¹

, So Young Jo¹

, Jongchan Lee¹

, Cheol Min Shin^1,³

, Seulgi Kim¹

¹Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

²Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

³Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Corresponding author Nayoung Kim, MD, PhD Department of Internal Medicine, Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea E-mail: nakim49@snu.ac.kr

Received December 31, 2025; Revised February 17, 2026; Accepted February 27, 2026;

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives

Successful eradication of Helicobacter pylori is essential for improving patient outcomes and preventing gastric cancer; however, evidence regarding sex-specific differences in treatment success and adverse event profiles remain limited. This study investigated sex-based differences in eradication efficacy and treatment tolerability.

Methods

We retrospectively reviewed patients who underwent diagnostic testing, received eradication therapy, and completed post-treatment confirmation testing between 2003 and 2024 at Seoul National University Bundang Hospital. First-line therapy consisted of 10-day sequential therapy, while second-line treatment included 14-day bismuth-based quadruple therapy or 14-day moxifloxacin-based triple therapy. Treatment success and adverse events were evaluated by sex and treatment regimen.

Results

Females had lower eradication rates in the overall cohort. The intention-to-treat analysis showed significantly higher success rates in males compared to females in the total population (71.1% vs. 65.1%, p<0.001) and in sequential therapy (70.5% vs. 62.1%, p<0.001), although this pattern was not replicated in the per-protocol results. Adverse events were reported nearly twice as often in females, regardless of the regimen, which may partly explain the reduced rates of successful eradication and increased discontinuation.

Conclusions

Sex-based differences influence H. pylori eradication outcomes, with females showing lower treatment success rates and substantially more adverse events. Higher therapy intolerance and dropout rates in females may partially account for reduced effectiveness of eradication therapy, highlighting the need for sex-specific strategies and improved supportive care.

Key words: Helicobacter pylori; Disease eradication; Drug-related side effects and adverse reactions; Sex characteristics

INTRODUCTION

Helicobacter pylori infection remains a significant public health challenge in South Korea, with a substantial proportion of the adult population showing evidence of infection [1]. Epidemiologic studies have shown historically high prevalence of H. pylori infection in South Korea, although recent trends indicate a gradual decline in prevalence, ranging from approximately 41.5% to 51.3% [2]. H. pylori is a well-established risk factor for chronic gastritis, peptic ulcer disease, and, importantly, gastric cancer (GC), which is one of the most common and lethal malignancies in South Korea and other East Asian countries [3]. The eradication of H. pylori significantly reduces the risk of GC development and recurrence, particularly in populations with high baseline GC incidence [4].

Given its role in the gastric carcinogenesis cascade and other serious gastrointestinal diseases, effective H. pylori eradication is critical for both individual patient outcomes and broader cancer prevention strategies. Despite international guidelines recommending eradication therapy for confirmed infections, varying rates of treatment success and adverse events remain a challenge, partly due to increasing antibiotic resistance and patient-specific factors including adherence [5]. While the overall benefits of H. pylori eradication have been extensively documented, relatively few studies have systematically analyzed sex-specific differences in eradication outcomes, including treatment success and adverse event profiles. Existing studies suggest that older women may exhibit lower eradication and higher recurrence rates than men, but the results are inconsistent and sex-stratified analyses are often limited or underpowered [6]. Furthermore, some investigations indicate that metabolic and other long-term effects following eradication may differ by sex, further supporting the need for sex-disaggregated research [7].

Therefore, in this study, we aimed to examine sex-based differences in H. pylori eradication outcomes, specifically treatment success rates and adverse event incidence, among patients treated at a single tertiary care center in South Korea, focusing on both efficacy and safety outcomes.

METHODS

Study population

This study included patients who underwent diagnostic testing for H. pylori infection, received eradication treatment, and subsequently underwent follow-up confirmation testing at Seoul National University Bundang Hospital (SNUBH) from 2003 to 2024. The present study is an observational prospective study rather than a retrospective study because of enrollment protocol for diagnosis, symptoms, smoking and alcohol consumption, and follow-up protocol regarding compliance and adverse events with eradication outcomes. Relevant demographic and clinical variables, such as age, sex, prior eradication history, and endoscopic examination findings with histological or clinical diagnoses were extracted from the enrollment protocol. All participants provided informed consent, and the study protocol of the original observational cohort study was approved by the Institutional Review Board of SNUBH (Approval Nos. B-0602-030-001, B-0903-071-001, B-2011-648-005, and B-2011-649-004).

H. pylori testing and eradication regimens

H. pylori infection was considered present if at least one of the following diagnostic modalities yielded a positive result: histological examination, Campylobacter-like organism test (Delta West), or microbial culture. All endoscopic biopsy procedures were performed by a single endoscopist with >30 years of clinical experience (N.K.), ensuring procedural consistency throughout the study period. For histological assessment, a minimum of two biopsy specimens were obtained from both the mid-antrum and mid-body and subsequently stained using hematoxylin-eosin and modified Giemsa staining methods. H. pylori-positive status was determined according to the updated Sydney classification system [8].

H. pylori eradication therapy was administered according to contemporary clinical guidelines [5,9-11]. Before 2012, the standard first-line regimen consisted of a 7-day twice-daily triple therapy comprising esomeprazole (40 mg), amoxicillin (1000 mg), and clarithromycin (500 mg). Due to declining eradication efficacy associated with increasing clarithromycin resistance, treatment protocols were revised after 2012, replacing the 7-day triple regimen with a 10-day sequential therapy. This sequential regimen included esomeprazole (40 mg) twice daily and amoxicillin (1000 mg) twice daily for the first 5 days, followed by esomeprazole (40 mg) and clarithromycin (500 mg) both twice daily plus metronidazole (500 mg) thrice daily for the subsequent 5 days. Eradication success was confirmed using the ¹³C-urea breath test (UBT; UBiT-IR300; Otsuka Electronics) performed ≥4 weeks after completion of treatment. Patients in whom first-line therapy failed received either 14-day bismuth-based quadruple therapy or 14-day moxifloxacin-based triple therapy. The quadruple regimen consisted of esomeprazole (40 mg) twice daily, tripotassium dicitrate bismuthate (300 mg) twice daily (Denol; Greencross Co.), tetracycline (500 mg) four times daily, and metronidazole (500 mg) thrice daily. Alternatively, the moxifloxacin-based triplet regimen consisted of moxifloxacin (400 mg) once daily (Avelox; Bayer Health Care, AG) plus esomeprazole (40 mg) and amoxicillin (1000 mg) both twice daily.

Statistical analysis

For comparisons between groups, categorical variables were analyzed using the chi-square test, whereas continuous variables were assessed using the Student’s t-test. Univariate and multivariate regression analyses were performed to identify risk factors associated with eradication failure, and variables with a p-value <0.2 in the univariate analysis were subsequently included in the multivariate model. Statistical significance was defined as a two-tailed p-value <0.05. All analyses were performed using the SPSS software (version 25.0; IBM Corp.).

RESULTS

Study population and demographics

The study flow diagram is shown in Fig. 1. A total of 4748 patients were prescribed H. pylori eradication therapy. After excluding 927 individuals lost to follow-up and 121 patients with low compliance, 3408 individuals (1664 males and 1744 females) were included in the per-protocol (PP) analysis; 2107 patients received the sequential regimen as first-line eradication therapy. Second-line therapy consisted of bismuth-based quadruple therapy in 870 patients and moxifloxacin-based triple therapy in 431 patients (Fig. 1). The baseline demographics of the participants in the intention-to-treat (ITT) and PP protocols are summarized in Table 1. The baseline demographics of the ITT and PP groups were largely similar; the mean age was approximately 58 years, females comprised slightly over half of each cohort, and most individuals had a body mass index within the normal range. Non-smoking and non-drinking status was predominant, and sequential therapy was the most frequently administered eradication regimen.

H. pylori eradication rates by sex and regimens

The eradication success rate showed a slight sex-based difference (Fig. 2, Table 2). Stratified analysis by sex and eradication regimen under the ITT protocol showed that males had a significantly higher eradication success rate than females (71.1% vs. 65.1%, p<0.001). Notably, the greatest difference was observed in the sequential therapy group (70.5% in males vs. 62.1% in females; p<0.001). Although no statistically significant sex-based differences were detected in the bismuth quadruple therapy group (73.1% vs. 72.1%, p=0.717) or the moxifloxacin triple therapy group (70.3% vs. 67.2%, p=0.354), eradication rates were consistently higher among males (Fig. 2A). Under the PP protocol, the eradication success rate did not significantly differ between males and females (87.0% vs. 85.7%, p=0.270). When stratified by eradication regimen, the results were as follows: sequential therapy (87.7% vs. 85.4%, p=0.121), bismuth quadruple therapy (86.5% vs. 89.1%, p=0.233), and moxifloxacin triple therapy (85.0% vs. 80.7%, p=0.243). Although the eradication rates tended to be higher in males across all regimens except bismuth quadruple therapy, none of these differences were statistically significant (Fig. 2B).

In the PP protocol, univariate and multivariate regression analyses were performed to assess predictors of eradication failure. However, sex was not a significant risk factor (Supplementary Table 1 in the online-only Data Supplement).

The differences in eradication success rates between males and females according to the year of treatment initiation are presented in Supplementary Table 2 (in the online-only Data Supplement). Over time, the eradication success rate of sequential regimen showed a decreasing trend. However, no clear or consistent trend was observed in sex-based differences in eradication success rates across the treatment periods.

Rates of dropout and side effects by sex and regimens

As noted previously, among the 4748 patients included in the ITT analysis, 927 did not respond to follow-up. When stratified by sex, the dropout rate was higher in females (21.7% [549/2535]) than in males (17.1% [378/2213]). In addition, among the 3720 patients who reported side effects (1753 males and 1967 females), adverse events were nearly twice as common in females (60.2% [1184/1967]) than in males (37.9% [664/1753]) (p<0.001). This pattern was consistently observed across the treatment regimens: sequential therapy (35.3% vs. 60.7%, p<0.001), bismuth quadruple therapy (45.5% vs. 65.7%, p<0.001), and moxifloxacin triple therapy (30.1% vs. 40.4%, p=0.078), indicating a higher likelihood of adverse event reporting among females across all regimens (Fig. 3, Table 3).

DISCUSSION

In this study, we aimed to investigate whether sex-based differences exist in the success rates and adverse event profiles of H. pylori eradication therapies. In the ITT analysis, females showed a significantly lower eradication success rate compared to males. However, this difference was attenuated and was no longer evident in the PP analysis. These findings suggest that the observed disparities in the ITT population may not necessarily reflect intrinsic differences in treatment efficacy. Notably, adverse events were reported nearly twice as frequently in females across all treatment regimens and higher dropout rates were observed in this group. Therefore, the lower eradication rates observed in the ITT analysis may be partly explained by the higher frequency of adverse events and treatment discontinuation in female patients.

Epidemiological data consistently indicate a higher prevalence of H. pylori among males, a pattern thought to be related to sex hormone–mediated modulation of immune responses and mucosal defense [12]. Biologically, estrogen is known to enhance gastric mucosal integrity through antioxidative and anti-inflammatory mechanisms, whereas androgen exposure may facilitate bacterial persistence and impair mucosal healing [13,14]. Furthermore, sex-related variations in gastric physiology, such as acid secretion and motility, may contribute to divergent treatment responses [15,16].

Whether age- and sex-related differences exist in the eradication rate of H. pylori remains unclear. Nevertheless, several clinical studies have reported sex-specific differences in treatment outcomes, with female sex being associated with lower eradication success rates [6,17-19]. In a recent large-scale population-based study involving 81754 individuals from Gansu Province, no significant sex-based difference in eradication rates was observed in young or middle-aged groups. However, among older patients, females showed significantly lower eradication rates than males. The PP and ITT eradication rates in older females were 78.38% and 82.27%, respectively, compared to 87.25% and 89.39%, respectively, in older males (both p<0.05) [6]. Similarly, studies conducted in China [17], South Korea [18], and Spain [19] have also reported lower eradication rates in females, supporting the possibility of sex-based differences in treatment response.

These findings may be due to the following reasons. Several studies have reported that females may more frequently harbor H. pylori strains carrying the A2143G mutation [6] and may exhibit higher rates of clarithromycin resistance [20-22], both of which are associated with treatment failure. In addition, as H. pylori infection is a key etiological factor in peptic ulcer disease, unsuccessful eradication could potentially delay ulcer healing, particularly in female patients. Taken together, these observations suggest that sex-related factors should be considered when managing H. pylori infections. Sex-based differences have also been observed in drug-related adverse reactions. One possible explanation is the variability in metabolic enzyme activity between males and females, which may influence systemic drug exposure, efficacy, and drug–drug interaction profiles. For example, females generally demonstrate higher CYP3A4 activity, whereas CYP2C19 activity may vary based on genetic polymorphisms and sex-related factors [23,24].

However, sex-related differences were observed only in the ITT analysis and not in the PP analysis in this study. This discrepancy may be attributed to other confounding factors, including age, regional differences, bacterial strain variability, and patterns of antibiotic resistance. In previous studies, lower eradication success rates observed in females have often been attributed to clarithromycin resistance. However, the regimens included in the present study, namely sequential therapy, bismuth quadruple therapy, and quinolone-based regimens, are relatively less affected by clarithromycin resistance. Therefore, sex-based differences in eradication outcomes may have been attenuated in our cohort. Another important consideration is that females consistently reported a higher incidence of adverse events than males across all eradication regimens. Increased adverse events in females may have led to higher dropout rates and lower treatment compliance, thereby contributing to the lower eradication rates observed in the ITT analysis. Females also generally report adverse drug reactions more frequently than males [25], and this tendency has been observed with the use of proton pump inhibitors and antibiotics as well [26]. In addition, data suggest that females demonstrate greater awareness of medication-related adverse effects, express more concern, and are more likely to discontinue therapy, compared to males [27]. These findings highlight the potential importance of incorporating sex-specific considerations into H. pylori eradication strategies to optimize treatment effectiveness and minimize adverse events. Although considerable research has focused on overcoming antibiotic resistance and refining eradication regimens, relatively few studies have addressed sexrelated differences in this context. Therefore, in clinical practice, not just biological differences between sexes, but differences in adverse event profiles and treatment adherence should also be considered when prescribing eradication therapy. Well-designed, large-scale studies are needed to further clarify these issues and inform individualized treatment approaches.

This study has several limitations. First and most importantly, antibiotic resistance was not evaluated in all patients. As discussed above, one of the proposed mechanisms underlying the biological differences between sexes is a higher rate of antibiotic resistance in females. Previous studies have reported higher clarithromycin resistance rates in females, which may partly explain the lower success rates of conventional triple therapy in this group [20-22]. We are currently planning a subgroup analysis of patients within this cohort with available antibiotic susceptibility data, to further investigate sex-based differences in resistance patterns and treatment outcomes. Second, male and female participants were not strictly controlled under identical conditions. However, the side effects of the eradication regimen were analyzed using a protocol-based treatment during patient visit after UBT or endoscopic follow-up. Although this was an observational prospective study rather than a typical retrospective study, a potential risk of selection bias and unmeasured confounding factors remains. In addition, a more rigorous evaluation of sex-related differences would have required formal modeling of adherence, adverse events, and dropout as potential mediators or confounders; however, such analyses were not feasible because this was a simple comparison of eradication results and adverse effects or dropout for a prolonged duration. Third, because this was a single-center study, the study population may be regionally skewed and may not fully represent the broader population. Nevertheless, this study included a relatively large number of patients with long-term data, which allowed a comprehensive analysis of sex-related differences. By identifying potential disparities in eradication outcomes and adverse event profiles, this study may serve as an exploratory hypothesis-generating investigation that provides a basis for well-designed prospective studies in the future.

In conclusion, this study suggests that sex-based factors may be associated with differences in eradication outcomes and treatment tolerability in H. pylori infection. Although eradication success was not consistently lower in females across all analyses, adverse events and treatment discontinuation were more frequently observed in women, which may have contributed, at least in part, to the differences in overall effectiveness. These findings indicate that sex is one of several factors to be considered when selecting eradication regimens and planning follow-up strategies. Further large-scale prospective investigations are needed to confirm these observations and to clarify whether incorporating sex-specific considerations into treatment strategies may improve clinical outcomes.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.7704/kjhugr.2025.0094.

Supplementary Table 1.

Risk factors for treatment failure

kjhugr-2025-0094-Supplementary-Table-1.pdf

Supplementary Table 2.

Sex-based differences in H. pylori eradication success rates by treatment year

kjhugr-2025-0094-Supplementary-Table-2.pdf

Notes

Availability of Data and Material

The necessary data have been included in the manuscript and table.

Conflicts of Interest

Yonghoon Choi, a contributing editor of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, was not involved in editorial evaluation or the decision to publish this article. All remaining authors have declared no conflicts of interest.

Funding Statement

This study was supported by the National Institute of Health (NIH) research project (Project No. 2025-ER1104-01).

Acknowledgements

None

Authors’ Contribution

Conceptualization: Yonghoon Choi, Nayoung Kim. Data curation: Nayoung Kim, Moon Chul Lee, June Young Lim, Seung Teak Lee, Jung Hyun Noh, Hee-Eon Lim, Wootaek Seo, So Young Jo, Jongchan Lee, Cheol Min Shin, Seulgi Kim. Formal analysis: Yonghoon Choi. Funding acquisition: Nayoung Kim. Investigation: Yonghoon Choi, Nayoung Kim. Methodology: Yonghoon Choi, Nayoung Kim. Project administration: Nayoung Kim. Resources: Nayoung Kim, Cheol Min Shin. Software: Yonghoon Choi. Supervision: Nayoung Kim. Validation: Cheol Min Shin. Visualization: Yonghoon Choi. Writ ing—original draft: Yonghoon Choi. Writing—review & editing: all authors. Approval of final manuscript: all authors.

Fig. 1.

Study flowchart. ITT, intention-to-treat; M, male; F, female.

Fig. 2.

Eradication success rate by sex. A: In the ITT analysis, males showed significantly higher eradication success rates than females, both overall and within the sequential regimen subgroup. B: In the PP analysis, a similar trend was observed, although the difference was not statistically significant. ITT, intention-to-treat; PP, per-protocol.

Fig. 3.

Presence of sex-based side effects. The reporting rate of adverse events was highest with the bismuth quadruple regimen, followed by the sequential regimen, and the moxifloxacin triple regimen, and in all regimens, females reported adverse events more frequently than males.

Table 1.

Baseline demographics

	Males (n=1664)	Females (n=1744)	p-value
Age (yr)	58.50±12.61	58.23±15.73	0.577
BMI (kg/m²)^*	24.37±2.96	23.23±10.28	<0.001
BMI group^*			<0.001
<18.5 kg/m²	27 (2.0)	81 (5.7)
18.5–22.9 kg/m²	404 (30.1)	704 (49.2)
23.0–24.9 kg/m²	398 (29.7)	317 (22.2)
≥25.0 kg/m²	512 (38.2)	329 (23.0)
Smoking^*			<0.001
None	630 (49.8)	1312 (96.0)
Ex	384 (30.4)	22 (1.6)
Current	251 (19.8)	32 (2.3)
Alcohol^*			<0.001
None	701 (55.4)	1237 (90.7)
Ex	111 (8.8)	22 (1.6)
Current	453 (35.8)	105 (7.7)
Treatment regimen			0.560
Sequential	1014 (60.9)	1093 (62.7)
Bismuth quadruple	437 (26.3)	433 (24.8)
Moxifloxacin triple	213 (12.8)	218 (12.5)
Eradication rate			0.270
Success	1448 (87.0)	1495 (85.7)
Failure	216 (13.0)	249 (14.3)
Side effect^*			<0.001
No	965 (66.1)	653 (42.3)
Yes	496 (33.9)	890 (57.7)

Values are presented as mean±standard deviation or number (%).

^* Variables with missing data.

BMI, body mass index.

Table 2.

Eradication success rate by sex

	Total	Male	Female	p-value
ITT
Sequential	1754/2661 (65.9)	849/1204 (70.5)	905/1457 (62.1)	<0.001
Bismuth quadruple	704/970 (72.6)	340/465 (73.1)	364/505 (72.1)	0.717
Moxifloxacin triple	533/777 (68.6)	244/347 (70.3)	289/430 (67.2)	0.354
PP
Sequential	1822/2107 (86.5)	889/1014 (87.7)	933/1093 (85.4)	0.121
Bismuth quadruple	764/870 (87.8)	378/437 (86.5)	386/433 (89.1)	0.233
Moxifloxacin triple	357/431 (82.8)	181/213 (85.0)	176/218 (80.7)	0.243

Values are presented as n/n (%).

ITT, intention-to-treat; PP, per-protocol.

Table 3.

Presence of sex-based side effects

	Total	Male	Female	p-value
Total	1848/3720 (49.7)	664/1753 (37.9)	1184/1967 (60.2)	<0.001
Sequential	1185/2428 (48.8)	400/1134 (35.3)	785/1294 (60.7)	<0.001
Bismuth quadruple	560/1008 (55.6)	230/506 (45.5)	330/502 (65.7)	<0.001
Moxifloxacin triple	103/284 (36.3)	34/113 (30.1)	69/171 (40.4)	0.078

Values are presented as n/n (%).

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