Serum Interleukin-6 Levels in Endometriosis and Endometriosis-Associated Ovarian Cancer: A Systematic Review and Meta-Analysis Demonstrating a Biological Gradient

Abstract

Objective

This study quantifies serum/plasma interleukin-6 levels across the healthy–nonendometriosis, benign–endometriosis–ovarian cancer spectrum, focusing on pooled geometric means stratified by control type.

This study quantifies serum/plasma interleukin-6 levels across the healthy–nonendometriosis, benign–endometriosis–ovarian cancer spectrum, focusing on pooled geometric means stratified by control type.

Data Sources

PubMed (MEDLINE;1971-present), Scopus (2004-present), CINAHL (1981-present), and Google Scholar were systematically searched from inception to October 31, 2025. Reference lists of included studies and prior meta-analyses were hand-searched.

PubMed (MEDLINE;1971-present), Scopus (2004-present), CINAHL (1981-present), and Google Scholar were systematically searched from inception to October 31, 2025. Reference lists of included studies and prior meta-analyses were hand-searched.

Methods of Study Selection

All articles with quantitative serum/plasma interleukin-6 data in ovarian cancer and/or endometriosis vs at least one control group (healthy, nonendometriosis benign, or endometriosis) were included. Endometriosis was included as a comparator to permit direct evaluation of the biological gradient across the healthy–benign–endometriosis–ovarian cancer spectrum, the primary objective of this study. Exclusions were tissue or peritoneal fluid-only measurements, nonhuman studies, reviews, editorials, or studies without extractable data. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool, Risk of Bias in Nonrandomized Studies of Interventions tool, and the Newcastle–Ottawa Scale. Means and standard deviations were log-transformed; results are presented as geometric means approximating medians. Random-effects meta-analyses and meta-regression were performed for each diagnostic category, with exploratory analyses for endometrioid and clear cell subtypes, endometriosis stage, and ovarian cancer stage. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

All articles with quantitative serum/plasma interleukin-6 data in ovarian cancer and/or endometriosis vs at least one control group (healthy, nonendometriosis benign, or endometriosis) were included. Endometriosis was included as a comparator to permit direct evaluation of the biological gradient across the healthy–benign–endometriosis–ovarian cancer spectrum, the primary objective of this study. Exclusions were tissue or peritoneal fluid-only measurements, nonhuman studies, reviews, editorials, or studies without extractable data. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool, Risk of Bias in Nonrandomized Studies of Interventions tool, and the Newcastle–Ottawa Scale. Means and standard deviations were log-transformed; results are presented as geometric means approximating medians. Random-effects meta-analyses and meta-regression were performed for each diagnostic category, with exploratory analyses for endometrioid and clear cell subtypes, endometriosis stage, and ovarian cancer stage. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Tabulation, Integration, and Results

Of 1903 records identified, 106 studies (>16 000 participants) were included (63 ovarian cancer [18 with endometriosis], 50 endometriosis-only). Geometric mean interleukin-6 levels increased progressively: healthy controls 5.10 pg/mL (95% CI 3.22%–8.1095% PI 0.11–231.45; 42 studies) < nonendometriosis benign 5.89 pg/mL (95% CI 3.24–10.71; 95% PI 0.06–578.65; 28 studies) < endometriosis 10.68 pg/mL (95% CI 6.39–17.84; 95% PI 0.37–312.82; 50 studies) < ovarian cancer 21.67 pg/mL (95% CI 12.27–38.26; 95% PI 0.42–1124.76; 63 studies). Ovarian cancer vs endometriosis: 2.03-times higher (95% CI 0.95–4.33; p = .068). Endometrioid: 8.65 pg/mL (5 studies, I² = 94%); clear cell: 12.77 pg/mL (4 studies, I² = 98%; overlapping CIs).

Of 1903 records identified, 106 studies (>16 000 participants) were included (63 ovarian cancer [18 with endometriosis], 50 endometriosis-only). Geometric mean interleukin-6 levels increased progressively: healthy controls 5.10 pg/mL (95% CI 3.22%–8.1095% PI 0.11–231.45; 42 studies) < nonendometriosis benign 5.89 pg/mL (95% CI 3.24–10.71; 95% PI 0.06–578.65; 28 studies) < endometriosis 10.68 pg/mL (95% CI 6.39–17.84; 95% PI 0.37–312.82; 50 studies) < ovarian cancer 21.67 pg/mL (95% CI 12.27–38.26; 95% PI 0.42–1124.76; 63 studies). Ovarian cancer vs endometriosis: 2.03-times higher (95% CI 0.95–4.33; p = .068). Endometrioid: 8.65 pg/mL (5 studies, I² = 94%); clear cell: 12.77 pg/mL (4 studies, I² = 98%; overlapping CIs).

Conclusion

Interleukin-6 approximately doubles from endometriosis to ovarian cancer overall, supporting inflammation-driven progression. Stratifying endometriosis as a distinct comparator group clarifies the incremental inflammatory burden beyond that seen in other benign conditions and resolves inconsistencies in prior meta-analyses that grouped endometriosis with heterogeneous benign controls. More prospective subtype-specific trials are needed.

Interleukin-6 approximately doubles from endometriosis to ovarian cancer overall, supporting inflammation-driven progression. Stratifying endometriosis as a distinct comparator group clarifies the incremental inflammatory burden beyond that seen in other benign conditions and resolves inconsistencies in prior meta-analyses that grouped endometriosis with heterogeneous benign controls. More prospective subtype-specific trials are needed.