Review Reports - Physical Activity, Metabolic Dysfunction, and the Kynurenine Pathway in Endometriosis and Polycystic Ovary Syndrome: A Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reviews the intersecting roles of physical activity (PA), insulin resistance/metabolic dysfunction, chronic low-grade inflammation, and the tryptophan–kynurenine pathway (KP) in two prevalent reproductive disorders—endometriosis and polycystic ovary syndrome (PCOS). The topic is timely and fits the scope of Biomolecules given the immunometabolic emphasis and the mechanistic framing around KP regulation. However, the manuscript would benefit substantially from a clearer review methodology, a more critical/quantitative synthesis of the clinical evidence (especially for exercise effects on KP in these patient groups), and improved precision in several mechanistic claims and citation usage.

Major concerns

1) Review methodology is insufficiently described

Although the article is positioned as a narrative review, Biomolecules readers still expect transparency: databases searched, keywords, date range, inclusion/exclusion approach, and how evidence was prioritized. Without this, the review risks selection bias and uneven coverage.

Recommendations

Add a short Methods/Approach subsection specifying: databases (e.g., PubMed/Scopus/Web of Science), search terms (PA/exercise; KP/tryptophan/kynurenine; endometriosis/PCOS; insulin resistance/inflammation), date range, and selection principles (clinical trials, meta-analyses, mechanistic studies, etc.).
If a formal systematic review was not performed, explicitly state this and clarify the intent (conceptual synthesis vs. comprehensive evidence mapping).

2) Evidence synthesis on “exercise → KP” in endometriosis/PCOS is still too inferential

A central promise of the manuscript is PA modulation of KP as a unifying mechanism, but the review currently relies heavily on:

general exercise–KP biology (often from non-gynecologic populations), and
inferred links to endometriosis/PCOS symptoms.

Recommendations

Add a table summarizing human studies that measured KP metabolites (Trp, KYN, KYNA, QUIN, 3-HK, KYN/Trp ratio) in endometriosis and PCOS, and separately those that assessed changes with PA/exercise (even if indirect or in related insulin-resistant cohorts). Include sample size, phenotype (lean/obese PCOS; endometriosis stage), method (LC–MS/MS vs other), and main findings.
Distinguish clearly between (i) demonstrated effects and (ii) hypothesized pathways.

3) Need more critical appraisal of heterogeneity and conflicting findings

The manuscript notes inconsistency in circulating kynurenine levels in PCOS, attributing it to heterogeneity/methodological variation, but does not dissect this enough.

Recommendations

Expand discussion on likely sources of heterogeneity:

PCOS phenotypes (Rotterdam categories; hyperandrogenic vs non-hyperandrogenic; lean vs obese; insulin-resistant vs insulin-sensitive)
contraceptive/metformin use and other medications
sampling phase (follicular vs luteal), fasting status
analytical methods and reporting units

Similarly for endometriosis: stage, lesion subtype (ovarian endometrioma vs deep infiltrating), inflammatory profile, and comorbid IBS/mood disorders that also influence Trp metabolism.

4) Exercise prescription discussion is not sufficiently actionable or nuanced

The manuscript emphasizes “structured exercise” but offers limited practical granularity (FITT: frequency, intensity, time, type) and limited discussion of feasibility given pelvic pain/fatigue and adherence barriers in endometriosis.

Recommendations

Provide a concise framework (even as narrative guidance) for different modalities (aerobic, resistance, combined, mind–body) and how they might be tailored in endometriosis vs PCOS, including caution about high-intensity unsupervised exercise and symptom flares.
Clearly separate evidence supported in PCOS trials (more abundant) from endometriosis trials (comparatively fewer), rather than treating them as symmetrical.

5) Mechanistic claims need tightening and, in places, more careful wording

Some mechanistic statements appear broad or potentially overgeneralized—for example, about estrogen receptor activation leading to insulin secretion/β-cell dysfunction, or the directionality between hyperinsulinemia and obesity (“obesity as a consequence”). These are debated areas and require careful phrasing and balanced citation.

Recommendations

Where evidence is associative or indirect, qualify language (e.g., “may contribute,” “is consistent with,” “has been proposed”).
Ensure key mechanistic statements are supported by primary mechanistic citations (human or robust animal/cellular evidence).

Minor comments

Terminology consistency: Use consistent abbreviations and formatting (e.g., “Trp,” “KYN,” “KYNA,” “KP”) throughout; ensure first-use definitions are complete and consistent.

Figure legends: The figure legends are helpful, but consider adding 1–2 lines on “take-home message” per figure (especially Figure 4 on exercise-KP steps) to improve standalone interpretability.
Reference accuracy/duplication: Check for duplicated citations (e.g., repeated numbering for similar statements) and ensure references match claims (particularly for exercise-induced KAT expression and human evidence).
Balance psychosocial discussion: The manuscript connects KP to mood and pain sensitization; consider briefly discussing bidirectionality (stress/inflammation → KP activation; KP metabolites → neuroimmune effects) and avoid implying causality where not established.
Conclusions: The conclusion is strong but could be slightly more conservative by clearly separating “evidence-supported” vs “hypothesis-generating” claims, especially regarding KP as a therapeutic target in endometriosis.

Author Response

Comments 1:This manuscript reviews the intersecting roles of physical activity (PA), insulin resistance/metabolic dysfunction, chronic low-grade inflammation, and the tryptophan–kynurenine pathway (KP) in two prevalent reproductive disorders—endometriosis and polycystic ovary syndrome (PCOS). The topic is timely and fits the scope of Biomolecules given the immunometabolic emphasis and the mechanistic framing around KP regulation. However, the manuscript would benefit substantially from a clearer review methodology, a more critical/quantitative synthesis of the clinical evidence (especially for exercise effects on KP in these patient groups), and improved precision in several mechanistic claims and citation usage.

Response 1: Thank you for your comments, which have contributed to improving the quality of the manuscript. We have made the requested revisions.

Comments 2: Major concerns

1) Review methodology is insufficiently described

Although the article is positioned as a narrative review, Biomolecules readers still expect transparency: databases searched, keywords, date range, inclusion/exclusion approach, and how evidence was prioritized. Without this, the review risks selection bias and uneven coverage.

Recommendations

Add a short Methods/Approach subsection specifying: databases (e.g., PubMed/Scopus/Web of Science), search terms (PA/exercise; KP/tryptophan/kynurenine; endometriosis/PCOS; insulin resistance/inflammation), date range, and selection principles (clinical trials, meta-analyses, mechanistic studies, etc.).

If a formal systematic review was not performed, explicitly state this and clarify the intent (conceptual synthesis vs. comprehensive evidence mapping).

Response 2: Thank you for your comment. As this is a narrative review, we believe that the inclusion of a separate Methods section is not required. We have clarified the narrative nature of the review in the Introduction and, in accordance with the reviewer’s request, we have also specified the search criteria used.

Comments 3: 2) Evidence synthesis on “exercise → KP” in endometriosis/PCOS is still too inferential. A central promise of the manuscript is PA modulation of KP as a unifying mechanism, but the review currently relies heavily on:

general exercise–KP biology (often from non-gynecologic populations), and

inferred links to endometriosis/PCOS symptoms.

Recommendations

Add a table summarizing human studies that measured KP metabolites (Trp, KYN, KYNA, QUIN, 3-HK, KYN/Trp ratio) in endometriosis and PCOS, and separately those that assessed changes with PA/exercise (even if indirect or in related insulin-resistant cohorts). Include sample size, phenotype (lean/obese PCOS; endometriosis stage), method (LC–MS/MS vs other), and main findings.

Distinguish clearly between (i) demonstrated effects and (ii) hypothesized pathways.

Response 3: Thank you for the suggestion! We have inserted the requested figure into the section before the conclusion.

Comments 4: 3) Need more critical appraisal of heterogeneity and conflicting findings

The manuscript notes inconsistency in circulating kynurenine levels in PCOS, attributing it to heterogeneity/methodological variation, but does not dissect this enough.

Recommendations

Expand discussion on likely sources of heterogeneity:

PCOS phenotypes (Rotterdam categories; hyperandrogenic vs non-hyperandrogenic; lean vs obese; insulin-resistant vs insulin-sensitive)

contraceptive/metformin use and other medications

sampling phase (follicular vs luteal), fasting status

analytical methods and reporting units

Similarly for endometriosis: stage, lesion subtype (ovarian endometrioma vs deep infiltrating), inflammatory profile, and comorbid IBS/mood disorders that also influence Trp metabolism.

Response 4: We would also like to thank you for these comments, which we have incorporated into the second chapter.

Comments 5: 4) Exercise prescription discussion is not sufficiently actionable or nuanced

Recommendations

Provide a concise framework (even as narrative guidance) for different modalities (aerobic, resistance, combined, mind–body) and how they might be tailored in endometriosis vs PCOS, including caution about high-intensity unsupervised exercise and symptom flares.

Clearly separate evidence supported in PCOS trials (more abundant) from endometriosis trials (comparatively fewer), rather than treating them as symmetrical.

Response 5: We also thank you for this suggestion. Accordingly, we have expanded Chapter 5 and refined the statements to ensure greater precision and clarity.

Comments 6: 5) Mechanistic claims need tightening and, in places, more careful wording

Recommendations

Where evidence is associative or indirect, qualify language (e.g., “may contribute,” “is consistent with,” “has been proposed”). Ensure key mechanistic statements are supported by primary mechanistic citations (human or robust animal/cellular evidence).

Response 6: Thank you, we have modified the text according to the request.

Comments 7: Minor comments

Terminology consistency: Use consistent abbreviations and formatting (e.g., “Trp,” “KYN,” “KYNA,” “KP”) throughout; ensure first-use definitions are complete and consistent.

Response 7: Thank you for the comment; we have revised the use of abbreviations throughout the manuscript.

Comments 8: Figure legends: The figure legends are helpful, but consider adding 1–2 lines on “take-home message” per figure (especially Figure 4 on exercise-KP steps) to improve standalone interpretability.

Response 8: Thank you for the suggestion; we have expanded the figure legend accordingly.

Comments 9: Reference accuracy/duplication: Check for duplicated citations (e.g., repeated numbering for similar statements) and ensure references match claims (particularly for exercise-induced KAT expression and human evidence).

Response 9: Thank you for pointing this out. One reference was indeed listed twice consecutively within the parentheses; we have corrected this. We have also revised the wording in several parts of the text to improve clarity.

Comments 10: Balance psychosocial discussion: The manuscript connects KP to mood and pain sensitization; consider briefly discussing bidirectionality (stress/inflammation → KP activation; KP metabolites → neuroimmune effects) and avoid implying causality where not established.

Response 10: In the text, we have indicated in each section that the KP is associated with inflammation, which may activate the KP. Where there is no clear causality with the KP, we have explicitly noted the uncertainty in the text.

Comments 11: Conclusions: The conclusion is strong but could be slightly more conservative by clearly separating “evidence-supported” vs “hypothesis-generating” claims, especially regarding KP as a therapeutic target in endometriosis.

Response 11: We have modified the indicated text.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript clearly frames the clinical and public‑health importance of endometriosis and PCOS, links both disorders to insulin resistance and chronic inflammation, and proposes the kynurenine pathway as a potential mechanistic bridge. It highlights physical activity as a modifiable factor and calls for better long‑term studies.

The manuscript poses clear, relevant context; prevalence, diagnostic delay, and socioeconomic impact are well presented. Furthermore, interdisciplinary perspective of the manuscript integrates immunometabolism, neuroendocrine signaling, and reproductive health, while kynurenine pathway has been described as a mechanistic link as well as pathway of translational interest.

Major revision requested.

Objective and study type are unclear. State whether this is a narrative review, systematic review, meta‑analysis… Include a concise aim. Briefly report search strategy, inclusion criteria, and time frame.

Evidence level is not specified. Qualify claims about kynurenine pathway modulation and exercise with the type of supporting evidence (preclinical, observational, interventional).

Tighten language for flow and precision; correct small grammatical inconsistencies.

The Introduction should also include several sentences on PCOS pathophysiology to match the level of detail provided for endometriosis.

Cite or indicate source for prevalence and diagnostic-delay statistics in the manuscript.

The manuscript is conceptually strong and relevant but needs clarity about mentioned issues.

Author Response

Comments 1: The manuscript clearly frames the clinical and public‑health importance of endometriosis and PCOS, links both disorders to insulin resistance and chronic inflammation, and proposes the kynurenine pathway as a potential mechanistic bridge. It highlights physical activity as a modifiable factor and calls for better long‑term studies.

Response 1: Thank you for your comments and suggestions. We have revised the manuscript accordingly.

Comments 2: Major revision requested.

Response 2: We have revised the last paragraph of the Introduction as requested.

Comments 3: Evidence level is not specified. Qualify claims about kynurenine pathway modulation and exercise with the type of supporting evidence (preclinical, observational, interventional).

Response 3: We have modified the text as requested.

Comments 4: Tighten language for flow and precision; correct small grammatical inconsistencies.

Response 4: Thank you for your comment. The errors have been corrected.

Comments 5: The Introduction should also include several sentences on PCOS pathophysiology to match the level of detail provided for endometriosis.

Response 5: We have expanded this section of the Introduction.

Comments 6: Cite or indicate source for prevalence and diagnostic-delay statistics in the manuscript.

Response 6: We have modified this section of the abstract.

Comments 7: The manuscript is conceptually strong and relevant but needs clarity about mentioned issues.

Response 7: Thank you once again for your comments, which have contributed to improving the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript presents very detailed literature review focused on metabolic disorders with emphasis on the kynurenine pathway in endometriosis and PCOS, and summarizes the data on the positive role of physical activity.

This topic is of interest and aligns with the main goals of Biomolecules journal. Although the review is not systematic, the manuscript was reviewed using the «PRISMA 2020 check-list» https://www.equator-network.org/reporting-guidelines/prisma/. Despite the overall positive impression of the manuscript, there are some remarks and comments. The comments by sections are as follows:

In the title, consider to identify the report as a literature review. The abstract represents the main content of the article, nevertheless, it looks reasonable to provide the main objectives of the review in the abstract.

Introduction. The rationale for the review in the context of existing knowledge and the study objectives are presented in the Introduction section. At the same time, the authors don’t report a search strategy with the specification of the information sources used to identify the articles and the search depth by dates. These details and inclusion/exclusion criteria for publications should be described in the manuscript.

The review itself is divided into several parts (on endometriosis and PCOS clinical, metabolic and inflammatory features, as well as on the role of physical activity) and covers the problem in detail. Importantly, the authors present the interesting data on the kynurenine system which is considered as a potential link between inflammation, metabolic and reproductive disorders in endometriosis and PCOS.

The decision is: accept the manuscript after minor revision.

Author Response

Comments 1: The manuscript presents very detailed literature review focused on metabolic disorders with emphasis on the kynurenine pathway in endometriosis and PCOS, and summarizes the data on the positive role of physical activity.

This topic is of interest and aligns with the main goals of Biomolecules journal. Although the review is not systematic, the manuscript was reviewed using the «PRISMA 2020 check-list» https://www.equator-network.org/reporting-guidelines/prisma/. Despite the overall positive impression of the manuscript, there are some remarks and comments. The comments by sections are as follows:

Response 1: Thank you for your feedback!

Comments 2: In the title, consider to identify the report as a literature review. The abstract represents the main content of the article, nevertheless, it looks reasonable to provide the main objectives of the review in the abstract.

Response 2: We have modified the title and abstract according to the request.

Comments 3: Introduction. The rationale for the review in the context of existing knowledge and the study objectives are presented in the Introduction section. At the same time, the authors don’t report a search strategy with the specification of the information sources used to identify the articles and the search depth by dates. These details and inclusion/exclusion criteria for publications should be described in the manuscript.

Response 3: We indicated in the introduction that this is a narrative review.

Comments 4: The review itself is divided into several parts (on endometriosis and PCOS clinical, metabolic and inflammatory features, as well as on the role of physical activity) and covers the problem in detail. Importantly, the authors present the interesting data on the kynurenine system which is considered as a potential link between inflammation, metabolic and reproductive disorders in endometriosis and PCOS.

Response 4: Thank you for your comments, which contributed to improving the quality of the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author did a good work for their revised-manuscript. The authors also fully answered my questions and provided excellent responses. I recommend accepting and publishing this article.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is now suitable for publication.