Is Adenomyosis Associated with Systemic Vascular Complications?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled "IS ADENOMYOSIS ASSOCIATED WITH SYSTEMIC VASCUALR COMPLICATIONS?" is a review article which focuses the attention of the reader on the potential connections between adenomyosis and vascular complications.

The idea of such manuscript seems very strange. Many works cited in the manuscript are questionable, and authors underlie this. Therefore, it seems more like a speculations. The general conclusion is that there is not correlation between adenomyosis and vascular complications. I am agree that it is importnat to report negative results but it is important for experimental data, it is very strange to see review reporting negative result. The current manuscript seems more like a list of clinical cases. I think that it will be better to significantly rearrange and rewrite the manuscript. Probably, discussing models of adenomyosis in animals and related complications. And on basis of this find clinical cases in humans of such diseases.

 

Minor

1. Line 108 DVT. Deabbreviate

2. Table 1 DIC? CA? Deabbreviate.

3. LINE 197 ESCs? ESCs are embryonic stem cells. There is another acronym?

4. Title: VASCUALR - check spelling

5. Line 254: HRT Deabbreviate

6. In Tables some lines are written in bold and other lines not. Why?

7. Few times in the article you mention Far East. What is it? Which countries do you mean?

Author Response

The manuscript entitled "IS ADENOMYOSIS ASSOCIATED WITH SYSTEMIC VASCUALR COMPLICATIONS?" is a review article which focuses the attention of the reader on the potential connections between adenomyosis and vascular complications.

The idea of such manuscript seems very strange. Many works cited in the manuscript are questionable, and authors underlie this. Therefore, it seems more like a speculations. The general conclusion is that there is not correlation between adenomyosis and vascular complications. I am agree that it is important to report negative results, but it is important for experimental data, it is very strange to see review reporting negative result. The current manuscript seems more like a list of clinical cases. I think that it will be better to significantly rearrange and rewrite the manuscript. Probably, discussing models of adenomyosis in animals and related complications. And on basis of this find clinical cases in humans of such diseases.

We agree with the reviewer that the manuscript concludes by reporting, on the main, negative results. Having said this, we believe that analyses of literature are useful irrespective of the findings, since negative conclusions can stimulate additional, better planned, and methodologically more rigorous research. Our approach was designed to be an unbiased analysis of a growing body of literature that suggested a relationship between adenomyosis and vascular and hematological events. As our review documented, published literature is large in volume but limited in quality. We hope that our review provides a balanced framework to understand the current state of knowledge. We take on board the suggestion made by the referee for a manuscript that addresses adenomyosis in  animal models and related complications. This was not what we set to do, as we wanted to focus on human disease. We are also aware of the significant differences between adenomyosis in humans and in animal model.

Minor

1. Line 108 DVT. De-abbreviate

We have now corrected to Deep vein thrombosis

 

2. Table 1 DIC? CA? De-abbreviate.

We have now corrected to Cancer antigen, Disseminated intravascular coagulation.

3. LINE 197 ESCs? ESCs are embryonic stem cells. There is another acronym?

We have now corrected to endometrial stromal cell

4. Title: VASCUALR - check spelling

Our apologies. The misspelling has been corrected.

5. Line 254: HRT De abbreviate

Done: we have pointed out that this means hormone replacement therapy.

6. In Tables some lines are written in bold and other lines not. Why?

This seems to be an issue with software downloading rather than a choice of the authors. We are happy to work with the journal to address the issue.

7. Few times in the article you mention Far East. What is it? Which countries do you mean?

This is commonly used to refer China, Korea and Japan. At any rate, the country of the studies appears in the tables. We have referred to the three countries in the text)

Reviewer 2 Report

Comments and Suggestions for Authors

A very interesting analysis of the available literature on whether the presence of adenomyosis plays a pathogenetic role in causing vascular events. The article under review is interestingly written. I agree with the authors that the available literature is dominated by case reports, making it difficult to draw accurate conclusions. In my opinion, the manuscript under review has great educational value and fully deserves to be published.

But as a  reviewer, I have one comment: in my opinion, it is worth re-editing the conclusions section to make it less extensive and part of the text should be moved to the discussion section.

Author Response

REVIEWER 2

 

A very interesting analysis of the available literature on whether the presence of adenomyosis plays a pathogenetic role in causing vascular events. The article under review is interestingly written. I agree with the authors that the available literature is dominated by case reports, making it difficult to draw accurate conclusions. In my opinion, the manuscript under review has great educational value and fully deserves to be published.

Many thanks for your comment.

 

But as a reviewer, I have one comment: in my opinion, it is worth re-editing the conclusions section to make it less extensive and part of the text should be moved to the discussion section.

Many thanks for the insight, we have followed your suggestion

Reviewer 3 Report

Comments and Suggestions for Authors

This is a comprehensive review focus on the rarity of systemic vascular complications in adenomyosis and underscores the need for rigorous research to confirm causality.  It could serve as a robust reference for clinicians and researchers exploring gynecologic-vascular intersections. It successfully raises awareness and frames adenomyosis not just as a disease of the uterus but as one with potential systemic implications, similar to the conceptual shift that has occurred with endometriosis. However, I believe there are important questions that need to be answered and corrections that need to be made. My suggestions:

1.Can you provide a complete PRISMA checklist and flow diagram with accurate numbers? Studies included in the quantitative synthesis are stated as “N=35”, but the text presents the full review as “63 relevant articles”. The discrepancy between the flowchart (35) and the text (63) should be clarified. What about the other 28 articles?

2.There are no risk analyses for the aforementioned studies. Plase add the quality assessment of included studies.

3. The article notes that anemia itself can lead to a hypercoagulable state. Anemia itself causes hypercoagulability. This is a significant confounding factor. In discussing studies comparing coagulation parameters, is it possible to examine further whether the studies adequately controlled for anemia as an independent factor?
4. Similarly, the use of OCPs is a confounding factor. Several case reports cited indicate that patients were receiving hormonal therapies such as oral contraceptives. Hormonal therapies are known to affect the risk of thrombosis. The article would be further enriched with a more comprehensive discussion of whether these therapies are the primary cause of vascular events. Adenomyosis may be the cause of the treatment, not the direct cause of the thrombosis.
5. The review frequently mentions "giant," "massive," or significantly enlarged uteri in the case reports. Could the mechanical effects of such a large pelvic mass (e.g., compressing pelvic veins) contribute to the risk of DVT, independent of any systemic biochemical changes? This could be another important confounding factor to discuss.
6. Co-existing pathology such as uterin fibroids and the medications of the AUB depended the adenomyosis (such as progestins and anti-fibrinolytic treatments) could be another important confounding factor.

7.Please create a dedicated subsection or a more detailed paragraph in the discussion to systematically address the major confounding variables.

8. Is hypercoagulability a compensatory response to local bleeding and tissue damage that then becomes excessive and causes systemic problems? Further investigation into this hypothesis could be an important contribution.
9. Are there control studies showing thrombotic event rates in adenomyosis vs. matched controls?
10. High CA-125 is important as a mechanism (lines 122-127), but it is not specific to CA-125 and works well in many cases.
11. Have systemic coagulation markers been compared between adenomyosis patients with/without thrombotic events?
12. Have any prospective cohort studies been conducted following adenomyosis patients for thrombotic events?
13. You must match the tone of the summary to the cautious conclusion. Because the current framework asks “is there a relationship?” but answers “probably not, except maybe in extreme cases.”

Comments for author File: Comments.pdf

Author Response

REVIEWER 3

This is a comprehensive review focus on the rarity of systemic vascular complications in adenomyosis and underscores the need for rigorous research to confirm causality. It could serve as a robust reference for clinicians and researchers exploring gynecologic-vascular intersections. It successfully raises awareness and frames adenomyosis not just as a disease of the uterus but as one with potential systemic implications, similar to the conceptual shift that has occurred with endometriosis. However, I believe there are important questions that need to be answered and corrections that need to be made. My suggestions:

1. Can you provide a complete PRISMA checklist and flow diagram with accurate numbers? Studies included in the quantitative synthesis are stated as “N=35”, but the text presents the full review as “63 relevant articles”. The discrepancy between the flowchart (35) and the text (63) should be clarified. What about the other 28 articles?

Please accept our apologies. We have included the corrected the figures which reflect the articles as numbered in the tables (n=41). The additional references are concern possible pathophysiological mechanisms.

2. There are no risk analyses for the aforementioned studies. Please add the quality assessment of included studies.

We appreciate the comment, but this was not feasible given that in a majority of cases these were individual case reports

 

3. The article notes that anemia itself can lead to a hypercoagulable state. Anemia itself causes hypercoagulability. This is a significant confounding factor. In discussing studies comparing coagulation parameters, is it possible to examine further whether the studies adequately controlled for anemia as an independent factor?

Many thanks for your comment. Anemia was highlighted in our text line 131 as a possible confounder. We have clarified that this was not considered in the published articles.

 

4. Similarly, the use of OCPs is a confounding factor. Several case reports cited indicate that patients were receiving hormonal therapies such as oral contraceptives. Hormonal therapies are known to affect the risk of thrombosis. The article would be further enriched with a more comprehensive discussion of whether these therapies are the primary cause of vascular events. Adenomyosis may be the cause of the treatment, not the direct cause of the thrombosis.

Many thanks for your comment. The table highlighted patients who were on the pill, and - although the risk of thrombosis (PE) is increased with the use of the pill - the article itself (Okuda) was concerned with the anesthetic management and the removal of the uterus, as it was considered to be the source of the thrombi. We have added the relevant comment.

 

5. The review frequently mentions "giant," "massive," or significantly enlarged uteri in the case reports. Could the mechanical effects of such a large pelvic mass (e.g., compressing pelvic veins) contribute to the risk of DVT, independent of any systemic biochemical changes? This could be another important confounding factor to discuss.

To follow your suggestion, we have included a comment on this aspect in our original article and have highlighted the relevant point in the text.

 

6. Co-existing pathology such as uterine fibroids and the medications of the AUB depended the adenomyosis (such as progestins and anti-fibrinolytic treatments) could be another important confounding factor.

Many thanks. We have added a relevant comment in the text.

7. Please create a dedicated subsection or a more detailed paragraph in the discussion to systematically address the major confounding variables.

Many thanks. This was added

8. Is hypercoagulability a compensatory response to local bleeding and tissue damage that then becomes excessive and causes systemic problems? Further investigation into this hypothesis could be an important contribution.

Could be. But this has not been investigated yet. Alternatively, since coagulation and inflammation are intimately linked, the presence of inflammation would activate the coagulation pathways, leading to thrombosis.

 

9. Are there control studies showing thrombotic event rates in adenomyosis vs. matched controls?

We are not aware of any.

10. High CA-125 is important as a mechanism (lines 122-127), but it is not specific to CA-125 and works well in many cases.

 

11. Have systemic coagulation markers been compared between adenomyosis patients with/without thrombotic events?

 

12. Have any prospective cohort studies been conducted following adenomyosis patients for thrombotic events?

Points 7-12: we have included a section that explicitly focusses on these points.

13. You must match the tone of the summary to the cautious conclusion. Because the current framework asks “is there a relationship?” but answers “probably not, except maybe in extreme cases”.

Your comment is perfectly valid! We have corrected this in the conclusion section.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors performed still minor corrections which were asked during the first round of review. However, they did not significantly rearrengered the manuscript as it was required. There is no added informatiuon about animal models. The manuscript is still enumeration of clinical cases and not a review.