Limitations of hormonal and clinical markers in predicting GnRH agonist trigger success in polycystic ovary syndrome: A critical reappraisal

Fazilet Kubra Boynukalin; Zalihe Yarkıner; Meral Gultomruk; Ozkan Ozdamar; Peter Humaidan; Mustafa Bahceci; Gurkan Bozdag

doi:10.1371/journal.pone.0332813

Peer Review History

Original SubmissionMay 15, 2025
15 Aug 2025 Decision Letter - Wan-Xi Yang, Editor Dear Dr. Boynukalin, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== 2- Manuscript content: Rationale is missing which should be part of the Introduction ============================== Please submit your revised manuscript by Sep 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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There is no requirement to cite these works unless the editor has indicated otherwise. ?> 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: A much needed topic. A well written Manuscript supported with evidence based data. 1- Abstract: The short Background is missing. 2- Manuscript content: Rationale is missing which should be part of the Introduction 3- Discussion: Recommendations need to be added after the limitations of the study. Reviewer #2: Determining predictors for poor responses in PCOS is certainly a challenge and I applaud the authors for their attempt, even if it was not the outcome they may have hoped for. I would suggest another limitation is the use of MPA prior to stim start instead of utilizing laboratory values to ensure patients were at the same phase of cycle (ie early follicular) vs. a "random start." ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: Yes: Sara J. Mucowski, M.D. ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0332813.r002
Revision 1
1 Sep 2025 Author Response Dear Editor, We sincerely thank the Academic Editor and the reviewers for their thoughtful and constructive comments. We have carefully considered each point and revised the manuscript accordingly. Below, we provide a detailed response to every comment, indicating how and where changes were made in the revised manuscript. We hope that the revisions and clarifications adequately address all concerns and improve the quality and clarity of our work. Response to Reviewers Reviewer #1: Comment 1: "Abstract: The short Background is missing." Author Response: We thank the reviewer for this insightful comment. In accordance with the suggestion, we have revised the abstract to include a concise background section. The revised version now briefly explains the clinical relevance of GnRH agonist triggers in PCOS patients and the rationale for investigating predictors of oocyte yield. This addition helps contextualize the study aim for readers from the outset. Revised Abstract Opening: “Background: Polycystic ovary syndrome (PCOS) is associated with altered hypothalamic-pituitary-ovarian function, which may affect the success of GnRH agonist triggers used during IVF. Identifying reliable predictors of oocyte yield in these patients remains a clinical challenge.” We hope this revision meets the reviewer’s expectations and improves the clarity and completeness of the abstract. Comment 2: "Manuscript content: Rationale is missing which should be part of the Introduction." Author Response: We appreciate the reviewer’s comment regarding the importance of clearly presenting the rationale in the Introduction section. To address this, we have added a concise explanation highlighting the current uncertainty in identifying reliable predictors of oocyte yield in PCOS patients undergoing GnRH agonist trigger. This paragraph now establishes the unmet clinical need and positions our study as a focused attempt to address this gap. Added Text in the Introduction (last paragraph): While the use of GnRH agonist triggers offers clear clinical benefits for PCOS patients undergoing IVF, accurately predicting suboptimal oocyte yield remains a significant challenge. Identifying reliable pre-trigger predictors could enhance patient selection and improve treatment outcomes. Nevertheless, the existing literature presents inconsistent findings, and studies focusing exclusively on PCOS cohorts are notably scarce. Determining predictors for poor responses in PCOS is certainly a challenge and I applaud the authors for their attempt, even if it was not the outcome they may have hoped for. I would suggest another limitation is the use of MPA prior to stim start instead of utilizing laboratory values to ensure patients were at the same phase of cycle (ie early follicular) vs. a "random start." We appreciate the reviewer’s insightful comment regarding the need to further elaborate on the clinical implications of post-trigger hormonal assessment and the potential limitations in intervention once the trigger has been administered. In response, we have added the following paragraph to the Discussion section to clarify our clinical rationale and emphasize the importance of pre-trigger evaluation: “Considering that corrective options are limited once a suboptimal hormonal response is detected after the trigger, it becomes increasingly important to focus on the factors within our control prior to triggering. In our clinical practice, therefore, comprehensive evaluation of pre-trigger parameters—including AFC, baseline LH, BMI, and patient history—is emphasized to anticipate the likelihood of a suboptimal response. This proactive strategy is particularly relevant for PCOS patients, in whom altered gonadotropin dynamics may not always translate into predictable post-trigger outcomes.” We believe this addition strengthens the clinical relevance of our findings and addresses the reviewer’s concern. Response to Reviewer 2: We sincerely thank the reviewer for the valuable observation regarding the use of MPA prior to stimulation and the potential implications for cycle phase standardization. We agree that initiating stimulation based on laboratory-confirmed early follicular phase could offer tighter control over the baseline hormonal milieu. However, in patients with PCOS—who often experience oligo/anovulation—this approach may not always be practical. In our study, we chose to administer MPA to induce withdrawal bleeding, thereby ensuring a standardized and timely initiation of ovarian stimulation across participants. In addition to facilitating synchronization, the use of MPA may have also contributed to the suppression of elevated basal LH levels—a common feature in PCOS—which could otherwise interfere with the interpretation of pre-trigger hormonal profiles. This rationale has now been clarified and acknowledged as both a methodological choice and a potential limitation in the revised Discussion section. We appreciate the reviewer’s thoughtful input, which helped improve the clarity of our design considerations. Attachments Attachment Submitted filename: letter-plos.docx https://doi.org/10.1371/journal.pone.0332813.r003
4 Sep 2025 Decision Letter - Wan-Xi Yang, Editor Limitations of hormonal and clinical markers in predicting GnRH agonist trigger success in polycystic ovary syndrome: A critical reappraisal PONE-D-25-23181R1 Dear Dr. Boynukalin, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Wan-Xi Yang, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0332813.r004
Formally Accepted
Acceptance Letter - Wan-Xi Yang, Editor PONE-D-25-23181R1 PLOS ONE Dear Dr. Boynukalin, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Wan-Xi Yang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0332813.r005

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