The Differences Between Dopamine Agonist-Resistant and -Non-Resistant Prolactinomas: Are There Any Predictors of a Good Response?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. In the abstract, the first sentence of the Results section (line 29) gives the impression that the study included only male participants. The authors should revise this sentence to accurately describe the entire cohort. The statements under the Conclusions section are actually results rather than conclusions. The authors should formulate a concluding statement based on their findings.
2. In the introduction, the authors cite two guidelines, but the older guideline is placed immediately after the statement that ‘the approach to the concept of resistance has evolved over the years.’ This placement is confusing. It would be more logical to highlight the newer guideline in that position, unless there is a compelling rationale for emphasizing the older one. If such a rationale exists, the authors should clarify it.”
3. I recommend avoiding abbreviations that may not be familiar to most readers. For example, ‘ER’ in line 66 and ‘PRL’ in line 67 are used without definition. Similarly, abbreviations such as ‘TV’ and ‘MTD’ may not be widely recognized. In addition, using ‘Me’ to represent median in Table 1 is confusing. The authors should define all abbreviations at first use or replace them with full terms to improve clarity.
4. The definitions of responders, partial responders, and resistance to dopamine agonists (lines 109–115) are unclear. The authors explicitly define only ‘responders.’ The statement ‘otherwise, the patients were classified as partial responders’ suggests that participants were categorized into only two groups: responders and partial responders. However, the following sentence—‘Among partial responders, we classified patients with resistant prolactinomas’—introduces an additional subgroup and creates confusion. The authors should provide clear, mutually exclusive definitions for all categories (responders, partial responders, and resistant cases) and clarify how these groups relate to one another.
5. The authors mentioned “giant prolactinoma” many times, but did not define it.
6. The sentence in lines 118–119 is unclear. It states that the maximum is defined by the median, which is contradictory.
7. Comparing patients with resistant prolactinomas versus those without resistance is not a subgroup analysis.
8. In the flow chart, the box labeled ‘40 participants excluded’ is redundant. It would be clearer and more conventional to place the total number excluded (‘40 participants excluded’) directly within the box that lists the exclusion reasons on the right.
9. In the Results section, the authors state that ‘insufficiencies of other pituitary axes were relatively rare.’ However, Table 1 reports central hypothyroidism at 24.7% and central hypocortisolism at 22.4%, which cannot be considered rare.
10. The authors mentioned two guidelines in the introduction. Why did the authors use the old guideline in the results and describe≥ 50% tumor volume reduction? How many achieved > 30% tumor diameter reduction?
11. KNOSP has a grade 0. What does the author mean by “in 15 patients non-applicable = 0” in Table 1?
12. The authors should consider restructuring Table 1 so that baseline, 6-month, 12-month, and last follow-up data are presented in four columns. Additional descriptive information, such as symptoms, does not need to be included in the table and can instead be described in the text.
13. When comparing males vs. females, the authors should list the number (%) of patients with resistance to DA.
14. In Section 3.5.2, I recommend using the term ‘association’ rather than ‘predictive model,’ as the analyses presented evaluate associations but do not include measures of predictive performance.

Author Response

We want to thank the Reviewer for the detailed and thoughtful evaluation of our manuscript and for the numerous constructive comments. We greatly appreciate the opportunity to clarify and improve our work. Below, we provide a point-by-point response to all comments and describe the corresponding revisions made in the manuscript.

1. Reviewer's comment: "In the abstract, the first sentence of the Results section (line 29) gives the impression that the study included only male participants. The authors should revise this sentence to accurately describe the entire cohort. The statements under the Conclusions section are actually results rather than conclusions. The authors should formulate a concluding statement based on their findings."

1. Authors’ response: The first sentence of the Results section in the abstract has been revised, including both male and female participants (line 29). The conclusions section of the abstract has been reformulated to provide a true concluding statement derived from the findings (lines 38-41).

2. Reviewer’s comment: "In the introduction, the authors cite two guidelines, but the older guideline is placed immediately after the statement that ‘the approach to the concept of resistance has evolved over the years.’ This placement is confusing. It would be more logical to highlight the newer guideline in that position, unless there is a compelling rationale for emphasizing the older one. If such a rationale exists, the authors should clarify it.”

2. Authors’ response:
The Introduction has been revised to emphasize the newer guideline in the context of the evolving concept of dopamine agonist resistance. The older is cited for historical context (lines 50-58).

3. Reviewer’s comment: "I recommend avoiding abbreviations that may not be familiar to most readers. For example, ‘ER’ in line 66 and ‘PRL’ in line 67 are used without definition. Similarly, abbreviations such as ‘TV’ and ‘MTD’ may not be widely recognized. In addition, using ‘Me’ to represent median in Table 1 is confusing. The authors should define all abbreviations at first use or replace them with full terms to improve clarity."

3. Authors’ response:
All abbreviations are now defined at first mention or replaced with full terms where appropriate. "ER" explained in line 68; "PRL" explained firstly in abstract in line 28 and then in line 56; "Me" - explained when firstly appear in the text (line 131), moreover abbreviation is explained below the Table 1, 2, 3 and 4.  "TV" and "MTD" are explained in the "Materials and Methods section" and used only in this section to facilitate the explanation of the performed calculations. In further parts of the manuscript and in tables authors do not use these abbreviations (TV and MTD) to improve the clarity of the text. 

4. Reviewer’s comment: "The definitions of responders, partial responders, and resistance to dopamine agonists (lines 109–115) are unclear. The authors explicitly define only ‘responders.’ The statement ‘otherwise, the patients were classified as partial responders’ suggests that participants were categorized into only two groups: responders and partial responders. However, the following sentence—‘Among partial responders, we classified patients with resistant prolactinomas’—introduces an additional subgroup and creates confusion. The authors should provide clear, mutually exclusive definitions for all categories (responders, partial responders, and resistant cases) and clarify how these groups relate to one another."

4. Authors’ response:

 In the revised manuscript, we clarified all criteria as follows:

• Responders - patients who achieved normopolactinemia and at least a 30% reduction in the maximal tumor dimension after at least 6 months of DA treatment, irrespective of the administered DA dose. (line 112-114)
• Partial responder – patients who did not meet the criteria for DA resistance and could not be classified as responders were classified as partial responders:  1) the patients achieving normoprolactinemia without at least 30% reduction in the maximal tumor diameter treated with lower than standard DA doses (< 7.5 mg per day of bromocriptine or < 2.0 mg per week of cabergoline), 2) the patients not achieving normoprolactinemia with at least 30% reduction in the maximal tumor diameter treated with lower than standard DA doses, 3) the patients not achieving normoprolactinemia and not achieving at least 30% reduction in the maximal diameter, treated with lower than standard DA doses. (lines 119-126)
• Resistant – patients failing to achieve prolactin normalization OR at least a 30% reduction in the maximal tumor diameter despite treatment with standard or maximally tolerated DA doses for ≥6 months. (line 115-118)

5. Reviewer’s comment: "The authors mentioned “giant prolactinoma” many times, but did not define it."

5. Authors’ response: A clear definition of giant prolactinoma at its first occurrence in the text was added (lines 62-64).

 6. Reviewer’s comment: "The sentence in lines 118–119 is unclear. It states that the maximum is defined by the median, which is contradictory."

6. Authors’ response:
The sentence was rewritten to improve clarity: "The maximum cabergoline dose was defined as the highest dose used during the 6- or 12-month follow-up period and was expressed as median (Me) and interquartile range (IQR)."  (line 130-132)

Moreover, in lines 196-199 and 210-216 the authors also provided the data, including the lowest and the highest doses of cabergoline used in the cohort at 6-month and 12-month follow-ups. 

7. Reviewer’s comment: "Comparing patients with resistant prolactinomas versus those without resistance is not a subgroup analysis."

7. Authors’ response:
The terminology has been corrected, and this comparison is now referred to as a group comparison rather than a subgroup analysis. 

8. Reviewer’s comment: "In the flow chart, the box labeled ‘40 participants excluded’ is redundant. It would be clearer and more conventional to place the total number excluded (‘40 participants excluded’) directly within the box that lists the exclusion reasons on the right."

8.Authors’ response:
The flow chart has been revised in accordance with the Reviewer’s suggestion. 

9. Reviewer’s comment: "In the Results section, the authors state that ‘insufficiencies of other pituitary axes were relatively rare.’ However, Table 1 reports central hypothyroidism at 24.7% and central hypocortisolism at 22.4%, which cannot be considered rare."

9. Authors’ response:
Revised sentence is placed in the result section: "Insufficiencies of other pituitary axes were less common; both corticotropic and thyroid axis insufficiency were observed in approximately one-quarter of patients." (lines 172-174)

10. Reviewer’s comment: "The authors mentioned two guidelines in the introduction. Why did the authors use the old guideline in the results and describe≥ 50% tumor volume reduction? How many achieved > 30% tumor diameter reduction?"

10. Authors’ response:
The rationale for using the older guideline criterion has now been explicitly stated in the Methods, thus the approach to the resistance has evolved through the years, and we cited the older guideline also for historical context. Moreover, the authors aim to evaluate how many patients achieve the ≥ 50% tumor volume reduction. We added data on patients achieving >30% reduction in tumor diameter, enabling comparison with newer guideline recommendations.

11. Reviewer’s comment: "KNOSP has a grade 0. What does the author mean by “in 15 patients non-applicable = 0” in Table 1?"

11. Authors’ response:
This has now been clarified in Table 1. Grade 0 refers to tumors without cavernous sinus invasion, which was observed in 15 patients. 

12. Reviewer’s comment: "The authors should consider restructuring Table 1 so that baseline, 6-month, 12-month, and last follow-up data are presented in four columns. Additional descriptive information, such as symptoms, does not need to be included in the table and can instead be described in the text."

12. Authors’ response:
Table 1 has been restructured and data divided into 2 tables to improve the clarity for the reader. We provide the population characteristics in Table 1 (including symptoms, KNOPS classification to underline the baseline characteristics of patients. In Table 2 we included the data from the follow-ups (6 month, 12 month and last visit). 

13. Reviewer’s comment: "When comparing males vs. females, the authors should list the number (%) of patients with resistance to DA."

13. Authors’ response:
This information (% of the resistant prolactinomas in females and males at 6 months, 12 months and last follow-up) has now been added to the Results section lines (292-295) and included in Table 4. 

 

14. Reviewer’s comment: "In Section 3.5.2, I recommend using the term ‘association’ rather than ‘predictive model,’ as the analyses presented evaluate associations but do not include measures of predictive performance."

14. Authors’ response:
We have replaced “predictive model” with “Association with resistance and response to DA"  in section 3.5.2.

 We believe that the revisions made in response to these suggestions have significantly improved the clarity, methodological rigor, and overall quality of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents retrospective analysis of DA resistance predictors in prolactinomas. The authors pointed clinically relevant findings on early radiological response. 

Minor revisions - Uniformly report tumor volume reductions as medians (IQR) across all timeline, matching the style in Table 2, for consistency. Check for minor typos (e.g., "aOR = 7.25" likely intends unadjusted OR; clarify). The work adds practical value to DA management in high-risk prolactinomas but needs small clarifications.

Author Response

We sincerely thank the Reviewer for the positive evaluation of our work and for the constructive comments, which will undoubtedly improve the manuscript's clarity and consistency.

Below, we provide detailed responses to the suggested revisions.

Comment: “Uniformly report tumor volume reductions as medians (IQR) across all timeline, matching the style in Table 2, for consistency.”
Response: We have revised the manuscript so that all tumor volume reduction data are now presented uniformly as median values with interquartile ranges (IQR), matching the formatting used in Table 2.

Comment: “Check for minor typos (e.g., ‘aOR = 7.25’ likely intends unadjusted OR; clarify).”
Response:  This value indeed referred to the unadjusted odds ratio. The text has been corrected accordingly.

We trust that these changes address the concerns raised and further strengthen the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

The article investigated the response of prolactinomas to DA in order to identify predictor of response.  The subject of the study is interesting, however, few important points points need to be clarified.

Lines110-115: Please describe more precisely the definition of partial responder and resistant prolactinoma. Moreover, the DA dose is not reported in the definition. I would suggest adding to avoid misclassification of patients treated with low-dose of cabergoline since the median dose reported by the authors in lines 222-224 for patients classified as resistant is relatively low (2 mg/week)

Lines 166-172: Please report the number of patients classified as responder, partial responder or resistant to DA after 6 months treatment. Moreover, I would suggest adding the max DA dose at 6 months.

Lines 173-183: please report how many patients previously considered partial responder or resistant became responder and how many patients classified as resistant became partial responder. Moreover, I would suggest adding the max DA dose at 12 months.

Line 194: The authors state “surgical treatment was performed in 15.5% (13/85) of patients”. In the next line they state “In one of these four patients, the surgery 194 was performed twice”. Please explain the discrepancy.

Lines 222-224: The median dose of prolactinoma was relative low in patients classified as resistant. I suggest adding how many patients in the resistant group were intolerant to higher doses of DA.

Author Response

We thank the Reviewer for the careful evaluation of our manuscript and for the constructive comments that significantly improved the clarity and clinical relevance of the work. Below we provide detailed responses and list all changes introduced in the revised version.

Comment 1 (Lines 110–115):

Please describe more precisely the definition of partial responder and resistant prolactinoma. Moreover, the DA dose is not reported in the definition. I would suggest adding to avoid misclassification of patients treated with low-dose of cabergoline since the median dose reported by the authors in lines 222-224 for patients classified as resistant is relatively low (2 mg/week).

Response:

In the revised manuscript, we clarified all criteria as follows:

• Responders - patients who achieved normopolactinemia and at least a 30% reduction in the maximal tumor dimension after at least 6 months of DA treatment, irrespective of the administered DA dose. (line 112-114)
• Partial responder – patients who did not meet the criteria for DA resistance and could not be classified as responders were classified as partial responders:  1) the patients achieving normoprolactinemia without at least 30% reduction in the maximal tumor diameter treated with lower than standard DA doses (< 7.5 mg per day of bromocriptine or < 2.0 mg per week of cabergoline), 2) the patients not achieving normoprolactinemia with at least 30% reduction in the maximal tumor diameter treated with lower than standard DA doses, 3) the patients not achieving normoprolactinemia and not achieving at least 30% reduction in the maximal diameter, treated with lower than standard DA doses. (lines 119-126) 
• Resistant – patients failing to achieve prolactin normalization OR at least a 30% reduction in the maximal tumor diameter despite treatment with standard or maximally tolerated DA doses for ≥6 months. (line 115-118)

To address the Reviewer's comment on dosing, we added information specifying that resistance classification was based on adequate DA exposure and clarified the threshold doses in accordance with international guidelines. A dedicated sentence describing DA doses used in the definitions has been added. 

Comment 2 (Lines 166–172):

Please report the number of patients classified as responder, partial responder or resistant to DA after 6 months treatment. Moreover, I would suggest adding the max DA dose at 6 months.

Response:
This information has now been added. The revised Results section reports:

• number of responders, partial responders, and resistant cases at 6 months (included in the revised Table 2)
• maximum cabergoline dose reached at 6 months (median and IQR) - in the revised Table 2

Comment 3 (Lines 173–183):

Please report how many patients previously considered partial responder or resistant became responder and how many patients classified as resistant became partial responder. Moreover, I would suggest adding the max DA dose at 12 months.

Response:
We agree this adds valuable longitudinal insight. The updated manuscript includes:

• number of patients who changed categories between 6 and 12 months (in the paragraph "3.2.2. Evaluation at 12 months"; lines 214-216 and paragraph "3.2.3. Long-term follow-up"; lines 224-228)
• maximum DA dose administered at 12 months (median and IQR) - the doses of DA can be found in the revised Table 2

Comment 4 (Line 194):

The authors state “surgical treatment was performed in 15.5% (13/85) of patients”. In the next line they state “In one of these four patients, the surgery was performed twice”. Please explain the discrepancy.

Response:
Thank you for highlighting the ambiguity. The corrected text clarifies that:

• 13 patients underwent surgery, and the word ‘four’ was inadvertently included in the text and has now been removed in the revised version of the manuscript - we revised the paragraph for clarity and removed the discrepancy (lines 231-238).

 

Comment 5 (Lines 222–224):

The median dose of DA was relatively low in patients classified as resistant. I suggest adding how many patients in the resistant group were intolerant to higher doses of DA.

Response:
We agree this is essential information. Due to the retrospective nature of the study, intolerance was not consistently documented for every patient. However, we added the available data to the revised manuscript:

• number of documented cases of DA intolerance in the resistant group (one patient)
• explanation that lower DA dosing in some patients, especially those in partially responsive group, likely reflects intolerance rather than insufficient treatment intensity.

We added a paragraph acknowledging this limitation in the Discussion section (lines 373-388)

Reviewer 4 Report

Comments and Suggestions for Authors

The article submitted for review, "Differences between resistant and non-resistant to dopamine agonists prolactinomas. Are there any predictors of a good response?" is an original work that further expands existing knowledge on the risk factors for resistance to dopamine agonists in prolactinomas, based on a cohort of patients from Poland. Despite the retrospective nature of the study, which resulted in significant patient loss, the authors were able to statistically demonstrate risk factors for resistance: male gender, larger tumor size, and higher baseline prolactin levels. The contribution of baseline prolactin levels and tumor volume to the overall risk appears to be very modest. In the discussion, the authors provide a good description of various resistance assessments and tumor characteristics that may influence these criteria (e.g., cystic tumor), reflecting their high clinical expertise. The discussion section could be supplemented with additional treatment options (line 383+) or a summary of them. Line 406 also includes the abbreviation NGFR, which is not previously expanded earlier or in the abbreviations section. The conclusion section recommends further consideration of the problem which should be slightly expanded. Overall, the conclusions follow from the data obtained.

Author Response

We would like to thank the Reviewer for the thorough evaluation of our manuscript and for the positive assessment of its originality and clinical relevance. We greatly appreciate the constructive comments, which have helped us to improve the clarity and completeness of the manuscript. Our responses to the specific remarks are provided below.

1. Contribution of baseline prolactin levels and tumor volume

We agree that the contribution of baseline prolactin levels and tumor volume to the overall risk of dopamine agonist (DA) resistance appears modest. We modified the "Discussion" section to emphasize that the higher prolactin concentration can be associated with DA resistance. (Discussion; lines 449-457)

2. Additional treatment options (line 383+)

We have expanded the Discussion section by adding a concise summary of alternative treatment options for patients with DA-resistant prolactinomas. (Discussion; lines 466-480)

3. Undefined abbreviation “NGFR” (line 406)

The abbreviation NGFR has now been fully defined at its first occurrence in the text and added to the list of abbreviations to ensure consistency and clarity. (Discussion, line 511)

4. Expansion of the Conclusion section

We have slightly expanded the Conclusion section. The revised conclusion now more explicitly highlights the clinical implications of our findings, emphasizes the need for careful interpretation of modest predictors, and underscores the importance of further prospective studies to refine risk stratification and treatment algorithms in prolactinomas (lines 516-531)

We believe that the revisions made in response to these suggestions have strengthened the manuscript and improved its clinical and scientific value.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed my previous comments, and the manuscript has improved. I have no additional comments.

Author Response

We sincerely thank the Reviewer for the careful re-evaluation of our manuscript and for acknowledging the improvements made. We greatly appreciate the Reviewer’s time and constructive feedback, which significantly contributed to enhancing the quality and clarity of our work.

Reviewer 3 Report

Comments and Suggestions for Authors

The Authors sufficiently addressed my previous comments. 

I have few minor comments. 

Table 2 title: "Evaluation of the study population (n=85) at the follow-up visits" please modify to "Evaluation of the study population (n=85) at 6 months, 12 months and at the last follow-up visit"  

Lines 342-354: was sex included in the multivariable logistic regression model?

Author Response

Comment 1: Table 2 title:

"Evaluation of the study population (n=85) at the follow-up visits" please modify to "Evaluation of the study population (n=85) at 6 months, 12 months and at the last follow-up visit"  

Authors response 1:

The title of Table 2 has been revised accordingly and now reads: “Evaluation of the study population (n = 85) at 6 months, 12 months, and at the last follow-up visit”, to improve clarity and precision.

 

Comment 2: "Lines 342-354: was sex included in the multivariable logistic regression model?"

Authors response 2:

Yes, sex was included as a covariate in the multivariable logistic regression model, along with other clinically relevant variables, as it is stated in lines 342-345, in the multivariable model, sex did not reach statistical significance, probably due to its correlation with other variables included in the model as the maximum diameter of the tumor and prolactin concentration. 

We sincerely thank the Reviewer for the careful re-evaluation of our manuscript and for acknowledging the improvements made.