Effects of Resveratrol on Metabolic, Biochemical, and Endocrine Manifestations in Polycystic Ovary Syndrome

Round 1

Reviewer 1 Report

Reviewer Comments

Title: Effects of resveratrol on metabolic abnormalities in Polycystic Ovary Syndrome

The title is not reflective of the content of the review.

The submitted manuscript has NO line numbers. This makes it extremely difficult to refer comments to the authors. Please resubmit with line numbering.

Effects of resveratrol on metabolic, biochemical and endocrine manifestations in polycystic ovary syndrome………..may be more representative?

Abstract:

Please remove reference 1 from the abstract and include in the text.

Introduction:

Paragraph 1: is too long and contains too many topics put together in a disjointed way. ie. first 3 sentences on hyperandrogenism, followed by treatment, then health effects then back to treatment.

Suggest, start with the metabolic, biochemical and hormonal comments, and have a separate paragraph on treatment that includes reference to diet, exercise, lifestyle (as per the International Guidelines [Teede 2018], pharmaceuticals [metformin and OCP] and nutraceuticals and supplements [resveratrol, inisitols, berberine, omega 3, probiotics etc].

Paragraph 2: is too long. Define phytoalexin, either in brackets or in a separate sentence. This is an important concept as it provides a rationale for its antioxidant effects in humans.

After reference (14)….discuss the limited bioavailability of polyphenols (ie only 5% absorbed intact into the circulation), role of the microbiome and the extensive biotransformation prior to absorption, and the fact that the observed biological effects are mostly due to absorbed metabolites.

Start a new paragraph …………….Within the human body………………………

Reference 16 is a RAT study. The sentence starts with “Patients treated ……..(16).

I would suggest revising the manuscript and making it clear what comments refer to animal studies and which ones refer to human studies.

The last sentence of paragraph 2 needs a reference.

Paragraph 3: “preclinical research (17)”. Reference 17 is a clinical RCT trial in humans. This is not preclinical. The end of this sentence should have references to the trial alluded too.

The next sentence says “four recent RCT”. Table 1 contains summaries of 16 studies (10 animal and 6 human).

This table would be clearer if it was divided into 2 tables, one for animal and one for human studies.

Section 1: Inflammatory markers

Either remove “androgen levels” or add metabolic markers to the first sentence.

“bodies” should be changed to another term. “keep our bodies healthy” is simplistic, consider “maintain health”.

All abbreviations are usually spelled out on first use. Tumour Necrosis Factor(TNF)-alpha etc.

Paragraph 2 requires more references following each of the claims made.

“root” = root cause.

Section 2: PCOS markers including hormones

This title is vague (markers = ?). Suggest something more representative of the studies discussed.

“PCOS hormonal, ovarian and reproductive effects of resveratrol”

Paragraph 1: Most of this paragraph is on a rat study. The results are then extrapolated to humans. Are there any human studies you could refer to that look at hormones, inflammatory markers (TNF-alpha) or oxidative stress (MDA) that would support this rat study?

Paragraph 2: Abbreviations need spelling. The conclusion is not supported by the brief discussion. Suggest more comprehensive discussion of “damage to the ovaries” and “glycolytic activity”.

Section 3: Metabolic markers and insulin resistance

“glycoinsulinemic index” is not a term usually used. Suggest ?? “glucose and insulin profiles”.

Paragraph 1: has NO references to support the statements made.

Paragraph 2: is disjointed. Suggest rewriting. Also, important to discuss the role of the microbiome in the pathogenesis of PCOS and how this may affect the biotransformation of resveratrol. Metformin also effects the microbiome.

“Currently, the clinical recommendation……..” I would reference the International Guidelines.

Paragraph 4: “The clinical data described on reversing insulin resistance with resveratrol have been variable”.

The reference to this study is not given. A statement needs to be made about why you think these results were different to other studies.

I would suggest that the rat studies are discussed together followed by the human studies. A concluding sentence/paragraph needs to sum up the clinical implications of all these research findings.

Section 4: Markers of oxidative stress

I would expand this section by having an introductory paragraph on oxidative stress and what is known about the action of resveratrol as an antioxidant.

Discussion:

This is a long paragraph that is disjointed and only has one reference. It would be improved by being divided into 3 paragraphs with appropriate references.

The statement “there is insufficient data on human subjects” doesn’t seem to be supported by the 6 studies in table one and the discussion of the findings in humans throughout the paper. I would summarise what is known from the human data and identify specific areas requiring more research.

Limitations:

This is the first time “limited bioavailability of resveratrol” is discussed. It should be elaborated in more detail earlier in the paper, as discussed above in comments on paragraph 2.

Conclusion:

This short statement is weak and does not do justice to the review and the findings of many studies included in this paper.

Suggestion: Make separate comments on the findings and implications of rat and human studies, and point out the implications of the research to the “metabolic abnormalities in PCOS” in more detail. ie as per the title of the paper.

Do you recommend that resveratrol has a place in the management of PCOS? If so, when would you advise it be used and on which type of PCOS patients etc.

Any specific recommendations for future studies?

Recommendations:

I believe this review could potentially add to the existing literature, need significant revisions.

Author Response

Title: Effects of resveratrol on metabolic abnormalities in Polycystic Ovary Syndrome

The title is not reflective of the content of the review.

The submitted manuscript has NO line numbers. This makes it extremely difficult to refer comments to the authors. Please resubmit with line numbering.

Response: The article has been lined. 

Effects of resveratrol on metabolic, biochemical and endocrine manifestations in polycystic ovary syndrome………..may be more representative?

Response: Thank you for the excellent recommendation . The title has been changed. 

Abstract:

Please remove reference 1 from the abstract and include in the text.

Response: Done

Introduction:

Paragraph 1: is too long and contains too many topics put together in a disjointed way. ie. first 3 sentences on hyperandrogenism, followed by treatment, then health effects then back to treatment.

Suggest, start with the metabolic, biochemical and hormonal comments, and have a separate paragraph on treatment that includes reference to diet, exercise, lifestyle (as per the International Guidelines [Teede 2018], pharmaceuticals [metformin and OCP] and nutraceuticals and supplements [resveratrol, inisitols, berberine, omega 3, probiotics etc].

Response: Has been improved accordingly. 

Paragraph 2: is too long. Define phytoalexin, either in brackets or in a separate sentence. This is an important concept as it provides a rationale for its antioxidant effects in humans.

Response: Has been defined accordingly. 

After reference (14)….discuss the limited bioavailability of polyphenols (ie only 5% absorbed intact into the circulation), role of the microbiome and the extensive biotransformation prior to absorption, and the fact that the observed biological effects are mostly due to absorbed metabolites.

Response: Has been defined accordingly. 

Start a new paragraph …………….Within the human body………………………

Response: Has been done accordingly. 

Reference 16 is a RAT study. The sentence starts with “Patients treated ……..(16).

I would suggest revising the manuscript and making it clear what comments refer to animal studies and which ones refer to human studies.

The last sentence of paragraph 2 needs a reference.

Paragraph 3: “preclinical research (17)”. Reference 17 is a clinical RCT trial in humans. This is not preclinical. The end of this sentence should have references to the trial alluded too.

The next sentence says “four recent RCT”. Table 1 contains summaries of 16 studies (10 animal and 6 human).

Response: Has been defined accordingly. Original manuscript mentioned fourteen studies. 

This table would be clearer if it was divided into 2 tables, one for animal and one for human studies.

Response: Has been refined but too primitive to divide since the outcomes are the same. 

Section 1: Inflammatory markers

Either remove “androgen levels” or add metabolic markers to the first sentence.

“bodies” should be changed to another term. “keep our bodies healthy” is simplistic, consider “maintain health”.

All abbreviations are usually spelled out on first use. Tumour Necrosis Factor(TNF)-alpha etc.

Response: Has been defined accordingly. 

Paragraph 2 requires more references following each of the claims made.

“root” = root cause.

Section 2: PCOS markers including hormones

This title is vague (markers = ?). Suggest something more representative of the studies discussed.

Response: Has been defined accordingly. 

“PCOS hormonal, ovarian and reproductive effects of resveratrol”

Paragraph 1: Most of this paragraph is on a rat study. The results are then extrapolated to humans. Are there any human studies you could refer to that look at hormones, inflammatory markers (TNF-alpha) or oxidative stress (MDA) that would support this rat study?

Paragraph 2: Abbreviations need spelling. The conclusion is not supported by the brief discussion. Suggest more comprehensive discussion of “damage to the ovaries” and “glycolytic activity”.

Response: Has been defined accordingly. 

Section 3: Metabolic markers and insulin resistance

“glycoinsulinemic index” is not a term usually used. Suggest ?? “glucose and insulin profiles”.

Response: Has been defined accordingly. The term used is perfectly acceptable in clinical setting. 

Paragraph 1: has NO references to support the statements made.

Paragraph 2: is disjointed. Suggest rewriting. Also, important to discuss the role of the microbiome in the pathogenesis of PCOS and how this may affect the biotransformation of resveratrol. Metformin also effects the microbiome.

Response: Has been defined accordingly. 

“Currently, the clinical recommendation……..” I would reference the International Guidelines.

Paragraph 4: “The clinical data described on reversing insulin resistance with resveratrol have been variable”.

Response: Has been defined accordingly. This statement has been made in accordance with the studies mentioned in the review. All studies cannot be mentioned again. 

The reference to this study is not given. A statement needs to be made about why you think these results were different to other studies.

I would suggest that the rat studies are discussed together followed by the human studies. A concluding sentence/paragraph needs to sum up the clinical implications of all these research findings.

Section 4: Markers of oxidative stress

I would expand this section by having an introductory paragraph on oxidative stress and what is known about the action of resveratrol as an antioxidant.

Response: Has been defined accordingly. Authors have already published a review on oxidative stress in PCOS and have mentioned the flavones and polyphenols. Suitable citations have been given. 

Discussion:

This is a long paragraph that is disjointed and only has one reference. It would be improved by being divided into 3 paragraphs with appropriate references.

The statement “there is insufficient data on human subjects” doesn’t seem to be supported by the 6 studies in table one and the discussion of the findings in humans throughout the paper. I would summarise what is known from the human data and identify specific areas requiring more research.

Response: Has been defined accordingly. 

Limitations:

This is the first time “limited bioavailability of resveratrol” is discussed. It should be elaborated in more detail earlier in the paper, as discussed above in comments on paragraph 2.

Response: Has been defined accordingly. The limitations of the review being narrative in nature cannot be defined extensively at this time. 

Conclusion:

This short statement is weak and does not do justice to the review and the findings of many studies included in this paper.

Response: Has been defined accordingly. 

Suggestion: Make separate comments on the findings and implications of rat and human studies, and point out the implications of the research to the “metabolic abnormalities in PCOS” in more detail. ie as per the title of the paper.

Do you recommend that resveratrol has a place in the management of PCOS? If so, when would you advise it be used and on which type of PCOS patients etc.

Response: Has been defined accordingly. Since there have been inconclusive studies on resveratrol, no definitive recommendations can be made. 

Any specific recommendations for future studies?

Author Response File: Author Response.docx

Reviewer 2 Report

1. The abstract is empty and unfocused content. Although the clinical issue of RSV and PCOS is mentioned should provide more detailed information.
2. The writing of the article is not rigorous, such as

- The word "Patients" is used in lines 5-6 on page 2, however, the reference (ref16) is for rats.

- No bibliographic citations in lines 6-10 of the second page. RCT abbreviation does not indicate the full name, RCT refers to randomized clinical trials?

- The date listed in ref 19 is different from the text, indicating that the manuscript was not rigorously written.

- Page 6, Line 1, Manuscript Description" Ghowsi et al. conducted a study in which PCOS induced Wistar rats received resveratrol 10 mg/kg intraperitoneally for 28 days, after which their Tnf-α and Il-6 mRNA expression was measured against control and non-treated PCOS rats (23).”, but in fact, the original manuscript has no data on Tnf-α and Il-6 mRNA. There are things that are made up that don't exist.

3. The content of Table 1 is inconsistent with the content of the first paragraph on page 5.
4. There are considerable problems with citations throughout the article

Author Response

1. The abstract is empty and unfocused content. Although the clinical issue of RSV and PCOS is mentioned should provide more detailed information. Response: The abstract has been improved according to the recommendation 
2. The writing of the article is not rigorous, such as

• The word "Patients" is used in lines 5-6 on page 2, however, the reference (ref16) is for rats.. Response: The citation has been updated. 
• No bibliographic citations in lines 6-10 of the second page. RCT abbreviation does not indicate the full name, RCT refers to randomized clinical trials?
• Response: RCT is a very generalized term and has been used in the manuscript several times as Randomized clinical trial

- The date listed in ref 19 is different from the text, indicating that the manuscript was not rigorously written. Response: the study was published in 2009 and was online in 2010. The year has been updated to 2010. 

• Page 6, Line 1, Manuscript Description" Ghowsi et al. conducted a study in which PCOS induced Wistar rats received resveratrol 10 mg/kg intraperitoneally for 28 days, after which their Tnf-α and Il-6 mRNA expression was measured against control and non-treated PCOS rats (23).”, but in fact, the original manuscript has no data on Tnf-α and Il-6 mRNA. There are things that are made up that don't exist.
• Response: There is a problem with the endnote update when the manuscript is being uploaded in to the system. It was not made up but a typographical error of endnote citing the other publication. IT has been updated . 

3. The content of Table 1 is inconsistent with the content of the first paragraph on page 5. Response: Page 5 lists the inflammatory markers and the effect of resveratrol. The authors could not point towards any inconsistencies. Contents of the Table 1 do not only have inflammatory but insulin resistance, oxidative stress and hormonal markers as well. 
4. There are considerable problems with citations throughout the article Response: There has been issue with the endnote update but the authors could not find any other inconsistencies apart from the two pointed above. 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Title: Effects of resveratrol on metabolic, biochemical and endocrine abnormalities in polycystic ovary syndrome

Thank-you for the opportunity to review the revised version of the manuscript. Many of the suggested revisions have not been addressed.

Line 19:  Androgens are also produced in the adrenal gland and other cells. Suggest add “are predominantly caused” …

Line 32: Paragraph 1 has been improved, but the range of treatment options has not been addressed. As previously advised,

Suggest, start with the metabolic, biochemical and hormonal comments, and have a separate paragraph on treatment that includes reference to diet, exercise, lifestyle (as per the International Guidelines [Teede 2018], pharmaceuticals [metformin and OCP] and nutraceuticals and supplements [resveratrol, inisitols, berberine, omega 3, probiotics etc].

Line 40-43: This sentence is inaccurate and poorly worded. “However, due to resveratrol belonging to the class of polyphenols, there is a limited bioavailability of polyphenols in the body as they are poorly absorbed in the small intestine after being conjugated in the liver (13)”.

Consider including comments on some of the following: Polyphenols are the most abundant antioxidant in the human diet. Polyphenols vary in structure, size, and complexity and are, in general, poorly absorbed. It has been estimated that less than 5% of ingested polyphenols reach the circulation intact. Polyphenols undergo intensive biotransformation by the gastrointestinal microbiota or are metabolised within enterocytes. A large number of microbial products can be detected in plasma compared with extremely low levels of the parent compounds. Despite their low bioavailability, numerous studies have reported significant biological effects related to dietary polyphenols such as resveratrol.

Line 78: Has not been amended. “bodies” should be changed to another term. “keep our bodies healthy” is simplistic, consider “maintain health”.

Line 79-94: Contains multiple claims that are poorly referenced. It would be helpful if readers have references to refer too.

Line 99: “root” = root cause.

Line 117-141: This paragraph is too long. Please divide into 2 or 3 paragraphs that discuss separate issues.

Line 171: Please add a concluding paragraph that provides a summary overview of this section.

Line 189: “with no pharmacological interventions available for these women”. This is not true. Please refer to the International Guidelines (Teede 2018) for extensive discussion on medical treatments for impaired glucose tolerance, acne, hirsuitism and infertility.

Line 231: Section 4: Markers of oxidative stress

I would expand this section by having an introductory paragraph on oxidative stress and what is known about the action of resveratrol as an antioxidant.

Response: Has been defined accordingly. Authors have already published a review on oxidative stress in PCOS and have mentioned the flavones and polyphenols. Suitable citations have been given. 

One paragraph on oxidative stress is inadequate in a paper stating that oxidative stress is an important part of the pathophysiology of PCOS. I suggest addressing this issue as previously recommended.

Line 241: Discussion:

This is a long paragraph that is disjointed and only has one reference. It would be improved by being divided into 3 paragraphs with appropriate references.

The statement “there is insufficient data on human subjects” doesn’t seem to be supported by the 6 studies in table one and the discussion of the findings in humans throughout the paper. I would summarise what is known from the human data and identify specific areas requiring more research.

Response: Has been defined accordingly. 

Although the authors state “has been defined accordingly” no changes have been made to this paragraph and the issues raised have not been addressed.

Line 261: The limited bioavailability of the parent compound is not an issue as the biological effects are due numerous metabolites.

Line 268: The comment “certain human CVD” does not fit with the topic of the paper (PCOS). Please define what is meant by CVD and how this relates to PCOS.

Line 269: The conclusion section has not addressed any of the issues raised in the review comments despite the authors comment “has been defined accordingly”.

Suggestion: Make separate comments on the findings and implications of rat and human studies, and point out the implications of the research to the “metabolic abnormalities in PCOS” in more detail. ie as per the title of the paper.

Summary of second review:

I believe the authors have made an inadequate attempt to address the issues raised in the first review comments. I have again outlined some of the areas that have NOT been adequately addressed.

The authors have made many comments “Has been defined accordingly” without making any of the suggested changes or addressing the issues identified.

I would ask the authors to outline in more detail what they have done to address the issues raised.

I believe this manuscript has not been significantly improved and requires further revision.

Author Response

Line 19:  Androgens are also produced in the adrenal gland and other cells. Suggest add “are predominantly caused” …

Response: The reviewer is implying on adding the statement that the androgens are prominently caused by action of adrenal gland. The authors disagree with the statement since androgens is a broad term and are differentially produced in ovary and adrenal glands. For example, Androstenedione is generated in the ration of 45:70:60 in the early follicular, midcycle, late luteal phase while only      30–55 % in adrenal gland. If the reviewer is implying on androgen=testosterone, still this statement will not hold true since testosterone is also produced between 40-60 % in the ovarian cells versus only 30-40% in the adrenal cells. Moreover, the condition of hyperandrogenism the authors are implying to especially in PCOS is not due to the over production of androgens from the adrenal glands, but ovarian theca cells.

Conclusion: The authors deem this statement to be fit according to the manuscript and will not be changed.

Line 32: Paragraph 1 has been improved, but the range of treatment options has not been addressed. As previously advised,

Suggest, start with the metabolic, biochemical and hormonal comments, and have a separate paragraph on treatment that includes reference to diet, exercise, lifestyle (as per the International Guidelines [Teede 2018], pharmaceuticals [metformin and OCP] and nutraceuticals and supplements [resveratrol, inisitols, berberine, omega 3, probiotics etc].

Response: This review does not highlight or focus on general treatment options. There have been many systematic reviews and meta-analysis done on the treatment of PCOS with hormonal methods, alternative medicine etc. The Authors do not think there is a necessity to addressed and discuss other treatment options since there has been so many reviews out on treatment options. The authors have already referenced their paper which have discussed nutritional supplementation for PCOS. It has been published in Nutrition and is being currently cited in other manuscripts. This is common knowledge amongst gynecologists that metformin, weight loss, exercise and nutrition is imperative for PCOS, although except for metformin, none of the therapeutic interventions have been approved for PCOS.

Conclusion: The authors think there is no need to address treatment options since the paper does not focus on generalized treatment options.

Line 40-43: This sentence is inaccurate and poorly worded. “However, due to resveratrol belonging to the class of polyphenols, there is a limited bioavailability of polyphenols in the body as they are poorly absorbed in the small intestine after being conjugated in the liver (13)”.

Consider including comments on some of the following: Polyphenols are the most abundant antioxidant in the human diet. Polyphenols vary in structure, size, and complexity and are, in general, poorly absorbed. It has been estimated that less than 5% of ingested polyphenols reach the circulation intact. Polyphenols undergo intensive biotransformation by the gastrointestinal microbiota or are metabolised within enterocytes. A large number of microbial products can be detected in plasma compared with extremely low levels of the parent compounds. Despite their low bioavailability, numerous studies have reported significant biological effects related to dietary polyphenols such as resveratrol.

Response: Thank you for the suggestion. The paragraph has been reworded as: However, due to resveratrol belonging to the class of polyphenols, there is a limited bioavailability of polyphenols in the body as they are poorly absorbed in the small intestine after being conjugated in the liver (13). Polyphenols vary in structure, size, and complexity and are, in general, poorly absorbed. It has been estimated that less than 5% of ingested polyphenols reach the circulation intact. Despite their low bioavailability, numerous studies have reported significant biological effects related to dietary polyphenols such as resveratrol.

Conclusion: Changes have been made, however the intent of the authors was to focus on the poor bioavailability of resveratrol, which is very much described here.

Line 78: Has not been amended. “Bodies” should be changed to another term. “Keep our bodies healthy” is simplistic, consider “maintain health”.

Response: The sentence was not wrong, however, it has been changed to maintain health.

Line 79-94: Contains multiple claims that are poorly referenced. It would be helpful if readers have references to refer too.

Response: Line 79: There has been a line about interleukins, the authors think there is no need to reference the function of interleukins, and this is not a claim but a fact. Any clinical scientist, biochemist or clinician would be aware of the function of interleukins.

For Duleba et al study, there has already been a reference (18).

Again for TNF and IL-6 only their functions have been described which would not solicit any references. The functions of TNF and IL-6 are common textbook knowledge. For example: Barnes TC, Anderson ME, Moots RJ. The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. Int J Rheumatol. 2011; 2011:721608. doi:10.1155/2011/721608. The paper focuses on IL-6 but the generalized functions have not been cited. There has not been a single reference in the introduction since the statements are textbook knowledge.

Line 93: suitable citations have been updated on treatment of arthritis and Crohn’s disease. Citations 19 and 20.

Line 99: “root” = root cause.

Response: changed to root cause

Line 117-141: This paragraph is too long. Please divide into 2 or 3 paragraphs that discuss separate issues.

Response: The paragraph has been divided into three separate paragraphs.

Line 171: Please add a concluding paragraph that provides a summary overview of this section.

Response:   “In conclusion, with the use of resveratrol, changes in ovarian morphology was observed, in a few patient trials there was a slight improvement in the androgen homeostasis while animal models showed better improvement rates in term of ovarian morphology and hormone balance.” Paragraph has been added.

Line 189: “with no pharmacological interventions available for these women”. This is not true. Please refer to the International Guidelines (Teede 2018) for extensive discussion on medical treatments for impaired glucose tolerance, acne, hirsutism and infertility.

Response: In the revised manuscript, the authors changed “no” to few.

Line 231: Section 4: Markers of oxidative stress

I would expand this section by having an introductory paragraph on oxidative stress and what is known about the action of resveratrol as an antioxidant.

Response: Has been defined accordingly. Authors have already published a review on oxidative stress in PCOS and have mentioned the flavones and polyphenols. Suitable citations have been given. 

One paragraph on oxidative stress is inadequate in a paper stating that oxidative stress is an important part of the pathophysiology of PCOS. I suggest addressing this issue as previously recommended.

Response: This review is about effect of resveratrol on various components of PCOS, not oxidative stress. The authors have suggested that oxidative stress is important but so are the other aspects of PCOS which have been stated in different parts of the manuscript. The authors feel one paragraph is enough for stressing on the role of oxidative stress.

Line 241: Discussion:

This is a long paragraph that is disjointed and only has one reference. It would be improved by being divided into 3 paragraphs with appropriate references.

The statement “there is insufficient data on human subjects” doesn’t seem to be supported by the 6 studies in table one and the discussion of the findings in humans throughout the paper. I would summarize what is known from the human data and identify specific areas requiring more research.

Response: Discussion is usually summarized in three paragraphs. The authors have previously published in other top peer reviewed journals and they are aware of the manuscript formats, the common format of discussion is divided into three paragraphs of 400 words or so. International guidelines and recommendations for writing manuscript have been followed.

Response: Has been defined accordingly. 

Although the authors state “has been defined accordingly” no changes have been made to this paragraph and the issues raised have not been addressed.

Response: The authors did not feel the reviewer’s comments were appropriate or relevant wherever the changes were not made.

Line 261: The limited bioavailability of the parent compound is not an issue as the biological effects are due numerous metabolites.

Response: This is in contradiction to the reviewers stressing too much on the importance of limited bioavailability of the parent compound. Reviewers should consider making up one opinion on whether they consider parent compound’s limited availability or the enhanced bioavailability of the metabolites. Both statements cannot be used at once.

Line 268: The comment “certain human CVD” does not fit with the topic of the paper (PCOS). Please define what is meant by CVD and how this relates to PCOS.

Response: The statement has been revised accordingly.

Line 269: The conclusion section has not addressed any of the issues raised in the review comments despite the authors comment “has been defined accordingly”.

Suggestion: Make separate comments on the findings and implications of rat and human studies, and point out the implications of the research to the “metabolic abnormalities in PCOS” in more detail. ie as per the title of the paper.

Response: the conclusion section is usually three to four lines concluding and summarizing the whole manuscript. Since this is not a method paper nor a clinical trial and suitable conclusions have been provided after each section, the authors do not think there is a need to enhance the conclusion section. The overall summary of the manuscript was to emphasize that resveratrol has been more effective in rat models and less effective in human models in terms of insulin sensitivity and androgen profile which has been clearly stated in the manuscript.

Summary of second review:

I believe the authors have made an inadequate attempt to address the issues raised in the first review comments. I have again outlined some of the areas that have NOT been adequately addressed.

The authors have made many comments “Has been defined accordingly” without making any of the suggested changes or addressing the issues identified.

I would ask the authors to outline in more detail what they have done to address the issues raised.

Response: The authors believe there was more of an emphasis on the style of writing by the reviewers than actual comment on the theme, and science of the manuscript. Most of the comments were not required and in the second revision, there have been additional comments which were not included in the previous revision. There have been attempts to change the writing style of the paper.

The authors in their first revision have stated “has been defined accordingly” but did not change the sentences because there was no need to change the statements. This was a narrative review not a textbook chapter that everything has to be defined and role of interleukins needs citations. According to the authors, if a clinical researcher is looking for an overall summary of RCTs on resveratrol, the primary focus would be to look on its effectiveness on certain aspects of PCOS and not describe what interleukins or TNF does in the body.

The authors wish to make an appeal to the editor regarding the harsh comments sent to the authors regarding this whole review process and possibly change the reviewer prior to publishing this manuscript. This is our first experience of so many comments on the writing style and although neither the grammar nor the sentence was incorrect, the reviewers were still trying to imply their writing styles into the manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

The author has corrected the article as suggested.

Author Response

Thank you very much for your inputs and reviewing our manuscript.